Détail Unités

AP/HP Pôle 5

- Anatomie Pathologique -

Réponses affichées : 452

Congenital hyperinsulinism

ARNOUX JB, DE LONLAY P, RIBEIRO MJ, HUSSAIN K, BLANKENSTEIN O, MOHNIKE K, VALAYANNOPOULOS V, ROBERT JJ, RAHIER J, SEMPOUX C, BELLANNE C, VERKARRE V, AIGRAIN Y, JAUBERT F, BRUNELLE F, NIHOUL-FEKETE C

2010 - Early Hum Dev 86(5):287-294

Congenital hyperinsulinism (CHI or HI) is a condition leading to recurrent hypoglycemia due to an inappropriate insulin secretion by the pancreatic islet beta cells. HI has two main characteristics: a high glucose requirement to correct hypoglycemia and a responsiveness of hypoglycemia to exogenous glucagon. HI is usually isolated but may be rarely part of a genetic syndrome (e.g. Beckwith-Wiedemann syndrome, Sotos syndrome etc.). The severity of HI is evaluated by the glucose administration rate required to maintain normal glycemia and the responsiveness to medical treatment. Neonatal onset HI is usually severe while late onset and syndromic HI are generally responsive to a medical treatment. Glycemia must be maintained within normal ranges to avoid brain damages, initially with glucose administration and glucagon infusion then, once the diagnosis is set, with specific HI treatment. Oral diazoxide is a first line treatment. In case of unresponsiveness to this treatment, somatostatin analogues and calcium antagonists may be added, and further investigations are required for the putative histological diagnosis: pancreatic (18)F-fluoro-l-DOPA PET-CT and molecular analysis. Indeed, focal forms consist of a focal adenomatous hyperplasia of islet cells, and will be cured after a partial pancreatectomy. Diffuse HI involves all the pancreatic beta cells of the whole pancreas. Diffuse HI resistant to medical treatment (octreotide, diazoxide, calcium antagonists and continuous feeding) may require subtotal pancreatectomy which post-operative outcome is unpredictable. The genetics of focal islet-cells hyperplasia associates a paternally inherited mutation of the ABCC8 or the KCNJ11 genes, with a loss of the maternal allele specifically in the hyperplasic islet cells. The genetics of diffuse isolated HI is heterogeneous and may be recessively inherited (ABCC8 and KCNJ11) or dominantly inherited (ABCC8, KCNJ11, GCK, GLUD1, SLC16A1, HNF4A and HADH). Syndromic HI are always diffuse form and the genetics depend on the syndrome. Except for HI due to potassium channel defect (ABCC8 and KCNJ11), most of these HI are sensitive to diazoxide. The main points sum up the management of HI: i) prevention of brain damages by normalizing glycemia and ii) screening for focal HI as they may be definitively cured after a limited pancreatectomy.

Unité(s) : Anatomie Pathologique, Chirurgie Viscérale Pédiatrique, Métabolisme, Radiologie Pédiatrique

Long-Term Follow-Up of Patients With Newly Diagnosed Follicular Lymphoma in the Prerituximab Era: Effect of Response Quality on Survival--A Study From the Groupe d'Etude des Lymphomes de l'Adulte

BACHY E, BRICE P, DELARUE R, BROUSSE N, HAIOUN C, LE GOUILL S, DELMER A, BORDESSOULE D, TILLY H, CORRONT B, ALLARD C, FOUSSARD C, BOSLY A, COIFFIER B, GISSELBRECHT C, SOLAL-CELIGNY P, SALLES G

2010 - J Clin Oncol 28(5):822-29

PURPOSE: First-line treatment for patients with newly diagnosed follicular lymphoma (FL) still remains debated, even in the rituximab-based combination therapy era. Few studies have addressed the question whether complete remission (CR) translates into better survival. The aim of this study was to assess the long-term follow-up of prospectively treated patients with FL and the potential correlation between response quality to first-line treatment and overall survival (OS). PATIENTS AND METHODS: Data from 536 patients with FL with low (n = 193) or high (n = 343) tumor burden enrolled from October 1986 to May 1995 in the French and Belgian GELF86 studies were analyzed. Data from these trials have been previously reported for low-tumor burden and high-tumor burden patients. RESULTS: Median follow-up was 14.9 years, and median OS was 9.8 years. Treated patients who achieved a complete response (CR; n = 194; 45%) had a significant longer OS than those only reaching a partial response (PR; n = 168; 39%) throughout treatment (hazard ratio [HR], 0.55; 95% CI, 0.42 to 0.72; P < .001) in an univariate time-dependent Cox model. Similar findings were found when response to treatment (CR v PR) was adjusted for potentially confounding factors in a multivariate model (HR, 0.53; 95% CI, 0.38 to 0.73; P < .001). CONCLUSION: These data provide a long follow-up of these patients' cohorts and indicate that a better response to first-line treatment translates into an improved survival for patients with FL. Therefore, response-adapted therapy aiming to achieve a CR should be considered as first-line treatment.

Unité(s) : Anatomie Pathologique

Neonatal and Early Infantile Cutaneous Langerhans Cell Histiocytosis: Comparison of Self-regressive and Non-Self-regressive Forms

BATTISTELLA M, FRAITAG S, TEILLAC DH, BROUSSE N, DE PROST Y, BODEMER C

2010 - Arch Dermatol 146(2):149-56

Objectives To describe clinical and immunohistochemical findings in patients with cutaneous Langerhans cell histiocytosis (LCH) beginning in the first 3 months of life and to define predictors of disease evolution. DESIGN: Observational retrospective survey from July 15, 1989, to April 30, 2007. SETTING: Referral center in pediatric dermatology. Patients Thirty-one patients with a diagnosis of cutaneous LCH in the first 3 months of life and no previous visceral LCH. MAIN OUTCOME MEASURES: Cutaneous lesion characteristics, regulatory T-lymphocyte density, and E-cadherin expression were assessed. Data were compared between the patient groups with self-regressive vs non-self-regressive forms of cutaneous LCH. Pathologic analysis was performed blinded to patient group. RESULTS: Self-regressive cutaneous LCH was found in 21 patients and non-self-regressive cutaneous LCH in 10 patients. Monolesional forms, necrotic lesions, hypopigmented macules at presentation, and distal topography of limb lesions were seen only in patients with self-regressive cutaneous LCH. Regulatory T-lymphocyte density correlated with interleukin 10 expression in lesions (r = 0.77, P = .003) but was not predictive of disease evolution. E-cadherin expression by Langerhans cells was found in 7 patients with disease limited to the skin whether self-regressive or not. One patient with secondary disseminated disease showed loss of E-cadherin expression in Langerhans cells. CONCLUSIONS: Some morphologic traits of skin lesions can orient the diagnosis to a self-regressive form of cutaneous LCH. Regulatory T-lymphocyte density does not seem to be predictive of disease evolution. E-cadherin expression seems to be an indicator of limited skin disease but not of disease regression. Additional immunohistochemical study is required to confirm these data.

Unité(s) : Anatomie Pathologique, Dermatologie

Calcinosis Cutis: A Rare Reaction to Subcutaneous Injections of Calcium-Containing Heparin in Patients With Renal Failure

BOCCARA O, PROST-SQUARCIONI C, BATTISTELLA M, BROUSSE N, RONGIOLETTI F, FRAITAG S

2010 - Am J Dermatopathol 32(1):52-55

Calcinosis of the cutis and the subcutis is a rare complication of calcium-containing heparin cutaneous injections, mostly occurring in a context of severe renal failure. We report 2 cases. The first patient developed firm erythematous nodules on his thighs and right arm, in a context of disseminated tuberculosis and acute severe renal failure related to human immunodeficiency virus nephropathy. Cutaneous location of tuberculosis was suspected. Histological features allowed to establish the diagnosis of calcinosis of the cutis and the subcutis, showing violaceous and crackled von Kossa-positive calcium deposits in the whole reticular dermis and in thin collagenous septa of subcutaneous tissue. A retrospective inquiry confirmed that subcutaneous injections of calcium-containing heparin had been performed on the sites where lesions occurred. The second patient developed similar lesions at injection sites of calcium-containing heparin, in a context of non-Hodgkin lymphoma and end-stage renal failure. Similar histological features were observed. Calcinosis of the cutis and the subcutis after subcutaneous injections of calcium-containing heparin is rare. It always occurs in a context of elevated calcium-phosphate product, a situation mostly encountered in severe renal failure. Early cutaneous lesions do not bear specific clinical features.

Unité(s) : Anatomie Pathologique, Dermatologie

Regulatory T-Cell Depletion in Angioimmunoblastic T-Cell Lymphoma

BRUNEAU J, CANIONI D, RENAND A, MARAFIOTI T, PATERSON JC, MARTIN-GARCIA N, GAULARD P, DELFAU MH, HERMINE O, MACINTYRE E, BROUSSE N, ASNAFI V

2010 - Am J Pathol 177(2):570-74

Angioimmunoblastic T-cell lymphoma (AITL) is the most frequent nodal T-cell lymphoma and is characterized by a polymorphic lymph node infiltrate, various dysimmune disorders, and a poor prognosis. Regulatory T-cells (Treg) play an emerging role in the prognosis of non-Hodgkin B-cell lymphoma and mediate significant autoreactive T-cell suppression. In this report, we demonstrate that numbers of Treg are significantly decreased in AITL lymph nodes [n = 30, 91 (40-195) per high power fields] compared with follicular lymphoma [n = 19, 179 (86-355)] and reactive lymph nodes [n = 8, 186 (140-265)]. Moreover, the few Treg in lymph nodes of AITL are resting Treg (rTreg) and have a naive CD45RA+, PD1-, and ICOS- phenotype [n = 5, 57% of Treg are CD45RA+ (16-96)], in contrast to the Treg in follicular lymphomas [n = 5, 7.4% (1-13)] or reactive lymph nodes [n = 7, 18.6% (6-48)]. Interestingly, Treg depletion was not observed in AITL peripheral blood at diagnosis. Altogether, these data suggest that Treg depletion could contribute to the nodal neoplastic TFH expansion and dysimmune symptoms in AITL.

Unité(s) : Anatomie Pathologique, Hématologie Adulte, UMR 8147

Targeting iron homeostasis induces cellular differentiation and synergizes with differentiating agents in acute myeloid leukemia

CALLENS C, COULON S, NAUDIN J, RADFORD-WEISS I, BOISSEL N, RAFFOUX E, WANG PH, AGARWAL S, TAMOUZA H, PAUBELLE E, ASNAFI V, RIBEIL JA, DESSEN P, CANIONI D, CHANDESRIS O, RUBIO MT, BEAUMONT C, BENHAMOU M, DOMBRET H, MACINTYRE E, MONTEIRO RC, MOURA IC, HERMINE O

2010 - J Exp Med 207(4):731-50

Differentiating agents have been proposed to overcome the impaired cellular differentiation in acute myeloid leukemia (AML). However, only the combinations of all-trans retinoic acid or arsenic trioxide with chemotherapy have been successful, and only in treating acute promyelocytic leukemia (also called AML3). We show that iron homeostasis is an effective target in the treatment of AML. Iron chelating therapy induces the differentiation of leukemia blasts and normal bone marrow precursors into monocytes/macrophages in a manner involving modulation of reactive oxygen species expression and the activation of mitogen-activated protein kinases (MAPKs). 30% of the genes most strongly induced by iron deprivation are also targeted by vitamin D3 (VD), a well known differentiating agent. Iron chelating agents induce expression and phosphorylation of the VD receptor (VDR), and iron deprivation and VD act synergistically. VD magnifies activation of MAPK JNK and the induction of VDR target genes. When used to treat one AML patient refractory to chemotherapy, the combination of iron-chelating agents and VD resulted in reversal of pancytopenia and in blast differentiation. We propose that iron availability modulates myeloid cell commitment and that targeting this cellular differentiation pathway together with conventional differentiating agents provides new therapeutic modalities for AML.

Unité(s) : Anatomie Pathologique, Hématologie Adulte, Histo-Embryologie - Cytogénétique, Laboratoire d'Hématologie, UMR 8147

Glomerular Collapse Associated With Subtotal Renal Infarction in Kidney Transplant Recipients With Multiple Renal Arteries

CANAUD G, BRUNEVAL P, NOEL LH, CORREAS JM, AUDARD V, ZAFRANI L, RABANT M, TIMSIT MO, MARTINEZ F, ANGLICHEAU D, THERVET E, PATEY N, LEGENDRE C, ZUBER J

2010 - Am J Kidney Dis 55(3):558-65

Collapsing glomerulopathy is an aggressive kidney disease with rapid progression toward end-stage renal disease. Rare cases of de novo collapsing glomerulopathy have been reported during the post-transplant course and, in some instances, have been associated with renal graft vascular lesions. This finding raises the important question of whether ischemia could induce podocyte transdifferentiation, a hypothesis supported by evidence of hypoxia-inducible factor-dependent podocyte proliferation in HIV-associated nephropathy. We describe here 3 HIV-negative kidney transplant recipients in whom early graft biopsy performed in the vicinity of segmental graft infarction disclosed the typical features of glomerular collapse. Podocyte transdifferentiation was characterized by hallmark lesions, such as loss of mature podocyte phenotype, podocyte proliferation, and acquisition of a macrophage-like phenotype. Together, these data suggest that acute glomerular ischemia may lead to glomerular collapse in kidney transplants.

Unité(s) : Anatomie Pathologique, Radiologie Adulte, Transplantation Adulte, Urologie

Recurrence of nephrotic syndrome after transplantation in a mixed population of children and adults: course of glomerular lesions and value of the Columbia classification of histological variants of focal and segmental glomerulosclerosis (FSGS)

CANAUD G, DION D, ZUBER J, GUBLER MC, SBERRO R, THERVET E, SNANOUDJ R, CHARBIT M, SALOMON R, MARTINEZ F, LEGENDRE C, NOEL LH, NIAUDET P

2010 - Nephrol Dial Transplant 25(4):1321-28

Introduction. Recurrence of nephrotic-range proteinuria in patients with idiopathic nephrotic syndrome (INS) and focal and segmental glomerulosclerosis (FSGS) on native kidneys is associated with poor graft survival. Identification of risk factors for recurrence is therefore an important issue. In 2004, Columbia University introduced a histological classification of FSGS that identifies five mutually exclusive variants. In non-transplant patients, the Columbia classification appears to predict the outcome and response to treatment better than clinical characteristics alone. However, the predictive value of this classification to assess the risk of recurrence after transplantation has not been addressed. METHODS: We retrospectively studied 77 patients with INS and FSGS on native kidneys who underwent renal transplantation. Of these, 42 recipients experienced recurrence of nephrotic range proteinuria. RESULTS: At time of recurrence, minimal-change disease (MCD) was the main histological feature. On serial biopsies, the incidence of MCD decreased over time, while the incidence of FSGS variants increased. The variant type observed in the native kidneys was not predictive of either recurrence or type of FSGS seen on the allograft. Patients with complete and sustained remission did not developed FSGS. CONCLUSION: In conclusion, the Columbia classification is of no help in predicting recurrence after renal transplantation or histological lesions in the case of recurrence of proteinuria.

Unité(s) : Anatomie Pathologique, Néphrologie Pédiatrique, Transplantation Adulte, U983

Granulocyte Colony Stimulating Factor-induced Exacerbation of Fungus-related Immune Restoration Inflammatory Syndrome: A Case of Chronic Disseminated Candidiasis Exacerbation

CHANDESRIS MO, KELAIDI C, MECHAI F, BOUGNOUX ME, BROUSSE N, VIARD JP, POIREE S, LECUIT M, HERMINE O, LORTHOLARY O

2010 - J Microbiol Immunol Infect 43(4):339-343

Chronic disseminated candidiasis is a complication of the intensive therapies of hematological malignancies revealed during hematopoietic recovery, a context reminiscent of the immune restoration inflammatory syndrome in human immunodeficiency virus patients receiving antiretroviral therapy. We report a case of severe exacerbation of chronic disseminated candidiasis after pegylated granulocyte-colony stimulating factor administration. We emphasize the major inflammatory substrate of the disease and suggest that immune-modulating strategies such as hematopoietic growth factors, should be used cautiously in such patients.

Unité(s) : Anatomie Pathologique, Hématologie Adulte, Laboratoire de Microbiologie, Maladies Infectieuses, Radiologie Adulte

Pathologic classification of diabetic nephropathy

COHEN-TERVAERT TW, MOOYAART AL, AMANN K, COHEN AH, COOK HT, DRACHENBERG CB, FERRARIO F, FOGO AB, HAAS M, DE HEER E, JOH K, NOEL LH, RADHAKRISHNAN J, SESHAN SV, BAJEMA IM, BRUIJN JA, RENAL PATHOLOGY S

2010 - J Am Soc Nephrol 21(4):556-63

Although pathologic classifications exist for several renal diseases, including IgA nephropathy, focal segmental glomerulosclerosis, and lupus nephritis, a uniform classification for diabetic nephropathy is lacking. Our aim, commissioned by the Research Committee of the Renal Pathology Society, was to develop a consensus classification combining type1 and type 2 diabetic nephropathies. Such a classification should discriminate lesions by various degrees of severity that would be easy to use internationally in clinical practice. We divide diabetic nephropathy into four hierarchical glomerular lesions with a separate evaluation for degrees of interstitial and vascular involvement. Biopsies diagnosed as diabetic nephropathy are classified as follows: Class I, glomerular basement membrane thickening: isolated glomerular basement membrane thickening and only mild, nonspecific changes by light microscopy that do not meet the criteria of classes II through IV. Class II, mesangial expansion, mild (IIa) or severe (IIb): glomeruli classified as mild or severe mesangial expansion but without nodular sclerosis (Kimmelstiel-Wilson lesions) or global glomerulosclerosis in more than 50% of glomeruli. Class III, nodular sclerosis (Kimmelstiel-Wilson lesions): at least one glomerulus with nodular increase in mesangial matrix (Kimmelstiel-Wilson) without changes described in class IV. Class IV, advanced diabetic glomerulosclerosis: more than 50% global glomerulosclerosis with other clinical or pathologic evidence that sclerosis is attributable to diabetic nephropathy. A good interobserver reproducibility for the four classes of DN was shown (intraclass correlation coefficient = 0.84) in a test of this classification.

Unité(s) : Anatomie Pathologique

Blastic plasmacytoid dendritic cell neoplasm: is transplantation the treatment of choice?

DALLE S, BEYLOT-BARRY M, BAGOT M, LIPSKER D, MACHET L, JOLY P, DOMPMARTIN A, D'INCAN M, MAUBEC E, GRANGE F, DEREURE O, PREY S, BARETE S, WETTERWALD M, FRAITAG S, PETRELLA T

2010 - Br J Dermatol 162(1):74-79

Summary Background Blastic plasmacytoid dendritic cell neoplasm (BPDCN) represents the malignant counterpart derived from plasmacytoid dendritic cells. This rare entity is usually revealed and diagnosed on cutaneous lesions associated or not with a leukaemic component. The prognosis associated with BPDCN is very poor. Objectives To perform a retrospective review of BPDCN cases registered in the French Study Group on Cutaneous Lymphoma database from June 1995 to May 2008. Methods Forty-seven patients were included. Demographic data, initial staging, therapeutic management and outcome were recorded. Results The mean survival was 16.7 months (95% confidence interval 12.6-20.8). Only eight (17%) and one (2%) patients reached respectively 2 and 5 years of survival. Initial spreading of the disease did not represent, in this cohort, a reliable prognosis factor. The outcome was overall influenced by treatment provided. While radiation therapy, monochemotherapy or even polychemotherapy regimens did not significantly affect the course of the disease, the survival of bone marrow transplanted patients was significantly higher. Conclusions Despite the fact that BPDCN is often initially limited to the skin, only an aggressive initial therapy may improve the patients' prognosis. Local treatments, such radiation therapy, are definitively useless. Regardless of the initial extension of the disease, in our experience only bone marrow transplantation significantly improved the outcome.

Unité(s) : Anatomie Pathologique

Diagnosing Xeroderma Pigmentosum Group C by Immunohistochemistry

DE FERAUDY S, BOUBAKOUR-AZZOUZ I, FRAITAG S, BERNEBURG M, CHAN L, CHEW K, CLERICUZIO CL, CUNNINGHAM B, TOPE WD, CLEAVER JE

2010 - Am J Dermatopathol 32(2):109-17

Xeroderma pigmentosum (XP) is a group of rare inherited human neurocutaneous diseases, and the group C (XPC) is the major group of patients with XP in Europe, North America, and South America. Current molecular diagnostic methods for XP require specialized, expensive, and time-consuming UV sensitivity and DNA repair assays followed by gene sequencing. To determine whether immunohistochemistry (IHC) would be a robust alternative method to diagnose patients with XPC, we stained sections of paraffin-embedded skin biopsies for XPC by IHC, using 69 archived blocks from confirmed or clinically suspect patients with XPA, XPC, XPD, XPE, and without XP. We found that XPC expression was strong in all skin biopsies from patients without (14 of 14) and other patients with XP (4 of 4), whereas XPC expression was lost in all biopsies from confirmed XPC patients (29 of 29). Patches of strong XPC signal could be detected in sun-damaged skin, squamous and basal cell carcinomas from patients with XPC that colocalized with strong expression of p53 and Ki-67. Patients with XPC can therefore be diagnosed by IHC from paraffin-embedded skin biopsies from regions of skin that are without sun damage or sun-induced tumors. IHC is therefore a robust alternative method to diagnose patients with XPC. This fast and inexpensive method should increase the options for the diagnosis of patients with XPC from paraffin-embedded skin biopsies and could be developed for other complementation groups.

Unité(s) : Anatomie Pathologique

Intragraft Th17 infiltrate promotes lymphoid neogenesis and hastens clinical chronic rejection

DETEIX C, ATTUIL-AUDENIS V, DUTHEY A, PATEY N, MCGREGOR B, DUBOIS V, CALIGIURI G, GRAFF-DUBOIS S, MORELON E, THAUNAT O

2010 - J Immunol 184(9):5344-51

To evaluate the influence of intragraft inflammatory infiltrate on the course of chronic rejection, 11 human renal grafts, detransplanted for terminal failure, were analyzed. Samples were divided into two groups according to their graft survival (> or < or = 8 y). In both groups, the main cell population infiltrating the graft interstitia was T lymphocytes. The extent of the lymphocytic infiltration and the distribution of naive and memory, CD4(+) and CD8(+) T cells, were similar in both groups. Although all types of Th polarization profiles can lead to terminal chronic rejection, a correlation between shorter graft survival and the presence of Th17 cells that produce IL-17 and IL-21 was observed. In contrast, grafts infiltrated by regulatory T cells survived significantly longer. The correlation between the expressions of activation-induced cytidine deaminase (the key enzyme of the germinal center reaction) and IL-21 suggests that Th17 could exert their deleterious effect by promoting lymphoid neogenesis, namely, the organization of inflammatory effectors into ectopic germinal centers in which a local humoral immune response is elicited. Further studies will determine whether Th17 infiltration can be used as a prognosis tool and whether the Th17 subset constitutes a therapeutic target for slowing down chronic rejection.

Unité(s) : Anatomie Pathologique

Cutaneous Richter's syndrome, prognosis, and clinical, histological and immunohistological patterns: report of four cases and review of the literature

DUONG T, GRANGE F, AUFFRET N, ARACTINGI S, BODEMER C, BROUSSE N, HERMINE O, FRAITAG S

2010 - Dermatology 220(3):226-33

BACKGROUND: Richter's syndrome (RS) corresponds to the transformation of chronic lymphocytic leukemia (CLL) into high-grade lymphoma. RS can involve extranodal sites including the gastrointestinal tract, lungs and skin. Cutaneous RS is rare, we describe 4 cases with clinical manifestations, histological and immunohistological patterns, and outcome. METHODS: Clinical data were analyzed and all patients' skin biopsy samples stained with HE for the CD20, CD5, CD3 and CD30 antigens. Epstein-Barr-virus (EBV)-encoded early RNA and clonal rearrangements were also analyzed. RESULTS: The patients' mean age at CLL diagnosis was 57 years (53-62 years), with a male/female sex ratio of 3:1. The transformation to cutaneous RS occurred between 8 and 75 months after initial diagnosis and progressed to a fatal systemic disease in 3 cases, between 24 and 129 months. Cutaneous CLL was associated with earlier transformation in our series and could not be distinguished from RS on clinical grounds alone. All patients had a large-cell infiltrate and clonal rearrangements. CONCLUSIONS: The precise mechanism of RS is unclear, but a role of EBV has been suggested in fludarabine-treated CLL. For all our patients, the diagnosis of transformation was made on the basis of cutaneous localizations and led to intensified CLL treatment.

Unité(s) : Anatomie Pathologique, Dermatologie, Hématologie Adulte

Unusual presentation of chromoblastomycosis due to Cladophialophora carrionii in a renal and pancreas transplant recipient patient successfully treated with posaconazole and surgical excision

DUPONT C, DUONG TA, MALLET S, MAMZER-BRUNEEL MF, THERVET E, BOUGNOUX ME, DUPONT B

2010 - Transpl Infect Dis 12(2):180-83

C. Dupont, T.A. Duong, S. Mallet, M.F. Mamzer-Bruneel, E. Thervet, M.E. Bougnoux, B. Dupont. Unusual presentation of chromoblastomycosis due to Cladophialophora carrionii in a renal and pancreas transplant recipient patient successfully treated with posaconazole and surgical excision. Transpl Infect Dis 2009. All rights reserved Abstract: Chromoblastomycosis is a chronic, tropical and subtropical, subcutaneous mycosis caused by inoculation of dematiaceous molds. This disease is uncommonly reported in patients who have undergone solid organ transplantation. We describe a case of chromoblastomycosis caused by Cladophialophora carrionii that occurred 7 years after transplantation in a 58-year-old male renal and pancreatic transplant recipient. Diagnosis was based on histopathology and isolation of multiple colonies of the dematiaceous mold in pure culture. Identification was achieved by sequencing of the internal transcribed spacer regions of the rRNA. The patient was successfully treated with posaconazole and surgical excision of a residual lesion.

Unité(s) : Anatomie Pathologique, Dermatologie, Laboratoire de Microbiologie, Maladies Infectieuses, Transplantation Adulte

Scoring system for renal pathology in Fabry disease: report of the International Study Group of Fabry Nephropathy (ISGFN)

FOGO AB, BOSTAD L, SVARSTAD E, COOK WJ, MOLL S, BARBEY F, GELDENHUYS L, WEST M, FERLUGA D, VUJKOVAC B, HOWIE AJ, BURNS A, REEVE R, WALDEK S, NOEL LH, GRUNFELD JP, VALBUENA C, OLIVEIRA JP, MULLER J, BREUNIG F, ZHANG X, WARNOCK DG

2010 - Nephrol Dial Transplant 25(7):2168-77

BACKGROUND: In Fabry nephropathy, alpha-galactosidase deficiency leads to accumulation of glycosphingolipids in all kidney cell types, proteinuria and progressive loss of kidney function. METHODS: An international working group of nephrologists from 11 Fabry centres identified adult Fabry patients, and pathologists scored histologic changes on renal biopsies. A standardized scoring system was developed with a modified Delphi technique assessing 59 Fabry nephropathy cases. Each case was scored independently of clinical information by at least three pathologists with an average final score reported. RESULTS: We assessed 35 males (mean age 36.4 years) and 24 females (43.9 years) who mostly had clinically mild Fabry nephropathy. The average serum creatinine was 1.3 mg/dl (114.9 mumol/l); estimated glomerular filtration rate was 81.7 ml/min/1.73 m(2) and urine protein to creatinine ratio was 1.08 g/g (122.0 mg/mmol). Males had greater podocyte vacuolization on light microscopy (mean score) and glycosphingolipid inclusions on semi-thin sections than females. Males also had significantly more proximal tubule, peritubular capillary and vascular intimal inclusions. Arteriolar hyalinosis was similar, but females had significantly more arterial hyalinosis. Chronic kidney disease stage correlated with arterial and glomerular sclerosis scores. Significant changes, including segmental and global sclerosis, and interstitial fibrosis were seen even in patients with stage 1-2 chronic kidney disease with minimal proteinuria. CONCLUSIONS: The development of a standardized scoring system of both disease-specific lesions, i.e. lipid deposition related, and general lesions of progression, i.e. fibrosis and sclerosis, showed a spectrum of histologic appearances even in early clinical stage of Fabry nephropathy. These findings support the role of kidney biopsy in the baseline evaluation of Fabry nephropathy, even with mild clinical disease. The scoring system will be useful for longitudinal assessment of prognosis and responses to therapy for Fabry nephropathy.

Unité(s) : Anatomie Pathologique, Néphrologie Adulte

[Langerhans cell histiocytosis.]

FRAITAG S

2010 - Ann Dermatol Venereol 137(2):163-6

Unité(s) : Anatomie Pathologique

Neonatal erythroderma

FRAITAG S, BODEMER C

2010 - Curr Opin Pediatr 22(4):438-44

PURPOSE OF REVIEW: Neonatal erythroderma is a potentially life-threatening condition in neonates less than 1 month old. During the first month of life, erythroderma is generally a presentation of genodermatosis, primary immune deficiency, or, more exceptionally, severe psoriasis, metabolic disease or infection. Atopic erythroderma is observed later in life, usually after the age of 1 month. Rapid determination of the underlying cause is crucial for better management. However, the diagnosis is often a challenge for the clinician and is frequently delayed due to the nonspecific nature of the clinical signs. We summarize the different causes of neonatal erythrodermas and list their clinical, biological, histological, and sometimes genetic characteristics. RECENT FINDINGS: Severe erythroderma, typified by early onset, skin induration, severe alopecia and failure to thrive, is immediately suggestive of immunodeficiency or Netherton syndrome. In such cases, an early skin biopsy may be particularly of use in allowing accurate differentiation between these two disorders. SUMMARY: This review outlines the clinical and histological features of these disorders and suggests an approach to their differential diagnosis and management.

Unité(s) : Anatomie Pathologique, Dermatologie

Accessory spleen: Differential diagnosis for lymphoma in autoimmune lymphoproliferative syndrome

GEORGIN-LAVIALLE S, AOUBA A, CANIONI D, RIEUX-LAUCAT F, FISCHER A, HERMINE O

2010 - Pediatr Blood Cancer 54(7):1020-22

Mutations of Fas or, less frequently, Fas ligand genes result in a rare inherited lymphoid disorder called autoimmune lymphoproliferative syndrome (ALPS) in which lymphoma frequency is increased. We report on a patient with ALPS who had been splenectomized for giant splenomegaly and progressively developed a voluminous abdominal tumor. The histology of the removed tumor revealed that it was an accessory spleen exhibiting typical features of ALPS involvement, as shown by the presence of a large excess of CD3(+)CD4(-)CD8(-) T cells and plasma cells without a detectable monoclonal population. This observation highlights the lymphoma's differential diagnosis in this context. Pediatr Blood Cancer (c) 2010 Wiley-Liss, Inc.

Unité(s) : Anatomie Pathologique, Hématologie Adulte, Immunologie-Hématologie Pédiatriques, U768, UMR 8147

No Correlation between the Molecular Subtype of COL1A1-PDGFB Fusion Gene and the Clinico-Histopathological Features of Dermatofibrosarcoma Protuberans

GIACCHERO D, MAIRE G, NUIN PA, BERTHIER F, EBRAN N, CARLOTTI A, CELERIER P, COINDRE JM, ESTEVE E, FRAITAG S, GUILLOT B, RANCHERE-VINCE D, SAIAG P, TERRIER P, LACOUR JP, PEDEUTOUR F

2010 - J Invest Dermatol 130(3):904-7

Unité(s) : Anatomie Pathologique

'Matchstick' eyebrow hairs: a dermoscopic clue to the diagnosis of Netherton syndrome

GOUJON E, BEER F, FRAITAG S, HOVNANIAN A, VABRES P

2010 - J Eur Acad Dermatol Venereol 24(6):740-41

Unité(s) : Anatomie Pathologique

NKX2-1 mutations leading to surfactant protein promoter dysregulation cause interstitial lung disease in "Brain-Lung-Thyroid Syndrome"

GUILLOT L, CARRE A, SZINNAI G, CASTANET M, TRON E, JAUBERT F, BROUTIN I, COUNIL F, FELDMANN D, CLEMENT A, POLAK M, EPAUD R

2010 - Hum Mutat 31(2):E1146-62

NKX2-1 (NK2 homeobox 1) is a critical regulator of transcription for the surfactant protein (SP)-B and -C genes (SFTPB and SFTPC, respectively). We identified and functionally characterized two new de novo NKX2-1 mutations c.493C>T (p.R165W) and c.786_787del2 (p.L263fs) in infants with closely similar severe interstitial lung disease (ILD), hypotonia, and congenital hypothyroidism. Functional analyses using A549 and HeLa cells revealed that NKX2-1-p.L263fs induced neither SFTPB nor SFTPC promoter activation and had a dominant negative effect on wild-type (WT) NKX2-1. In contrast,NKX2-1-p.R165W activated SFTPC, to a significantly greater extent than did WTNKX2-1, while SFTPB activation was only significantly reduced in HeLa cells. In accordance with our in vitro data, we found decreased amounts of SP-B and SP-C by western blot in bronchoalveolar lavage fluid (patient with p.L263fs) and features of altered surfactant protein metabolism on lung histology (patient with NKX2-1-p.R165W). In conclusion, ILD in patients with NKX2-1 mutations was associated with altered surfactant protein metabolism, and both gain and loss of function of the mutated NKX2-1 genes on surfactant protein promoters were associated with ILD in "Brain-Lung-Thyroid syndrome".

Unité(s) : Anatomie Pathologique, Endocrinologie Pédiatrique et Gynécologie, U845 (RS)

[Papillary renal cell carcinoma: Morphological subtypes, clinical and histopathological considerations.]

HENRY N, ROUACH Y, NGUYEN K, VERKARRE V, MEJEAN A, TIMSIT MO

2010 - Prog Urol 20(6):393-401

PURPOSE: We reviewed papillary renal cell carcinoma (PRCC) epidemiology, radiological and clinical presentations, and specific features of morphological subtypes focusing on genetic defects, risk of local and metastatic recurrence and frequency of multifocality. MATERIALS AND METHODS: The MEDLINE database of the US National Library of Medicine was searched for pertinent studies. RESULTS: According to multivariate analyses, PRCC histology was not retained as a prognostic factor. Reported rates of multifocality in PRCC are 22 to 41% but distinction between histological subtype or hereditary forms are barely detailed. Multifocality frequency is independent of size, stage or grade and is not associated with ipsilateral or controlateral recurrence or death from RCC. Thus, PRCC multifocality is not an argument against nephron-sparing surgery. Antiangionenic therapies are being evaluated for the Metastatic PRCC. CONCLUSION: According to the literature, specific prognostic features of PRCC remain controversial due to the lack of distinction between different PRCC subtypes. Genomic and cytogenetic characterizations have been used to establish an evolving classification of PRCC subtypes and may be a source of new markers that will eventually enable us to precise prognosis and identify targets for new adjuvant therapies.

Unité(s) : Anatomie Pathologique

Retrospective French nationwide survey of childhood aggressive vascular anomalies of bone, 1988-2009

HERITIER S, LE MERRER M, JAUBERT F, BIGORRE M, GILLIBERT-YVERT M, DE COURTIVRON B, ZIADE M, BERTRAND Y, CARRIE C, CHASTAGNER P, BOST-BRU C, LEONARD JC, OUACHE M, BOCCON-GIBOD L, MARY P, DE BLIC J, PIN I, WENDLING D, REVILLON Y, HOUDOIN V, FORIN V, LEPOINTE HD, LANGUEPIN J, WAGNON J, EPAUD R, FAUROUX B, DONADIEU J

2010 - Orphanet J Rare Dis 5(.):3

OBJECTIVE: To document the epidemiological, clinical, histological and radiological characteristics of aggressive vascular abnormalities of bone in children. STUDY DESIGN: Correspondents of the French Society of Childhood Malignancies were asked to notify all cases of aggressive vascular abnormalities of bone diagnosed between January 1988 and September 2009. RESULTS: 21 cases were identified; 62% of the patients were boys. No familial cases were observed, and the disease appeared to be sporadic. Mean age at diagnosis was 8.0 years [0.8-16.9 years]. Median follow-up was 3 years [0.3-17 years]. The main presenting signs were bone fracture (n = 4) and respiratory distress (n = 7), but more indolent onset was observed in 8 cases. Lung involvement, with lymphangiectasies and pleural effusion, was the most frequent form of extraosseous involvement (10/21). Bisphosphonates, alpha interferon and radiotherapy were used as potentially curative treatments. High-dose radiotherapy appeared to be effective on pleural effusion but caused major late sequelae, whereas antiangiogenic drugs like alpha interferon and zoledrenate have had a limited impact on the course of pulmonary complications. The impact of bisphosphonates and alpha interferon on bone lesions was also difficult to assess, owing to insufficient follow-up in most cases, but it was occasionally positive. Six deaths were observed and the overall 10-year mortality rate was about 30%. The prognosis depended mainly on pulmonary and spinal complications. CONCLUSION: Aggressive vascular abnormalities of bone are extremely rare in childhood but are lifethreatening. The impact of anti-angiogenic drugs on pulmonary complications seems to be limited, but they may improve bone lesions.

Unité(s) : Anatomie Pathologique, Centre de Génétique Médicale Jean Frézal, Chirurgie Viscérale Pédiatrique, Pneumologie et Asthmologie Pédiatriques

CD4+CD25+ T Cells Play a Complex Role in the Pediatric Combined Liver-Intestinal Graft Acceptance

JUGIE M, BADOUAL C, LE BIHAN C, CANIONI D, SARNACKI S, GOULET O, SAUTES-FRIDMAN C, DAMOTTE D

2010 - Transplantation 90(1):95-97

Unité(s) : Anatomie Pathologique, Biostatistique, Chirurgie Viscérale Pédiatrique, Gastro-Hépatologie et Nutrition Pédiatriques

Unusual virilization in girls with juvenile granulosa cell tumors of the ovary is related to intratumoral aromatase deficiency

KALFA N, MEDURI G, PHILIBERT P, PATTE C, BOIZET-BONHOURE B, THIBAUT E, PIENKOWSKI C, JAUBERT F, MISRAHI M, SULTAN C

2010 - Horm Res Paediatr 74(2):83-91

BACKGROUND: Hyperandrogenism is a rare symptom of juvenile ovarian granulosa cell- tumors (JGCTO). This study aimed to determine whether hyperandrogenism was related to overexpression of SOX9, decreased expression of FOXL2 or absent aromatase expression in tumor with particular scheme of expression of P450scc and P450c17alpha. METHODS: Through a nationwide study including the French Society of Pediatric Oncology, 6/30 patients with JGCTO presented with clinical hyperandrogenism and high plasma testosterone. Tumor specimens underwent immunofluorescence (SOX9, FOXL2) and immunochemistry (aromatase, P450scc, P450c17alpha). Results were compared with patients without hyperandrogenism. RESULTS: SOX9 was expressed in the granulosa cell nucleus in 2/6 cases but also in 9/24 tumors without hyperandrogenism (p=n.s.). FOXL2 was absent or decreased in 3/6 cases of JGCTO with hyperandrogenism with no statistical difference from the group without this symptom. In 6/6 patients, the intratumoral expression of aromatase was absent (n=5) or dramatically reduced (n=1). In contrast, 15/24 patients without virilization exhibited conserved aromatase expression in their tumor (p<0.05). A variable number of tumoral cells expressed P450scc while some interstitial cells were focally immunopositive for P450c17alpha. CONCLUSION: Unusual virilization in girls with JGCTO is not explained by a dysregulation in SOX9 or FOXL2 expression, but is related to a localized defect of aromatase expression in granulosa cells and to the ability of interstitial cells to produce testosterone.

Unité(s) : Anatomie Pathologique, Endocrinologie Pédiatrique et Gynécologie

Agminated Spitz nevi arising on a nevus spilus after chemotherapy

KHALED A, KHARFI M, SELLAMI A, HAMEL-TEILLAC D, FAAZA B, FRAITAG S, KAMOUN MR

2010 - Pediatr Dermatol 27(4):411-3

Agminated Spitz nevus arising on a background of nevus spilus (NS) is a rare condition. We report here a further case in a child that is original because it is induced by chemotherapy. A 3-year-old boy presented 3 months after the onset of a chemotherapy for a vesico-prostatic rhabdomyosarcoma, multiple pigmented papulo-nodules located on the face, neck, chest wall, and the higher back. These lesions have arose on a pre-existent large congenital histologically confirmed nevus spilus extending along the face, neck, the left shoulder and the left chest wall. Histological examination of three excised nodules led to the diagnosis of Spitz nevus. Our patient may have a high risk for melanoma since he has many criteria predisposing to this risk. Some of these criteria are related to NS but we should also take into account the chemotherapy induction and the high number of Spitz nevi.

Unité(s) : Anatomie Pathologique, Dermatologie

Fibroblastic rheumatism: fibromatosis rather than non-Langerhans cell histiocytosis

KLUGER N, DUMAS-TESICI A, HAMEL D, BROUSSE N, FRAITAG S

2010 - J. Cutan. Pathol. 37(5):587-592

Background: Fibroblastic rheumatism is a unique fibro-proliferative disease affecting the skin and joints. It is characterized by distinctive clinical and histological features related to benign spindle-shaped cells proliferation. Pediatric reports are scarce in the literature. Objective: We describe here a new case in a 10-year-old boy and discuss the potential origin of the cell proliferation. Methods: Clinical findings, radiology, microscopic examination and outcome are reviewed. Histopathology and immunochemistry studies were performed on skin biospies using CD68, CD163, desmin, factor XIIIa, CD34, smooth muscle actin, PS100, epithelial membrane antigen, and calponin. Results: Histological sections disclosed a rather circumscribed nonencapsulated nodular infiltrate, invading the dermis and the upper subcutaneous tissue, consisted of a proliferation of spindle or stellate-shaped cells and thickened collagen fibers. Orcein staining showed disappearance of the elastic network. Aponeurosis and muscle were normal. A mild perivascular lymphohistiocytic infiltrate was noted. Calponin-staining was less strongly expressed as SMA, and some of them but not all were CD68 positive, as well. On the other hand, all were CD34, CD163, FXIIIa, PS100, EMA and desmin-negative. Conclusion: The true origin of these cells remains unclear. Some authors have speculated a histiocytic origin. However, immunochemical staining in our case failed to confirm this hypothesis and instead supported a fibroblastic/myofibroblastic origin. Given the clinical course and the histological and immunohistochemical results, we suggest that FR should be added to the group of fibromatoses.

Unité(s) : Anatomie Pathologique, Dermatologie

Why puncturing a lumbar tattoo during epidural analgesia cannot induce an epidermoid tumor

KLUGER N, FRAITAG S, GUILLOT B, SLETH JC

2010 - Reg Anesth Pain Med 35(3):317

Unité(s) : Anatomie Pathologique

Early skin biopsy is helpful for the diagnosis and management of neonatal and infantile erythrodermas

LECLERC-MERCIER S, BODEMER C, BOURDON-LANOY E, LAROUSSERIE F, HOVNANIAN A, BROUSSE N, FRAITAG S

2010 - J Cutan Pathol 37(2):249-255

Background: Erythrodermas are often life-threatening conditions in infants. Determination of the underlying cause is crucial. Microscopic changes in adult erythroderma lack specificity. Objective: To determine if an early skin biopsy is helpful for the diagnosis of neonatal and infantile erythroderma. Methods: Seventy-two patients admitted for erythroderma in the first year of life were retrospectively included. One hundred and eleven skin biopsies (12-year period) were examined by 3 pathologists blinded to the clinical diagnosis, and classified into atopic dermatitis, immunodeficiency (ID), psoriasis, Netherton syndrome (NS), ichthyosis, other. From year 2000, LEKTI antibody was performed when NS was suspected. Pathological diagnosis was then compared with clinical diagnosis. Results: The final diagnosis was made in 69.3% of the cases. In 57.6%, pathological diagnosis was in accordance, and in 11.7%, it was in accordance, but other diagnosis had also been proposed. For ID, sensitivity and specificity were 58.5 and 98.5%, respectively. Before year 2000, NS was frequently misdiagnosed with psoriasis, but with the use of LEKTI antibody, sensitivity and specificity were 100%. Conclusion: Skin biopsy is helpful for etiologic diagnosis of early erythroderma of infancy, particularly in ID and NS, the most severe diseases. Consequently, these results justify an early systematic skin biopsy for a better and earlier management. Leclerc-Mercier S, Bodemer C, Bourdon-Lanoy E, Larousserie F, Hovnanian A, Brousse N, Fraitag S. Early skin biopsy is helpful for the diagnosis and management of Neonatal and Infantile Erythrodermas.

Unité(s) : Anatomie Pathologique, Dermatologie

IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease-associated inflammation and lymphomagenesis

MALAMUT G, EL MACHHOUR R, MONTCUQUET N, MARTIN-LANNEREE S, DUSANTER-FOURT I, VERKARRE V, MENTION JJ, RAHMI G, KIYONO H, BUTZ EA, BROUSSE N, CELLIER C, CERF-BENSUSSAN N, MERESSE B

2010 - J Clin Invest 120(6):2131-43

Enteropathy-associated T cell lymphoma is a severe complication of celiac disease (CD). One mechanism suggested to underlie its development is chronic exposure of intraepithelial lymphocytes (IELs) to potent antiapoptotic signals initiated by IL-15, a cytokine overexpressed in the enterocytes of individuals with CD. However, the signaling pathway by which IL-15 transmits these antiapoptotic signals has not been firmly established. Here we show that the survival signals delivered by IL-15 to freshly isolated human IELs and to human IEL cell lines derived from CD patients with type II refractory CD (RCDII) - a clinicopathological entity considered an intermediary step between CD and enteropathy-associated T cell lymphoma - depend on the antiapoptotic factors Bcl-2 and/or Bcl-xL. The signals also required IL-15Rbeta, Jak3, and STAT5, but were independent of PI3K, ERK, and STAT3. Consistent with these data, IELs from patients with active CD and RCDII contained increased amounts of Bcl-xL, phospho-Jak3, and phospho-STAT5. Furthermore, incubation of patient duodenal biopsies with a fully humanized human IL-15-specific Ab effectively blocked Jak3 and STAT5 phosphorylation. In addition, treatment with this Ab induced IEL apoptosis and wiped out the massive IEL accumulation in mice overexpressing human IL-15 in their gut epithelium. Together, our results delineate the IL-15-driven survival pathway in human IELs and demonstrate that IL-15 and its downstream effectors are meaningful therapeutic targets in RCDII.

Unité(s) : Anatomie Pathologique, U989

Tissue Accumulation of Lanthanum as Compared to Aluminum in Rats with Chronic Renal Failure - Possible Harmful Effects after Long-Term Exposure

NIKOLOV IG, JOKI N, VICCA S, PATEY N, AUCHERE D, BENCHITRIT J, FLINOIS JP, ZIOL M, BEAUNE P, DRUEKE TB, LACOUR B

2010 - Nephron Exp Nephrol 115(4):e112-e121

Background: Lanthanum (La) carbonate is a new treatment for hyperphosphatemia. We tested the effects of oral La carbonate and aluminum hydroxide, respectively, on tissue accumulation and liver function in rats with chronic renal failure (CRF). Methods: Adult male non-CRF and CRF rats were randomly assigned to 3 groups receiving either standard diet (St.D), or the same diet supplemented with 3% La carbonate (non-CRF La vs. CRF La) or 3% aluminum hydroxide (non-CRF Al vs. CRF Al). Results: After 12 weeks, serum phosphorus was decreased in both CRF La and Al groups. Urinary La and Al excretion was increased in these two groups, and so was liver and bone La content, and liver Al content. Both total body and liver weight were decreased in CRF La and CRF Al rats. Liver cell proliferation was decreased in these groups, while plasma total alkaline phosphatases and alanine aminotransferase were increased. Hepatic total cytochrome p450 content was reduced in CRF La, but not in CRF Al rats. Conclusion: Long-term oral La overload in rats with CRF was associated with a decrease in liver (and total body) weight and mild alterations of liver function, as was Al overload, possibly as a consequence of trace element accumulation.

Unité(s) : Anatomie Pathologique, Biochimie Générale, U845 (VW)

Clinical spectrum of tufted angiomas in childhood: a report of 13 cases and a review of the literature

OSIO A, FRAITAG S, HADJ-RABIA S, BODEMER C, DE PROST Y, HAMEL-TEILLAC D

2010 - Arch Dermatol 146(7):758-63

BACKGROUND: Tufted angioma (TA) is a rare benign vascular tumor that mostly appears during infancy or early childhood. Histologic tufts of capillaries infiltrating the whole dermis in a "cannonball" distribution pattern associated with dilated lymphatic vessels are characteristic of the disease and confirm the diagnosis. Few case series of TA have been published, and the morphologic structure and evolution of TA seem to vary. OBSERVATIONS: We describe the largest series to date of childhood TA, comprising 13 cases. All children developed lesions within the first year of life; 7 cases were congenital. We found a clear male predominance (9 of 13 children). Presentation was a nascent or florid tumor, usually a dusky red to violaceous plaque, that was indurated, firm, and sometimes associated with hyperhidrosis or hypertrichosis. Locations of the lesions included limbs, abdomen, and genitalia. Five children had spontaneous regression, 5 children had Kasabach-Merritt syndrome, and 1 child had a lesion that stabilized. Two children with painful TA had chronic coagulopathy without thrombocytopenia that was controlled by ticlopidine hydrochloride and aspirin. CONCLUSIONS: The following 3 clinical patterns could be distinguished: TA without complications, TA complicated by Kasabach-Merritt syndrome, and TA without thrombocytopenia but with chronic coagulopathy. To our knowledge, this study is the first to describe the third pattern. Because of the aggressive nature of Kasabach-Merritt syndrome, it is essential to obtain a complete blood cell count when evaluating a child with TA.

Unité(s) : Anatomie Pathologique, Dermatologie

Cidofovir may be deleterious in BK virus-associated nephropathy

PALLET N, BURGARD M, QUAMOUSS O, RABANT M, BERERHI L, MARTINEZ F, THERVET E, ANGLICHEAU D, NOEL LH, ROUZIOUX C, LEGENDRE C

2010 - Transplantation 89(12):1542-4

Unité(s) : Anatomie Pathologique, Laboratoire de Microbiologie, Transplantation Adulte

Superficial Punctate Keratitis and Conjunctival Erosions Associated with Congenital Tufting Enteropathy

ROCHE O, PUTTERMAN M, SALOMON J, LACAILLE F, BROUSSE N, GOULET O, DUFIER JL

2010 - Am J Ophthalmol 150(1):116-21

PURPOSE: To study the value of conjunctival biopsy in congenital tufting enteropathy diagnosis. DESIGN: Case-comparative study. METHODS: Between January 2000 and June 2007, all children seeking treatment with an early onset of intractable diarrhea were examined in the ophthalmology department of Necker-Enfants Malades Hospital, Assistance Publique-Hopitaux de Paris, France. Children underwent complete ophthalmologic examination with concurrent conjunctival and intestinal biopsies. Main outcome measures were age at diagnosis, associated disorders, parenteral nutrition, and ophthalmologic symptoms. Conjunctival biopsies support diagnosis in the presence of specific alteration. RESULTS: Twenty patients were included. The mean age of the population was 30.2 months. Congenital tufting enteropathy was diagnosed in 15 cases. In the congenital tufting enteropathy group, 10 children exhibited ophthalmic functional disorders since the first months of life, with superficial punctate keratitis and conjunctivitis and in addition alacrima and cataract in 1 case, respectively, whereas 5 children had asymptomatic conjunctival hyperemia at presentation. Conjunctival biopsies showed epithelial parakeratosis, hyperplasia, basal cells hyperplasia, and tufts. In some cases, the lamina propria contained inflammatory cells or fibrosis, and the density of goblet cells then was abnormal. In the comparison group of 5 children with early-onset intractable diarrhea but without congenital tufting enteropathy diagnosis, no tuft occurrence was observed. CONCLUSIONS: In cases of intractable diarrhea in infancy, even without ocular symptoms, a systematic ophthalmologic examination should be performed. It also should be associated with the pathologic examination of both the conjunctival and the intestine mucosae, which helps to diagnose congenital tufting enteropathy (adhesion molecules disease). Specific conjunctival findings allow affirmation of congenital tufting enteropathy before the genetic confirmation of an EpCAM gene mutation.

Unité(s) : Anatomie Pathologique, Gastro-Hépatologie et Nutrition Pédiatriques, Ophtalmologie

Capsular involvement in patients undergoing partial nephrectomy for localized renal cell carcinoma: an adverse pathological finding?

ROUACH Y, DELONGCHAMPS N, TIMSIT MO, VERKARRE V, FONTAINE E, PEYROMAURE M, MEJEAN A

2010 - BJU Int 105(5):616-9

OBJECTIVE To evaluate the prognostic impact of capsular involvement (CaI) in patients treated exclusively with partial nephrectomy (PN) for localized renal cell carcinoma (RCC), as in these patients CaI was recently reported as an adverse prognostic factor. PATIENTS AND METHODS We retrospectively reviewed the medical records of patients treated with PN for a sporadic and localized RCC (pT1-pT2N0M0) in our institution between 1985 and 2005. Univariate and multivariate analysis using a Cox proportional-hazards regression analysis were conducted to identify significant predictors of oncological outcome for several clinical and pathological factors, i.e. imperative indication, histological type, Fuhrman grade, tumour size, T stage, CaI, and surgical margins. Disease-free and -specific survival rates of patients with CaI and no evidence of CaI were compared using the log-rank test. RESULTS In all, 305 patients had a PN for localized RCC, of whom 22 (7.2%) had CaI in the PN specimen. The median (range) follow-up was 6 (1.5-23) years. Multivariate statistical analysis showed that imperative indication for PN and high-grade RCC were independently associated with worse disease-free and -specific survival, whereas CaI had no prognostic value. Disease-free and -specific survival in patients with and without CaI were not significantly different at 5 and 10 years. CONCLUSIONS In a contemporary series of patients exclusively treated with PN for localized RCC, CaI was not predictive of disease recurrence and disease-specific mortality. These results do not support the use of any change in postoperative management in patients with CaI after PN.

Unité(s) : Anatomie Pathologique, Urologie

Chronic Iron-deficiency Anemia Caused by a Jejunojejunal Intussusception on a Solitary Hamartomatous Polyp

RUBIO A, DE MONTALEMBERT M, VERKARRE V, FUSARO F, EMOND S, OLSCHWANG S, REVILLON Y, RUEMMELE FM

2010 - J Pediatr Gastroenterol Nutr 50(4):450-52

Unité(s) : Anatomie Pathologique, Chirurgie Viscérale Pédiatrique, Pédiatrie Générale, Radiologie Pédiatrique

Loss-of-function of MYO5B is the main cause of microvillus inclusion disease: 15 novel mutations and a CaCo-2 RNAi cell model

RUEMMELE FM, MULLER T, SCHIEFERMEIER N, EBNER HL, LECHNER S, PFALLER K, THONI CE, GOULET O, LACAILLE F, SCHMITZ J, COLOMB V, SAUVAT F, REVILLON Y, CANIONI D, BROUSSE N, DE SAINT-BASILE G, LEFEBVRE J, HEINZ-ERIAN P, ENNINGER A, UTERMANN G, HESS MW, JANECKE AR, HUBER LA

2010 - Hum Mutat 31(5):544-51

Autosomal recessive microvillus inclusion disease (MVID) is characterized by an intractable diarrhea starting within the first few weeks of life. The hallmarks of MVID are a lack of microvilli on the surface of villous enterocytes, occurrence of intracellular vacuoles lined by microvilli (microvillus inclusions) and the cytoplasmic accumulation of periodic acid-Schiff (PAS)-positive vesicles in enterocytes. Recently, we identified mutations in MYO5B, encoding the unconventional type Vb myosin motor protein, in a first cohort of nine MVID patients. In this study, we identified 15 novel nonsense and missense mutations in MYO5B in 11 unrelated MVID patients. Fluorescence microscopy, Western blotting and electron microscopy were applied to analyze the effects of MYO5B siRNA knock-down in polarized, brush border possessing CaCo-2 cells. Loss of surface microvilli, increased formation of microvillus inclusions and subapical enrichment of PAS-positive endomembrane compartments were induced in polarized, filter-grown CaCo-2 cells, following MYO5B knock-down. Our data indicate that MYO5B mutations are a major cause of microvillus inclusion disease and that MYO5B knock-down recapitulates most of the cellular phenotype in vitro, thus independently showing loss of MYO5B function as the cause of microvillus inclusion disease. (c) 2010 Wiley-Liss, Inc.

Unité(s) : U989, Anatomie Pathologique, Chirurgie Viscérale Pédiatrique, Gastro-Hépatologie et Nutrition Pédiatriques, U768

Germline mosaicism in keratitis-ichthyosis-deafness syndrome: pre-natal diagnosis in a familial lethal form

SBIDIAN E, FELDMANN D, BENGOA J, FRAITAG S, ABADIE V, DE PROST Y, BODEMER C, HADJ-RABIA S

2010 - Clin Genet 77(6):587-92

Sbidian E, Feldmann D, Bengoa J, Fraitag S, Abadie V, de Prost Y, Bodemer C, Hadj-Rabia S. Germline mosaicism in keratitis-ichthyosis-deafness syndrome: pre-natal diagnosis in a familial lethal form. Keratitis-ichthyosis-deafness (KID) syndrome is an autosomal dominant congenital ectodermal defect characterized by the association of skin lesions, hearing loss and keratitis. Most of the cases appear to be sporadic. KID syndrome is mostly related to mutations of GJB2 gene encoding connexin-26. Recently, a lethal form of the disease during the first year of life has been reported in two unrelated Caucasian patients. This rare lethal form is caused by the G45E mutation of GJB2 gene. We here report the first pre-natal molecular genetic diagnosis of the lethal form of KID syndrome relating to a G45E mutation. In the same family, the occurrence of this condition in three other siblings born to African non-consanguineous healthy parents lead to perform pre-natal diagnosis for this last pregnancy. Molecular analysis confirms the diagnosis of the lethal form of KID for the fetus. These results establish the role of germline mosaicism in KID syndrome and warrant careful genetic counseling. Furthermore, analysis of our cases and the literature allowed us to define a characteristic severe neonatal phenotype including facial dysmorphy, severe cornification with massive focal hyperkeratosis of the skin with erythroderma, dystrophic nails, complete atrichia and absence of foreskin.

Unité(s) : Anatomie Pathologique, Centre de Génétique Médicale Jean Frézal, Dermatologie, Pédiatrie Générale

Gastrointestinal involvement and manifestations in systemic mastocytosis

SOKOL H, GEORGIN-LAVIALLE S, GRANDPEIX-GUYODO C, CANIONI D, BARETE S, DUBREUIL P, LORTHOLARY O, BEAUGERIE L, HERMINE O

2010 - Inflamm Bowel Dis 16(7):1247-53

Mastocytosis is a rare and heterogeneous disease characterized by various biological and clinical features with different prognosis and treatments. The disease is usually divided into 2 categories: a pure cutaneous and a systemic disease. Clinical features can be related to mast cells' mediators release or to pathological mast cells infiltration. The diagnosis of mastocytosis is based on clinical, biological, histological, and molecular international criteria. Among all manifestations of the disease, gastrointestinal (GI) symptoms are common and can significantly impair the quality of life. The aim of this article is to review the data regarding GI involvement in mastocytosis. Articles dealing with clinical, pathophysiological, and therapeutic aspects of mastocytosis GI tract involvement were searched for using PubMed. GI manifestations in mastocytosis are reviewed. Pathogenesis of GI symptoms in systemic mastocytosis and their treatment are critically discussed. The most frequent GI symptoms are abdominal pain, diarrhea, nausea, and vomiting. GI lesions may involve all the digestive tract, from the esophagus to the rectum. The histological diagnosis of GI involvement is difficult. The treatment of GI symptoms aims to prevent and limit mast cells degranulation and/or its consequences and more rarely to control tumoral mast cells infiltration. The high prevalence of GI symptoms in mastocytosis and their important functional impact deserves better characterization and treatment in order to improve patients' quality of life. Diagnosis of mastocytosis GI manifestations should be evoked in the case of unexplained severe GI disorders.

Unité(s) : Anatomie Pathologique, Hématologie Adulte, Maladies Infectieuses, UMR 8147

Chronic rejection triggers the development of an aggressive intragraft immune response through recapitulation of lymphoid organogenesis

THAUNAT O, PATEY N, CALIGIURI G, GAUTREAU C, MAMANI-MATSUDA M, MEKKI Y, DIEU-NOSJEAN MC, EBERL G, ECOCHARD R, MICHEL JB, GRAFF-DUBOIS S, NICOLETTI A

2010 - J Immunol 185(1):717-28

The unwarranted persistence of the immunoinflammatory process turns this critical component of the body's natural defenses into a destructive mechanism, which is involved in a wide range of diseases, including chronic rejection. Performing a comprehensive analysis of human kidney grafts explanted because of terminal chronic rejection, we observed that the inflammatory infiltrate becomes organized into an ectopic lymphoid tissue, which harbors the maturation of a local humoral immune response. Interestingly, intragraft humoral immune response appeared uncoupled from the systemic response because the repertoires of locally produced and circulating alloantibodies only minimally overlapped. The organization of the immune effectors within adult human inflamed tissues recapitulates the biological program recently identified in murine embryos during the ontogeny of secondary lymphoid organs. When this recapitulation was incomplete, intragraft B cell maturation was impeded, limiting the aggressiveness of the local humoral response. Identification of the molecular checkpoints critical for completion of the lymphoid neogenesis program should help develop innovative therapeutic strategies to fight chronic inflammation.

Unité(s) : Anatomie Pathologique, U783

Experimental treatment of human diffuse large B-cell lymphoma xenografts by doxycycline alone or in combination with the anti-CD20 chimeric monoclonal antibody rituximab

ASSAYAG F, BROUSSE N, COUTURIER J, MACINTYRE E, MATHIOT C, DEWULF S, FROGET B, VINCENT-SALOMON A, DECAUDIN D

2009 - Am J Hematol 84(6):387-8

Unité(s) : Anatomie Pathologique, Laboratoire d'Hématologie

[Lymphoid neogenesis and lymphangiogenesis: Two newcomers in the pathophysiology of chronic rejection.]

ATTUIL-AUDENIS V, DUTHEY A, PATEY N, GAUTREAU C, MCGREGOR B, MORELON E, MICHEL JB, NICOLETTI A, THAUNAT O

2009 - Nephrol Ther 5(2):91-6

Chronic rejection is one of the main causes of late allograft failure and no therapy is currently available to prevent efficiently its development. Improving the comprehension of the mechanisms involved in the pathophysiology of chronic rejection is a mandatory step to propose innovative therapies that would prolong grafts' survival. Using the rat aortic interposition model of chronic vascular rejection, we have demonstrated that the intragraft inflammatory infiltrate progressively organized itself into a functional ectopic lymphoid tissue (tertiary lymphoid organ) supporting the local synthesis of alloantibody. Thus, during chronic rejection the graft is at the same time the target and the site of elaboration of the humoral allo-immune response. This hypothesis has been confirmed in the clinical setting by the analysis of human grafts (kidneys, hearts and lungs) removed for terminal failure due to chronic rejection. This lymphoid neogenesis process, previously identified in other chronic inflammatory diseases, occurs with a strikingly high frequency in chronically rejected grafts, suggesting that an additional mechanism synergizes to initiate the development of tertiary lymphoid organs during chronic rejection. We propose that the defective lymphatic drainage of chronically rejected organs triggers lymphoid neogenesis and we discuss the complex crosstalk between lymphoid neogenesis and lymphangiogenesis that takes place during chronic rejection.

Unité(s) : Anatomie Pathologique

Management of Wilms tumors in Drash and Frasier syndromes

AUBER F, JEANPIERRE C, DENAMUR E, JAUBERT F, SCHLEIERMACHER G, PATTE C, CABROL S, LEVERGER G, NIHOUL-FEKETE C, SARNACKI S

2009 - Pediatr. Blood Cancer 52(1):55-59

BACKGROUND: Children with WT1 gene-related disorders such as Denys-Drash syndrome (DDS) and Frasier syndrome (FS) are at increased risk of Wilms tumor and end-stage renal disease. We investigated whether Wilms tumors in these patients displayed a specific phenotype or behavior and whether nephron-sparing surgery was beneficial. PROCEDURE: We retrospectively studied all patients with DDS, FS, or other WT1 mutations treated at our institutions between 1980 and 2007. RESULTS: We identified 20 patients, of whom 18 had benign or malignant tumors. Wilms tumors occurred in 15 patients, being unilateral in 10 and bilateral in 5 (20 tumors). Median age at Wilms tumor diagnosis was 9 months. No patients had metastases. According to the International Society of Pediatric Oncology Working Classification, there were 19 intermediate-risk tumors and one high-risk tumor; no tumor was anaplastic. In patients with nephropathy who underwent unilateral nephrectomy for Wilms tumor or nephron-sparing surgery for bilateral Wilms tumor, mean time to dialysis was 11 or 9 months, respectively. Other tumors included three gonadoblastomas (in two patients), one retroperitoneal soft-tissue tumor, and one transitional cell papilloma of the bladder. Two patients, both with stage I Wilms tumor, died from end-stage renal disease-related complications. The median follow-up time for the 18 survivors was 136 months (range, 17-224 months). CONCLUSION: Most Wilms tumors in children with WT1-related disorders were early-stage and intermediate-risk tumors, with a young age at diagnosis. In patients without end-stage renal disease, nephron-sparing surgery should be considered for delaying the onset of renal failure.

Unité(s) : Anatomie Pathologique, Chirurgie Viscérale Pédiatrique, U574

A Unique Presentation of Eccrine Hamartoma: Eccrine Nevus With Abnormal Eccrine Structures and Angiomyxoid Stroma

BATTISTELLA M, FRAITAG S, CRIBIER B

2009 - Am J Dermatopathol 31(7):682-684

Eccrine hamartomas are very rare lesions usually presenting in early childhood, with variable clinical presentations. Local hyperhidrosis is often noticed. These lesions are all characterized by an increase in number and/or size of normal eccrine glands. We report the case of a hamartomatous lesion composed of eccrine structures and prominent angiomyxoid stroma, diagnosed in a 9-year-old girl. In this lesion, eccrine structures were not normal eccrine coils or ducts but ramified strands of small eosinophilic cells, containing a few eccrine ducts. These epithelial structures expressed carcinoembryonic antigen, cytokeratin 14, and cytokeratin 77, in a pattern suggesting ductal eccrine differentiation. The mesenchymatous component contained numerous capillary vessels in an abundant myxoid stroma. It was organized concentrically around the epithelial structures. This angiomyxoid stroma was somewhat reminiscent of mucinous eccrine nevi and eccrine angiomatous hamartomas. We propose to describe this unique lesion inside the group of eccrine nevi with the term "angiomyxoid eccrine nevus."

Unité(s) : Anatomie Pathologique

Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study

BEAUGERIE L, BROUSSE N, BOUVIER AM, COLOMBEL JF, LEMANN M, COSNES J, HEBUTERNE X, CORTOT A, BOUHNIK Y, GENDRE JP, SIMON T, MAYNADIE M, HERMINE O, FAIVRE J, CARRAT F, GROUP CS

2009 - Lancet 374(9701):1617-25

BACKGROUND: Reports of an increased risk of lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease are controversial. We assessed this risk in a prospective observational cohort study. METHODS: 19,486 patients with inflammatory bowel disease, of whom 11,759 (60.3%) had Crohn's disease and 7727 (39.7%) had ulcerative colitis or unclassified inflammatory bowel disease, were enrolled in a nationwide French cohort by 680 gastroenterologists, who reported details of immunosuppressive therapy during the observation period, cases of cancer, and deaths. The risk of lymphoproliferative disorder was assessed according to thiopurine exposure. Median follow-up was 35 months (IQR 29-40). FINDINGS: At baseline, 5867 (30.1%) of patients were receiving, 2809 (14.4%) had discontinued, and 10,810 (55.5%) had never received thiopurines. 23 new cases of lymphoproliferative disorder were diagnosed, consisting of one case of Hodgkin's lymphoma and 22 cases of non-Hodgkin lymphoproliferative disorder. The incidence rates of lymphoproliferative disorder were 0.90 per 1000 (95% CI 0.50-1.49) patient-years in those receiving, 0.20/1000 (0.02-0.72) patient-years in those who had discontinued, and 0.26/1000 (0.10-0.57) patient-years in those who had never received thiopurines (p=0.0054). The multivariate-adjusted hazard ratio of lymphoproliferative disorder between patients receiving thiopurines and those who had never received the drugs was 5.28 (2.01-13.9, p=0.0007). Most cases associated with thiopurine exposure matched the pathological range of post-transplant disease. INTERPRETATION: Patients receiving thiopurines for inflammatory bowel disease have an increased risk of developing lymphoproliferative disorders. FUNDING: Programme Hospitalier de Recherche Clinique National (AOM05157), Association Francois Aupetit, Delegation Inter-regionale de la Recherche clinique Ile de France-Assistance Publique Hopitaux de Paris (AP-HP), Ligue contre le Cancer, and Fonds de Recherche de la Societe Nationale Francaise de Gastro-enterologie.

Unité(s) : Anatomie Pathologique, Hématologie Adulte

Nonbacterial purpura fulminans and severe autoimmune acquired protein S deficiency associated with human herpesvirus-6 active replication

BOCCARA O, LESAGE F, REGNAULT V, LASNE D, DUPIC L, BOURDON-LANOY E, PANNIER S, FRAITAG S, AUDAT F, LECOMPTE T, HUBERT P, BODEMER C

2009 - Br J Dermatol 161(1):181-183

Nonbacterial purpura fulminans (PF) is rare, usually follows viral infection in young children, and is characterized by specific coagulation disorders, requiring specific therapy. Following a transient rash, a 2-year-old previously healthy girl developed PF without haemodynamic impairment. Laboratory data revealed disseminated intravascular coagulation and a severe transient protein S deficiency. Antiprotein S autoantibodies and active human herpesvirus-6 (HHV6) replication were demonstrated. Purpuric skin lesions spread very rapidly despite broad-spectrum antibiotics and right leg amputation. Plasmapheresis and intravenous immunoglobulins gave complete clinical recovery and normalization of protein S level within 10 days, with progressive clearance of antiprotein S autoantibodies. Transient severe protein S deficiencies have previously been reported in patients with nonbacterial PF, usually after varicella infection. This is the first documented case of PF after HHV6 infection.

Unité(s) : Dermatologie, Laboratoire d'Hématologie, Réanimation Pédiatrique & Néonatologie, Anatomie Pathologique, Traumatologie et Orthopédie Pédiatriques, Transfusion Sanguine

Thrombotic microangiopathy secondary to VEGF pathway inhibition by sunitinib

BOLLEE G, PATEY-MARIAUD DE SERRE N, CAZAJOUS G, ROBERT C, GOUJON JM, FAKHOURI F, BRUNEVAL P, NOEL LH, KNEBELMANN B

2009 - Nephrol. Dialysis Transplant. 24(2):682-685

BACKGROUND: Drugs targeting the VEGF pathway are associated with renal adverse events, including proteinuria, hypertension and thrombotic microangiopathy (TMA). Most cases of TMA are reported secondary to bevacizumab. It was shown recently that sunitinib, a small molecule inhibiting several tyrosine kinase receptors, including VEGF receptors, can also induce proteinuria, hypertension and biological features of TMA. Case. A 44-year-old woman with a history of malignant skin hidradenoma was started on sunitinib for refractory disease. She developed hypertension after 2 weeks and low-grade proteinuria after 4 weeks. Renal function remained normal, and biological signs of TMA were absent. A renal biopsy was performed 6 months later as proteinuria persisted, demonstrating typical features of TMA. The patient was given irbesartan, and sunitinib was continued for 3 months after diagnosis. Over this period, blood pressure and renal function remained stable and proteinuria became undetectable. CONCLUSION: We report on the first case of histologically documented TMA secondary to sunitinib and provide detailed description of renal histological involvement. This suggests that all anti-VEGF drugs may share a common risk for developing renal adverse events, including TMA. Our case highlights the possible discrepancy between mild clinical manifestation on one hand and severe TMA features on renal biopsy on the other hand and pleads for large indication of renal biopsy in this setting. The renin-angiotensin system blockers may be considered in patients with mild clinical manifestations and in the absence of therapeutic alternative to anti-VEGF drugs.

Unité(s) : Anatomie Pathologique, Néphrologie Adulte, U845 (VW)

Plasma exchange for disseminated cryptococcosis

BOLLEE G, TOUZOT M, MECHAI F, ROYAL V, LEFRERE F, BOUGNOUX ME, DUVIVIER C, VIARD JP, LORTHOLARY O, FAKHOURI F

2009 - Am J Kidney Dis 53(4):673-6

Acute renal failure is frequent in HIV-infected patients and may be related to HIV-associated nephropathy, drugs, or opportunistic infections. We report a peculiar case of disseminated cryptococcosis complicated by acute renal failure associated with obstruction of intrarenal capillaries by Cryptococus neoformans dead bodies and successfully treated with plasma exchanges.

Unité(s) : Maladies Infectieuses, Laboratoire de Microbiologie, Néphrologie Adulte, Anatomie Pathologique, Hématologie Adulte

Clinical Challenges and Images in GI

CANAUD G, VASSILIU V, SUAREZ F

2009 - Gastroenterology 136(5):1508

Unité(s) : Anatomie Pathologique, Hématologie Adulte

Intensive and Prolonged Treatment of Focal and Segmental Glomerulosclerosis Recurrence in Adult Kidney Transplant Recipients: A Pilot Study

CANAUD G, ZUBER J, SBERRO R, ROYALE V, ANGLICHEAU D, SNANOUDJ R, GAHA K, THERVET E, LEFRERE F, CAVAZZANA-CALVO M, NOEL LH, MEJEAN A, LEGENDRE C, MARTINEZ F

2009 - Am J Transplant 9(5):1081-1086

No treatment has consistently induced long-term remission of proteinuria in adult patients with focal segmental glomerulosclerosis (FSGS) recurrence after kidney transplantation. We undertook an open-label, nonrandomized pilot trial of intensive and prolonged treatment of FSGS recurrence. Over an 18-month period, 10 adult kidney transplant recipients with FSGS recurrence received concomitantly high-dose steroids, intravenous cyclosporine for 14 days followed by oral cyclosporine therapy, and an intensive and prolonged course of plasma exchanges (PE). We compared this treatment with those of a control group of 19 patients with a FSGS recurrence transplanted between 1997 and 2005. Complete, rapid (mean 23 +/- 7 days) and sustained remission was obtained in 9/10 patients (90%) as opposed to 27% in the control group. At month 3 and month 12, proteinuria was 0.16 g/day (range 0.05-0.3 g/day) and 0.19 g/day (range 0.05-1 g/day) respectively. Only one patient remained in partial remission at month 12 but he had already lost two previous grafts due to FSGS recurrence. PEs were stopped at month 9 in all patients except for the patient with a partial remission who remains PE-dependent. This small pilot study provides very encouraging results demonstrating that this treatment rapidly achieves complete and sustained remission in a high proportion of patients.

Unité(s) : Anatomie Pathologique, Biothérapie, transplantation Adulte, Urologie

Prognostic significance of new immunohistochemical markers in refractory classical Hodgkin lymphoma: a study of 59 cases

CANIONI D, DEAU-FISCHER B, TAUPIN P, RIBRAG V, DELARUE R, BOSQ J, RUBIO MT, ROUX D, VASILIU V, VARET B, BROUSSE N, HERMINE O

2009 - PLoS ONE 4(7):e6341

Although most classical Hodgkin lymphoma patients are cured, a significant minority fail after primary therapy and may die as result of their disease. To date, there is no consensus on biological markers that add value to usual parameters (which comprise the International Prognostic Score) used at diagnosis to predict outcome. We evaluated 59 patients (18 with primary refractory or early relapse disease and 41 responders) for bcl2, Ki67, CD20, TiA1 and c-kit expression by semi-quantitative immunohistochemical study and correlated the results with the response to treatment.The results showed that expression of bcl2 and CD20 in Hodgkin and Reed Sternberg cells, and expression of TiA1 in micro-environmental lymphocytes, and c-kit positive mast cells in microenvironment, were independent prognostic markers. These novel cHL markers could be used in association with clinical parameters to identify newly diagnosed patients with favorable or unfavorable prognosis and to better tailor treatment for different risk groups.

Unité(s) : Anatomie Pathologique, Biostatistique, Hématologie Adulte

Neonatal bilateral ovarian sex cord stromal tumors

CAPITO C, FLECHTNER I, THIBAUD E, EMOND S, KALFA N, JAUBERT F, SARNACKI S

2009 - Pediatr Blood Cancer 52(3):401-3

A child was referred for evaluation after prenatal diagnosis with macrosomia, clitoromegaly, labial hypertrophy, and a left ovarian cyst. The karyotype was 46,XX. The postnatal pelvic ultrasound was normal. High levels of anti-mullerian hormone and testosterone led to a hCG stimulation test, which was followed by isosexual precocious puberty and the appearance of a bilateral ovarian enlargement with a left tumoral mass. A left ovarian tumorectomy revealed a fibrothecoma. Six weeks later, a tumoral relapse occurred and completion of oophorectomy revealed a juvenile granulosa cell tumor (JGCT). Whereas hormonal levels decreased after surgery, a new rise associated with an enlargement of the right ovary led to the diagnosis of right JGCT. A right oophorectomy was proposed to the parents, who declined further surgery. After 2 months, the hormonal levels normalized. This case illustrates the confusing overlap between developmental and neoplastic biology in neonates.

Unité(s) : Anatomie Pathologique, Chirurgie Viscérale Pédiatrique, Endocrinologie Pédiatrique et Gynécologie, Radiologie Pédiatrique

Value of 18F-fluoro-L-dopa PET in the preoperative localization of focal lesions in congenital hyperinsulinism

CAPITO C, KHEN-DUNLOP N, RIBEIRO MJ, BRUNELLE F, AIGRAIN Y, CRETOLLE C, JAUBERT F, DE LONLAY P, NIHOUL-FEKETE C

2009 - Radiology 253(1):216-22

PURPOSE: To retrospectively compare fluorine 18 ((18)F) fluoro-L-dopa positron emission tomography (PET) and pancreatic venous sampling (PVS) in the preoperative differentiation of diffuse from focal congenital hyperinsulinism (CHI) and localization of focal lesions. MATERIALS AND METHODS: This study was approved by the institutional ethical committee, and informed consent for the research study was obtained from the parents of all subjects. Fifty-one patients evaluated for focal CHI between January 1, 1995, and January 31, 2008, were included. Thirty five underwent PVS evaluation alone, and 16 underwent a PET evaluation alone. The sensitivity values of each technique for the diagnosis and localization of focal lesions were compared in regard to results of surgery and pathologic analyses. In each patient, perioperative treatment was reviewed, and the presence of postoperative hypoglycemia was assessed as evidence of incomplete resection. Comparisons of the sensitivity values and recurrence rates were performed by using the Fisher exact test in regard to the number of patients. Comparisons of median age, weight, or number of biopsies were performed with a two-tailed unpaired Mann-Whitney U test. A difference with P < .05 was considered significant. RESULTS: For PVS and PET groups, there was no error in differentiating focal from diffuse forms. PVS was not completed in four of 35 patients. In 27 (87%) of 31 patients in whom PVS was completed and 13 (81%) of 16 patients in whom PET was completed, preoperative localization of the focal lesion was in accordance with the surgical findings (P = .7). Although not significant, the number of biopsies performed before discovering the focal lesion was higher in the PET group compared with the PVS group (P = .06). Inadequate localization occurred in two (6%) patients in the PVS group and five (31%) patients in the PET group at initial preoperative imaging study; these patients underwent repeat surgery for residual CHI (P = .03). CONCLUSION: (18)F-fluoro-L-dopa PET is equivalent to PVS in the characterization of CHI but does not provide localization of the lesion as precisely as does PVS.

Unité(s) : Anatomie Pathologique, Chirurgie Viscérale Pédiatrique, Pédiatrie Générale, Radiologie Pédiatrique

Unusual Location of an Inoculation Lesion in a Traveler with African Tick-Bite Fever Returning from South Africa

CONSIGNY PH, SCHUETT I, FRAITAG S, ROLAIN JM, BUFFET P

2009 - J. Travel Med. 16(6):439-440

African tick-bite fever is a common tick-borne rickettsiosis in sub-Saharan Africa. It is an acute febrile illness associated with one (or more) inoculation eschar, an inconstant eruption, and local lymphadenopathies. We describe the first case of mucosal inoculation lesion on the vulva in a female traveler returning from South Africa.

Unité(s) : Anatomie Pathologique

Intracranial ependymomas in children: society of pediatric oncology experience with postoperative hyperfractionated local radiotherapy

CONTER C, CARRIE C, BERNIER V, GEOFFRAY A, PAGNIER A, GENTET JC, LELLOUCH-TUBIANA A, CHABAUD S, FRAPPAZ D

2009 - Int J Radiat Oncol Biol Phys 74(5):1536-42

PURPOSE: To prospectively investigate the role of local hyperfractionated radiotherapy (RT) after surgical resection in the treatment of intracranial ependymomas in children. PATIENTS AND METHODS: Postoperative local hyperfractionated RT was proposed for every child (>5 years old at diagnosis) with localized intracranial ependymoma. The planned dose was 60 Gy after complete resection (CR) and 66 Gy after partial resection, delivered in two daily fractions of 1 Gy, according to the early postoperative imaging findings. RESULTS: Between November 1996 and December 2002, 24 children with infratentorial (n = 20) or supratentorial (n = 4) intracranial ependymoma were included. The median age was 8.6 years (range, 5-17). The World Health Organization grade was anaplastic in 10 of the 24 patients (not assessable in 1). After a retrospective central review, a CR was reported in 16 patients, partial resection in 4, and doubtful resection in 4. The radiation dose was 60 Gy in 18 cases (one partial resection), 66 Gy in 5 cases (one CR), and 54 Gy in 1 case (CR). The 5-year overall survival rate was 74.8%, and the progression-free survival rate was 54.2%. Of the 24 patients, 11 developed a relapse: 7 local only and 4 metastatic and local. The histological grade and extent of resection were not prognostic factors. More than 3 in 4 children had no sequelae of RT at a median follow-up of 7 years (95% confidence interval, 66.4-90.0 months). CONCLUSION: The results of our study have shown that hyperfractionated RT is safe but provides no outcome benefit compared with other strategies of RT such as standard fractionated regimens.

Unité(s) : Anatomie Pathologique

WNT/beta-catenin pathway activation in Wilms tumors: A unifying mechanism with multiple entries?

CORBIN M, DE REYNIES A, RICKMAN DS, BERREBI D, BOCCON-GIBOD L, COHEN-GOGO S, FABRE M, JAUBERT F, FAUSSILLON M, YILMAZ F, SARNACKI S, LANDMAN-PARKER J, PATTE C, SCHLEIERMACHER G, ANTIGNAC C, JEANPIERRE C

2009 - Genes Chromosomes Cancer 48(9):816-827

Based on characterization of both genomic and expression status of WT1 and CTNNB1 (beta-catenin) in a series of 60 Wilms tumor samples, combined with genome-wide expression profiling of these tumors, normal mature and fetal kidney controls, we show that WT1/beta-catenin expression was a better classifier than WT1/CTNNB1 mutations. We present molecular data supporting that the WNT pathway is involved in both tumor classes, with and without WT1/beta-catenin alterations. In the tumor class with WT1/beta-catenin alterations, we identified overexpression of 14 previously unreported WNT target genes, including TWIST1. We show that the TWIST1 protein was specifically expressed in these tumors, where staining was restricted to the stromal, nuclear beta-catenin positive, component. By comparing the state of the WNT pathway in tumors without WT1/beta-catenin alterations and fetal kidneys we provide evidence that suggests that these tumors have a heightened level of pathway activation. We characterized mutations of the WNT pathway regulator gene WTX in 16% of this tumor class. Moreover, genome-transcriptome correlation analysis allowed us to identify three other WNT pathway regulator genes that could participate in the activation of the WNT pathway: BCL9 (1p36.2), CTNNBIP1 (1p36.2), and CBY1 (22q13.1). These genes thus represent new potential important actors in WT tumorigenesis. (c) 2009 Wiley-Liss, Inc.

Unité(s) : Centre de Génétique Médicale Jean Frézal, Anatomie Pathologique, Chirurgie Viscérale Pédiatrique, U574, U781

Shrinkage of skin excision specimens: formalin fixation is not the culprit

DAUENDORFFER JN, BASTUJI-GARIN S, GUERO S, BROUSSE N, FRAITAG S

2009 - Br J Dermatol 160(4):810-814

Summary Background Discrepancies between cutaneous specimen sizes reported by the dermatosurgeon and the pathologist are important to evaluate because of their legal implications for malignant tumours and the downcoding of surgical acts. Objectives The objective of this study was to determine the magnitude of changes in size and the factors influencing the retraction of routine skin excision specimens. Methods Three measurements of 82 skin excision specimens-consisting of length and width of the planned surgical excision (in vivo), length, width and depth of the specimens following excision (ex vivo) and of the specimens after formalin fixation (in vitro)-were performed and compared using a nonparametric paired test. Factors (age, sex, type and location of the lesions and initial measures) that could influence the amount of shrinkage were analysed using multiple linear regression models. Results The mean in vivo to in vitro shrinkage was 16% for length and 18% for width (P < 0.001). The shrinkage was significant between in vivo and ex vivo measures (P < 0.001), while no difference was observed between ex vivo to in vitro measures. In multivariate analysis, length shrinkage increased significantly with initial length (regression coefficient of 0.24, P = 0.001) and limb location (1.25, P = 0.048), and decreased significantly with initial width (-0.19, P = 0.016). After adjusting for initial width, width shrinkage was neither significantly associated with type of lesion (malignant or not, P = 0.20), nor with location (P = 0.35). Conclusions Shrinkage of skin excision specimens occurred immediately after surgical excision and prior to formalin fixation. Patients' age, sex and type of skin lesion did not influence the amount of shrinkage. Length shrinkage was more important for specimens excised from the extremities and increased with initial length and smaller width.

Unité(s) : Anatomie Pathologique

Congenital erosive and vesicular dermatosis with reticulated scarring in a newborn: an innovative treatment using a silicone dressing

DE LANGE A, BAYET B, DEBAUCHE C, FRAITAG S, LACHAPELLE JM, MAROT L, VANWIJCK R

2009 - Pediat. Dermatol. 26(6):735-738

Congenital erosive and vesicular dermatosis healing with reticulated supple scarring is a rare entity presenting in the newborn with crusted erosions and vesicles that heal relatively rapidly, forming unique reticulated scars. We report the case of a premature baby 31 weeks old. Diagnosis was confirmed by skin biopsies, and the clinical improvement was excellent, with complete healing observed within 7 weeks. This report highlights clinical and histopathologic features, and a new successful treatment approach using a silicone dressing.

Unité(s) : Anatomie Pathologique

Mutational, functional, and expression studies of the TCF4 gene in Pitt-Hopkins syndrome

DE PONTUAL L, MATHIEU Y, GOLZIO C, RIO M, MALAN V, BODDAERT N, SOUFFLET C, PICARD C, DURANDY A, DOBBIE A, HERON D, ISIDOR B, MOTTE J, NEWBURRY-ECOB R, PASQUIER L, TARDIEU M, VIOT G, JAUBERT F, MUNNICH A, COLLEAUX L, VEKEMANS M, ETCHEVERS H, LYONNET S, AMIEL J

2009 - Hum Mutat 30(4):669-76

Pitt-Hopkins syndrome is a severe congenital encephalopathy recently ascribed to de novo heterozygous TCF4 gene mutations. We report a series of 13 novel PHS cases with a TCF4 mutation and show that EEG, brain magnetic resonance imagain (MRI), and immunological investigations provide valuable additional clues to the diagnosis. We confirm a mutational hot spot in the basic domain of the E-protein. Functional studies illustrate that heterodimerisation of mutant TCF4 proteins with a tissue-specific transcription factor is less effective than that homodimerisation in a luciferase reporter assay. We also show that the TCF4 expression pattern in human embryonic development is widespread but not ubiquitous. In summary, we further delineate an underdiagnosed mental retardation syndrome, highlighting TCF4 function during development and facilitating diagnosis within the first year of life.

Unité(s) : Anatomie Pathologique, Radiologie Pédiatrique, Centre de Génétique Médicale Jean Frézal, U663, U768, U781

Hybrid tumour 'oncocytoma-chromophobe renal cell carcinoma' of the kidney: a report of seven sporadic cases

DELONGCHAMPS NB, GALMICHE L, EISS D, ROUACH Y, VOGT B, TIMSIT MO, VIEILLEFOND A, MEJEAN A

2009 - BJU Int 103(10):1381-4

OBJECTIVES: To determine whether renal hybrid tumours (HT) appear as a specific clinical and radiological entity, as HT are characterized by the association of both oncocytes and chromophobe cells within the same tumour, and have been described in patients with oncocytosis and Birt-Hogg-Dube syndrome. PATIENTS AND METHODS: We reviewed the medical charts of 67 patients who had a partial or radical nephrectomy in our institution for renal oncocytoma (RO, 24), chromophobe renal cell carcinoma (CRCC, 36) and HT (seven), from January 2006 to October 2007. We report the clinical, radiological and pathological characteristics of the seven cases of HT. RESULTS: The mean (range) age of the patients was 56 (41-68) year. None of the seven patients had any suspicion of RO, based on computed tomography (CT). Two patients had a history of kidney cancer. Five patients had partial and two a radical nephrectomy. The mean (range) maximum tumour diameter was 5.5 (1.8-9) cm. Two tumours were pT1a, two were pT1b and three were pT2. Pathological analysis showed RO-like and CRCC-like cells intermixed (six patients) or distinct (one). After a median (range) follow-up of 20 (8-25) months, none of the patients had any evidence of disease recurrence. CONCLUSIONS: In a large series of patients with sporadic RO and CRCC, 10% of the tumours had hybrid morphological features, as described in oncocytosis and Birt-Hogg-Dube syndrome. We were unable to identify any specific clinical characteristic. Most importantly, none of these HT showed any of the radiological characteristics of RO.

Unité(s) : Anatomie Pathologique, Urologie, Radiologie Adulte

FoxP3 positive T cells in graft biopsies from living donor kidney transplants after donor-specific transfusions

EISENBERGER U, SEIFRIED A, PATEY N, KAPPELER A, NOEL LH, FREY FJ, KORNER M

2009 - Transplantation 87(1):138-142

Donor-specific transfusions (DST) induce allograft tolerance in animals. Evidence is growing that FoxP3+ regulatory T cells are associated with tolerance in humans. Forty-four biopsies from 69 living donor kidney transplant recipients (LDT) after DST, 53 biopsies from 69 matched deceased donor transplant recipients (DDT), obtained for graft dysfunction, and 12 biopsies from LDT without DST were retrospectively analyzed. FoxP3 positivity was more frequent in LDT/DST than in DDT biopsies (67% vs. 44%, P=0.02). Considering only biopsies with acute rejection, FoxP3 positivity was observed in 92% (11/12) after LDT/DST, but only in 50% (6/12) after DDT (P=0.03). The number of FoxP3+ T cells per total infiltrating cells in rejection biopsies was higher (P<0.05) from LDT/DST (4.1%) than from DDT or LDT (2.6%) without DST (2.5%). Six-year graft survival was better in patients with LDT/DST than with DDT (87.5% vs. 79.7%, P=0.04). The present investigation demonstrates an association between DST and FoxP3+ T cells. The effect of DST on regulatory T cells deserves further analysis in transplantation.

Unité(s) : Anatomie Pathologique

Beta-catenin status in paediatric medulloblastomas: correlation of immunohistochemical expression with mutational status, genetic profiles, and clinical characteristics

FATTET S, HABERLER C, LEGOIX P, VARLET P, LELLOUCH-TUBIANA A, LAIR S, MANIE E, RAQUIN MA, BOURS D, CARPENTIER S, BARILLOT E, GRILL J, DOZ F, PUGET S, JANOUEIX-LEROSEY I, DELATTRE O

2009 - J Pathol 218(1):86-94

Medulloblastoma is the most frequent malignant paediatric brain tumour. The activation of the Wnt/beta-catenin pathway occurs in 10-15% of medulloblastomas and has been recently described as a marker for favourable patient outcome. We report a series of 72 paediatric medulloblastomas evaluated for beta-catenin protein expression, CTNNB1 mutations, and comparative genomic hybridization. Gene expression profiles were also available in a subset of 40 cases. Immunostaining of beta-catenin showed extensive nuclear staining (>50% of the tumour cells) in six cases and focal nuclear staining (<10% of cells) in three cases. The other cases either exhibited a signal strictly limited to the cytoplasm (58 cases) or were negative (five cases). CTNNB1 mutations were detected in all beta-catenin extensively nucleopositive cases. The expression profiles of these cases documented strong activation of the Wnt/beta-catenin pathway. Remarkably, five out of these six tumours showed a complete loss of chromosome 6. In contrast, cases with focal nuclear beta-catenin staining, as well as tumours with negative or cytoplasmic staining, never demonstrated CTNNB1 mutation, Wnt/beta-catenin pathway activation or chromosome 6 loss. Patients with extensive nuclear staining were significantly older at diagnosis and were in continuous complete remission after a mean follow-up of 75.7 months (range 27.5-121.2 months) from diagnosis. All three patients with focal nuclear staining of beta-catenin died within 36 months from diagnosis. Altogether, these data confirm and extend previous observations that CTNNB1-mutated tumours represent a distinct molecular subgroup of medulloblastomas with favourable outcome, indicating that therapy de-escalation should be considered. International consensus on the definition criteria of this distinct medulloblastoma subgroup should be achieved.

Unité(s) : Anatomie Pathologique, Neurochirurgie Pédiatrique

Myenteric plexus alterations downstream from a prenatal intestinal obstruction in a rat model

FOURCADE L, MOUSSEAU Y, JAUBERT F, STURTZ FG

2009 - Neurosci Lett 461(2):126-30

The enteric nervous system maturation occurs during embryonic life and continues after birth. Some prenatal events on the digestive tract such as intestinal atresia have been shown to dramatically alter this maturation. Thus, we developed a fetal rat model of intestinal atresia by surgically obstructing the small bowel at embryonic day E18. Fetuses were removed at day E21, and small bowels sections were examined by immuno-histochemistry. Synaptophysin and smooth muscle actin staining was used to define the cellular aspect. Labeling revealed marked alterations of the myenteric plexus in the lower extremity of the occluded small bowel. At day E21, the myenteric plexus of the lower part and the 2 muscle layers surrounding it, retained the staining pattern observed at day E17. This cellular pattern was classified as: immature (aspect at day E17) vs. mature (aspect of day E21) by 3 pathologists not familiar with the study. The number of samples with an immature cellular pattern at the lower end of the occluded bowel was different from that observed for the upper end (Mac Nemar test, p<0.008). Our study suggests that a prenatal obstruction induces a maturation delay of the myenteric plexus downstream of the obstruction. This might be important for pediatric purposes.

Unité(s) : Anatomie Pathologique

[Connective tissue tumors of the skin. Giant cell fibroblastoma]

FRAITAG S

2009 - Ann Pathol 29(5):390-4

Unité(s) : Anatomie Pathologique

[Connective tissue tumors of the skin. Plexiform fibro-histiocytic tumor]

FRAITAG S

2009 - Ann Pathol 29(5):385-9

Unité(s) : Anatomie Pathologique

Multiple nodules in a newborn infant

FRAITAG S, BODEMER C

2009 - Ann Dermatol Venereol 136(2):211-3

Unité(s) : Anatomie Pathologique, Dermatologie

Skin biopsy is helpful for the diagnosis of incontinentia pigmenti at late stage (IV): a series of 26 cutaneous biopsies

FRAITAG S, RIMELLA A, DE PROST Y, BROUSSE N, HADJ-RABIA S, BODEMER C

2009 - J. Cutan. Pathol. 36(9):966-971

Background. Hypochromic streaks can be the only cutaneous sign of incontinentia pigmenti (IP) in adulthood (stage IV). Discovery of such lesions in an adult female with no family history of IP is essential for appropriate genetic counselling. Objective. To describe and to validate the histological features of residual skin lesions in adult IP. Methods. The analysis and comparison of skin biopsies of 26 women affected with molecularly confirmed IP. Results. Most biopsies showed slight atrophy and some scattered apoptotic cells in the epidermis, epidermal hypopigmentation and reduced melanocyte number. The dermis appeared thickened and homogeneous and revealed a complete absence of hair follicles (23/26) and sweat glands (22/26). There was no melanin incontinence or inflammatory cells, and the elastic network was normal. Conclusion. These features lead unequivocally to the diagnosis of a stage IV IP skin lesion. Consequently, histology is a major confirmatory criterion for diagnoses of these mild clinical forms of IP. It is therefore a useful tool in genetic counselling and prenatal diagnosis. Moreover, the observations described here may contribute to understanding the physiopathology of the late stages of IP.

Unité(s) : Anatomie Pathologique, Dermatologie

Spitz tumor and pigmented epithelioid melanocytoma: New nosological frameworks for commonly ill-defined tumors

FRAITAG S, VIGNON-PENNAMEN MD

2009 - Ann Dermatol Venereol 136(2):133-44

Unité(s) : Anatomie Pathologique

Cutaneous manifestations of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome

HALABI-TAWIL M, RUEMMELE FM, FRAITAG S, RIEUX-LAUCAT F, NEVEN B, BROUSSE N, DE PROST Y, FISCHER A, GOULET O, BODEMER C

2009 - Br. J. Dermatol. 160(3):645-651

Background Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare disorder characterized by neonatal autoimmune enteropathy, diabetes and thyroiditis, food allergies and skin rash. IPEX syndrome is caused by mutations in FOXP3, a master control gene of regulatory T cells (Tregs), resulting in absent or dysfunctional Tregs. Data in the literature are scarce and the cutaneous manifestations are rarely depicted. Objectives To evaluate the frequency and characteristics of cutaneous manifestations found in IPEX. Methods Retrospective single-centre study of a case series of IPEX. Patients' data were retrieved from medical files and numerous parameters concerning general and cutaneous characteristics of the disease were recorded. Results Ten children with IPEX were studied. Cutaneous involvement was present in seven of 10 chidren; age at onset was 0-4 months, median 1.5. All patients presented with atopic dermatitis (AD). Three presented more psoriasiform lesions. Eczema was severe; most affected areas were lower limbs, trunk and face. Pruritus was present in four of seven, and painful fissurary cheilitis in four of seven. Hyper-IgE was found in seven of 10 and hypereosinophilia in five of 10. Skin biopsies showed eczematiform or psoriasiform features. Affected patients were improved by dermocorticoids; no clear improvement was obtained with immunosuppressive regimens. Other features were urticaria secondary to food allergies and staphylococcal sepsis, mostly Staphylococcus aureus and catheter related. Conclusions AD seems to be a frequent finding in IPEX syndrome, which is characterized by Treg anomalies. This hints to a possible role of Tregs in AD, which is then discussed in this study.

Unité(s) : Anatomie Pathologique, Dermatologie, Gastro-Hépatologie et Nutrition Pédiatriques, U768, U793, Immunologie-Hématologie Pédiatriques

Is granulomatous mastitis a localized form of hidradenitis suppurativa?

JOIN-LAMBERT O, FRAITAG S, RIBADEAU-DUMAS F, LEGUERN AS, BEHILLIL S, DEL CASTILLO FJ, CONSIGNY PH, AUQUIER F, EB F, SEVESTRE H, LORTHOLARY O, NASSIF X, NASSIF A

2009 - Eur J Dermatol 19(5):513-514

Unité(s) : Laboratoire de Microbiologie, Anatomie Pathologique, Maladies Infectieuses

Anti-Factor H Autoantibodies in a Fifth Renal Transplant Recipient with Atypical Hemolytic and Uremic Syndrome

LE QUINTREC M, ZUBER J, NOEL LH, THERVET E, FREMEAUX-BACCHI V, FRIDMAN WH, LEGENDRE C, DRAGON-DUREY MA

2009 - Amer. J. Transplant. 9(5):1223-1229

Hemolytic uremic syndrome (HUS) associated with anti-Factor H (anti-FH) autoantibodies is a recently described pathophysiological entity. Monitoring of anti-FH IgG titer may be a sensitive marker of disease activity and guide treatment to eliminate circulating anti-FH antibodies. We report here a case of atypical HUS (aHUS) in which anti-FH autoantibodies were detected during the course of a fifth kidney transplant, 30 years after the first flare of aHUS. This exceptional case suggests that early, specific management based on immunosuppressive therapy and plasma exchanges monitored by anti-FH IgG titer may result in long-term graft survival.

Unité(s) : Anatomie Pathologique, Transplantation Adulte

Anti-Factor H autoantibodies in a fifth renal transplant recipient with atypical hemolytic and uremic syndrome (erratum vol.9, pg1223)

LE QUINTREC M, ZUBER J, NOEL LH, THERVET E, FREMEAUX-BACCHI V, NIAUDET P, FRIDMAN WH, LEGENDRE C, DRAGON-DUREY MA

2009 - Am J Transplant 9(9):2205

Unité(s) : Anatomie Pathologique, Transplantation Adulte, Néphrologie Pédiatrique

Is plexiform fibro-histiocytic tumor a deep form of cellular neurothekeoma?

LECLERC-MERCIER S, BROUSSE N, FRAITAG S

2009 - J Cutan Pathol 36(10):1123-5

Unité(s) : Anatomie Pathologique

Medallion-like dermal dendrocyte hamartoma: the main diagnostic pitfall is congenital atrophic dermatofibrosarcoma

MARQUE M, BESSIS D, PEDEUTOUR F, VISEUX V, GUILLOT B, FRAITAG-SPINNER S

2009 - Br. J. Dermatol. 160(1):190-193

Medallion-like dermal dendrocyte hamartoma is a newly described and rare clinical and pathological entity. This congenital, round, erythematous and atrophic lesion in the thoracic area is histologically characterized by a CD34+ dermal and hypodermal spindle-cell infiltration. We describe the clinical, histopathological, cytological and molecular features of three cases of dermal dendrocyte hamartoma. In all the cases, atrophic congenital dermatofibrosarcoma protuberans (DFSP) was the first histological diagnosis. In one case, wide surgery had been performed on the basis of the clinical and histological presentation. The histological pattern was similar in all the cases: epidermal atrophy and a spindle to ovoid cell proliferation in the dermis and in the subcutaneous fat. Immunochemical staining for CD34 and factor XIIIa was positive. Cytogenetic and molecular studies were performed; no chromosomal abnormality nor translocation t(17;22)(q22;q13) was observed. Fluorescence in situ hybridization analysis did not reveal the DFSP fusion gene COL1A1-PDGFB. We observed that the main diagnostic pitfall of medallion-like dermal dendrocyte hamartoma is atrophic congenital DFSP due to clinical and histological similarities. We emphasize that molecular studies to eliminate the t(17;22)(q22;q13) translocation of DFSP may provide determinant elements for diagnosis in order to avoid unnecessary mutilating surgery.

Unité(s) : Anatomie Pathologique

Low Renal Mineralocorticoid Receptor Expression at Birth Contributes to Partial Aldosterone Resistance in Neonates

MARTINERIE L, VIENGCHAREUN S, DELEZOIDE AL, JAUBERT F, SINICO M, PREVOT S, BOILEAU P, MEDURI G, LOMBES M

2009 - Endocrinology 150(9):4414-4424

The human neonatal period is characterized by renal immaturity with impaired capacity to regulate water and sodium homeostasis, resembling partial aldosterone resistance. Since aldosterone effects are mediated by the mineralocorticoid receptor (MR), we postulated that this hormonal unresponsiveness could be related to low MR expression in the distal nephron. We measured aldosterone and renin levels in umbilical cord blood of healthy newborns. We used qPCR and immunohistochemistry to analyze the expression of MR and key players of the mineralocorticoid signaling pathway, during human and mouse renal development. High aldosterone and renin levels were found at birth. MR mRNA was detected in mouse kidney at day 16 postcoitum (E16), peaking at E18, but its expression was surprisingly very low at birth, rising progressively afterwards. Similar biphasic temporal expression was observed during human renal embryogenesis, with a transient expression between 15 and 24 weeks of gestation but an undetectable immunoreactive MR in late gestational and neonatal kidneys. This cyclic MR expression was tightly correlated with the evolution of the 11beta-hydroxysteroid dehydrogenase type 2 and the epithelial sodium channel alpha-subunit. In contrast, glucocorticoid and vasopressin receptors, and aquaporin 2 followed a progressive and sustained evolution during renal maturation. Our study provides first evidence for a low renal MR expression level at birth, despite high aldosterone levels, which could account for compromised postnatal sodium handling. Elucidation of regulatory mechanisms governing MR expression should lead to new strategies for the management of sodium waste in preterms and neonates.

Unité(s) : Anatomie Pathologique

Serous and seromucinous infantile ovarian cystadenomas--a study of 42 cases

MASSICOT R, ROUSSEAU V, DARWISH AA, SAUVAT F, JAUBERT F, NIHOUL-FEKETE C

2009 - Eur J Obstet Gynecol Reprod Biol 142(1):64-7

The rarity of infantile ovarian cystadenoma (CA) accounts for the very little knowledge about their behaviour. The aim of this retrospective study is to highlight the modes of presentation and to evaluate the treatments and the recurrence risks of these benign tumours. Relation to adult epithelial ovarian tumours is discussed. The medical records and imaging studies of 42 CA in 31 children less than 16 years of age operated at our institution between 1985 and 2003 were retrospectively evaluated. Mean age of first surgery was 11.5 years. 7/31 girls (22.6%) presented with a bilateral CA, four of them were synchronous. 8/42 (19%) CA were in torsion at surgery, conservative management was possible in four cases. 31/42 (74%) CA were treated conservatively. 4/42 CA recurred 1-3.5 years after complete cyst removal. All were endocervical type CA, there was no intestinal type. The 42 CA were serous in 18/42, mucinous in 23/42 and unqualified in one. Mucinous epithelial cells were often sparse and focal along the cyst wall. Four CA presented with micropapillae in post-pubertal girls. No borderline tumours were observed. Mucinous cystadenomas (MCA) are better described as seromucinous cystadenoma (SMCA) because of the mucinous cells localisation. CA occurs early in life, we surmise that they may need hormonal stimulation to develop micropapillae. Complete removal of these potentially low-grade malignant ovarian tumours precursors is advocated. Conservative surgery is recommended to preserve ovarian function.

Unité(s) : Anatomie Pathologique, Chirurgie Viscérale Pédiatrique

Rituximab in Severe Lupus Nephritis: Early B-Cell Depletion Affects Long-Term Renal Outcome

MELANDER C, SALLEE M, TROLLIET P, CANDON S, BELENFANT X, DAUGAS E, REMY P, ZARROUK V, PILLEBOUT E, JACQUOT C, BOFFA JJ, KARRAS A, MASSE V, LESAVRE P, ELIE C, BROCHERIOU I, KNEBELMANN B, NOEL LH, FAKHOURI F

2009 - Clin J Am Soc Nephrol 4(3):579-587

BACKGROUND AND OBJECTIVES: Standard treatment for lupus nephritis, including corticosteroids and cyclophosphamide, is efficient but is still associated with refractory or relapsing disease, or severe deleterious effects. Rituximab, a monoclonal chimeric anti-B cell antibody, is increasingly used in patients with lupus nephritis, but reported series were small and had a short follow-up. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The authors analyzed clinical and histologic data of 20 patients who were treated with rituximab for lupus nephritis and followed up for at least 12 mo. RESULTS: Nineteen women and one man received rituximab as induction treatment for an active class IV (15 cases) or class V (5 cases) lupus nephritis. Rituximab was given for lupus nephritis refractory to standard treatment (12 cases), for relapsing disease (6 cases), or as first-line treatment (2 cases). Three patients received cyclophosphamide concomitantly with rituximab. Ten received new injections of rituximab as maintenance therapy. Side effects included mainly five infections and four moderate neutropenias. After a median follow-up of 22 mo, complete or partial renal remission was obtained in 12 patients (60%). Lupus nephritis relapsed in one patient, who responded to a new course of rituximab. The achievement of B cell depletion 1 mo after rituximab, which negatively correlated with black ethnicity and hypoalbuminemia, was strongly associated with renal response. Rapidly progressive glomerulonephritis did not respond to rituximab. CONCLUSION: Rituximab is an interesting therapeutic option in relapsing or refractory lupus nephritis when early B cell depletion is obtained.

Unité(s) : Anatomie Pathologique, Biostatistique, Néphrologie Adulte, Laboratoire d'Immunologie

Digestive histopathological presentation of IPEX syndrome

PATEY-MARIAUD DE SERRE N, CANIONI D, GANOUSSE S, RIEUX-LAUCAT F, GOULET O, RUEMMELE F, BROUSSE N

2009 - Modern Pathol. 22(1):95-102

Immunodysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX) syndrome is a well recognized and particularly severe form of autoimmune enteropathy. It has an X-linked recessive transmission, and is caused by mutations in the FOXP3 gene. We studied the intestinal morphological changes characterizing IPEX syndrome in a series of 12 children with a molecularly confirmed diagnosis. Histological examination of duodenal, gastric and colonic biopsies were retrospectively reviewed and compared by two independent experienced pathologists. In parallel, the presence of circulating anti-enterocyte antibodies was analysed using an indirect immunofluorescence technique and a quantitative radioligand assay against the 75-kDa autoantigen. The morphology of the inflammatory gut lesions could be categorized into three different entities, namely graft-vs-host disease-like changes (9/12 patients), a coeliac disease-like pattern (2/12) and an enteropathy with a complete depletion of goblet cells (1/12). Our results do not suggest any phenotype-genotype correlation. Circulating antibodies were detected in all 12 patients, with an anti-brush border pattern (11/12) and anti-goblet cell antibodies (1/12), as well as by a radioligand assay. The histological presentation of autoimmune enteropathy is rather variable. However, a graft-vs-host disease-like pattern associated with positive anti-enterocyte antibodies is the most frequent intestinal presentation of IPEX syndrome, and constitutes a very valuable tool for pathologists to suspect this diagnosis.Modern Pathology advance online publication, 26 September 2008; doi:10.1038/modpathol.2008.161.

Unité(s) : Anatomie Pathologique, Gastro-Hépatologie et Nutrition Pédiatriques, U768

Actinomyces in chronic granulomatous disease: an emerging and unanticipated pathogen

REICHENBACH J, LOPATIN U, MAHLAOUI N, BEOVIC B, SILER U, ZBINDEN R, SEGER RA, GALMICHE L, BROUSSE N, KAYAL S, GUNGOR T, BLANCHE S, HOLLAND SM

2009 - Clin Infect Dis 49(11):1703-10

BACKGROUND: Chronic granulomatous disease (CGD) is a rare inherited disease of the phagocyte NADPH oxidase system that causes defective production of toxic oxygen metabolites, impaired bacterial and fungal killing, and recurrent life-threatening infections, mostly by catalase-producing organisms. We report for the first time, to our knowledge, chronic infections with Actinomyces species in 10 patients with CGD. Actinomycosis is a chronic granulomatous condition that commonly manifests as cervicofacial, pulmonary, or abdominal disease, caused by slowly progressive infection with oral and gastrointestinal commensal Actinomyces species. Treatment of actinomycosis is usually simple in immunocompetent individuals, requiring long-term, high-dose intravenous penicillin, but is more complicated in those with CGD because of delayed diagnosis and an increased risk of chronic invasive or debilitating disease. METHODS: Actinomyces was identified by culture, staining, 16S ribosomal DNA polymerase chain reaction, and/or a complement fixation test in 10 patients with CGD. RESULTS: All 10 patients presented with a history of fever and elevated inflammatory signs without evident focus. Diagnosis was delayed and clinical course severe and protracted despite high-dose intravenous antibiotic therapy and/or surgery. These results suggest an unrecognized and unanticipated susceptibility to weakly pathogenic Actinomyces species in patients with CGD because these are catalase-negative organisms previously thought to be nonpathogenic in CGD. CONCLUSIONS: Actinomycosis should be vigorously sought and promptly treated in patients with CGD presenting with uncommon and prolonged clinical signs of infection. Actinomycosis is a catalase-negative infection important to consider in CGD.

Unité(s) : Laboratoire de Microbiologie, Anatomie Pathologique, Immunologie-Hématologie Pédiatriques

Coeliac disease and aplastic anaemia: a specific entity?

SALMERON G, PATEY N, DE LATOUR RP, RAFFOUX E, GLUCKMAN E, BROUSSE N, SOCIE G, ROBIN M

2009 - Br J Haematol 146(1):122-4

Unité(s) : Anatomie Pathologique

Nephrotoxicity of calcineurin inhibitors: presentation, diagnostic problems and risk factors

SNANOUDJ R, RABANT M, ROYAL V, PALLET N, NOEL LH, LEGENDRE C

2009 - Néphrol. Ther. 5(Suppl.6):S365-S370

Nephrotoxicity of calcineurin inhibitors (CNIs) is an acute, reversible and chronic, irreversible pathology. Histologically, acute nephrotoxicity manifests as hemodynamic modifications caused by vasoconstriction of the essentially afferent arterioles resulting in a drop in the glomerular filtration rate. Chronic nephrotoxicity is characterized by arteriolar hyalinosis resulting in a variety of tubulointerstitial and glomerular lesions with an essentially ischemic mechanism. However, these histological lesions, whether chronic or acute, are not specific of CNI toxicity and can be seen in the course of many pathological circumstances in kidney transplantation. This absence of specificity makes the histological diagnosis of CNI nephrotoxicity difficult. In addition, the individual risk of developing CNI nephrotoxicity, difficult to predict based solely on the pharmacokinetic parameters of systemic CNI exposure, also involves local exposure (CNI concentrations in the graft) modulated by several, notably pharmacogenetic factors. The difficulty of diagnosing CNI nephrotoxicity and the interindividual variability of its risk require development of new diagnostic tools so that the patients at highest risk of developing severe CNI nephrotoxicity lesions, in whom minimization protocols would produce the best risk-benefit ratio, can be identified. (C) 2009 Elsevier Masson SAS et Association Societe de Nephrologie. All rights reserved.

Unité(s) : Anatomie Pathologique, Transplantation Adulte

Neonatal cases of infantile myofibromatosis do not derive from maternal cells transferred during pregnancy

YOUSEFI P, KHOSROTEHRANI K, OSTER M, DE PROST Y, FRAITAG S, ARACTINGI S

2009 - Br J Dermatol 160(6):1356-7

Unité(s) : Anatomie Pathologique, Dermatologie

FOXP3-enriched infiltrates associated with better outcome in renal allografts with inflamed fibrosis

ZUBER J, BRODIN-SARTORIUS A, LAPIDUS N, PATEY N, TOSOLINI M, CANDON S, RABANT M, SNANOUDJ R, PANTERNE C, THERVET E, LEGENDRE C, CHATENOUD L

2009 - Nephrol Dial Transplant 24(12):3847-54

BACKGROUND: FOXP3-expressing regulatory T cells (Tregs) play a crucial role in maintaining allogeneic transplant tolerance in experimental models. In clinical transplantation, there are few data about their role in chronic inflammation. We hypothesized that Tregs might accumulate within the graft since enrichment of Tregs has been frequently described in chronically inflamed tissues. METHODS: Sixty-seven biopsies, indicated by a rise in creatinine level, were studied. Thirty-four biopsies showing acute T-cell-mediated rejection and 33 displaying inflamed fibrosis were selected. Tregs frequency was calculated for each infiltrate by counting FOXP3+ and CD3+ cells on two contiguous serial sections. RESULTS: A total of 121 infiltrates were scored with a mean of 309 CD3+ cells per infiltrate (range: 50-700). Tregs were enriched within allografts exhibiting inflamed fibrosis versus acute cellular rejection (10.6 +/- 6.8% versus 5.5 +/- 2.6%, respectively, P = 0.005). In those with inflammation within scarred areas, the subset of patients with a low FOXP3/CD3 ratio (below the median value) displayed a lower frequency of B-cell-enriched nodular cell clusters (20% versus 86%, P = 0.001) and had a significantly lower graft survival (log-rank, P = 0.02). In multivariate analysis, the low FOXP3/CD3 ratio remained an independent indicator of outcome (P = 0.03). Consistently, the FOXP3+/IL-17+ cell ratio was higher in nodular than in diffuse infiltrates. CONCLUSIONS: Our results suggest that Tregs may dampen the graft injury in chronic (versus acute) inflammation and stress the importance of devising strategies to enhance Tregs efficiency.

Unité(s) : Anatomie Pathologique, Transplantation Adulte, U580

Allergic rhinitis in children

ABOU-TAAM R, DE BLIC J, SCHEINMANN P

2008 - Rev. Fr. Allergol. Immunol. Clin. 48(5):394-398

Allergic rhinitis has for long time been considered to be a relatively minor allergic symptom, much less important than anaphylaxis and asthma. Its true frequency was unknown. Its management remained empiric. Its association with asthma was not clearly determined, although concerning adults, this association was rather well-known. A number of studies in children have now made more certain the association between asthma and allergic rhinitis, the impact of rhinitis on the child's quality of life, and the significance of allergic rhinitis in the natural history of allergy and asthma. This review will Cover some Current aspects of allergic rhinitis: its association with asthma and food allergy. quantification of atopy, and its impact on daily life. It leads to recommendations for everyday practice of allergy in pediatrics. Given that allergic rhinitis probably begins earlier and earlier. children with this condition need to be followed closely and. if necessary, have their allergy tests repeated. Specific immunotherapy certainly merits to be used more frequently. (C) 2007 Elsevier Masson SAS. Tous droits reserves.

Unité(s) : Pneumologie et Asthmologie Pédiatriques, Anatomie Pathologique

Constitutively active Akt1 expression in mouse pancreas requires S6 kinase 1 for insulinoma formation

ALLIOUACHENE S, TUTTLE RL, BOUMARD S, LAPOINTE T, BERISSI S, GERMAIN S, JAUBERT F, TOSH D, BIRNBAUM MJ, PENDE M

2008 - J. Clin. Invest. 118(11):3629-3638

Factors that promote pancreatic beta cell growth and function are potential therapeutic targets for diabetes mellitus. In mice, genetic experiments suggest that signaling cascades initiated by insulin and IGFs positively regulate beta cell mass and insulin secretion. Akt and S6 kinase (S6K) family members are activated as part of these signaling cascades, but how the interplay between these proteins controls beta cell growth and function has not been determined. Here, we found that although transgenic mice overexpressing the constitutively active form of Akt1 under the rat insulin promoter (RIP-MyrAkt1 mice) had enlarged beta cells and high plasma insulin levels, leading to improved glucose tolerance, a substantial proportion of the mice developed insulinomas later in life, which caused decreased viability. This oncogenic transformation tightly correlated with nuclear exclusion of the tumor suppressor PTEN. To address the role of the mammalian target of rapamycin (mTOR) substrate S6K1 in the MyrAkt1-mediated phenotype, we crossed RIP-MyrAkt1 and S6K1-deficient mice. The resulting mice displayed reduced insulinemia and glycemia compared with RIP-MyrAkt1 mice due to a combined effect of improved insulin secretion and insulin sensitivity. Importantly, although the increase in beta cell size in RIP-MyrAkt1 mice was not affected by S6K1 deficiency, the hyperplastic transformation required S6K1. Our results therefore identify S6K1 as a critical element for MyrAkt1-induced tumor formation and suggest that it may represent a useful target for anticancer therapy downstream of mTOR.

Unité(s) : Anatomie Pathologique, U845 (MP)

A simple clinico-histopathological composite scoring system is highly predictive of graft outcomes in marginal donors

ANGLICHEAU D, LOUPY A, LEFAUCHEUR C, PESSIONE F, LETOURNEAU I, COTE I, GAHA K, NOEL LH, PATEY N, DROZ D, MARTINEZ F, ZUBER J, GLOTZ D, THERVET E, LEGENDRE C

2008 - Amer. J. Transplant. 8(11):2325-2334

The predictive value of pre-implantation biopsies versus clinical scores has not been studied extensively in marginal donors. Pre-implantation biopsies were performed in 313 kidneys from donors that were >/= 50 years of age (training set, n = 191; validation set, n = 122). The value of the donor clinical parameters and histological results in predicting 1-year estimated glomerular filtration rate (eGFR) <25 mL/min/1.73 m(2) was retrospectively evaluated. In multivariate analysis, the only clinical parameters associated with low eGFR were donor hypertension and a serum creatinine level >/=150 mumol/L before organ recovery. Clinical scores (Nyberg and Pessione) were not significantly associated with graft function. Regarding histological parameters, univariate analysis showed that glomerulosclerosis (GS) (p = 0.02), arteriolar hyalinosis (p = 0.03) and the Pirani (p = 0.02) and chronic allograft damage index (CADI) (p = 0.04) histological scores were associated with low eGFR. The highest performance in predicting low eGFR was achieved using a composite score that included donor serum creatinine (>/=150 mumol/L or <150 mumol/L), donor hypertension and GS (>/=10% or <10%). The validation set confirmed the critical importance of taking into account biopsy and clinical parameters during marginal donor evaluation. In conclusion, clinical scores are weak predictors of graft outcomes with marginal donors. Instead, a simple and convenient composite score strongly predicts graft function and survival and may facilitate optimal allocation of marginal donors.

Unité(s) : Anatomie Pathologique, Transplantation Adulte

Diffuse lymphoplasmacytic bronchiolitis in cartilage-hair hypoplasia

BAILLY-BOTUHA C, JAUBERT F, TAAM RA, GALMICHE L, PICARD C, BELLON G, DE BLIC J

2008 - J. Pediat. 152(3):429-433

Three children with cartilage-hair hypoplasia presented with chronic obstructive symptoms and bronchiolar wall thickening on high-resolution computed tomography scanning. In all children, surgical lung biopsy demonstrated diffuse dilated lymphoplasmacytic bronchiolitis. The bronchiolar wall was infiltrated by a lymphocyte sheath with plasma cell differentiation and dispersed secondary follicles. Clarithromycin substantially improved respiratory symptoms and pulmonary function, allowing children to return home.

Unité(s) : Immuno-Hématologie-Rhumatologie Pédiatriques, Pneumologie et Asthmologie Pédiatriques, Anatomie Pathologique

T Cell Receptor Genotyping and HOXA/TLX1 Expression Define Three T Lymphoblastic Lymphoma Subsets which Might Affect Clinical Outcome

BALEYDIER F, DECOUVELAERE AV, BERGERON J, GAULARD P, CANIONI D, BERTRAND Y, LEPRETRE S, PETIT B, DOMBRET H, BELDJORD K, MOLINA T, ASNAFI V, MACINTYRE E

2008 - Clin. Cancer Res. 14(3):692-700

PURPOSE: T lymphoblastic lymphomas (T-LBL) are rare disorders of immature T cells which predominantly involve the mediastinum. Their oncogenic pathways and prognostic variables are not clear. EXPERIMENTAL DESIGN: We undertook a retrospective study of 41 cytoplasmic CD3+ T-LBL (nine cases aged <16 years) by assessing stage of maturation arrest based on T cell receptor (TCR) immunogenotyping, immunohistochemistry, and quantification of the oncogenes thought to be important in immature T cell malignancies. RESULTS: Application of a TCR-based immunogenetic classification allowed the identification of three subcategories: 11 immature IM0/D-LBL showed no TCR or only incomplete TCRD DJ rearrangement and corresponded to cytoplasmic CD3+ precursors of uncertain lineage. Sixteen mature TCRD(del)-LBL showed biallelic TCRD deletion and both TCRG and TCRB rearrangement, consistent with TCRalphabeta lineage restriction. Fourteen intermediate LBL (Int-LBL) showed complete TCRD VDJ and TCRG VJ rearrangement, with TCRB VDJ rearrangement in the majority. All Int-LBL expressed HOX11/TLX1 or HOXA9 transcripts and a proportion of the latter were associated with CALM-AF10 or NUP214-ABL fusion transcripts. IM0/D-LBL were restricted to adults with extrathymic disease and bone marrow involvement, whereas Int-LBL and TCRD(del)-LBL were found in children and adults with predominantly thymic disease. In adults, the Int-LBL subgroup was associated with a significantly superior clinical outcome. This subgroup can be identified either by TCR immunogenotyping or HOXA9/TLX1 transcript quantification. CONCLUSION: Application of this molecular classification will allow the prospective evaluation of prognostic effects within pediatric and adult protocols.

Unité(s) : E 0210, Laboratoire d'Hématologie, Anatomie Pathologique

Human CD4+ CD25+ Foxp3+ regulatory T cells do not constitutively express IL-35

BARDEL E, LAROUSSERIE F, CHARLOT-RABIEGA P, COULOMB-L'HERMINE A, DEVERGNE O

2008 - J. Immunol. 181(10):6898-6905

EBV-induced gene 3 (EBI3) can associate with p28 to form the heterodimeric cytokine IL-27, or with the p35 subunit of IL-12 to form the EBI3/p35 heterodimer, recently named IL-35. In mice, IL-35 has been shown to be constitutively expressed by CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg cells) and suggested to contribute to their suppressive activity. In this study, we investigated whether human Treg cells express IL-35. Double-staining analysis of human thymuses showed that neither Foxp3(+) nor CD25(+) cells coexpressed EBI3. Similarly, Foxp3(+) cells present in human lymph nodes, tonsils, spleens, and intestines did not express EBI3. Consistent with these in situ observations, Treg cells purified from blood or tonsils were negative for EBI3 by immunoblotting. Other human T cell subsets, including effector T cells, naive and memory CD4(+) T cells, CD8(+) and gammadelta T cells also did not constitutively express EBI3, which contrasts with IL-35 expression observed in murine CD8(+) and gammadelta T cells. Furthermore, although CD3/CD28 stimulation consistently induced low levels of EBI3 in various CD4(+) T cell subsets, no EBI3 could be detected in CD3/CD28-stimulated Treg cells. RT-PCR analysis showed that, whereas p35 transcripts were detected in both Teff and Treg cells, EBI3 transcripts were detected only in activated Teff cells, but not in resting or activated Treg cells. Thus, in contrast to their murine counterpart, human Treg cells do not express detectable amounts of IL-35.

Unité(s) : Anatomie Pathologique, UMR 8147

Rabeprazole induced acute interstitial nephritis

BAUDEAU C, DARD S, ZYLBERBERG H, PATEY-MARIAUD DE SERRE N

2008 - Rev Med Interne 29(10):834-6

A 84-year-old women underwent renal biopsy because of rapidly progressive renal failure. Rabeprazole induced interstitial nephritis was diagnosed. Interstitial nephritis may complicate the course of any proton pump inhibitor treatment. It is a rare and serious complication. Clinician's awareness of this adverse event is essential for early diagnosis and prompt recovery.

Unité(s) : Anatomie Pathologique

Stable and Functional Lymphoid Reconstitution in Artemis-deficient Mice Following Lentiviral Artemis Gene Transfer Into Hematopoietic Stem Cells

BENJELLOUN F, GARRIGUE A, DEMERENS-DE CHAPPEDELAINE C, SOULAS-SPRAUEL P, MALASSIS-SERIS M, STOCKHOLM D, HAUER J, BLONDEAU J, RIVIERE J, LIM A, LE LORC'H M, ROMANA S, BROUSSE N, PAQUES F, GALY A, CHARNEAU P, FISCHER A, DE VILLARTAY JP, CAVAZZANA-CALVO M

2008 - Mol. Ther. 16(8):1490-1499

Patients with mutations in the Artemis gene display a complete absence of T- and B lymphocytes, together with increased cellular radiosensitivity; this leads to a radiosensitive severe combined immunodeficiency (RS-SCID). Allogenic hematopoietic stem-cell (HSC) transplantation is only partially successful in the absence of an human leukocyte antigen-genoidentical donor, and this has prompted a search for alternative therapeutic approaches such as gene therapy. In this study, a self-inactivated lentiviral vector expressing Artemis was used to complement the Artemis knockout mouse (Art(-/-)). Transplantation of Artemis-transduced HSCs into irradiated Art(-/-) mice restored a stable (over a 15-month period of follow-up) and functional T- and cell repertoire that was comparable to that of control mice. The success of secondary transplantations demonstrated that the HSCs had been transduced. One of thirteen mice developed a thymoma 6 months after gene therapy. Although thymic cells were seen to be carrying two lentiviral integration sites, there was no evidence of lentivirus-driven oncogene activation. The Art(-/-) mice were found to be prone to develop T-cell lymphomas, either spontaneously or after irradiation. These data indicate that the observed lymphoproliferation was probably the consequence of the chromosomal instability associated with the Artemis-deficient background. As a whole, our work provides a basis for supporting the gene therapy approach in Artemis-deficient SCID.Molecular Therapy (2008); doi:10.1038/mt.2008.118.

Unité(s) : Anatomie Pathologique, Biothérapie, Hématologie Adulte, Histo-Embryologie - Cytogénétique, Immuno-Hématologie-Rhumatologie Pédiatriques, U768

High-dosage intravenous immunoglobulin-associated macrovacuoles are associated with chronic tubulointerstitial lesion worsening in renal transplant recipients

BOLLEE G, ANGLICHEAU D, LOUPY A, ZUBER J, PATEY N, MAC GREGOR D, MARTINEZ F, MAMZER-BRUNEEL MF, SNANOUDJ R, THERVET E, LEGENDRE C, NOEL LH

2008 - Clin. J. Amer. Soc. Nephrol. 3(5):1461-1468

BACKGROUND AND OBJECTIVES: Intravenous immunoglobulins (IVIg) may induce acute renal failure associated with tubular vacuolization. Although the use of IVIg is increasing in kidney transplantation, their impact on graft histology and function remains unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Twenty-seven kidney transplant recipients who had high immunologic risk and were treated with four courses of IVIg after transplantation were studied retrospectively at a transplant center, and findings were compared with those of 27 control subjects. Protocol kidney biopsies were performed at time of transplantation and at 3 mo and 1 yr after transplantation. RESULTS: No episode of IVIg-related acute renal failure occurred. Nevertheless, screening biopsies revealed the presence of "microvacuoles" and "macrovacuoles." Widespread microvacuolizations were often detected (70%) on preimplantation biopsy and not associated with IVIg. Macrovacuoles, which were absent on preimplantation biopsies, were observed exclusively in IVIg-treated patients. Macrovacuoles among IVIg-treated patients were seen in kidneys from older donors and were associated with chronic tubulointerstitial changes at 3 mo, with similar trends at 1 yr. Macrovacuoles were associated with lower creatinine clearance at last follow-up in IVIg-treated patients. CONCLUSIONS: IVIg frequently induce tubular macrovacuoles in kidney transplant recipients. These are more frequently observed in grafts from older donors, suggesting a higher vulnerability to IVIg. These data suggest a deleterious impact of IVIg-induced macrovacuoles on chronic tubulointerstitial changes and long-term renal function.

Unité(s) : Anatomie Pathologique, Transplantation Adulte

Intracerebral small round cell tumor: an unusual case with EWS-WT1 translocation

BOUCHIREB K, AUGER N, BHANGOO R, DI ROCCO F, BROUSSE N, DELATTRE O, VARLET P, GRILL J

2008 - Pediatr. Blood Cancer 51(4):545-548

Desmoplastic small round cell tumor (DSRCT) is a rare tumor, seen both in children and young adults with a marked predilection for the peritoneal cavity. Histology showed a small round cell tumor with a fibromyxoid stroma and immunohistochemistry indicated neural and mesenchymal differentiation, and diagnosis was made by molecular detection of the EWS-WT1 fusion gene product. DSRCT should be considered in the differential diagnosis of intracranial small round cell tumors.

Unité(s) : Anatomie Pathologique, Neurochirurgie Pédiatrique

High Numbers of Tumor-Associated Macrophages Have an Adverse Prognostic Value That Can Be Circumvented by Rituximab in Patients With Follicular Lymphoma Enrolled Onto the GELA-GOELAMS FL-2000 Trial

CANIONI D, SALLES G, MOUNIER N, BROUSSE N, KEUPPENS M, MORCHHAUSER F, LAMY T, SONET A, ROUSSELET MC, FOUSSARD C, XERRI L

2008 - J. Clin. Oncol. 26(3):440-446

PURPOSE: High amounts of intratumoral macrophages have been shown to correlate with poor prognosis in patients with follicular lymphoma (FL) treated with chemotherapy without rituximab. We tried to establish whether intratumoral macrophage count (MC) definitely is able to predict the outcome of FL patients in the rituximab era. PATIENTS AND METHODS: We analyzed immunohistochemical CD68 expression in 194 FL patients from the FL-2000 trial, randomly assigned to receive cyclophosphamide, doxorubicin, etoposide, prednisolone, and interferon (CHVP-I) or rituximab plus CHVP-I. Immunohistochemistry was performed on paraffin sections using anti-CD68 KP1 antibody, and stained macrophages were scored on high-power field (hpf) in either intrafollicular (IF) or extrafollicular (EF) areas. RESULTS: For IF MC, the best cutoff point was estimated at 10 macrophages/hpf. Low IF MC was significantly associated with a better event-free survival (EFS; P = .011). However, this effect was observed only in the CHVP-I arm (P = .012) and not in the rituximab plus CHVP-I arm. Using a cutoff of 15 IF MC, we found no significant association with EFS. For EF MC, fewer than 22 macrophages/hpf were associated with better EFS in the CHVP-I arm (P = .02) but not in the rituximab plus CHVP-I arm. CONCLUSION: These results show that MC can predict outcome of FL patients and that rituximab is able to circumvent the unfavorable outcome associated with high MC.

Unité(s) : Anatomie Pathologique

Long-term followup and comparison between genotype and phenotype in 29 cases of complete androgen insensitivity syndrome

CHEIKHELARD A, MOREL Y, THIBAUD E, LORTAT-JACOB S, JAUBERT F, POLAK M, NIHOUL-FEKETE C

2008 - J. Urol. 180(4):1496-1501

PURPOSE: Diagnosis and management of the complete androgen insensitivity syndrome have dramatically changed in the last few decades, with earlier diagnosis and the development of molecular biology. Some phenotypic features such as development of wolffian and mullerian remnants have been suggested to be an index of subtle residual androgen activity. Variations of these features clearly exist among patients and may influence treatment. Our aim was to assess the safety of keeping gonads in place for spontaneous puberty in a cohort of patients with genetically proved complete androgen insensitivity syndrome. In parallel to the risks of virilization at puberty and gonadal tumor some additional features, such as need for vaginal surgery, were investigated. MATERIALS AND METHODS: We studied the genotype, phenotype, anatomy of the internal and external genitalia, and clinical outcome of 29 cases of complete androgen insensitivity syndrome, managed by the same team from diagnosis (frequently in early childhood) to adulthood. RESULTS: All patients had a complete female phenotype. A total of 19 different mutations (including 7 unreported) were found. Each family presented with a different mutation. No somatic mosaicism was detected. Vas deferens and epididymis were found in all types of mutations (missense, nonsense and frameshift). Of the patients 23 were postpubertal (19 spontaneously). No postpubertal virilization occurred. Only 1 carcinoma in situ was detected (postpubertally). Vaginal surgery was rarely necessary. CONCLUSIONS: Our data advocate for keeping the gonads in the complete androgen insensitivity syndrome, at least until completion of spontaneous puberty. The risk of virilization at puberty should be ruled out for each androgen receptor mutation before management decisions and genetic counseling. Vaginal surgery should not be indicated as first line treatment.

Unité(s) : Anatomie Pathologique, Chirurgie Viscérale Pédiatrique, Endocrinologie Pédiatrique et Gynécologie

Liver hepatoblastoma and multiple OXPHOS deficiency in the follow-up of a patient with methylmalonic aciduria

COSSON MA, TOUATI G, LACAILLE F, VALAYANNNOPOULOS V, GUYOT C, GUEST G, VERKARRE V, CHRETIEN D, RABIER D, MUNNICH A, BENOIST JF, DE KEYZER Y, NIAUDET P, DE LONLAY P

2008 - Mol. Genet. Metab. 95(1-2):107-109

A boy who was diagnosed with methylmalonic aciduria (MMA) at the age of 10 days developed persistent hepatomegaly and raised transaminases from the age of 4 years. He was subsequently diagnosed with Leigh syndrome and required a kidney transplantation for end-stage renal failure. A massive hepatoblastoma led to his death by the age of 11 years. Methylmalonyl-CoA mutase activity was undetectable on both cultured skin fibroblasts and kidney biopsy and multiple respiratory chain deficiency was demonstrated in the kidney. Mitochondrial dysfunction and/or post-transplant immunosuppressive therapy should be considered as a possible cause of liver cancer in this patient.

Unité(s) : Anatomie Pathologique, Biochimie Métabolique, Gastro-Hépatologie et Nutrition Pédiatriques, Métabolisme, Néphrologie Pédiatrique, U781

Spectrum of HLXB9 gene mutations in Currarino syndrome and genotype-phenotype correlation

CRETOLLE C, PELET A, SANLAVILLE D, ZERAH M, AMIEL J, JAUBERT F, REVILLON Y, BAALA L, MUNNICH A, NIHOUL-FEKETE C, LYONNET S

2008 - Hum. Mutat. 29(7):903-910

Currarino syndrome (CS) is a rare congenital malformation described in 1981 as the association of three main features: typical sacral malformation (sickle-shaped sacrum or total sacral agenesis below S2), hindgut anomaly, and presacral tumor. In addition to the triad, tethered cord and/or lipoma of the conus are also frequent and must be sought, as they may lead to severe complications if not treated. The HLXB9 gene, located at 7q36, is disease-causing. It encodes the HB9 transcription factor and interacts with DNA through a highly evolutionarily conserved homeodomain early in embryological development. Thus far, 43 different heterozygous mutations have been reported in patients fulfilling CS criteria. Mutation detection rate is about 50%, and reaches 90% in familial cases. Here, we report 23 novel mutations in 26 patients among a series of 50 index cases with CS, and review mutational reports published since the identification of the causative gene. Three cytogenetic anomalies encompassing the HLXB9 gene are described for the first time. Truncating mutations (frameshifts or nonsense mutations) represent 57% of those identified, suggesting that haploinsufficiency is the basis of CS. No obvious genotype-phenotype correlation can be drawn thus far. Genetic heterogeneity is suspected, since at least 19 of the 24 patients without HLXB9 gene mutation harbor subtle phenotypic variations. Hum Mutat 29(7), 903-910, 2008. (c) 2008 Wiley-Liss, Inc.

Unité(s) : Anatomie Pathologique, Chirurgie Viscérale Pédiatrique, Neurochirurgie Pédiatrique, U781

Thalidomide in advanced mastocytosis

DAMAJ G, BERNIT E, GHEZ D, CLAISSE JF, SCHLEINITZ N, HARLE JR, CANIONI D, HERMINE O

2008 - Br. J. Haematol. 141(2):249-253

Mastocytosis is an acquired orphan disease characterized by the abnormal accumulation of mast cells responsible for organ failure and systemic symptoms. Cytoreductive drugs have been shown to be effective, but have rarely resulted in complete or long-term remission. We report two patients with advanced systemic mastocytosis (SM) who were treated successfully with thalidomide, given at the maximal tolerated dosage. B and C-findings as well as clinical symptoms rapidly improved. After a follow-up of more than 1 year, the patients remained in partial remission. Thalidomide seems to be an active drug in advanced SM. However, clinical trials are warranted to define its efficacy and safety profiles.

Unité(s) : Hématologie Adulte, Anatomie Pathologique, UMR 8147

Chromosome 11p15 paternal isodisomy in focal forms of neonatal hyperinsulinism

DAMAJ L, LE LORCH M, VERKARRE V, WERL C, HUBERT L, NIHOUL-FEKETE C, AIGRAIN Y, DE KEYZER Y, ROMANA SP, BELLANNE-CHANTELOT C, DE LONLAY P, JAUBERT F

2008 - J. Clin. Endocrinol. Metabol. 93(12):4941-4947

Context: Focal forms of congenital hyperinsulinism are due to a constitutional heterozygous mutation of paternal origin in the ABCC8 gene, more often than the KCNJ11 gene, located in the 11p11 region. This mutation is associated with the loss of the maternally inherited 11p11 to 11p15 region in the lesion. We investigated the possible occurrence of a compensatory duplication of the paternal 11p11-11p15 region. Materials and Methods: A combined immunohistochemistry and fluorescent in situ hybridization (FISH) study on beta-cell interphase nuclei with probes covering two genes located in this region (ABCC8 and CDKN1C genes) was performed in four cases of focal forms of hyperinsulinism. Results: i) beta-cells in the lesions of four cases of focal congenital hyperinsulinism were diploid for chromosomes 11 and 13, and ii) the 11p11 to 11p12 and the 11p14 to 11p15 regions containing ABCC8 and CDKN1C genes respectively were present with two copies. Loss of the maternal allele was confirmed in these focal lesions with microsatellite markers flanking the ABCC8 and CDKN1C genes, while a heterozygous mutation in the ABCC8 gene was inherited from the father. Conclusion: there is a duplication of the paternal allele on chromosome 11 in the focal forms of hyperinsulinism lesion. The paternal isodisomy observed rendered the beta-cells homozygous for ABCC8 mutation and harbored a K channel defect in the lesion similar to that observed in diffuse forms of congenital hyperinsulinism.

Unité(s) : Anatomie Pathologique, Chirurgie Viscérale Pédiatrique, Génétique Médicale Pédiatrique, U781

Nodular fasciitis of childhood: A clinicopathological analysis of 10 cases

DAUENDORFFER JN, ORTONNE N, BODEMER C, BROUSSE N, FRAITAG S

2008 - Ann. Dermatol. Vénéréolog. 135(8-9):553-558

BACKGROUND: Nodular fasciitis rarely affects children. To date, apart from isolated cases, only two series comprising respectively 15 and six children have been reported. PATIENTS AND METHODS: We carried out a retrospective study of the clinical and pathological aspects of 10 cases of nodular fasciitis involving children under 15 years of age diagnosed at the pathology laboratory of the Necker Children's Hospital (Paris, France) between 1992 and 2006. RESULTS: In comparison with previously reported data, our study highlights four new factors: (1) nodular fasciitis affected girls more often than boys; (2) it occurred predominantly on the trunk; (3) follow-up showed a high recurrence rate (22%) after surgical removal; (4) immunohistochemical analysis revealed a high level of expression of p53 by tumour cells; this was much higher than in adults. DISCUSSION: The high expression of p53 in nodular fasciitis, which has never been described in children, seems to point towards its preneoplastic rather than reactive nature.

Unité(s) : Anatomie Pathologique, Dermatologie

Molecular cytogenetic anomalies and phenotype alterations in a newly established cell line from Wilms tumor with diffuse anaplasia

FAUSSILLON M, MURAKAMI I, BICHAT M, TELVI L, JEANPIERRE C, NEZELOF C, JAUBERT F, GOGUSEV J

2008 - Cancer Genet. Cytogenet. 184(1):22-30

The novel continuous cell line WT-Pe.1 was established in vitro from Wilms tumor with histological features of diffuse anaplasia. The cultures grew as poorly differentiated epithelial-like cells with pleomorphic polygonal shapes and formation of typical monolayers. WT-Pe.1 cells were immunoreactive for cytokeratin, vimentin, laminin, villin, CD10, and CD24 proteins. Conventional cytogenetic analysis by RHG-banding revealed a hypotriploid karyotype with numerous abnormalities including ring chromosomes, double-minutes, homogeneous staining regions, radial structures, dicentrics, and several marker chromosomes. Comparative genomic hybridization analysis revealed DNA copy numbers losses on chromosome segments 1p, 3p, 6q, 9q34.1 approximately q34.3, 11q24 approximately q25, 14q12 approximately qter, 16q, 18q, and 22q11 approximately q13; gain of genomic material was localized on chromosome arms 1q, 4p, 6q, and 7p and the entire chromosome 12. With DNA from the original tumor, copy number losses were detected on chromosomes 1p, 14q, 16q, 17q, and 22q and gains were observed on 1q, 4p, 8q, 12p, 12q, and chromosome 14p. Copy number amplifications of distinct loci were found on 1q21.1 and 4p15.3, as well as an elevated copy number of cyclin D2 (CCND2) and cyclin D associated kinase (CDK4) genes on chromosome 12 (confirmed by fluorescence in situ hybridization).

Unité(s) : Anatomie Pathologique, U574, U845 (VW)

Transcription factors involved in pancreas development are expressed in paediatric solid pseudopapillary tumours

GALMICHE L, SARNACKI S, VERKARRE V, BOIZET B, DUVILLIE B, FABRE M, JAUBERT F

2008 - Histopathology 53(3):318-324

Aims: Solid pseudopapillary tumours (SPT) are rare pancreatic tumours, especially in children. The origin of this benign tumour remains unknown. Mutations of beta-catenin, a gene essential for pancreatic development, are constantly found, leading to delocalization of immunohistochemical signals from the cytoplasm to the nuclei of tumour cells. The aim was to report clinical and histological data of eight children with SPT and explore the immunohistochemical expression of pancreatic duodenal homeobox (PDX) 1 and Sox9, known to be crucial for pancreatic development and linked to the beta-catenin cascade. Methods and results: Eight children with features suggestive of SPT underwent surgical resection. Tumours displayed typical histological appearances. One was incompletely resected and recurred. Immunolabelling revealed nuclear location of beta-catenin in all cases and strong cytoplasmic but no nuclear expression of PDX1 or Sox9 in all but one case. Conclusions: The clinical behaviour of SPT in the paediatric population is similar to its adult counterpart. Complete surgical resection is essential. PDX1 and Sox9 proteins are exclusively expressed in the cytoplasmic compartment in SPT, suggesting overexpression of the corresponding genes linked to beta-catenin mutations. These findings favour the hypothesis that SPT originates from transformation of normally quiescent pancreatic stem cells.

Unité(s) : Anatomie Pathologique, Chirurgie Viscérale Pédiatrique, U845 (RS)

Induction of NKG2D Ligands by Gamma Radiation and Tumor Necrosis Factor-alpha May Participate in the Tissue Damage During Acute Graft-Versus-Host Disease

GANNAGE M, BUZYN A, BOGIATZI SI, LAMBERT M, SOUMELIS V, DAL-CORTIVO L, CAVAZZANA-CALVO M, BROUSSE N, CAILLAT-ZUCMAN S

2008 - Transplantation 85(6):911-915

Immunopathology of acute graft-versus-host disease (aGVHD) involves secretion of proinflammatory cytokines with subsequent expression of danger signals by injured host tissues. This explanation, however, does not explain the cluster of aGVHD target organs (skin, gut, and liver). NKG2D ligands (MICA/B and ULBP1-3 proteins) are stress-induced molecules that act as danger signals to alert NK and alphabeta or gammadelta CD8 T cells through engagement of the activating NKG2D receptor. We observed a strong and reversible induction of MICA/B expression in skin and liver sections during aGVHD. Tumor necrosis factor-alpha and gamma-radiation up-regulated expression of MICA/B and ULBP proteins in vitro on skin and intestine epithelial cell lines and ex vivo in normal skin explants. This NKG2D-ligand induction was regulated by a complex interplay between NFkB and JNK activation pathways. Our data suggest that NKG2D ligand induction might participate in the amplification loop that leads to tissue damage during aGVHD.

Unité(s) : Anatomie Pathologique, Biothérapie, Laboratoire d'Hématologie

Syndromic (phenotypic) diarrhea in early infancy

GOULET O, VINSON C, ROQUELAURE B, BROUSSE N, BODEMER C, CEZARD JP

2008 - Orphanet. J. Rare Dis. 3(.):6

Syndromic diarrhea (SD), also known as phenotypic diarrhea (PD) or tricho-hepato-enteric syndrome (THE), is a congenital enteropathy presenting with early-onset of severe diarrhea requiring parenteral nutrition (PN). To date, no epidemiological data are available. The estimated prevalence is approximately 1/300,000-400,000 live births in Western Europe. Ethnic origin does not appear to be associated with SD. Infants are born small for gestational age and present with facial dysmorphism including prominent forehead and cheeks, broad nasal root and hypertelorism. Hairs are woolly, easily removed and poorly pigmented. Severe and persistent diarrhea starts within the first 6 months of life (

Unité(s) : Anatomie Pathologique, Dermatologie, Gastro-Hépatologie et Nutrition Pédiatriques

Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1

HACEIN-BEY S, GARRIGUE A, WANG GP, SOULIER J, LIM A, MORILLON E, CLAPPIER E, CACCAVELLI L, DELABESSE E, BELDJORD K, ASNAFI V, MACINTYRE E, DAL-CORTIVO L, RADFORD-WEISS I, BROUSSE N, SIGAUX F, MOSHOUS D, HAUER J, BORKHARDT A, BELOHRADSKY BH, WINTERGERST U, VELEZ MC, LEIVA L, SORENSEN R, WULFFRAAT N, BLANCHE S, BUSHMAN FD, FISCHER A, CAVAZZANA-CALVO M

2008 - J. Clin. Invest. 118(9):3132-3142

Previously, several individuals with X-linked SCID (SCID-X1) were treated by gene therapy to restore the missing IL-2 receptor gamma (IL2RG) gene to CD34(+) BM precursor cells using gammaretroviral vectors. While 9 of 10 patients were successfully treated, 4 of the 9 developed T cell leukemia 31-68 months after gene therapy. In 2 of these cases, blast cells contained activating vector insertions near the LIM domain-only 2 (LMO2) proto-oncogene. Here, we report data on the 2 most recent adverse events, which occurred in patients 7 and 10. In patient 10, blast cells contained an integrated vector near LMO2 and a second integrated vector near the proto-oncogene BMI1. In patient 7, blast cells contained an integrated vector near a third proto-oncogene,CCND2. Additional genetic abnormalities in the patients' blast cells included chromosomal translocations, gain-of-function mutations activating NOTCH1, and copy number changes, including deletion of tumor suppressor gene CDKN2A, 6q interstitial losses, and SIL-TAL1 rearrangement. These findings functionally specify a genetic network that controls growth in T cell progenitors. Chemotherapy led to sustained remission in 3 of the 4 cases of T cell leukemia, but failed in the fourth. Successful chemotherapy was associated with restoration of polyclonal transduced T cell populations. As a result, the treated patients continued to benefit from therapeutic gene transfer.

Unité(s) : Anatomie Pathologique, Biothérapie, E 0210, Immuno-Hématologie-Rhumatologie Pédiatriques, Laboratoire d'Hématologie, U768, CIC-BT

Case-control cohort study of patients' perceptions of disability in mastocytosis

HERMINE O, LORTHOLARY O, LEVENTHAL PS, CATTEAU A, SOPPELSA F, BAUDE C, COHEN-AKENINE A, PALMERINI F, HANSSENS K, YANG Y, SOBOL H, FRAYTAG S, GHEZ D, SUAREZ F, BARETE S, CASASSUS P, SANS B, AROCK M, KINET JP, DUBREUIL P, MOUSSY A

2008 - PLoS ONE 3(5):e2266

BACKGROUND: Indolent forms of mastocytosis account for more than 90% of all cases, but the types and type and severity of symptoms and their impact on the quality of life have not been well studied. We therefore performed a case-control cohort study to examine self-reported disability and impact of symptoms on the quality of life in patients with mastocytosis. METHODOLOGY/PRINCIPAL FINDINGS: In 2004, 363 mastocytosis patients and 90 controls in France were asked to rate to their overall disability (OPA score) and the severity of 38 individual symptoms. The latter was used to calculate a composite score (AFIRMM score). Of the 363 respondents, 262 were part of an ongoing pathophysiological study so that the following data were available: World Health Organization classification, standard measures of physical and psychological disability, existence of the D816V KIT mutation, and serum tryptase level. The mean OPA and AFIRMM scores and the standard measures of disability indicated that most mastocytosis patients suffer from disabilities due to the disease. Surprisingly, the patient's measurable and perceived disabilities did not differ according to disease classification or presence or absence of the D816V KIT mutation or an elevated (> or = 20 ng/mL) serum tryptase level. Also, 32 of the 38 AFIRMM symptoms were more common in patients than controls, but there were not substantial differences according to disease classification, presence of the D816V mutation, or the serum tryptase level. CONCLUSIONS: On the basis of these results and for the purposes of treatment, we propose that mastocytosis be first classified as aggressive or indolent and that indolent mastocytosis then be categorized according to the severity of patients' perceived symptoms and their impact on the quality of life. In addition, it appears that mastocytosis patients suffer from more symptoms and greater disability than previously thought, that mastocytosis may therefore be under-diagnosed, and that the symptoms of the indolent forms of mastocytosis might be due more to systemic release of mediators than mast cell burden.

Unité(s) : Anatomie Pathologique, Dermatologie, Hématologie Adulte, Infectiologie

Early epithelial phenotypic changes predict graft fibrosis

HERTIG A, ANGLICHEAU D, VERINE J, PALLET N, TOUZOT M, ANCEL PY, MESNARD L, BROUSSE N, BAUGEY E, GLOTZ D, LEGENDRE C, RONDEAU E, XU-DUBOIS YC

2008 - J. Amer. Soc. Nephrol. 19(8):1584-1591

Chronic allograft nephropathy accounts for the loss of approximately 40% of allografts at 10 yr. Currently, no biomarker is available to detect interstitial fibrosis and tubular atrophy in the renal graft at an early stage, when intervention may be beneficial. Because tubular epithelial cells have been shown to exhibit phenotypic changes suggestive of epithelial-to-mesenchymal transition, we studied whether these changes predict the progression of fibrosis in the allograft. Eighty-three kidney transplant recipients who had undergone a protocol graft biopsy at both 3 and 12 mo after transplantation were enrolled. De novo vimentin expression and translocation of beta-catenin into the cytoplasm of tubular cells were detected on the first biopsy by immunohistochemistry. Patients with expression of these markers in >or=10% of tubules at 3 mo had a higher interstitial fibrosis score at 1 yr and a greater progression of this score between 3 and 12 mo. The intensity of these phenotypic changes positively and significantly correlated with the progression of fibrosis, and multivariate analysis showed that their presence was an independent risk factor for this progression. In addition, the presence of early phenotypic changes was associated with poorer graft function 18 mo after transplantation. In conclusion, early phenotypic changes indicative of epithelial-to-mesenchymal transition predict the progression toward interstitial fibrosis in human renal allografts.

Unité(s) : Anatomie Pathologique, Transplantation Adulte

Renal carcinoma associated with MiTF/TFE translocation: Report of six cases in young adults

HINTZY MC, CAMPARO P, VASILIU V, PEYROMAURE M, VIEILLEFOND A

2008 - Prog. Urol. 18(5):275-280

OBJECTIVE: The authors present six cases of renal carcinoma associated with MiTF/TFE translocation in young adults. This tumour is one of the newly identified entities of the WHO 2004 classification. MATERIALS: Six patients with MiTF/TFE translocation were identified in a series of 636 adults operated between 2001 and 2005. The diagnosis was based on cytogenetic analysis and immunohistochemistry (IHC) in three patients and IHC alone in the other three patients. RESULTS: Four women and two men between the ages of 28 and 42 years presented a tumour with a mean diameter of 6cm (range: 3-15cm). The TNM classification of these tumours was pT1N0 (n=2), pT2N0 (n=1), pT3aN+M0 (n=1), and pT3aN+M+ (n=2). The mean follow-up was 32 months. One M+ patient died six months after the operation, another two pT3 patients developed metastatic disease and pT1 or pT2 patients were alive without recurrence. The histological features comprised a typical papillary architecture with large eosinophil and/or clear cells. IHC showed TFE3 (n=5) or TFEB (n=1) expression. Cytogenetic analysis demonstrated a t(X;1)(p11.2;p34) or t(X;17)(p11.2;q25) translocation in two patients expressing TFE3 and a t(6;11)(p21; q13) translocation in the patient expressing TFEB. CONCLUSION: Renal carcinoma associated with MiTF/TFE translocation can be diagnosed by IHC. However, cytogenetic analysis on fresh or frozen material allows characterization of the translocation and should be performed on all renal tumours in young adults. Prognosis is related to stage. In the future, the diagnosis of more cases of this type of carcinoma will allow more precise definition of the clinicopathological profile and the most appropriate management.

Unité(s) : Anatomie Pathologique

Herpes-virus infection in patients with langerhans cell histiocytosis: a case-controlled sero-epidemiological study, and in situ analysis

JEZIORSKI E, SENECHAL B, MOLINA TJ, DEVEZ F, LERUEZ-VILLE M, MORAND P, GLORION C, MANSUY L, GAUDELUS J, DEBRE M, JAUBERT F, SEIGNEURIN JM, THOMAS C, JOAB I, DONADIEU J, GEISSMANN F

2008 - PLoS ONE 3(9):e3262

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare disease that affects mainly young children, and which features granulomas containing Langerhans-type dendritic cells. The role of several human herpesviruses (HHV) in the pathogenesis of LCH was suggested by numerous reports but remains debated. Epstein-barr virus (EBV, HHV-4), & Cytomegalovirus (CMV, HHV-5) can infect Langerhans cells, and EBV, CMV and HHV-6 have been proposed to be associated with LCH based on the detection of these viruses in clinical samples. METHODOLOGY: We have investigated the prevalence of EBV, CMV and HHV-6 infection, the characters of antibody response and the plasma viral load in a cohort of 83 patients and 236 age-matched controls, and the presence and cellular localization of the viruses in LCH tissue samples from 19 patients. PRINCIPAL FINDINGS: The results show that prevalence, serological titers, and viral load for EBV, CMV and HHV-6 did not differ between patients and controls. EBV was found by PCR in tumoral sample from 3/19 patients, however, EBV small RNAs EBERs -when positive-, were detected by in situ double staining in bystander B CD20+ CD79a+ lymphocytes and not in CD1a+ LC. HHV-6 genome was detected in the biopsies of 5/19 patients with low copy number and viral Ag could not be detected in biopsies. CMV was not detected by PCR in this series. CONCLUSIONS/SIGNIFICANCE: Therefore, our findings do not support the hypothesis of a role of EBV, CMV, or HHV-6 in the pathogenesis of LCH, and indicate that the frequent detection of Epstein-barr virus (EBV) in Langerhans cell histiocytosis is accounted for by the infection of bystander B lymphocytes in LCH granuloma. The latter observation can be attributed to the immunosuppressive micro environment found in LCH granuloma.

Unité(s) : U838, Anatomie Pathologique, Immuno-Hématologie-Rhumatologie Pédiatriques, Laboratoire de Microbiologie, Traumatologie et Orthopédie Pédiatriques

A familial case of Keratitis-Ichthyosis-Deafness (KID) syndrome with the GJB2 mutation G45E

JONARD L, FELDMANN D, PARSY C, FREITAG S, SINICO M, KOVAL C, GRATI M, COUDERC R, DENOYELLE F, BODEMER C, MARLIN S, HADJ-RABIA S

2008 - Eur. J. Med. Genet 51(1):35-43

Keratitis-Ichthyosis-Deafness (KID) syndrome (OMIM 148210) is a congenital ectodermal defect. KID consists of an atypical ichthyosiform erythroderma associated with congenital sensorineural deafness. A rare form of the KID syndrome is a fatal course in the first year of life due to severe skin lesion infections and septicaemia. KID appears to be genetically heterogeneous and may be caused by mutations in connexin 26 or connexin 30 genes. GJB2 mutations in the connexin 26 gene are the main cause of the disease. Most of the cases caused by GJB2 mutations are sporadic, but dominant transmission has also been described. To date, the rare lethal form of the disease has been only observed in two Caucasian sporadic patients with the GJB2 mutation, with the p.Gly45Glu (G45E) arising de novo. We have reported an African family with dizygotic twins suffering from a lethal form of KID. The dizygosity of the twins was confirmed by microsatellite markers. The two patients were heterozygous for the G45E mutation of GJB2, whereas the mutation was not detected in the two parents. The unusual transmission of the disease observed in this family could be explained by the occurrence of a somatic or more probably a germinal mosaic in one of the parents.

Unité(s) : Anatomie Pathologique, Dermatologie, Département de Pédiatrie

Aberrant expression of ovary determining gene FOXL2 in the testis and juvenile granulosa cell tumor in children

KALFA N, FELLOUS M, BOIZET-BONHOURE B, PATTE C, DUVILLARD P, PIENKOWSKI C, JAUBERT F, ECOCHARD A, SULTAN C

2008 - J. Urol. 180(4 Suppl.):1810-1813

PURPOSE: FOXL2 is the earliest known marker of ovarian differentiation in mammals. It is involved in ovarian somatic cell differentiation and further follicle maintenance. FOXL2 is not implicated in determination of the male gonad and it is absent in the testis. We investigated whether the rare JGCTT (juvenile granulose cell tumor of the testis), named for its histological similarity to ovarian tumor, could be the first illustration of aberrant expression of this ovary determining gene in the human testis. MATERIALS AND METHODS: Between 1990 and 2004, 3 boys with JGCTT were reported from the TGM95 database of the French Society for Childhood Cancer and from 8 pediatric endocrinology centers. Orchiectomy was performed in these patients. Immunohistochemistry of FOXL2, and co-immunofluorescence of FOXL2 and SOX9 were performed on tumor sections. RESULTS: Testicular tumor cells showed aberrant expression of FOXL2, which resembled normal ovarian granulosa cells. The localization of FOXL2 expression was nuclear without any cytoplasmic sequestration, suggesting that FOXL2 had biological activity. Conversely SOX9, which is present in the nucleus of normal testicular cells, was sequestered in the cytoplasm of granulosa tumor cells or markedly under expressed in the nuclei. In this case of residual SOX9 nuclear expression the expression of FOXL2 and SOX9 was mutually exclusive. CONCLUSIONS: To our knowledge we report the first human model of aberrant intratesticular expression of an ovary determining gene along with the extinction of SOX9 and the transdifferentiation of a testicular cell into a granulosa tumor cell.

Unité(s) : Anatomie Pathologique

Granulomatous mycosis fungoides and granulomatous slack skin: a multicenter study of the Cutaneous Lymphoma Histopathology Task Force Group of the European Organization For Research and Treatment of Cancer (EORTC)

KEMPF W, OSTHEEREN-MICHAELIS S, PAULLI M, LUCIONI M, WECHSLER J, AUDRING H, ASSAF C, RUDIGER T, WILLEMZE R, MEIJER CJ, BERTI E, CERRONI L, SANTUCCI M, HALLERMANN C, BERNEBURG M, CHIMENTI S, ROBSON A, MARSCHALKO M, KAZAKOV DV, PETRELLA T, FRAITAG S, CARLOTTI A, COURVILLE P, LAENG H, KNOBLER R, GOLLIN

2008 - Arch. Dermatol. 144(12):1609-1617

BACKGROUND: Granulomatous cutaneous T-cell lymphomas (CTCLs) are rare and represent a diagnostic challenge. Only limited data on the clinicopathological and prognostic features of granulomatous CTCLs are available. We studied 19 patients with granulomatous CTCLs to further characterize the clinicopathological, therapeutic, and prognostic features. OBSERVATIONS: The group included 15 patients with granulomatous mycosis fungoides (GMF) and 4 with granulomatous slack skin (GSS) defined according to the World Health Organization-European Organization for Research and Treatment of Cancer classification for cutaneous lymphomas. Patients with GMF and GSS displayed overlapping histologic features and differed only clinically by the development of bulky skin folds in GSS. Histologically, epidermotropism of lymphocytes was not a prominent feature and was absent in 9 of 19 cases (47%). Stable or progressive disease was observed in most patients despite various treatment modalities. Extracutaneous spread occurred in 5 of 19 patients (26%), second lymphoid neoplasms developed in 4 of 19 patients (21%), and 6 of 19 patients (32%) died of their disease. Disease-specific 5-year survival rate in GMF was 66%. CONCLUSIONS: There are clinical differences between GMF and GSS, but they show overlapping histologic findings and therefore cannot be discriminated by histologic examination alone. Development of hanging skin folds is restricted to the intertriginous body regions. Granulomatous CTCLs show a therapy-resistant, slowly progressive course. The prognosis of GMF appears worse than that of classic nongranulomatous mycosis fungoides.

Unité(s) : Anatomie Pathologique

Long-term outcome, growth and digestive function in children 2 to 18 years after intestinal transplantation

LACAILLE F, VASS N, SAUVAT F, CANIONI D, COLOMB V, TALBOTEC C, DE SERRE NP, SALOMON J, HUGOT JP, CEZARD JP, REVILLON Y, RUEMME FM, GOULET O

2008 - Gut 57(4):455-461

OBJECTIVE: Small bowel (SB) transplantation (Tx), long considered a rescue therapy for patients with intestinal failure, is now a well recognised alternative treatment strategy to parental nutrition (PN). In this retrospective study, we analysed graft functions in 31 children after SBTx with a follow-up of 2-18 years (median 7 years). PATIENTS: Twelve children had isolated SBTx, 19 had combined liver-SBTx and 17 received an additional colon graft. Growth, nutritional markers, stool balance studies, endoscopy and graft histology were recorded every 2-3 years post-Tx. RESULTS: All children were weaned from PN after Tx and 26 children remained PN-free. Enteral nutrition was required for 14/31 (45%) patients at 2 years post-Tx. All children had high dietary energy intakes. The degree of steatorrhoea was fairly constant, with fat and energy absorption rates of 84-89%. Growth parameters revealed at transplantation a mean height Z-score of -1.17. After Tx, two-thirds of children had normal growth, whereas in one-third, Z-scores remained lower than -2, concomitant to a delayed puberty. Adult height was normal in 5/6. Endoscopy and histology analyses were normal in asymptomatic patients. Chronic rejection occurred only in non-compliant patients. Five intestinal grafts were removed 2.5-8 years post-Tx for acute or chronic rejection. CONCLUSIONS: This series indicates that long-term intestinal autonomy for up to 18 years is possible in the majority of patients after SBTx. Subnormal energy absorption and moderate steatorrhoea were often compensated for by hyperphagia, allowing normal growth and attainment of adult height. Long-term compliance is an important pre-requisite for long-term graft function.

Unité(s) : Chirurgie Viscérale Pédiatrique, Gastro-Hépatologie et Nutrition Pédiatriques, Anatomie Pathologique

Phenotypic and genotypic characteristics of mastocytosis according to the age of onset

LANTERNIER F, COHEN-AKENINE A, PALMERINI F, FEGER F, YANG Y, ZERMATI Y, BARETE S, SANS B, BAUDE C, GHEZ D, SUAREZ F, DELARUE R, CASASSUS P, BODEMER C, CATTEAU A, SOPPELSA F, HANSSENS K, AROCK M, SOBOL H, FRAITAG S, CANIONI D, MOUSSY A, LAUNAY JM, DUBREUIL P, HERMINE O, LORTHOLARY O

2008 - PLoS ONE 3(4):e1906

Adult's mastocytosis is usually associated with persistent systemic involvement and c-kit 816 mutation, while pediatrics disease is mostly limited to the skin and often resolves spontaneously. We prospectively included 142 adult patients with histologically proven mastocytosis. We compared phenotypic and genotypic features of adults patients whose disease started during childhood (Group 1, n = 28) with those of patients whose disease started at adult's age (Group 2, n = 114). Genotypic analysis was performed on skin biopsy by sequencing of c-kit exons 17 and 8 to 13. According to WHO classification, the percentage of systemic disease was similar (75 vs. 73%) in 2 groups. C-kit 816 mutation was found in 42% and 77% of patients in groups 1 and 2, respectively (p<0.001). 816 c-kit mutation was associated with systemic mastocytosis in group 2 (87% of patients with systemic mastocytosis vs. 45% with cutaneous mastocytosis, p = 0.0001). Other c-kit activating mutations were found in 23% of patients with mastocytosis' onset before the age of 5, 0% between 6 and 15 years and 2% at adults' age (p<0.001). In conclusion, pathogenesis of mastocytosis significantly differs according to the age of disease's onset. Our data may have major therapeutic relevance when considering c-kit-targeted therapy.

Unité(s) : Anatomie Pathologique, Hématologie Adulte, Infectiologie, Dermatologie, UMR 8147

Fixed drug eruption caused by iodixanol

LE BETTER C, FRAITAG S, JACQUOT C, LOUET ALL, AUFFRET N

2008 - Ann. Dermatol. Vénéréolog. 135(10):684-685

Unité(s) : Anatomie Pathologique, Dermatologie

Presentation and Long-term Follow-up of Refractory Celiac Disease: Comparison of Type I with Type II

MALAMUT G, AFCHAIN P, VERKARRE V, LECOMTE T, AMIOT A, DAMOTTE D, BOUHNIK Y, COLOMBEL JF, DELCHIER JC, ALLEZ M, COSNES J, LAVERGNE-SLOVE A, MERESSE B, TRINQUART L, MACINTYRE E, RADFORD-WEISS I, HERMINE O, BROUSSE N, CERF-BENSUSSAN N, CELLIER C

2008 - Gastroenterology 136(1):81-90

BACKGROUND & AIMS: Refractory celiac disease (RCD) was recently subdivided into 2 subtypes (RCD I and II) based on a normal or an abnormal phenotype of intraepithelial lymphocytes (IELs), respectively. It is not clear, however, if these 2 entities differ in their presentation at diagnosis or long-term outcome. We compared the clinical and biological characteristics of RCD I and RCD II at diagnosis, the risk of developing an overt lymphoma, and the predictive factors of survival. METHODS: Medical files of 14 patients with RCD I and 43 with RCD II were analyzed retrospectively. Predictive factors of overt lymphoma and survival were studied in univariate and multivariate analyses. RESULTS: At diagnosis, malnutrition, ulcerative jejunitis, and lymphocytic gastritis were more common in patients with RCD II than RCD I (P < .05). Overt lymphomas occurred in 2 patients with RCD I and 16 with RCD II. In the univariate analysis, abnormal IEL phenotype and increased age at diagnosis of RCD were predictive factors for overt lymphoma. Abnormal IEL phenotype (P < .01), clonality (P = .01), and overt lymphoma (P = .001) predicted short survival time. Only abnormal IEL phenotype (P = .03) and overt lymphoma (P = .04) were predictive in the multivariate analysis. The 5-year survival rate was 93% in patients with RCD I and 44% with RCD II. CONCLUSIONS: Patients with RCD II have a much more severe presentation and prognosis than patients with RCD I; <44% of patients with RCD II survive 5 years after diagnosis. Abnormal IEL phenotype is a predictive factor but not a necessary condition for the development of overt lymphoma.

Unité(s) : Anatomie Pathologique, Hématologie Adulte, U793, Laboratoire d'Hématologie, Histo-Embryologie - Cytogénétique

Adult celiac disease with severe or partial villous atrophy: A comparative study

MALAMUT G, MATYSIAK-BUDNIK T, GROSDIDER E, JAIS JP, MORALES E, DAMOTTE D, CAILLAT-ZUCMAN S, BROUSSE N, CERF-BENSUSSAN N, JIAN R, CELLIER C

2008 - Gastroentérol. Clin. Biol. 32(3):236-242

BACKGROUND AND AIMS: While severe villous atrophy (SVA) is the most typical histological feature in adult celiac disease (ACD), partial villous atrophy (PVA) is now also frequently found. So far, the impact of the severity of villous atrophy on the clinical presentation of ACD has been scarcely investigated. We aimed to compare the clinical, biological and immune features and outcomes in ACD patients presenting with PVA at diagnosis versus patients with SVA. PATIENTS AND METHODS: Medical files of 48 patients with ACD diagnosed between 1992 and 2003 were retrospectively studied. The diagnosis was based on the presence of intestinal villous atrophy, with increases in intraepithelial lymphocytes and circulating celiac specific antibodies. Villous atrophy was classified as severe (subtotal and total) or partial. Symptoms, biological signs of malabsorption, immune markers, bone mineral density at diagnosis and response to gluten-free diet were recorded. RESULTS: At diagnosis, ten patients (four M/six F) had PVA and 38 patients (five M/33 F) had SVA, with a median age of 54 and 33 years, respectively (p<0.05). Positivity for specific antibodies, HLA typing and frequency of autoimmune disease at diagnosis were similar in both PVA and SVA patients, as was their response to gluten-free diet. Diarrhea, malabsorption syndrome and osteopenia were independent of the degree of villous atrophy. CONCLUSION: PVA was observed in 21% of patients with ACD. Except for their older age at diagnosis, patients with PVA presented with similar clinical, biological and immune characteristics and outcomes as did patients with SVA.

Unité(s) : Anatomie Pathologique, Biostatistique, Immuno-Hématologie-Rhumatologie Pédiatriques, U793

Nodular regenerative hyperplasia: The main liver disease in patients with primary hypogammaglobulinemia and hepatic abnormalities

MALAMUT G, ZIOL M, SUAREZ F, BEAUGRAND M, VIALLARD JF, LASCAUX AS, VERKARRE V, BECHADE D, POYNARD T, HERMINE O, CELLIER C

2008 - J. Hepatol. 48(1):74-82

BACKGROUND/AIMS: Liver lesions associated with primary hypogammaglobulinemia have been poorly described. We aimed to assess the clinical, histological and immune features and outcome of hepatic injury in patients with primary hypogammaglobulinemia. METHODS: The medical records of 51 patients (23 patients with liver biopsy) with primary hypogammaglobulinemia and liver abnormalities were retrospectively reviewed. Forty-three controls with primary hypogammaglobulinemia but with no hepatic manifestations were analyzed in parallel. RESULTS: Cholestasis (65%), mainly anicteric, and portal hypertension (50%) were the main hepatic manifestations. Histological analysis revealed non-fibrosing architectural abnormalities consistent with nodular regenerative hyperplasia (NRH) in 84% of CVID patients and in all HIGM and XLA patients. Intrasinusoidal lymphocytic infiltration, abnormalities of portal vessels and epithelioid granulomas were observed in 90%, 43% and 44% of patients, respectively. NRH was associated with portal hypertension in 75% of the cases. These patients more often presented with autoimmune diseases and peripheral lymphocytic abnormalities than control patients (p<0.05). CONCLUSIONS: Liver involvement in primary hypogammaglobulinemia mainly consists of NRH leading to chronic cholestasis and portal hypertension. Association with intrasinusoidal T cell infiltration, portal vein endotheliitis, autoimmune diseases and peripheral lymphocytic abnormalities suggests an autoimmune mechanism.

Unité(s) : Hématologie Adulte, Anatomie Pathologique

Brief communication: the relationship of regression of cirrhosis to outcome in chronic hepatitis C

MALLET V, GILGENKRANTZ H, SERPAGGI J, VERKARRE V, VALLET-PICHARD A, FONTAINE H, POL S

2008 - Ann. Intern. Med. 149(6):399-403

BACKGROUND: The effect of regression of cirrhosis in chronic hepatitis C is unknown. OBJECTIVE: To evaluate the relation between regression of cirrhosis and clinical outcome in patients with chronic hepatitis C after antiviral therapy. DESIGN: A cohort of patients with cirrhosis treated between 1988 and 2001. SETTING: Hepatology unit of a tertiary care center in France. PATIENTS: 96 patients with chronic hepatitis C and biopsy-proven cirrhosis (METAVIR score F4) who were treated with an interferon-based regimen and had at least 1 posttreatment liver biopsy. Patients were followed until November 2006. MEASUREMENTS: Occurrence of a combined end point of liver-related events (ascites, hepatic encephalopathy, variceal bleeding, spontaneous bacterial peritonitis, hepatocellular carcinoma, or liver transplantation) and death in patients with regression of cirrhosis (defined as a decrease from 4 to

Unité(s) : Anatomie Pathologique

Arteriolar hyalinization predicts delayed graft function in deceased donor renal transplantation

MATIGNON M, DESVAUX D, NOEL LH, ROUDOT-THORAVAL F, THERVET E, AUDARD V, DAHAN K, LANG P, GRIMBERT P

2008 - Transplantation 86(7):1002-1005

Delayed renal graft function (DGF) remains a largely unpredictable and burdensome consequence of deceased donor renal transplantation. There is growing evidence that histologic and molecular analyses of baseline donor kidney biopsies can predict both short- and long-term graft outcome. We performed histologic analyses of 172 preimplantation kidney biopsies to determine reliable histologic risk factors for DGF. Fifty-six recipients presented a DGF (incidence 32%). Univariate analysis revealed that arteriolar hyalinization (P=0.019), arterial intima fibrosis (0.004), donor age (P=0.001), duration of cold ischemia time (P=0.001), and recipient age (P=0.001) were significantly associated with DGF. Multivariate analysis revealed that the only independent histologic factor was arteriolar hyalinization (P=0.036). This histologic predictive factor, together with previously identified clinical risk factors, could guide clinical decisions regarding use, allocation, or immunosuppression protocols for minimization of DGF.

Unité(s) : Anatomie Pathologique, Transplantation Adulte

Unusual presentation of a severe autosomal recessive anhydrotic ectodermal dysplasia with a novel mutation in the EDAR gene

MEGARBANE H, CLUZEAU C, BODEMER C, FRAITAG S, CHABABI-ATALLAH M, MEGARBANE A, SMAHI A

2008 - Amer. J. Med. Genet. A 146A(20):2657-2662

We report on an 18-year-old woman, born to first-cousin parents, presenting with a severe form of anhydrotic ectodermal dysplasia (EDA/HED). She had sparse hair, absent limb hair, absent sweating, episodes of hyperpyrexia, important hypodontia, and hyperconvex nails. She also showed unusual clinical manifestations such as an absence of breasts, a rudimentary extranumerary areola and nipple on the left side, and marked palmo-plantar hyperkeratosis. Light microscopy of skin biopsies showed orthokeratotic hyperkeratosis and absence of sweat glands. A novel homozygous mutation (IVS9 + 1G > A) in the EDAR gene was identified. This mutation results in a total absence of EDAR transcripts and consequently of the EDAR protein, which likely results in abolition of all ectodysplasin-mediated NF-kappaB signaling. This is the first complete loss-of-function mutation in the EDAR gene reported to date, which may explain the unusual presentation of HED in this patient, enlarging the clinical spectrum linked to the dysfunction of the ectodysplasin mediated NF-kappaB signaling.

Unité(s) : Anatomie Pathologique, Dermatologie, Génétique Médicale Pédiatrique, U781

Hodgkin Lymphoma-Associated Hemophagocytic Syndrome: A Disorder Strongly Correlated with Epstein-Barr Virus

MENARD F, BESSON C, RINCE P, LAMBOTTE O, LAZURE T, CANIONI D, HERMINE O, BROUSSET P, MARTIN A, GAULARD P, RAPHAEL M, LARROCHE C

2008 - Clin. Infect. Dis. 47(4):531-534

The retrospective study of 34 patients with Hodgkin lymphoma-associated hemophagocytic syndrome led us to define this association as a specific disorder. Its characteristics are male predominance (male-to-female sex ratio, 3.3:1), immunodeficiency-like histological features (lymphocyte depletion, 45% of cases; mixed cellularity Hodgkin lymphoma subtype, 40%), and strong association with Epstein-Barr virus (94%).

Unité(s) : Anatomie Pathologique, Hématologie Adulte, UMR 8147

Development of liver disease despite mannose treatment in two patients with CDG-Ib

MENTION K, LACAILLE F, VALAYANNOPOULOS V, ROMANO S, KUSTER A, CRETZ M, ZAIDAN H, GALMICHE L, JAUBERT F, KEYZER YD, SETA N, DE LONLAY P

2008 - Mol. Genet. Metab. 93(1):40-43

We report here the 6- and 2-year follow-up of two patients diagnosed at 2months of age with CDG-Ib who were treated with mannose, with digestive symptoms, liver involvement and hyperinsulinemic hypoglycaemia. Both developed liver fibrosis while general condition improved and other symptoms disappeared.

Unité(s) : Métabolisme, U781, Anatomie Pathologique

Primary Leptomeningeal ALK(+) Lymphoma in a 13-year-old Child

MERLIN E, CHABRIER S, VERKARRE V, CRAMER E, DELABESSE E, STEPHAN JL

2008 - J. Pediat. Hematol. Oncol. 30(12):963-967

A distinct pathologic entity characterized by expression of the anaplastic lymphoma kinase (ALK) protein (hence described as ALK(+) lymphoma) has emerged within the heterogeneous group of CD30(+) anaplastic large-cell lymphomas. Central nervous system (CNS) involvement is extremely rare in anaplastic large-cell lymphoma. In children, only isolated cases have been reported, mainly Lis secondary CNS involvement. We report on a 13-year-old boy presenting with headaches and diplopia. Cerebrospinal fluid was infiltrated with atypical large granular lymphocytes. Magnetic resonance imaging of the brain revealed leptomeningeal enhancement. A frontal lobe biopsy showed a pleomorphic neoplasm diffusely infiltrating the meninges composed of large cells with bizarre nuclei similar to those evidenced in cerebrospinal fluid. Immunohistochemical stains showed diffuse strong positivity for CD8, CD30, anaplastic lymphoma kinase protein: p80 and negative monocyte-macrophage and B cell markers. TCR gamma was clonally rearranged. This finding was confirmed by reverse transcription-polymerase chain reaction analysis of the NPM/ALK fusion protein. Epstein-Barr virus was not detected. No evidence of extra-CNS disease was found by imaging study, cytologic examination, or molecular studies. The patient underwent complete remission with polychemotherapy followed by a CNS irradiation. At + 10 months from onset, he suffered a full relapse. After a short-term remission with vinblastine, lie underwent nonmyeloablative allogeneic bone marrow transplantation, but unfortunately died from multiple organ failure. This case is the first reported Occurrence of a primary meningeal ALK(+) lymphoma in a child.

Unité(s) : Anatomie Pathologique, Laboratoire d'Hématologie

Interest of screening biopsies in renal transplantation

NO‘L LH, LEGENDRE C

2008 - Néphrol. Ther. 4(Suppl.):S18-S24

Renal. biopsy is an invaluable tool. used for the monitoring of grafts and the management of their survival. Since 1993, thanks to research on biopsy tissues that enabled to distinguish the different types of rejection and to find markers of reversible or irreversible rejection, a classification of renal Lesions has been established to achieve the regularly updated Banff classification. The Last in date (2005) has defined the antibody-mediated chronic rejection, forsaken the term "chronic allograft nephropathy" and described a new class with interstitial. fibrosis and tubular atrophy (IF/TA). Systematic or screening biopsies allow revealing infraclinical. rejection lesions before any renal function degradation, better understanding of allograft nephropathy pathophysiology, confirming the diagnostic, but also displaying other more specific lesions that could benefit from a treatment. However, the interest of biopsies is limited by interpretation problems and risks for the patient. (C) 2008 Elsevier Masson SAS et Association Societe de Nephrologie. Tous droits reserves.

Unité(s) : Anatomie Pathologique, Transplantation Adulte

A Griscelli syndrome type 2 murine model of hemophagocytic lymphohistiocytosis (HLH)

PACHLOPNIK-SCHMID J, HO CH, DIANA J, PIVERT G, LEHUEN A, GEISSMANN F, FISCHER A, DE SAINT-BASILE G

2008 - Eur. J. Immunol. 38(11):3219-3225

Griscelli syndrome type 2 is caused by mutations in the RAB27A gene and is a rare and potentially fatal immune disorder associated with hemophagocytic lymphohistiocytosis (HLH). Animal models could provide assistance for better understanding the mechanisms and finding new treatments. Rab27a-deficient (ashen) mice do not spontaneously develop HLH. When injected with lymphocytic choriomeningitis virus (LCMV) strain WE, Rab27a-deficient C57BL/6 mice developed wasting disease, hypothermia, splenomegaly, cytopenia (anemia, neutropenia and thrombocytopenia), hypertriglyceridemia and increased levels of IFN-gamma, TNF-alpha, GM-CSF, IL-12, CCL5 and IL-10. Activated macrophages with hemophagocytosis were found in liver sections of these mice. Compared with perforin-deficient mice, LCMV-infected Rab27a-deficient mice showed a substantially better survival rate and slightly higher viral doses were needed to trigger HLH in Rab27a-deficient mice. This study demonstrates that LCMV-infected Rab27a-deficient C57BL/6 mice develop features consistent with HLH and, therefore, represent a murine model of HLH in human Griscelli syndrome type 2.

Unité(s) : Anatomie Pathologique, Immuno-Hématologie-Rhumatologie Pédiatriques, U768, U838

Evaluation of C4d Deposition and Circulating Antibody in Small Bowel Transplantation

PATEY-MARIAUD DE SERRE N, CANIONI D, LACAILLE F, TALBOTEC C, DION D, BROUSSE N, GOULET O

2008 - Amer. J. Transplant. 8(6):1290-1296

Antibody-mediated rejection (AMR) consensus criteria are defined in kidney and heart transplantation by histological changes, circulating donor-specific antibody (DSA), and C4d deposition in affected tissue. AMR consensus criteria are not yet identified in small bowel transplantation (SBTx). We investigated those three criteria in 12 children undergoing SBTx, including one retransplantation and four combined liver-SBTx (SBTx), with a follow-up of 12 days to 2 years. All biopsies (91) were evaluated with a standardized grading scheme for acute rejection (AR), vascular lesions and C4d expression. Sera were obtained at day 0 and during the follow-up. C4d was expressed in 37% of biopsies with or without AR, but in 50% of biopsies with severe vascular lesions. In addition, vascular lesions were always associated with AR and a poor outcome. All children with AR (grade 2 or 3) observed before the third month died or lost the graft. DSA were never found in any studied sera. We found no evidence that C4d deposition was of any clinical relevance to the outcome of SBTx. However, the grading of vascular lesions may constitute a useful marker to identify AR that is potentially resistant to standard treatment, and for which an alternative therapy should be considered.

Unité(s) : Anatomie Pathologique, Gastro-Hépatologie et Nutrition Pédiatriques

Collagen alpha5 and alpha2 (IV) chain coexpression: The procedure of choice to diagnose Alport syndrome from skin biopsies

PATEY-MARIAUD DE SERRE N, NO‘L LH

2008 - Ann. Pathol. 28(3):182-186

We describe a simple procedure to use skin biopsies for the diagnosis of Alport syndrome. The technique is based on the codetection of alpha5 and alpha2 chains of collagen IV along the basal lamina of epidermis through an immunfluorescence technique. Eighty-five per cent of the cases of Alport syndrome are due to a mutation in the gene COL4A5, located on chromosome X, encoding the alpha5 chain of collagen IV. In this situation, the tissue expression of alpha5 chain is abnormal; in males, the absence of expression of alpha5 chain is pathognomonic for Alport syndrome; in females, the expression of alpha5 chain may be discontinuous because of X inactivation. The alpha2 chain is used as a positive control. We have studied skin biopsies from 55 patients (35 females, 20 males) with a suspicion of Alport syndrome, along with five controls. Immunofluorescence was performed on frozen tissue samples; for lecture, epifluorescence and confocal microscopy were compared. In controls, both chains were codetected. In nine males out of 20, the expression of alpha5 was undetectable; it was preserved in the remaining cases. In female patients, the expression was discontinuous in 16 cases and undetectable in one. There was no difference in sensitivity between the two microscopic techniques. The codetection of alpha5 and alpha2 chains of collagen IV in frozen skin biopsies is therefore proposed as a simple technique to diagnose Alport syndrome, but requires a good knowledge of the conditions of interpretation.

Unité(s) : Anatomie Pathologique, U845 (VW)

Functional histology of dermis

PROST-SQUARCIONI C, FRAITAG S, HELLER M, BOEHM N

2008 - Ann. Dermatol. Vénéréolog. 135(1):S5-S20

The skin is composed of epidermis, dermis and subcutaneous tissue that interconnect anatomically. The dermis is an integrated system of fibrous and amorphous connective tissue that accommodates nerve and vascular networks, epidermally derived appendages, fibroblasts, macrophages and mast cells. Elastic and collagen tissue are the main types of fibrous connective tissue. The elastic connective tissue is assembled in a continuous network including mature elastic fibers, immature elaunin fibers and oxytalan fibers. Mature elastic fibers and elaunin have microfibrillar and amorphous matrix components while oxytalan fibers only contain microfibrils. Several molecules have been identified as constituents of the elastic fibers. Among the most characterized of these molecules is elastin in amorphous matrix, fibrillins 1 and 2 and LTBP-2 (ligand of latent TGF beta) in microfibrils and fibulins which interconnect elastin and fibrillins. Elastic fibers provides elasticity to the skin. Under electron microscope, collagen fibers appears as of bundles of periodically banded fibrils which are composed of collagens types I, III and V; type V collagen is believed to assist in regulating fibril diameter. They are associated with FACITs (fibril-associated collagen with interrupted triple helixes) collagens types XIV et XVI. Collagen fibers provide tensile strenght to the skin. Non fibrous connective tissue molecules include finely filamentous glycoproteins, glycosaminoglycans and proteoglycans of "the ground substance" (hyaluronic acid and chondroitin sulphate, dermatan sulphate, versican, decorin). Fibroblasts, macrophages and mast cells are regular residents of the dermis. The main function of these cells are well known. Fibroblasts are responsible for the synthesis and the degradation of fibrous and non fibrous connective tissue matrix proteins. Macrophages are phagocytic; they process and present antigen to immunocompetent lymphoid cells. Mast cells are responsible for IgE mediated acute, subacute and chronic inflammation. All these cells have a long list of other functions, in particular they are involved in coagulation, wound healing and tissue remodeling. (c) 2008 Elsevier Masson SAS. Tous droits reserves.

Unité(s) : Anatomie Pathologique

Genetic inactivation of the laminin {alpha}5 chain receptor Lu/BCAM leads to kidney and intestinal abnormalities in the mouse

RAHUEL C, FILIPE A, RITIE L, EL NEMER W, PATEY-MARIAUD N, ELADARI D, CARTRON JP, SIMON-ASSMANN P, LE VAN KIM C, COLIN Y

2008 - Amer. J. Physiol. - Renal Physiol. 294(2):F393-F406

Lutheran blood group and basal cell adhesion molecule (Lu/BCAM) has been recognized as a unique receptor for laminin alpha(5) chain in human red blood cells and as a coreceptor in epithelial, endothelial, and smooth muscle cells. Because limited information is available regarding the function of this adhesion glycoprotein in vivo, we generated Lu/BCAM-null mice and looked for abnormalities in red blood cells as well as in kidney and intestine, two tissues showing alteration in laminin alpha(5) chain-deficient mice. We first showed that, in contrast to humans, wild-type murine red blood cells failed to express Lu/BCAM. Lu/BCAM-null mice were healthy and developed normally. However, although no alteration of the renal function was evidenced, up to 90% of the glomeruli from mutant kidneys exhibited abnormalities characterized by a reduced number of visible capillary lumens and irregular thickening of the glomerular basement membrane. Similarly, intestine analysis of mutant mice revealed smooth muscle coat thickening and disorganization. Because glomerular basement membrane and smooth muscle coat express laminin alpha(5) chain and are in contact with cell types expressing Lu/BCAM in wild-type mice, these results provide evidence that Lu/BCAM, as a laminin receptor, is involved in vivo in the maintenance of normal basement membrane organization in the kidney and intestine.

Unité(s) : Anatomie Pathologique, Néphrologie Adulte

Bilateral MALT-type ocular adnexal lymphoma with marginal zone lymphoma leukaemic cells and ophthalmological diffuse large B cell lymphoma

SAHLI R, CANIONI D, COUTURIER J, SOLER G, MATHIOT C, GALATOIRE O, LUMBROSO-LE ROUIC L, PUTTERMANN M, HERMINE O, VALIDIRE P, MORAX S, BROUSSE N, DECAUDIN D

2008 - Br. J. Ophthalmol. 92(4):579-580

Unité(s) : Anatomie Pathologique, Hématologie Adulte

Collapsing glomerulopathy in Galloway-Mowat syndrome: A case report and review of the literature

SARTELET H, PIETREMENT C, NOEL LH, SABOURAUD P, BIREMBAUT P, OLIGNY LL, ROUSSEL B, DOCO-FENZY M

2008 - Pathol. Res. Pract. 204(6):401-406

The Galloway-Mowat syndrome (GMS) (MIM251300) is described as an autosomal recessive disorder, the gene of which has not yet been identified. We report the case of a boy presenting with an early nephrotic syndrome, microcephaly, seizures, and psychomotor retardation. He died at 3 years and 11 months in a context of end-stage renal function consistent with a GMS. He was the second child of a non-consanguineous marriage. There was no family history of nephrotic syndrome or end-stage renal failure, but his mother had a moderate mental retardation complicated by seizures. He presented dysmorphologic features, including micrognathia and large and floppy ears. Renal biopsy showed a focal segmental glomerulosclerosis with a collapsing glomerulopathy and abundant visceral epithelial cell proliferation. The majority of the glomeruli were sclerotic. We report the first case of GMS associated with a collapsing glomerulopathy.

Unité(s) : Anatomie Pathologique

Impact of Rituximab and/or High-Dose Therapy With Autotransplant at Time of Relapse in Patients With Follicular Lymphoma: A GELA Study

SEBBAN C, BRICE P, DELARUE R, HAIOUN C, SOULEAU B, MOUNIER N, BROUSSE N, FEUGIER P, TILLY H, SOLAL-CELIGNY P, COIFFIER B

2008 - J. Clin. Oncol. 26(21):3614-3620

PURPOSE: The treatment of patients with follicular lymphoma has changed with the introduction of high-dose therapy (HDT) with autologous stem-cell transplant then with rituximab. The effect of these two strategies on the outcome of relapsing patients with follicular lymphoma has never been compared. PATIENTS AND METHODS: We analyzed two cohorts of patients treated in two successive randomized studies with the same treatment, cyclophosphamide, doxorubicin, teniposide, and prednisolone plus interferon, to evaluate the role of rituximab and HDT in salvage therapy after first disease progression or relapse. RESULTS: Of the 364 patients included in these two studies, 254 progressed or relapsed and constitute the population of this analysis. Among them, 98 had been treated with HDT, including 33 of them after rituximab-containing salvage regimen, and 69 with rituximab alone or combined with chemotherapy but without HDT. Patients' characteristics at diagnosis were similar in all subgroups. If event-free survival was identical for patients treated within Groupe d'Etude des Lymphomes Folliculaires (GELF) -86 or GELF-94 studies, overall survival was longer in GELF-94 study. HDT was associated with a statistically significant benefit in terms of event-free survival from relapse and survival after relapse (SAR). Rituximab was associated with a greater benefit than HDT for these two end points. When both treatments were combined, patients treated with rituximab-containing salvage regimen followed by HDT had 5-year SAR more than 90%. CONCLUSION: In follicular lymphoma, for patients treated with first-line chemotherapy the combination of a salvage regimen containing rituximab with or without HDT leads to a dramatic improvement of long-term outcome.

Unité(s) : Anatomie Pathologique

Late-onset nephropathic cystinosis: clinical presentation, outcome, and genotyping

SERVAIS A, MORINIERE V, GRŸNFELD JP, NO‘L LH, GOUJON JM, CHADEFAUX-VEKEMANS B, ANTIGNAC C

2008 - Clin. J. Amer. Soc. Nephrol. 3(1):27-35

BACKGROUND AND OBJECTIVES: Cystinosis is an autosomal recessive disease characterized by the intralysosomal accumulation of cystine, as a result of a defect in cystine transport across the lysosomal membrane. Three clinical forms have been described on the basis of severity of symptoms and age of onset: infantile cystinosis, characterized by renal proximal tubulopathy and progression to end-stage renal disease before 12 yr of age; juvenile form, with a markedly slower rate of progression; and adult form, with only ocular abnormalities. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Fourteen patients in nine unrelated families with noninfantile cystinosis were studied. Information about clinical outcome, biochemical data, renal histopathologic data, and genotyping was collected. RESULTS: Eight patients had Fanconi syndrome. Proteinuria was present in all patients. Serum creatinine at last follow-up, without specific treatment, ranged between 69 and 450 mumol/L, at an age of 12 to 56 yr. Four patients reached end-stage renal disease by 12 to 28 yr. Renal biopsies, available in four cases, disclosed focal segmental glomerulosclerosis in three and crystals in three. Genetic screening showed that patients were compound heterozygous for mutations in the CTNS gene in four families and homozygous in two families. Patients had at least one "mild" mutation. A single heterozygous mutation was identified in one family and none in two families (only 72% mutations found). CONCLUSION: Renal involvement is heterogeneous in patients with noninfantile cystinosis even within families, and renal disease should be assessed even in families of patients with seemingly isolated ocular forms.

Unité(s) : Néphrologie Adulte, Néphrologie Pédiatrique, Anatomie Pathologique, Génétique Médicale Pédiatrique, Biochimie Métabolique, U574

Osteomalacia revealing cliac disease and primary biliary cirrhosis-related Fanconi syndrome in a patient with systemic sclerosis

TERRIER B, FAKHOURI F, BEREZNE A, BOULDOUYRE MA, GUILPAIN P, SOGNI P, TERRIS B, NOEL LH, GUILLEVIN L, MOUTHON L

2008 - Clin. Exp. Rheumatol. 26(3):467-470

Systemic sclerosis (SSc) may affect the gastrointestinal tract and cause very rarely malabsorption syndrome related to bacterial overgrowth. Malabsorption syndrome may be responsible for weight loss, diarrhea, osteomalacia, and iron and vitamins deficiency. We report the case of a SSc patient who developed osteomalacia caused by the combination of two exceptional conditions in the setting of SSc: celiac disease (CD) and primary biliary cirrhosis (PBC)-related Fanconi syndrome. Oral prednisone with angiotensin-converting enzyme inhibitors, was initiated because of active lesions of tubulitis, and led to the complete regression of bone pains, and by the improvement of renal function and regression of the features of proximal tubulopathy. Thus, in the presence of vitamin deficiencies in a patient with SSc, together with a search for malabsorption syndrome secondary to bacterial overgrowth, CD and/or PBC-associated Fanconi syndrome should be investigated.

Unité(s) : Anatomie Pathologique, Néphrologie Adulte

B Cell Survival in Intragraft Tertiary Lymphoid Organs After Rituximab Therapy

THAUNAT O, PATEY N, GAUTREAU C, LECHATON S, FREMEAUX-BACCHI V, DIEU-NOSJEAN MC, CASSUTO-VIGUIER E, LEGENDRE C, DELAHOUSSE M, LANG P, MICHEL JB, NICOLETTI A

2008 - Transplantation 85(11):1648-1653

BACKGROUND.: Rituximab is emerging as a potent therapeutic option in chronic inflammatory diseases associated with a prominent humoral component. Recent studies have demonstrated that chronic inflammatory infiltrate organize progressively themselves into ectopic lymphoid tissues (tertiary lymphoid organs; TLOs) supporting a local humoral immune response. In the present study, we evaluated the impact of rituximab therapy on TLOs associated with chronic active antibody-mediated rejection, a prototypic humoral chronic inflammatory condition. METHODS.: Renal allografts removed for terminal chronic rejection were prospectively collected in four transplantation centers over 4 years. Among 38 grafts collected, two were explanted after rituximab therapy for chronic active antibody-mediated rejection. Clinical characteristics and circulating B cell count were recorded for these two patients. The composition and the microarchitecture of the inflammatory infiltrate were analyzed by flow cytometry and immunohistochemistry. Organotypic cultures were performed to evaluate the intragraft production of alloantibody. Levels of expression of BAFF (Blys, CD257) were evaluated by quantitative reverse transcriptase-polymerase chain reaction. RESULTS.: Despite the complete depletion of circulating B cells in peripheral blood, TLOs were evidenced in the interstitium of both explanted grafts. Their functionality was assessed by the demonstration of a persistent local production of alloantibody. BAFF, a potent survival factor for B cells, was found to be overexpressed (both at the gene and the protein levels) in chronically rejected grafts when compared with normal kidneys and lymph nodes. CONCLUSIONS.: In certain patients, inflammatory microenvironment provides BAFF-dependent paracrine survival signal to B-cells in TLOs, allowing them to escape rituximab-induced apoptosis, thereby thwarting therapeutic efficiency.

Unité(s) : Transplantation Adulte, Anatomie Pathologique

Airway remodeling is correlated with obstruction in children with severe asthma

TILLIE-LEBLOND I, DE BLIC J, JAUBERT F, WALLAERT B, SCHEINMANN P, GOSSET P

2008 - Allergy 63(5):533-541

BACKGROUND: Severe asthma may involve an irreversible obstructive pattern, and structural changes in bronchial airways are believed to play a key role in this context. The aim of the present study was to compare airway remodeling in severe asthmatic children with or without obstructive pattern. METHODS: Two groups of children with severe asthma and persistent symptoms, 5-14 years old were included, 15 with persistent obstructive pattern (group O) and 10 without obstructive pattern (group N). Persistent obstructive pattern was defined as a forced expiratory volume in 1 s (FEV(1)) less than 80% of the predicted value after a course of systemic corticosteroids and no significant improvement after bronchodilator. We examined bronchial biopsies by pathological and immunochemical methods and quantified airway smooth muscle (ASM) and mucus gland areas, reticular basement membrane (RBM) thickening, distance between ASM and RBM, muscle light chain kinase (MLCK) expression and number of vessels (CD31 expression). RESULTS: Surface area of ASM (P = 0.009), MLCK expression (P = 0.03) and number of vessels (P = 0.0008) were increased in group O compared with group N. Distance of RBM-ASM was shorter in group O (P = 0.007). FEV(1) negatively correlated with ASM area (r = -0.6; P = 0.002), MLCK expression (r = -0.45; P = 0.02) and CD31 expression (r = -0.7; P = 0.0003), and positively correlated with the distance of RBM-ASM (r = 0.5; P = 0.007). CONCLUSIONS: Structural abnormalities of airway remodeling are present in children with severe asthma. Only an increase in surface area of ASM and the density of the vascular network are more pronounced in children with persistent obstructive pattern, while RBM thickening is similar. These results are concordant with longitudinal studies which emphasize the precocity of bronchial obstruction.

Unité(s) : Anatomie Pathologique, Pneumologie et Asthmologie Pédiatriques

Rhabdomyosarcoma an ubiquitous pediatric tumour

VERKARRE V, GALMICHE-ROLLAND L, SARNACKI S, JAUBERT F

2008 - Arkh. Patol. 70(3):50-53

Rhabdomyosarcoma is the most common soft tissue tumor in children. It occurs everywhere and its prognosis depends on the location and its histological type--embryonic or alveolar. The new immunohistochemical markers desmin and myogenin in combination with molecular biological detection of specific translocations in alveolar rhabdomyosarcoma improved diagnostic capacities. Less aggressive treatment in curable cases reduces the undesirable outcomes of therapy.

Unité(s) : Anatomie Pathologique, Chirurgie Viscérale Pédiatrique

Primary cutaneous Epstein-Barr virus-related lymphoproliferative disorders in 4 immunosuppressed children

WALLET-FABER N, BODEMER C, BLANCHE S, DELABESSE E, ESCHARD C, BROUSSE N, FRAITAG S

2008 - J. Amer. Acad. Dermatol. 58(1):74-80

Primary cutaneous Epstein-Barr virus-related lymphoproliferative disorders are rare. We describe 4 cases in children: two with acquired immunodeficiencies (HIV infection, heart transplantation) and two with congenital immunodeficiencies (ataxia-telangiectasia and an undetermined disease affecting the T lymphocytes). Two of the lymphoproliferative disorders were T-cell types and two were B-cell types. The two T-cell types were also Epstein-Barr virus positive, which is extremely rare. Three of the patients developed extracutaneous disease with poor outcome, resulting in death.

Unité(s) : Anatomie Pathologique, Dermatologie, Immuno-Hématologie-Rhumatologie Pédiatriques

Posttransplant Prophylactic Intravenous Immunoglobulin in Kidney Transplant Patients at High Immunological Risk: A Pilot Study

ANGLICHEAU D, LOUPY A, SUBERBIELLE C, ZUBER J, PATEY-MARIAUD DE SERRE N, NOEL LH, CAVALCANTI R, LE QUINTREC M, AUDAT F, MEJEAN A, MARTINEZ F, MAMZER-BRUNEEL MF, THERVET E, LEGENDRE C

2007 - Amer. J. Transplant. 7(5):1185-1192

The effects of posttransplant prophylactic intravenous immunoglobulin (IVIg) were investigated in renal transplant recipients at high immunological risk. Thirty-eight deceased-donor kidney transplant recipients with previous positive complement-dependent cytotoxicity crossmatch (n = 30), and/or donor-specific anti-HLA antibodies (n = 14) were recruited. IVIg (2 g/kg) was administrated on days 0, 21, 42 and 63 with quadruple immunosuppression. Biopsy-proven acute cellular and humoral rejection rates at month 12 were 18% and 10%, respectively. Glomerulitis was observed in 31% and 60% of patients at months 3 and 12, respectively, while allograft glomerulopathy rose from 3% at month 3 to 28% at 12 months. Interstitial fibrosis/tubular atrophy increased from 18% at day 0 to 51% and 72% at months 3 and 12 (p < 0.0001). GFR was 50 +/- 17 mL/min/1.73 m(2) and 48 +/- 17 mL/min/1.73 m(2) at 3 and 12 months. PRA decreased significantly after IVIg (class I: from 18 +/- 27% to 5 +/- 12%, p < 0.01; class II: from 25 +/- 30% to 7 +/- 16%, p < 0.001). Patient and graft survival were 97% and 95%, respectively and no graft was lost due to rejection (mean follow-up 25 months). In conclusion, prophylactic IVIg in high-immunological risk patients is associated with good one-year outcomes, with adequate GFR and a profound decrease in PRA level, but a significant increase in allograft nephropathy.

Unité(s) : Anatomie Pathologique, Biothérapie, Transplantation Adulte, Urologie

Hepatitis C virus infection and MALT-type ocular adnexal lymphoma

ARNAUD P, ESCANDE MC, LECUIT M, VALIDIRE P, LEVY C, PLANCHER C, VINCENT-SALOMON A, BROUSSE N, DE CREMOUX P, HERMINE O, DECAUDIN D

2007 - Ann. Oncol. 18(2):400-401

Unité(s) : Anatomie Pathologique, UMR 8147, Infectiologie

A 59-kD renal antigen as a new target for rapidly progressive glomerulonephritis

AUDARD V, HELLMARK T, EL KAROUI K, NOEL LH, PARDON A, DESVAUX D, TOUCHARD G, REMY P, LANG P, SAHALI D

2007 - Amer. J. Kidney Dis. 49(5):710-716

Anti-glomerular basement membrane (anti-GBM) antibodies are the hallmark of anti-GBM disease, which is characterized by rapidly progressive glomerulonephritis. We describe the case of a 58-year-old woman who presented with rapidly progressive glomerulonephritis with typical anti-GBM staining found by means of direct immunofluorescence microscopy, associated with linear immunoglobin G deposits on tubules. Serum analysis showed circulating anti-tubular basement membrane antibodies, but failed to detect anti-GBM antibodies. Immunoblotting showed that serum antibodies reacted with a 59-kd antigen found along both the GBM and tubular basement membrane.

Unité(s) : Anatomie Pathologique

Inhibition of TGF-beta signaling by IL-15: a new role for IL-15 in the loss of immune homeostasis in celiac disease

BENAHMED M, MERESSE B, ARNULF B, BARBE U, MENTION JJ, VERKARRE V, ALLEZ M, CELLIER C, HERMINE O, CERF-BENSUSSAN N

2007 - Gastroenterology 132(3):994-1008

BACKGROUND AND AIMS: Interleukin (IL)-15 delivers signals that drive chronic inflammation in several diseases, including celiac disease. Smad3-transforming growth factor-beta (TGF-beta) signaling is instrumental to counteract proinflammatory signals and maintain immune homeostasis. Our goal has been to investigate why the proinflammatory effects of IL-15 cannot be efficiently controlled by TGF-beta in celiac disease. METHODS: The impact of IL-15 on TGF-beta signaling in T cells and in the intestinal mucosa of celiac disease patients was analyzed by combining cell and organ cultures, immunohistochemistry, flow cytometry, real-time polymerase chain reaction, electromobility gel shift, and Western blot. RESULTS: IL-15 impaired Smad3-dependent TGF-beta signaling in human T lymphocytes downstream from Smad3 nuclear translocation. IL-15-mediated inhibition was associated with a long-lasting activation of c-jun-N-terminal kinase and reversed by c-jun antisense oligonucleotides, consistent with the demonstrated inhibitory effect of phospho-c-jun on the formation of Smad3-DNA complexes. In active celiac disease, intestinal lymphocytes showed impaired TGF-beta-Smad3-dependent transcriptional responses and up-regulation of phospho-c-jun. Anti-IL-15 antibody and c-jun antisense both downmodulated phospho-c-jun expression and restored TGF-beta-Smad-dependent transcription in biopsies of active celiac disease. c-jun antisense decreased interferon gamma transcription. CONCLUSIONS: Impairment of TGF-beta-mediated signaling by IL-15 might promote and sustain intestinal inflammation in celiac disease. More generally, our data provide a new rationale for the potent proinflammatory effects of IL-15, and further support the concept that IL-15 is a meaningful therapeutic target in inflammatory diseases associated with irreducible elevation of IL-15.

Unité(s) : Anatomie Pathologique, Hématologie Adulte, U793, UMR 8147

Association of killer cell immunoglobulin-like receptor genes with Hodgkin's lymphoma in a familial study

BESSON C, ROETYNCK S, WILLIAMS F, ORSI L, AMIEL C, LEPENDEVEN C, ANTONI G, HERMINE O, BRICE P, FERME C, CARDE P, CANIONI D, BRIERE J, RAPHAEL M, NICOLAS JC, CLAVEL J, MIDDLETON D, VIVIER E, ABEL L

2007 - PLoS ONE 2(5):e406

BACKGROUND: Epstein-Barr virus (EBV) is the major environmental factor associated with Hodgkin's lymphoma (HL), a common lymphoma in young adults. Natural killer (NK) cells are key actors of the innate immune response against viruses. The regulation of NK cell function involves activating and inhibitory Killer cell Immunoglobulin-like receptors (KIRs), which are expressed in variable numbers on NK cells. Various viral and virus-related malignant disorders have been associated with the presence/absence of certain KIR genes in case/control studies. We investigated the role of the KIR cluster in HL in a family-based association study. METHODOLOGY: We included 90 families with 90 HL index cases (age 16-35 years) and 255 first-degree relatives (parents and siblings). We developed a procedure for reconstructing full genotypic information (number of gene copies) at each KIR locus from the standard KIR gene content. Out of the 90 collected families, 84 were informative and suitable for further analysis. An association study was then carried out with specific family-based analysis methods on these 84 families. PRINCIPAL FINDINGS: Five KIR genes in strong linkage disequilibrium were found significantly associated with HL. Refined haplotype analysis showed that the association was supported by a dominant protective effect of KIR3DS1 and/or KIR2DS1, both of which are activating receptors. The odds ratios for developing HL in subjects with at least one copy of KIR3DS1 or KIR2DS1 with respect to subjects with neither of these genes were 0.44[95% confidence interval 0.23-0.85] and 0.42[0.21-0.85], respectively. No significant association was found in a tentative replication case/control study of 68 HL cases (age 18-71 years). In the familial study, the protective effect of KIR3DS1/KIR2DS1 tended to be stronger in HL patients with detectable EBV in blood or tumour cells. CONCLUSIONS: This work defines a template for family-based association studies based on full genotypic information for the KIR cluster, and provides the first evidence that activating KIRs can have a protective role in HL.

Unité(s) : Hématologie Adulte, U550, Anatomie Pathologique

Do Langerhans cells behave similarly in elderly and younger patients with chronic periodontitis ?

BODINEAU A, COULOMB B, FOLLIGUET M, IGONDJO-TCHEN S, GODEAU G, BROUSSE N, SEGUIER S

2007 - Arch. Oral Biol. 52(2):189-194

OBJECTIVE: The purpose of this study was to compare the number, the distribution and the expression of markers of maturation of Langerhans cells (LC) in elderly and younger patients with chronic periodontitis in order to evidence the effect of aging on LC in inflammatory gingival tissue. METHODS: Gingival tissue specimens presenting chronic periodontitis from 8 elderly patients aged >75 (group E) and from 8 younger patients aged 50-60 (considered as controls, group C) were used for immunohistochemistry with monoclonal antibodies against CD45RB (leucocytes), CD1a (LC), markers of LC maturation (DC-LAMP, CD83) and number of immunolabelled cell subsets was evaluated using image analysis. RESULTS: The difference in the number of CD45RB+ leucocytes in the upper connective tissue between groups was not significant. In group E, the number of CD1a+ LC was significantly decreased (P<0.002) in the epithelium and significantly increased (P<0.0004) in the upper connective tissue. Furthermore, in group E, intraepithelial CD1a+ LC are more often observed in the upper epithelium and their dendritic processes were shorter and less numerous. Concerning the expression of markers of maturation, the numbers of intraepithelial DC-LAMP+ cells and CD83+ cells were significantly increased (P<0.0007 and P<0.02, respectively) in group E. CONCLUSION: During chronic periodontitis in elderly patients, the decrease in the number of intraepithelial LC and the alteration of dendritic processes could be balanced by a cellular distribution often observed in the upper epithelium associated with changes in cell maturation in response to bacterial elements.

Unité(s) : Anatomie Pathologique

hSNF5/INI1-deficient tumours and rhabdoid tumours are convergent but not fully overlapping entities

BOURDEAUT F, FRENEAUX P, THUILLE B, LELLOUCH-TUBIANA A, NICOLAS A, COUTURIER J, PIERRON G, SAINTE-ROSE C, BERGERON C, BOUVIER R, RIALLAND X, LAURENCE V, MICHON J, SASTRE-GARAU X, DELATTRE O

2007 - J. Pathol. 211(3):323-330

Rhabdoid tumours (RTs) are rare but highly aggressive tumours of childhood. Their rarity and their miscellaneous locations make the diagnosis particularly challenging for pathologists. Central nervous system and peripheral RTs have been associated with biallelic inactivation of the hSNF5/INI1/SMARCB1 (hSNF5/INI1) tumour suppressor gene. Immunohistochemistry (IHC) with a monoclonal anti-hSNF5/INI1 antibody has recently been proposed as an efficient diagnostic tool for RTs. We have conducted a retrospective study of 55 tumours referred to our institution with a suspicion of RT. This analysis included pathological review, IHC with anti-hSNF5/INI1 antibody, and molecular investigation using quantitative DNA fluorescent analysis and sequencing of the nine exons of hSNF5/INI1. The molecular lesion could be detected in 37 of the 39 cases exhibiting negative staining for hSNF5/INI1. In the two discrepant cases, the lack of detection of genetic abnormality was probably owing to the presence of a high number of non-tumour cells in the samples. This indicates that hSNF5/INI1 IHC is very sensitive and highly specific for the detection of hSNF5/INI1 loss-of-function. Among the 38 cases with typical RT histological features, six failed to exhibit hSNF5/INI1 mutation and stained positive for hSNF5/INI1. This strongly supports the evidence of a second genetic locus, distinct from hSNF5/INI1, associated with RT. Conversely, seven tumours with histological features poorly compatible with RT stained negative for hSNF5/INI1; they nevertheless exhibited an age of onset and a clinical behaviour similar to RT. This suggests that hSNF5/INI1 inactivation is not strictly limited to typical RT but characterizes a wider family of hSNF5/INI1-deficient tumours. Consequently, we believe that anti-hSNF5/INI1 IHC should be performed widely, even when the pathological characteristics are not typical. The molecular investigation should be performed in infants when a rhabdoid predisposition syndrome is suspected.

Unité(s) : Anatomie Pathologique, Neurochirurgie Pédiatrique

Histologic Cutaneous Modifications After the Use of EMLA Cream, A Diagnostic Pitfall: Review of 13 Cases

CAZES A, PROST-SQUARCIONI C, BODEMER C, HELLER M, BROUSSE N, FRAITAG S

2007 - Arch. Dermatol. 143(8):1074-1076

Unité(s) : Dermatologie, Anatomie Pathologique

Small glomeruli in WAGR (Wilms Tumor, Aniridia, Genitourinary Anomalies and Mental Retardation) syndrome

DAHAN K, KAMAL M, NOEL LH, JEANPIERRE C, GUBLER MC, BROUSSE N, PATEY-MARIAUD DE SERRE N

2007 - Amer. J. Kidney Dis. 49(6):793-800

BACKGROUND: Wilms tumor, aniridia, genitourinary anomalies, and mental retardation (WAGR) syndrome is a genetic disorder caused by a deletion of band 11p13, which results in the loss of 1 allele of the Wilms tumor suppressor gene (WT1). It is not classically associated with nephropathies, but increased rates of renal failure are reported. Denys-Drash syndrome (DDS), caused by mutations in the WT1 gene affecting the third or second zinc finger, is characterized by a triad of glomerulopathy progressing rapidly to end-stage renal disease, male hermaphroditism, and Wilms tumor. In patients with DDS, small glomeruli were observed. METHODS: We reviewed histological findings of nontumoral kidney samples of 7 patients with WAGR syndrome at the time of tumor surgery. RESULTS: Median glomerular diameter was 110 +/- 37 microm in patients with WAGR syndrome versus 125 +/- 18.5 microm in controls (P < 0.0001). CONCLUSION: The presence of small glomeruli in patients with WAGR syndrome, as in those with DDS, suggests a specific defect of WT1 function in development and a specific role of WT1 allele loss in the development of renal failure in these patients.

Unité(s) : U574, U845 (VW), Anatomie Pathologique

A new phenotypical variant of intrauterine growth restriction?

DE FELICE C, TASSI R, DE CAPUA B, JAUBERT F, GENTILE M, QUARTULLI L, TONNI G, COSTANTINI D, STRAMBI M, LATINI G

2007 - Pediatrics 119(4):e983-e990

OBJECTIVES: A link between intrauterine growth restriction and major adult-onset diseases has been reported. In this study we observed a series of hitherto-unrecognized clinical features in a population of children with intrauterine growth restriction. PATIENTS AND METHODS: A total of 77 Italian children (aged 9.45 +/- 2.08 years) with antenatally diagnosed intrauterine growth restriction and small-for-gestational-age birth, along with their parents, were examined. The children with intrauterine growth restriction and were small for gestational age were subdivided into 2 groups ("variant" versus control subjects) according to evidence of auricle morphology deviation from normal. The following variables were determined: (1) external ear auricle geometry; (2) function of the posterior communicating arteries of the circle of Willis, as assessed by transcranial Doppler ultrasonography; (3) articular mobility, as assessed by Beighton's 9-point scale; (4) skin softness; and (5) distortion product-evoked otoacoustic emissions. RESULTS: Intrauterine growth restriction-variant children (n = 27) showed a significant female predominance, a lower proportion of maternal pregnancy-induced hypertension/preeclampsia, and a higher head circumference as compared with intrauterine growth restriction control subjects. Mothers of small-for-gestational-age-variant children showed significantly different auricular geometry parameters as compared with the intrauterine growth restriction controls mothers. An excess of bilaterally nonfunctioning posterior communicating arteries was observed both in the children with the intrauterine growth restriction-variant phenotype and their mothers as compared with the control groups. Significantly increased proportions of joint hypermobility and skin softness were observed in the intrauterine growth restriction-variant children as compared with controls subjects. Children with the intrauterine growth restriction-variant phenotype and their mothers showed bilateral distortion product-evoked otoacoustic emissions notches versus none in the control subjects, with an associated reduction of the area under the curve in both the intrauterine growth restriction-variant children and their mothers. No significant differences between the variant and control groups regarding the fathers were observed. CONCLUSIONS: We propose that the observed phenotypical constellation may represent an unrecognized variant of intrauterine growth restriction.

Unité(s) : Anatomie Pathologique

Neonatal hyperinsulinism: clinicopathologic correlation

DE LONLAY P, SIMON A, GALMICHE-ROLLAND L, GIURGEA I, VERKARRE V, AIGRAIN Y, SANTIAGO-RIBEIRO MJ, POLAK M, ROBERT JJ, BELLANNE-CHANTELOT C, BRUNELLE F, NIHOUL-FEKETE C, JAUBERT F

2007 - Hum. Pathol. 38(3):387-399

Neonatal hyperinsulinism is a life-threatening disease that, when treated by total pancreatectomy, leads to diabetes and pancreatic insufficiency. A more conservative approach is now possible since the separation of the disease into a nonrecurring focal form, which is cured by partial surgery, and a diffuse form, which necessitates total pancreas removal only in cases of medical treatment failure. The pathogenesis of the disease is now divided into K-channel disease (hyperinsulinemic hypoglycemia, familial [HHF] 1 and 2), which can mandate surgery, and other metabolic causes, HHF 3 to 6, which are treated medically in most patients. The diffuse form is inherited as a recessive gene on chromosome 11, whereas most cases of the focal form are caused by a sulfonylurea receptor 1 defect inherited from the father, which is associated with a loss of heterozygosity on the corresponding part of the mother's chromosome 11. The rare bifocal forms result from a maternal loss of heterozygosity specific to each focus. Paternal disomy of chromosome 11 is a rare cause of a condition similar to Beckwith-Wiedemann syndrome. A preoperative PET scan with fluorodihydroxyphenylalanine and perioperative frozen-section confirmation are the types of studies done before surgery when needed. Adult variants of the disease are less well defined at the present time.

Unité(s) : Chirurgie Viscérale Pédiatrique, Métabolisme, Radiologie Pédiatrique, Endocrinologie Pédiatrique et Gynécologie, Anatomie Pathologique, Diabétologie Pédiatrique

Cerebral localization of Rosai-Dorfman disease in a child

DI ROCCO F, GARNETT MR, PUGET S, PUYERREDON F, ROUJEAU T, JAUBERT F, SAINTE-ROSE C

2007 - J. Neurosurg. 107(2):147-151

Rosai-Dorfman disease (RDD) is a rare idiopathic histiocytic disorder that only occasionally involves the central nervous system (CNS). Previous cases of RDD involving the CNS were generally seen in adults. Pediatric cases of RDD are rare, and the disease in these cases typically has an indolent clinical course. In this report, the authors describe a pediatric case of intracranial RDD with rapid clinical and radiological progression. A previously healthy 13-year-old girl presented with a 15-day history of progressive left-sided headaches, vomiting, and fever. On examination she was pyrexial but otherwise normal. Neuroimaging results demonstrated an extraaxial left frontal lesion with peripheral enhancement. A bur hole was drilled over the lesion to obtain a tissue sample and debulk the lesion. The initial histological results showed a nonspecific inflammatory lesion. Postoperatively, the patient was asymptomatic, and neuroimaging results confirmed a significant reduction in the size of the lesion. Repeated neuroimaging 3 months later, however, revealed a large recurrence of the lesion, which was removed macroscopically by a craniotomy. Histological analysis of the tissue confirmed the RDD diagnosis. At the latest follow-up (12 months) the patient had remained asymptomatic with no evidence of recurrence on neuroimaging. This is the first reported case of intracranial RDD with an aggressive clinical course.

Unité(s) : Neurochirurgie Pédiatrique, Anatomie Pathologique

Significantly improved PCR-based clonality testing in B-cell malignancies by use of multiple immunoglobulin gene targets. Report of the BIOMED-2 Concerted Action BHM4-CT98-3936

EVANS PA, POTT CH, GROENEN PJ, SALLES G, DAVI F, BERGER F, GARCIA JF, VAN KRIEKEN JH, PALS S, KLUIN P, SCHUURING E, SPAARGAREN M, BOONE E, GONZALEZ D, MARTINEZ B, VILLUENDAS R, GAMEIRO P, DISS TC, MILLS K, MORGAN GJ, CARTER GI, MILNER BJ, PEARSON D, HUMMEL M, JUNG W, OTT M, CANIONI D, BELDJORD K, BA

2007 - Leukemia 21(2):207-214

Polymerase chain reaction (PCR) assessment of clonal immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements is an important diagnostic tool in mature B-cell neoplasms. However, lack of standardized PCR protocols resulting in a high level of false negativity has hampered comparability of data in previous clonality studies. In order to address these problems, 22 European laboratories investigated the Ig/TCR rearrangement patterns as well as t(14;18) and t(11;14) translocations of 369 B-cell malignancies belonging to five WHO-defined entities using the standardized BIOMED-2 multiplex PCR tubes accompanied by international pathology panel review. B-cell clonality was detected by combined use of the IGH and IGK multiplex PCR assays in all 260 definitive cases of B-cell chronic lymphocytic leukemia (n=56), mantle cell lymphoma (n=54), marginal zone lymphoma (n=41) and follicular lymphoma (n=109). Two of 109 cases of diffuse large B-cell lymphoma showed no detectable clonal marker. The use of these techniques to assign cell lineage should be treated with caution as additional clonal TCR gene rearrangements were frequently detected in all disease categories. Our study indicates that the BIOMED-2 multiplex PCR assays provide a powerful strategy for clonality assessment in B-cell malignancies resulting in high Ig clonality detection rates particularly when IGH and IGK strategies are combined.Leukemia (2007) 21, 207-214. doi:10.1038/sj.leu.2404479; published online 14 December 2006.

Unité(s) : Laboratoire d'Hématologie, Anatomie Pathologique

Mastocytoses cutanées

FRAITAG-SPINNER S

2007 - Ann. Dermatol. Vénéréolog. 134(6):589-592

Unité(s) : Anatomie Pathologique

Mutations in BHD and TP53 genes, but not in HNF1beta gene, in a large series of sporadic chromophobe renal cell carcinoma

GAD S, LEFEVRE SH, KHOO SK, GIRAUD S, VIEILLEFOND A, VASILIU V, FERLICOT S, MOLINIE V, DENOUX Y, THIOUNN N, CHRETIEN Y, MEJEAN A, ZERBIB M, BENOIT G, HERVE JM, ALLEGRE G, BRESSAC-DE PAILLERETS B, TEH BT, RICHARD S

2007 - Br. J. Cancer 96(2):336-340

BHD, TP53, and HNF1beta on chromosome 17 were studied in 92 cases of renal cell carcinoma (46 chromophobe, 19 clear cell, 18 oncocytoma, and nine papillary). Six, thirteen, and zero cases had, respectively BHD, TP53, and HNF1beta mutations, (84% mutations involved chromophobe), suggesting a role for BHD and TP53 in chromophobe subtype.British Journal of Cancer (2007) 96, 336-340. doi:10.1038/sj.bjc.6603492 www.bjcancer.com Published online 28 November 2006.

Unité(s) : Urologie, Anatomie Pathologique

Diagnosis of renal metanephric adenoma: relevance of immunohistochemistry and biopsy

GALMICHE L, VASILIU V, POIREE S, HELENON O, CASANOVA JM, BROUSSE N

2007 - Ann. Pathol. 27(5):365-368

Most renal tumors of the adult are carcinomas. Their treatment is surgical, consisting of limited excision or nephrectomy. In some instances, biopsy of the tumor can be performed in order to adapt treatment. We report the case of a 45 year-old woman presenting with renal tumor. A biopsy of the mass showed a metanephric adenoma. No surgical excision was performed because of the benignity of this tumor. Here we develop the interest of immunohistochemistry for differential diagnosis of metanephric adenoma and other "basophilic small cell tumors" of the kidney. We also put the stress on the growing role of biopsy of renal tumor allowing optimal treatment.

Unité(s) : Radiologie Adulte, Anatomie Pathologique

Intestinal epithelial dysplasia (tufting enteropathy

GOULET O, SALOMON J, RUEMMELE F, PATEY-MARIAUD DE SERRE N, BROUSSE N

2007 - Orphanet J. Rare Dis. 2(.):20

Intestinal epithelial dysplasia (IED), also known as tufting enteropathy, is a congenital enteropathy presenting with early-onset severe intractable diarrhea causing sometimes irreversible intestinal failure. To date, no epidemiological data are available, however, the prevalence can be estimated at around 1/50,000-100,000 live births in Western Europe. The prevalence seems higher in areas with high degree of consanguinity and in patients of Arabic origin. Infants develop within the first days after birth a watery diarrhea persistent in spite of bowel rest and parenteral nutrition. Some infants are reported to have associated choanal rectal or esophageal atresia. IED is thought to be related to abnormal enterocytes development and/or differentiation. Nonspecific punctuated keratitis was reported in more than 60% of patients. Histology shows various degree of villous atrophy, with low or without mononuclear cell infiltration of the lamina propria but specific histological abnormalities involving the epithelium with disorganization of surface enterocytes with focal crowding, resembling tufts. Several associated specific features were reported, including abnormal deposition of laminin and heparan sulfate proteoglycan (HSPG) in the basement membrane, increased expression of desmoglein and ultrastructural changes in the desmosomes, and abnormal distribution of alpha2beta1 integrin adhesion molecules. One model of transgenic mice in which the gene encoding the transcription factor Elf3 is disrupted have morphologic features resembling IED. Parental consanguinity and/or affected siblings suggest an autosomal recessive transmission but the causative gene(s) have not been yet identified making prenatal diagnosis unavailable. Some infants have a milder phenotype than others but in most patients, the severity of the intestinal malabsorption even with enteral feeding make them totally dependent on daily long-term parenteral nutrition with a subsequent risk of complications. IED becomes an indication for intestinal transplantation, while timing of referral for it is crucial before the onset of severe complications.

Unité(s) : Gastro-Hépatologie et Nutrition Pédiatriques, Anatomie Pathologique

Decreased expression of Intestinal I- and L-FABP levels in rare human genetic lipid malabsorption syndromes

GUILMEAU S, NIOT I, LAIGNEAU JP, DEVAUD H, PETIT V, BROUSSE N, BOUVIER R, FERKDADJI L, BESMOND C, AGGERBECK LP, BADO A, SAMSON-BOUMA ME

2007 - Histochem. Cell Biol. 128(2):115-123

We investigated, for the first time, the expression of I- and L-FABP in two very rare hereditary lipid malabsorption syndromes as compared with normal subjects. Abetalipoproteinemia (ABL) and Anderson's disease (AD) are characterized by an inability to export alimentary lipids as chylomicrons that result in fat loading of enterocytes. Duodeno-jejunal biopsies were obtained from 14 fasted normal subjects, and from four patients with ABL and from six with AD. Intestinal FABP expression was investigated by immuno-histochemistry, western blot, ELISA and Northern blot analysis. In contrast to normal subjects, the cellular immunostaining for both FABPs was clearly decreased in patients, as the enterocytes became fat-laden. In patients with ABL, the intestinal contents of I- (60.7 +/- 13.38 ng/mg protein) and L-FABP (750.3 +/- 121.3 ng/mg protein) are significantly reduced (50 and 35%, P < 0.05, respectively) as compared to normal subjects (I-135.3 +/- 11.1 ng, L-1211 +/- 110 ng/mg protein). In AD, the patients also exhibited decreased expression (50%, P < 0.05; I-59 +/- 11.88 ng, L-618.2 +/- 104.6 ng/mg protein). Decreased FABP expression was not associated with decreased mRNA levels. The results suggest that enterocytes might regulate intracellular FABP content in response to intracellular fatty acids, which we speculate may act as lipid sensors to prevent their intracellular transport.

Unité(s) : U781, Anatomie Pathologique

Extinction of FOXL2 expression in aggressive ovarian granulosa cell tumors in children

KALFA N, PHILIBERT P, PATTE C, ECOCHARD A, DUVILLARD P, BALDET P, JAUBERT F, FELLOUS M, SULTAN C

2007 - Fert. Steril. 87(4):896-901

OBJECTIVE: In the female gonad, FOXL2 is a key factor for proper differentiation of granulosa cells (GC) during folliculogenesis and its expression persists in the ovary after birth. The aim of this multicentric nationwide study was to determine whether FOXL2 expression varies during tumoral proliferation of GC cells in juvenile ovarian GC tumors (OGCT). DESIGN: Nationwide retrospective study. SETTING: University Hospital of Montpellier, Department of Hormonology. PATIENT(S): Between 1994 and 2004, 26 patients with juvenile OGCT were reported in the TGM95 database of the French Society for Childhood Cancer (SFCE) and from eight pediatric endocrinology centers. Immunohistochemistry was performed using an anti-FOXL2 antibody. INTERVENTION(S): Immunohistochemistry studies of FOXL2 on OGCT slides. MAIN OUTCOME MEASURE(S): Level of FOXL2 expression within the tumor, International Federation of Gynecology and Obstetrics classification, and tumor recurrences. RESULT(S): FOXL2 expression was absent in the GC of 10 patients and was markedly reduced in the cells of 4 patients. Precocious pseudopuberty was more frequently the revealing symptom in the children with conserved FOXL2 expression. Patients with no or reduced expression of FOXL2 more frequently exhibited associated hemorrhagic ascites, higher mitotic activity in the tumor, and significantly more advanced oncologic staging. All patients requiring complementary treatment (n = 7; chemotherapy or complementary surgery) had reduced expression of FOXL2 in the tumor. All recurring OGCT exhibited a complete extinction of FOXL2 expression (n = 3). CONCLUSION(S): These results show that FOXL2 is not expressed or is underexpressed in juvenile OGCT with an aggressive pattern of progression, and it thus may be a prognostic factor for these tumors.

Unité(s) : Anatomie Pathologique

ActA is required for crossing of the fetoplacental barrier by Listeria monocytogenes

LE MONNIER A, AUTRET N, JOIN-LAMBERT OF, JAUBERT F, CHARBIT A, BERCHE P, KAYAL S

2007 - Infect. Immun. 75(2):950-957

The facultative intracellular bacterial pathogen Listeria monocytogenes induces severe fetal infection during pregnancy. Little is known about the molecular mechanisms allowing the maternofetal transmission of bacteria. In this work, we studied fetoplacental invasion by infecting mice with various mutants lacking virulence factors involved in the intracellular life cycle of L. monocytogenes. We found that the placenta was highly susceptible to bacteria, including avirulent bacteria, such as an L. monocytogenes mutant with an hly deletion (DeltaLLO) and a nonpathogenic species, Listeria innocua, suggesting that permissive trophoblastic cells, trapping bacteria, provide a protective niche for bacterial survival. The DeltaLLO mutant, which is unable to escape the phagosomal compartment of infected cells, failed to grow in the trophoblast tissue and to invade the fetus. Mutant bacteria with inlA and inlB deletion (DeltaInlAB) grew in the placenta and fetus as well as did the wild-type virulent stain (EGDwt), indicating that in the murine model, internalins A and B are not involved in fetoplacental invasion by L. monocytogenes. Pregnant mice were then infected with an actA deletion (DeltaActA) strain, a virulence-attenuated mutant that is unable to polymerize actin and to spread from cell to cell. With the DeltaActA mutant, fetal infection occurs, but with a significant delay and restriction, and it requires a placental bacterial load 2 log units higher than that for the wild-type virulent strain. Definitive evidence for the role of ActA was provided by showing that a actA-complemented DeltaActA mutant was restored in its capacity to invade fetuses. ActA-mediated cell-to-cell spreading plays a major role in the vertical transmission of L. monocytogenes to the fetus in the murine model.

Unité(s) : Anatomie Pathologique, U570

Prevention of Mantle Lymphoma Tumor Establishment by Routing Transferrin Receptor toward Lysosomal Compartments

LEPELLETIER Y, CAMARA-CLAYETTE V, JIN H, HERMANT A, COULON S, DUSSIOT M, ARCOS-FAJARDO M, BAUDE C, CANIONNI D, DELARUE R, BROUSSE N, BENAROCH P, BENHAMOU M, RIBRAG V, MONTEIRO RC, MOURA IC, HERMINE O

2007 - Cancer Res. 67(3):1145-1154

Mantle cell lymphoma (MCL) is one of the most frequent of the newly recognized non-Hodgkin's lymphomas. The major problem of MCL therapy is the occurrence of relapse and subsequent resistance to chemotherapy and immunotherapy in virtually all cases. Here, we show that one injection of anti-human transferrin receptor (TfR) monoclonal antibody A24 totally prevented xenografted MCL tumor establishment in nude mice. It also delayed and inhibited tumor progression of established tumors, prolonging mice survival. In vitro, A24 induced up to 85% reduction of MCL cell proliferation (IC(50) = 3.75 nmol/L) independently of antibody aggregation, complement-dependent or antibody-dependent cell-mediated cytotoxicity. A24 induced MCL cell apoptosis through caspase-3 and caspase-9 activation, either alone or synergistically with chemotherapeutic agents. A24 induced TfR endocytosis via the clathrin adaptor protein-2 complex pathway followed by transport to lysosomal compartments. Therefore, A24-based therapies alone or in association with classic chemotherapies could provide a new alternative strategy against MCL, particularly in relapsing cases. [Cancer Res 2007;67(3):1145-54].

Unité(s) : Anatomie Pathologique, UMR 8147, Hématologie Adulte

A clinical, histologic, and molecular study of 9 cases of congenital dermatofibrosarcoma protuberans

MAIRE G, FRAITAG S, GALMICHE L, KESLAIR F, EBRAN N, TERRIER-LACOMBE MJ, DE PROST Y, PEDEUTOUR F

2007 - Arch. Dermatol. 143(2):203-210

BACKGROUND: The diagnosis of dermatofibrosarcoma protuberans (DFSP) in childhood is often difficult because of the deceptive appearance of the lesions. Little is known about congenital DFSP, the frequency of which is probably underestimated because the initial lesion may pass unnoticed. OBSERVATIONS: We studied 9 DFSP congenital cases (8 plaques and 1 nodule) initially suspected to be benign lesions. The first biopsies or excisions were performed after a delay of 5(1/2) months to 15 years. All cases were CD34+. Histologic patterns were similar to the DFSP adult classic pattern in 4 cases. One case was a Bednar tumor. The histologic diagnosis of the 4 remaining cases was difficult. The collagen, type I, alpha 1-platelet-derived growth factor beta fusion gene (COL1A1-PDGFB) was detected by means of reverse transcriptase-polymerase chain reaction or fluorescence in situ hybridization. CONCLUSIONS: All cases of congenital DFSP were difficult to identify clinically. The diagnosis was suspected by means of histologic and immunohistochemical evaluation and was confirmed using molecular analyses. This study illustrates the difficulties and pitfalls of the recognition of congenital DFSP and emphasizes the value of immunohistochemical study with anti-CD34 and complementary molecular analysis for all cutaneous spindle cell tumors and plaques in neonates and infants.

Unité(s) : Anatomie Pathologique, Dermatologie

Gastrointestinal diseases in primary immunodeficiency disorders

MALAMUT G, VERKARRE V, BROUSSE N, CELLIER C

2007 - Gastroentérol. Clin. Biol. 31(10):844-853

Gastrointestinal symptoms are common and often reveal primary immunodeficiency. Although they mimic gastrointestinal diseases observed in immunocompetent patients, there have diagnostic and therapeutic specificities that should be known for optimal management of these patients. This review describes the gastrointestinal diseases found in primary immunodeficiency and proposes some diagnostic and therapeutic strategies.

Unité(s) : Anatomie Pathologique

Nodular regenerative hyperplasia is a new cause of chronic liver disease in HIV-infected patients

MALLET V, BLANCHARD P, VERKARRE V, VALLET-PICHARD A, FONTAINE H, LASCOUX-COMBE C, POL S

2007 - AIDS 21(2):187-192

OBJECTIVE:: To describe and explain the syndrome of HIV-associated cryptogenic liver disease in eight consecutive patients suffering from portal hypertension. METHODS:: The study was undertaken at a liver disease centre in Paris and involved eight of 97 consecutive HIV-infected patients presenting abnormal liver function tests and/or symptomatic portal hypertension of unknown origin. Serology, pathology, and liver function tests were performed. RESULTS:: A clear nodular architecture corresponding to nodular regenerative hyperplasia was observed in seven patients and suggested in one, based on the presence of sinusoidal dilatation in a clinical context of portal hypertension, without overt liver disease. CONCLUSIONS:: Nodular regenerative hyperplasia appears to be a new cause of portal hypertension in HIV-infected patients. This syndrome can be of critical importance as patients can be exposed to the significant complications of portal hypertension and to refractory ascites which may require liver transplantation.

Unité(s) : Anatomie Pathologique

Reversibility of cirrhosis in HIV/HBV coinfection

MALLET VO, DHALLUIN-VENIER V, VERKARRE V, CORREAS JM, CHAIX ML, VIARD JP, POL S

2007 - Antivir. Ther. 12(2):279-283

HIV infection worsens the course and the natural history of chronic hepatitis B (HBV) leading to rapid progression to cirrhosis and to end-stage liver disease. Highly active antiretroviral therapy (HAART) regimens including nucleoside and/or nucleotide analogues with activity against both HIV reverse transcriptase and hepatitis B virus polymerase have clearly improved the survival rates of HIV/HBV-coinfected patients. How HAART beneficially affects the natural course of chronic hepatitis B in coinfected patients is not known. We report a biopsy-proven case of reversal of HBV-related cirrhosis in a coinfected patient, paralleling long-term suppression of HBV replication with tenofovir disoproxil fumarate as part of a HAART. Pathological reversibility of cirrhosis was ascertained by normalization of biochemical (platelet count) and morphological (abdominal ultrasonography and gastrointestinal endoscopy) tests as well as non-invasive markers of fibrosis. In conclusion, a HAART regimen including tenofovir disoproxil fumarate in a HBV/HIV-coinfected cirrhotic patient might lead to sustained HBV viral suppression and result in cirrhosis reversal.

Unité(s) : Infectiologie, Laboratoire de Microbiologie, Radiologie Adulte, Anatomie Pathologique

Collagen alpha5 and alpha2(IV) chain coexpression: Analysis of skin biopsies of Alport patients

PATEY-MARIAUD DE SERRE N, GARFA M, BESSIERES B, NOEL LH, KNEBELMANN B

2007 - Kidney Int. 72(4):512-516

Alport syndrome is a collagen type IV disease caused by mutations in the COL4A5 gene with the X-linked form being most prevalent. The resultant alpha5(IV) collagen chain is a component of the glomerular and skin basement membranes (SBMs). Immunofluorescent determination of the alpha5(IV) chain in skin biopsies is the procedure of choice to identify patients. In 30% of patients, however, the mutant protein is still found in the SBM resulting in a normal staining pattern. In order to minimize or eliminate false results, we compared the distribution of the alpha2(IV) chain (another SBM component) and the alpha5(IV) chain by standard double label immunofluorescence (IF) and by confocal laser scanning microcopy. The study was performed on 55 skin biopsies of patients suspected of Alports and five normal control specimens. In normal skin, IF showed the classical linear pattern for both collagens along the basement membrane. Additionally, decreased alpha5(IV) was found in the bottom of the dermal papillary basement membrane. Confocal analysis confirmed the results and show alpha5(IV) focal interruptions. In suspected patients, both techniques showed the same rate of abnormal alpha5(IV) expression: segmental in women and absent in men. Our results show a physiological variation of alpha5(IV) location with focal interruptions and decreased expression in the bottom of the dermal basement membrane. Comparison of alpha5(IV) with alpha2(IV) expression is simple and eliminates technical artifacts.Kidney International (2007) 72, 512-516; doi:10.1038/sj.ki.5002365; published online 6 June 2007.

Unité(s) : Anatomie Pathologique, Néphrologie Adulte, U845 (VW), U845 (FT)

Involvement of the fractalkine pathway in the pathogenesis of childhood hemolytic uremic syndrome

RAMOS MV, FERNANDEZ GC, PATEY-MARIAUD DE SERRE N, SCHIERLOH P, EXENI R, GRIMOLDI I, VALLEJO G, ELIAS-COSTA C, DEL CARMEN-SASIAIN M, TRACHTMAN H, COMBADIERE C, PROULX F, PALERMO MS

2007 - Blood 109(6):2438-2445

Thrombotic microangiopathy and acute renal failure are cardinal features of postdiarrheal hemolytic uremic syndrome (HUS). These conditions are related to endothelial and epithelial cell damage induced by Shiga toxin (Stx) through the interaction with its globotriaosyl ceramide receptor. However, inflammatory processes contribute to the pathogenesis of HUS by sensitizing cells to Stx fractalkine (FKN), a CX(3)C transmembrane chemokine expressed on epithelial and endothelial cells upon activation, is involved in the selective migration and adhesion of specific leukocyte subsets to tissues. Here, we demonstrated a selective depletion of circulating mononuclear leukocytes expressing the receptor for FKN (CX(3)CR1) in patients with HUS. We found a unique phenotype in children with HUS distinct from that seen in healthy, uremic, or infected controls, in which monocytes lost CX(3)CR1, down-modulated CD62L, and increased CD16. In addition, the CD56(dim) natural killer (NK) subpopulation was decreased, leading to an altered peripheral CD56(dim)/CD56(bright) ratio from 10.0 to 4.5. It is noteworthy that a negative correlation existed between the percentage of circulating CX(3)CR1(+) leukocytes and the severity of renal failure. Finally, CX(3)CR1(+) leukocytes were observed in renal biopsies from patients with HUS. We suggest that the interaction of CX(3)CR1(+) cells with FKN present on activated endothelial cells may contribute to renal injury in HUS.

Unité(s) : Anatomie Pathologique

The added value of [(18)F]fluoro-L: -DOPA PET in the diagnosis of hyperinsulinism of infancy: a retrospective study involving 49 children

RIBEIRO MJ, BODDAERT N, BELLANNE-CHANTELOT C, BOURGEOIS S, VALAYANNOPOULOS V, DELZESCAUX T, JAUBERT F, NIHOUL-FEKETE C, BRUNELLE F, DE LONLAY P

2007 - Eur. J. Nucl. Med. Mol. Imag. 34(12):2120-2128

PURPOSE: Neuroendocrine diseases are a heterogeneous group of entities with the ability to take up amine precursors, such as L: -DOPA, and convert them into biogenic amines, such as dopamine. Congenital hyperinsulinism of infancy (HI) is a neuroendocrine disease secondary to either focal adenomatous hyperplasia or a diffuse abnormal pancreatic insulin secretion. While focal hyperinsulinism may be reversed by selective surgical resection, diffuse forms require near-total pancreatectomy when resistant to medical treatment. Here, we report the diagnostic value of PET with [(18)F]fluoro-L: -DOPA in distinguishing focal from diffuse HI. METHODS: Forty-nine children were studied with [(18)F]fluoro-L: -DOPA. A thoraco-abdominal scan was acquired 45-65 min after the injection of 4.2 +/- 1.0 MBq/kg of [(18)F]fluoro-L: -DOPA. Additionally, 12 of the 49 children were submitted to pancreatic venous catheterisation for blood samples (PVS) and 31 were also investigated using MRI. RESULTS: We identified abnormal focal pancreatic uptake of [(18)F]fluoro-L: -DOPA in 15 children, whereas diffuse radiotracer uptake was observed in the pancreatic area in the other 34 patients. In children studied with both PET and PVS, the results were concordant in 11/12 cases. All patients with focal radiotracer uptake and nine of the patients with diffuse pancreatic radiotracer accumulation, unresponsive to medical treatment, were submitted to surgery. In 21 of these 24 patients, the histopathological results confirmed the PET findings. In focal forms, selective surgery was followed by clinical remission without carbohydrate intolerance. CONCLUSION: These data demonstrate that PET with [(18)F]fluoro-L: -DOPA is an accurate non-invasive technique allowing differential diagnosis between focal and diffuse forms of HI.

Unité(s) : Chirurgie Viscérale Pédiatrique, Radiologie Pédiatrique, Métabolisme, Anatomie Pathologique

Neoplasms and pathology of sexual developmental disorders (intersex)

ROBBOY SJ, JAUBERT F

2007 - Pathology 39(1):147-163

Continuing new insights into the biology of sexual development and advances in chromosome analysis have led to early identification and prompt treatment of the intersexual patient, the results of which facilitate a more normal life for affected individuals. Based on these advances, a classification of abnormal sexual development has been developed and refined that correlates the gonadal and genital anatomy with the chromosomal findings and specific genetic or metabolic defects. In a shift from a classification anchored on whether the intersex revolves about a specific gene or whole chromosomal abnormality, the current classification is organised by broader categories into which the intersexual disorders are divided into 'abnormalities of genital differentiation', due largely to the abnormal production or sensitivity of a single hormone, or 'abnormalities in sex determination', due to abnormal gonadal differentiation, usually testicular, with or without chromosomal aberration. The current classification is an integrated approach to this complex group of disorders and is organised according to the manner by which patients present as well as on the pathophysiological basis of the defect. The classification also groups patients who are at high risk for development of gonadal neoplasia.

Unité(s) : Anatomie Pathologique

Elastase-ANCA-associated idiopathic necrotizing crescentic glomerulonephritis--a report of three cases

SEIDOWSKY A, HOFFMANN M, RUBEN DUVAL S, MESBAH R, MASY E, KYNDT X, MAOUAD B, BILLION S, NOEL LH, VANHILLE P, BATAILLE P

2007 - Nephrol. Dialysis Transplant. 22(7):2068-2071

Unité(s) : Anatomie Pathologique

Expansion of Regulatory T Cells in Patients with Langerhans Cell Histiocytosis

SENECHAL B, ELAIN G, JEZIORSKI E, GRONDIN V, PATEY-MARIAUD-DE SERRE N, JAUBERT F, BELDJORD K, LELLOUCH A, GLORION C, ZERAH M, MARY P, BARKAOUI M, EMILE JF, BOCCON-GIBOD L, JOSSET P, DEBRE M, FISCHER A, DONADIEU J, GEISSMANN F

2007 - Plos Med. 4(8):1374-1384

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare clonal granulomatous disease that affects mainly children. LCH can involve various tissues such as bone, skin, lung, bone marrow, lymph nodes, and the central nervous system, and is frequently responsible for functional sequelae. The pathophysiology of LCH is unclear, but the uncontrolled proliferation of Langerhans cells (LCs) is believed to be the primary event in the formation of granulomas. The present study was designed to further investigate the nature of proliferating cells and the immune mechanisms involved in the LCH granulomas. METHODS AND FINDINGS: Biopsies (n = 24) and/or blood samples (n = 25) from 40 patients aged 0.25 to 13 y (mean 7.8 y), were studied to identify cells that proliferate in blood and granulomas. We found that the proliferating index of LCs was low ( approximately 1.9%), and we did not observe expansion of a monocyte or dendritic cell compartment in patients. We found that LCH lesions were a site of active inflammation, tissue remodeling, and neo-angiogenesis, and the majority of proliferating cells were endothelial cells, fibroblasts, and polyclonal T lymphocytes. Within granulomas, interleukin 10 was abundant, LCs expressed the TNF receptor family member RANK, and CD4(+) CD25(high) FoxP3(high) regulatory T cells (T-regs) represented 20% of T cells, and were found in close contact with LCs. FoxP3(+) T-regs were also expanded compared to controls, in the blood of LCH patients with active disease, among whom seven out of seven tested exhibited an impaired skin delayed-type hypersensitivity response. In contrast, the number of blood T-regs were normal after remission of LCH. CONCLUSIONS: These findings indicate that LC accumulation in LCH results from survival rather than uncontrolled proliferation, and is associated with the expansion of T-regs. These data suggest that LCs may be involved in the expansion of T-regs in vivo, resulting in the failure of the host immune system to eliminate LCH cells. Thus T-regs could be a therapeutic target in LCH.

Unité(s) : Immuno-Hématologie-Rhumatologie Pédiatriques, Laboratoire d'Hématologie, Neurochirurgie Pédiatrique, Traumatologie et Orthopédie Pédiatriques, U838, Anatomie Pathologique

Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome

SERVAIS A, FREMEAUX-BACCHI V, LEQUINTREC M, SALOMON R, BLOUIN J, KNEBELMANN B, GRUNFELD JP, LESAVRE P, NOEL LH, FAKHOURI F

2007 - J. Med. Genet. 44(3):193-199

INTRODUCTION: Abnormal control of the complement alternative pathway (CAP) (factor H, factor I and membrane cofactor protein (MCP) deficiencies) is a well established risk factor for the occurrence of haemolytic uraemic syndrome (HUS). In some instances, HUS may be associated with an unusual glomerulonephritis with isolated C3 deposits (glomerulonephritis C3). We determined whether HUS and glomerulonephritis C3 share common genetic susceptibility factors. METHODS: We identified 19 patients with glomerulonephritis C3. We measured levels of circulating complement components, performed assays for the detection of C3 nephritic factor (C3NeF) and screened factor H, factor I and MCP coding genes for the presence of mutations. RESULTS: Patients were divided in two groups based on renal pathology findings: group I (n = 13) had typical features of type I membranoproliferative glomerulonephritis (glomerulonephritis C3 with membranoproliferative glomerulonephritis (MPGN)) and group II (n = 6) was characterised by mesangial and epimembranous C3 deposits in the absence of mesangial proliferation (glomerulonephritis C3 without MPGN). Mutations in complement regulatory genes were detected in 4/6 patients with glomerulonephritis C3 without MPGN (heterozygous mutations in factor H gene (two patients) with low factor H antigenic level in one case, heterozygous mutations in factor I gene (two patients)) and in only 2/13 patients with glomerulonephritis C3 with MPGN (heterozygous mutations in factor H gene (one patient) and double heterozygous mutation in CD 46 gene (one patient)). In contrast, C3NeF was present in 5/13 patients with glomerulonephritis C3 with MPGN and in 2/6 patients with glomerulonephritis C3 without MPGN, one of whom had a factor H mutation. CONCLUSION: HUS and glomerulonephritis C3 without MPGN share common genetic risk factors. Constitutional or acquired dysregulation of the CAP is probably associated with a wide spectrum of diseases, ranging from HUS to glomerulonephritis C3 with MPGN.

Unité(s) : Néphrologie Adulte, Anatomie Pathologique

Is lymphoid neogenesis a therapeutic target for chronic rejection ?

THAUNAT O, PATEY-MARIAUD DE SERRE N, MICHEL JB, NICOLETTI A

2007 - Amer. J. Transplant. 7(5):1312-1313

Unité(s) : Anatomie Pathologique

Wells' syndrome after primoinfection by parvovirus B19 in a child

TOULON A, BOURDON-LANOY E, HAMEL D, FRAITAG S, LERUEZ-VILLE M, DE PROST Y, HADJ-RABIA S

2007 - J. Amer. Acad. Dermatol. 56(2 Suppl.):S50-S51

Unité(s) : Dermatologie, Anatomie Pathologique, Laboratoire de Microbiologie

Coexistence in the same family of both focal and diffuse forms of hyperinsulinism

VALAYANNOPOULOS V, VAXILLAIRE M, AIGRAIN Y, JAUBERT F, BELLANNE-CHANTELOT C, RIBEIRO MJ, BRUNELLE F, FROGUEL P, ROBERT JJ, POLAK M, NIHOUL-FEKETE C, DE LONLAY P

2007 - Diabetes Care 30(6):1590-1592

Unité(s) : Anatomie Pathologique, Chirurgie Viscérale Pédiatrique, Endocrinologie Pédiatrique et Gynécologie, Métabolisme, Radiologie Pédiatrique, Diabétologie Pédiatrique

FIB-4: an inexpensive and accurate marker of fibrosis in HCV infection. comparison with liver biopsy and fibrotest

VALLET PICHARD A, MALLET V, NALPAS B, VERKARRE V, NALPAS A, DHALLUIN VENIER V, FONTAINE H, POL S

2007 - Hepatology 46(1):32-36

To optimize the management of patients with chronic hepatitis C virus (HCV) infection, noninvasive tests to determine the degree of hepatic fibrosis have been developed. The aims of this study were (1) to validate a simple, inexpensive, noninvasive test called FIB-4, which combines standard biochemical values (platelets, ALT, AST) and age, in a series of 847 liver biopsies performed in HCV-monoinfected patients; and (2) to compare the results of 780 FIB-4 and FibroTests performed the same day in a series of 592 HCV-infected patients. The FIB-4 index enabled the correct identification of patients with severe fibrosis (F3-F4) and cirrhosis with an area under the receiver operating characteristic curve of 0.85 (95% CI 0.82-0.89) and 0.91 (95% CI 0.86-0.93), respectively. An FIB-4 index <1.45 had a negative predictive value of 94.7% to exclude severe fibrosis with a sensitivity of 74.3%. An FIB-4 index higher than 3.25 had a positive predictive value to confirm the existence of a significant fibrosis (F3-F4) of 82.1% with a specificity of 98.2%. Using these ranges, 72.8% of the 847 liver biopsies were correctly classified. The FIB-4 index was strongly correlated to the FibroTest results for a score <1.45 or >3.25 (kappa = 0.561, P < 0.01). A FIB-4 value <1.45 or >3.25 (64.6% of the cases) was concordant with FibroTest results in 92.1% and 76%, respectively. CONCLUSION: For values outside 1.45-3.25, the FIB-4 index is a simple, accurate, and inexpensive method for assessing liver fibrosis and proved to be concordant with FibroTest results.

Unité(s) : Anatomie Pathologique

The long-term followup of 33 cases of true hermaphroditism: a 40-year experience with conservative gonadal surgery

VERKAUSKAS G, JAUBERT F, LORTAT-JACOB S, MALAN V, THIBAUD E, NIHOUL-FEKETE C

2007 - J. Urol. 177(2):726-731

PURPOSE: Little is known about long-term outcomes of conservative gonadal surgery in true hermaphroditism. We present our experience with evaluation and treatment of a large series of children with this rare form of ambiguous genitalia, focusing on gonadal structure and function before and after conservative gonadal surgery. MATERIALS AND METHODS: We retrospectively reviewed 33 consecutive patients with histologically confirmed true hermaphroditism treated at the Hopital des Enfants-Malades between 1965 and 2005. RESULTS: The most common karyotype of true hermaphrodites was 46,XX, constituting 82% of our series. The frequency of finding the SRY gene in 46,XX cases was 35%. Ovotestis was the most frequent finding (65%) and testis the rarest (9%). Ovarian tissue was more often found on the left side, and testicular tissue on the right side (p <0.05). Proper gonadal tissue was preserved in 28 cases. No gonadal tumors were detected during followup. Ovarian tissue remained normal, while testicular tissue gradually developed signs of dysgenesis in all biopsied cases, confirmed by endocrinological studies. However, testosterone production remained satisfactory in the majority of cases during followup. CONCLUSIONS: Diagnosis of true hermaphroditism is well defined and the condition can be recognized even prenatally. Conservative gonadal surgery is the procedure of choice after a diagnosis of true hermaphroditism. Continued followup is necessary because of the multiple psychological, gynecological and urological problems encountered postpubertally by these patients.

Unité(s) : Anatomie Pathologique, Chirurgie Viscérale Pédiatrique, Endocrinologie Pédiatrique et Gynécologie, H

Intestinal transplantation

YANDZA T, SCHNEIDER SM, CANIONI D, SAINT-PAUL MC, GUGENHEIM J, CHEVALIER P, GOUBAUX B, BENCHIMOL D, HEBUTERNE X

2007 - Gastroentérol. Clin. Biol. 31(5):469-479

Even though surgical techniques for isolated intestine, liver-intestine, and multivisceral transplantations were developed in the 1960's, very few patients were transplanted before 1990 because initial immunosuppression regimens were insufficient, making intestine transplantation impossible. Intestine transplantation resulted in death in most patients within days or months. The discouraging results of the first clinical trials were due to technical complications, sepsis, and the failure of conventional immunosuppression to control rejection. By 1990 the development of tacrolimus-based immunosuppression and improved surgical techniques, the increased array of potent immunosuppressive medications, infection prophylaxis, and suitable patient selection helped improve actuarial graft and patient survival rates for all types of intestine transplantation. The aims of this review are to describe the current status of intestine transplantation including the underlying diseases and conditions that may be indications for intestine transplantation, to identify patient populations for this indication, to provide key steps for patient evaluation, to summarize current recommendations for immunosuppression, to list the most common postoperative complications, and to discuss the international experience of small bowel transplantation compiled and analyzed by the International Intestine Transplant Registry since 1985.

Unité(s) : Anatomie Pathologique

Severe FOXP3+ and naive T lymphopenia in a non-IPEX form of autoimmune enteropathy combined with an immunodeficiency

ZUBER J, VIGUIER M, LEMAITRE F, SENEE V, PATEY N, ELAIN G, GEISSMANN F, FAKHOURI F, FERRADINI L, JULIER C, BANDEIRA A

2007 - Gastroenterology 132(5):1694-1704

BACKGROUND & AIMS: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is the best-characterized form of a rare entity called autoimmune enteropathy (AIE). IPEX syndrome is due to mutations in the FOXP3 gene, a transcription factor essential for the development and function of the natural regulatory CD25(+)CD4(+) T cells. We studied a female patient with a polyautoimmune AIE syndrome resembling a mild form of IPEX syndrome but associated with recurrent bacterial infections and mild hypogammaglobulinemia. We hypothesized that this syndrome combined a deficit of FOXP3(+) cells and other lymphocyte populations. METHODS: We analyzed the major lymphocyte subsets and the FOXP3(+) regulatory system in blood samples obtained during the 2-year period that followed the last autoimmune manifestation. RESULTS: The patient had severe naive T lymphopenia and a major deficit of FOXP3(+)CD4(+) T cells, both in circulation and in the highly inflamed intestinal mucosa, but mutations in the FOXP3 locus were excluded. The blood FOXP3(+) pool was devoid of CD25(high) cells, but the few regulatory CD25(+) cells were functional. Intrinsic defects in the expression of CD25, FOXP3, and interleukin 2 were excluded. Upon activation, a small subset of cells, presumably committed to regulatory function, sustained expression of CD25 and FOXP3. CONCLUSIONS: Peripheral T lymphopenia of both naive and natural regulatory T cells might be the consequence of defective thymic production or the short life span of exported T cells. This case sheds new light in the etiology of autoimmune manifestations in T-cell immunodeficiencies and in the heterogeneity of AIE.

Unité(s) : Néphrologie Adulte, U838, Anatomie Pathologique

A Prospective Study of Upper Aerodigestive Tract Manifestations of Mucous Membrane Pemphigoid

ALEXANDRE M, BRETTE MD, PASCAL F, TSIANAKAS P, FRAITAG S, DOAN S, CAUX F, DUPUY A, HELLER M, LIEVRE N, LEPAGE V, DUBERTRET L, LAROCHE L, PROST-SQUARCIONI C

2006 - Medicine 85(4):239-252

ABSTRACT:: We conducted a prospective study between 1995 and 2002 to investigate nose and throat (NT) manifestations of mucous membrane pemphigoid (MMP). One hundred ten consecutive patients with clinical, histologic, and immunologic criteria of MMP were seen in 2 referral centers for bullous diseases. They were systematically asked about the existence of persistent NT symptoms. Patients who had any were examined with a flexible nasopharyngolaryngoscope by the same otorhinolaryngologist. When possible, NT mucous membrane (MM) biopsies were taken for direct immunofluorescence (IF) assays to determine lesion specificity.Thirty-eight (35%) patients (23 F/15 M; mean age, 58.5 yr) had the following NT symptoms: 35 (92%) nasal, 19 (50%) pharyngeal, and 10 (26%) laryngeal. Five (13%) had acute dyspnea. Thirty-three (87%) of the 38 symptomatic patients had lesions at physical examination: 30 (79%) nasal, 6 (16%) pharyngeal, and 19 (50%) laryngeal. Laryngeal involvement was asymptomatic in 11 patients. Lesions were mainly atrophic rhinitis and oropharyngeal and epiglottal erosions. Nasal valves, choanae, pharynx, and/or larynx were severely scarred in 7 (18%) patients, causing the death of 3. Direct IF showed malpighian epithelium associated with linear immune deposits (IgG, IgA, or C3) along the chorioepithelial junction in all 18 biopsies performed, including those of 4 symptomatic patients without lesions at physical examination.The presence of severe ophthalmologic lesions (p = 0.02) and >/=3 sites involved other than NT (p = 0.02) were predictive of laryngeal involvement. In contrast, laryngeal symptoms, disease duration, HLA DQB1*0301, and smoking were not significantly associated with laryngeal lesions.In conclusion, at least 35% of MMP patients had NT involvement. Atrophic rhinitis was the most frequent lesion. The most severe were the laryngeal lesions that were significantly associated with severe ocular involvement and disseminated disease, and could be fatal. Our results highlight the necessity of a multidisciplinary approach to MMP management to assure early diagnosis of NT involvement, to guide therapeutic choices, and to improve patient survival and functional outcomes.

Unité(s) : Anatomo-Pathologie

Dramatic clinical efficacy of cladribine in Rosai-Dorfman disease and evolution of the cytokine profile: towards a new therapeutic approach

AOUBA A, TERRIER B, VASILIU V, CANDON S, BROUSSE N, VARET B, HERMINE O

2006 - Haematologica 91(.):ECR52

Rosai-Dorfman disease (RDD) is a rare disorder, often benign but with possible life-threatening prognosis. In most cases, specific treatment is not necessary; when required, the management of RDD is not codified to date, and various chemotherapies have been shown to be ineffective. Here, we report a patient with RDD who presented a dramatic and sustained response with cladribine. Analysis of the cytokine profile evolution shows a clear correlation between serum levels of TNF-alpha and IL-6 and disease activity. Our findings show the promising efficacy of cladribine and suggest that therapies targeting specifically cytokines might be useful in some cases of active RDD.

Unité(s) : Anatomo-Pathologie, Hématologie Adulte

Minimal change nephrotic syndrome and classical Hodgkin's lymphoma: Report of 21 cases and review of the literature

AUDARD V, LAROUSSERIE F, GRIMBERT P, ABTAHI M, SOTTO JJ, DELMER A, BOUE F, NOCHY D, BROUSSE N, DELARUE R, REMY P, RONCO P, SAHALI D, LANG P, HERMINE O

2006 - Kidney Int. 69(12):2251-2260

Minimal change nephrotic syndrome (MCNS) is described as a paraneoplastic manifestation of classical Hodgkin's lymphoma (cHL). We reassessed the pathophysiological and clinical significance of this association. A retrospective study was performed to evaluate a cohort of adult patients who developed MCNS and cHL. Twenty-one patients recruited in 15 French centers were analyzed. cHL was associated with inflammatory and general symptoms in most cases. The morphological subtype was predominantly nodular sclerosis (71.4%). MCNS appeared before the diagnosis of lymphoma in eight patients (38.1%) and in this case, it was characterized by a nephrotic syndrome (NS) frequently resistant (50%) or dependent (12.5%) to steroid treatment. Interestingly, diagnosis (3-120 months after MCNS) and effective treatment of the hemopathy were associated with the disappearance of the MCNS. cHL was diagnosed before MCNS in nine patients (42.9%), and in this case, glomerulopathy was associated with cHL relapse in 55.5% of cases. In four patients (19%), the two diseases occurred simultaneously. Extensive immunohistochemical study of lymph nodes was performed in eight patients and did not reveal particular features. In conclusion, MCNS associated with cHL is frequently dependent or resistant to steroid regimen, but remission of NS is obtained with the cure of lymphoma.Kidney International (2006) 69, 2251-2260. doi:10.1038/sj.ki.5000341; published online 3 May 2006.

Unité(s) : Anatomo-Pathologie, Hématologie Adulte

Implication of TNF-Related Apoptosis-Inducing Ligand in Inflammatory Intestinal Epithelial Lesions

BEGUE B, WAJANT H, BAMBOU JC, DUBUQUOY L, SIEGMUND D, BEAULIEU JF, CANIONI D, BERREBI D, BROUSSE N, DESREUMAUX P, SCHMITZ J, LENTZE MJ, GOULET O, CERF-BENSUSSAN N, RUEMMELE FM

2006 - Gastroenterology 130(7):1962-1974

Background & Aims: Few data exist on the molecular events causing intestinal epithelial destruction during inflammatory processes, such as inflammatory bowel disease (IBD). In this work, we analyzed the potential implication of tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) in these inflammatory lesions. Methods: TRAIL and TRAIL-receptor expression were analyzed in normal, inflammatory ileum/colon and human intestinal epithelial cell (IEC) lines (HIEC), Caco-2, and HT-29 using RNase protection assay, real-time and reverse-transcription polymerase chain reaction (RT-PCR), immunohistochemistry, and Western blot analysis. TRAIL-induced activation of NF-kappaB was determined by electrophoretic mobility shift assay. Caspase-recruitment domain (CARD)15 expression and interleukin-(IL)8 production were studied by RT-PCR and enzyme-linked immunosorbent assay. Apoptosis was monitored using Annexin-V/caspase-3 assays. Results: Normal mature IEC expressed low TRAIL levels, whereas, in inflammatory lesions, TRAIL messenger RNA and protein were markedly up-regulated in IEC and lamina propria lymphocytes at levels comparable with trinitrobenzene sulfonic acid-induced colitis. Interferon-gamma and TNF-alpha potently induced TRAIL in IEC. In vitro analyses revealed a dual biologic effect of TRAIL on HIEC: Under noninflammatory conditions, TRAIL up-regulated via nuclear factor-kappaB CARD15 and IL-8, whereas, under inflammatory conditions, TRAIL became a potent inducer of apoptosis in HIEC, which was confirmed ex vivo using ileal organ cultures. TNF-alpha markedly increased the expression of the proapoptotic receptor TRAIL-R2. TRAIL-induced IEC apoptosis required a functional caspase cascade. Conclusions: TRAIL is a new inflammatory mediator implicated in the homeostasis of intestinal epithelial barrier functions. TRAIL is highly up-regulated in IEC in inflammatory ileum and colon. It may augment in an auto-/paracrine fashion the elimination of IEC via apoptosis.

Unité(s) : Anatomo-Pathologie, Gastroentérologie Pédiatrique, U793

Characteristics and Outcome of Diffuse Large B-Cell Lymphoma in Hepatitis C Virus-Positive Patients in LNH 93 and LNH 98 Groupe d'Etude des Lymphomes de l'Adulte Programs

BESSON C, CANIONI D, LEPAGE E, POL S, MOREL P, LEDERLIN P, VAN HOOF A, TILLY H, GAULARD P, COIFFIER B, GISSELBRECHT C, BROUSSE N, REYES F, HERMINE O

2006 - J. Clin. Oncol. 24(6):953-960

PURPOSE Epidemiologic studies show an association between hepatitis C virus (HCV) and B-cell non-Hodgkin's lymphoma (NHL). Treatment and outcome of patients with diffuse large-cell lymphoma (DLCL) and HCV infection are still a matter of debate. PATIENTS AND METHODS We studied the HCV-positive patients with B-cell DLCL included in the Groupe d'Etude des Lymphomes de l'Adulte (GELA) programs LNH 93 and LNH 98. They were compared with the other patients with DLCL included in these programs. HCV infection prevalence was 0.5% (26 of 5,586 patients). Results Histologic types of HCV-positive DLCL were more frequently transformed from low-grade lymphoma than DLCL in HCV-negative patients (32% v 6%, P = .02). This is also supported by more frequent spleen involvement in HCV-positive patients (46% v 17%, P < .001). HCV-positive patients had more frequently elevated lactate dehydrogenase levels than other patients (77% v 55%, P = .02). Outcome of HCV-positive patients was poorer for overall survival (P = .02) but not for event-free survival (P = .13). After matching on age and prognosis factors, at 2 years of follow-up, the overall survival was 56% (95% CI, 33% to 76%) among HCV-positive patients, versus 80% (70% to 89%), and the event-free survival was 53% (33% to 72%) versus 74% (64% to 84%). The short-term hepatic toxicity of chemotherapy was strongly increased among HCV-positive patients. After exclusion of the two subjects with chronic hepatitis B virus infection, the overall proportion of subjects undergoing hepatic toxicity was 65% (15 of 23 patients). CONCLUSION HCV-positive patients with DLCL differ from other patients both at presentation and during chemotherapy. Specific protocols evaluating antiviral therapy should be designed for these patients.

Unité(s) : Anatomo-Pathologie, Hématologie Adulte, Hépatologie Adulte

Langerhans cells express matrix metalloproteinases 9 and 2 and tissue inhibitors of metalloproteinases 1 and 2 in healthy human gingival tissue and in periodontitis

BODINEAU A, GODEAU G, BROUSSE N, PELLAT B, FOLLIGUET M, SEGUIER S

2006 - Oral Microbiol. Immunol. 21(3):197-200

Background: As antigen-presenting cells, Langerhans cells may play an important role in the initiation and maintenance of periodontal disease. This study is the first report that extends our knowledge of the expression of matrix metalloproteinases and their endogenous tissue inhibitors by Langerhans cells in healthy and diseased gingival tissues. Methods: Single and double immunolabeling procedures were carried out using monoclonal antibodies against CD1a, matrix metalloproteinases 2 and 9, and tissue inhibitors of matrix metalloproteinases 1 and 2, and analyzed by conventional and confocal microscopes. Results: Langerhans cells expressed matrix metalloproteinases 2 and 9, and tissue inhibitors of matrix metalloproteinases 1 and 2 in healthy and diseased gingival tissues. The tissue inhibitors of matrix metalloproteinase-positive Langerhans cells were mainly observed in the upper epithelial layers. Matrix metalloproteinase 9-positive Langerhans cells were observed especially during periodontitis and in the basal epithelial layer or crossing the basement membrane. Conclusion: During periodontal disease, changes in the expression of matrix metalloproteinases and their tissue inhibitors by gingival Langerhans cells could be implicated in the migration of the cells towards the connective tissue.

Unité(s) : Anatomo-Pathologie

Complexity of pathological interpretation in megacystis-microcolon-intestinal hypoperistalsis syndrome

BOMAN F, SFEIR R, BONNEVALLE M, BESSON R, GOTTRAND F, JAUBERT F

2006 - Ann. Pathol. 26(2):115-121

Megacystis-microcolon-intestinal hypoperistalsis syndrome is very rare, and is the most severe of the chronic intestinal pseudoobstructions. Diagnosis is usually made in the neonatal period, is clinical and radiological, and is confirmed by manometric studies. Microscopic abnormalities are variable, inconstant and nonspecific. They involve the smooth muscle more often than the intrinsic innervation of the gut and the bladder. A girl, currently seven years old, presented with megacystis observed on prenatal ultrasound at 21 weeks of gestation. At first, amniotic fluid volume was appropriate for gestational age, and then hydramnios appeared at 30 weeks of gestation. Microcolon was discovered at birth, with microileum, dilatation of the duodenum and proximal jejunum, intestinal malposition, and severe hypoperistalsis of the entire gastrointestinal tract, which indicated enterostomy and total parenteral nutrition from birth. At pathological examination, rectal biopsy and enteric nervous plexuses were normal. There was hypoplasia of the external longitudinal layer of the muscularis propria in the colon and ileum. Cajal cells could not be demonstrated immunohistochemically in the colon. This case highlights the complexity and difficulties of pathological interpretation in this syndrome, and the necessity of a large study of controls at different ages and different levels of the digestive tract and the bladder.

Unité(s) : Anatomo-Pathologie

A rare cause of meconial ileus and intestinal perforation in a neonate

BOMAN F, SFEIR R, MORINEAU M, UHLEN S, GOTTRAND F, JAUBERT F

2006 - Ann. Pathol. 26(3):220-222

Unité(s) : Anatomo-Pathologie

New clinical and therapeutic perspectives in Currarino syndrome (study of 29 cases)

CRETOLLE C, ZERAH M, JAUBERT F, SARNACKI S, REVILLON Y, LYONNET S, NIHOUL-FEKETE C

2006 - J. Pediat. Surg. 41(1):126-131

PURPOSE: The aim of the study was to clearly define the anomalies that compose the Currarino syndrome (CS). We highlight the frequency of associated malformations of the spinal cord and the possibility of a communication between the presacral tumor and the spinal canal, leading to neurological complications. METHODS: We studied 29 patients with CS, including 12 familial cases; histological examination of the presacral tumor was performed, and cytogenetic and molecular biology studies of the HLXB9 locus were carried out. RESULTS: All except 2 patients had a sacral malformation; 23 had an anorectal anomaly and 8 had isolated chronic intestinal pseudo-obstruction. There were 20 presacral tumors, one of which was malignant. There was a communication between the presacral tumor and the spinal canal in 12 cases, and tethering of the spinal cord in 17 cases. Twenty-five patients underwent surgery with a single-stage operation for 7, on both the intestinal and the presacral malformations, and, when required, the spinal cord anomalies. Twelve patients harbored a heterozygous point mutation of the coding sequence of HLXB9 gene. CONCLUSION: By accurate evaluation of the 4 main features in the CS, the correct surgical management, including neurosurgery, can be performed in a 1-stage approach.

Unité(s) : Chirurgie Pédiatrique, Génétique Médicale Pédiatrique, Anatomo-Pathologie, Neurochirurgie Pédiatriqu

Congenital Hyperinsulinism: Pancreatic [18F]Fluoro-L-Dihydroxyphenylalanine (DOPA) Positron Emission Tomography and Immunohistochemistry Study of DOPA Decarboxylase and Insulin Secretion

DE LONLAY P, SIMON-CARRE A, RIBEIRO MJ, BODDAERT N, GIURGEA I, LABORDE K, BELLANNE-CHANTELOT C, VERKARRE V, POLAK M, RAHIER J, SYROTA A, SEIDENWURM D, NIHOUL-FEKETE C, ROBERT JJ, BRUNELLE F, JAUBERT F

2006 - J. Clin. Endocrinol. Metabol. 91(3):933-940

Context: Congenital hyperinsulinism (HI) is characterized by hypoglycemia related to inappropriate insulin secretion. Focal and diffuse forms of hyperinsulinism share a similar clinical presentation, but their treatment is dramatically different. Preoperative differential diagnosis was based on pancreatic venous sampling, a technically demanding technique. Objective: Positron emission tomography (PET) after injection of [(18)F]fluoro-l-DOPA (l-dihydroxyphenylalanine) has been evaluated for the preoperative differentiation between focal and diffuse HI, by imaging uptake of radiotracer and the conversion of [(18)F]fluoro-l-DOPA into dopamine by DOPA decarboxylase. We propose to validate this test by immunohistochemical approach. Patients and Methods: Pancreatic surgical specimens of four focal and three diffuse HI were studied, using anti-DOPA decarboxylase and proinsulin antibodies. The effect of an inhibitor of DOPA decarboxylase (carbidopa) on insulin secretion was evaluated in vivo and in cultured INS-1 cells. Results: Immunohistochemical detection of DOPA decarboxylase showed diffuse staining of Langerhans islets in the whole pancreas in all diffuse cases, in contrast with dense focal staining in all focal cases. Staining of Langerhans islets outside the focal lesion was diffusely but weakly positive. We correlated the localization of DOPA decarboxylase and proinsulin in normal pancreas and in both diffuse and focal HI tissues. The diffuse PET uptake found before treatment in one child with diffuse HI disappeared completely after carbidopa administration, suggesting in vivo that pancreatic cells can take up amine precursors and contain DOPA decarboxylase. The insulin secretion measured in the supernatant was the same whether INS-1 cells were treated by dopamine or Lodosyn or untreated. Conclusion: We validate PET with as a consistent test to differentiate diffuse and focal HI.

Unité(s) : Anatomo-Pathologie, Chirurgie Pédiatrique, Département de Pédiatrie, Explorations Fonctionnelles, Ra

Mutations of the RET gene in isolated and syndromic Hirschsprung's disease in human disclose major and modifier alleles at a single locus

DE PONTUAL L, PELET A, TROCHET D, JAUBERT F, ESPINOSA-PARRILLA Y, MUNNICH A, BRUNET JF, GORIDIS C, FEINGOLD J, LYONNET S, AMIEL J

2006 - J. Med. Genet. 43(5):419-423

BACKGROUND: In Hirschsprung's disease (HSCR), a hypomorphic allele of a major gene, RET, accounts for most isolated (non-syndromic) cases, along with other autosomal susceptibility loci under a multiplicative model. However, some syndromic forms of HSCR are monogenic entities, for which the disease causing gene is known. OBJECTIVE: To determine whether RET could be considered a modifier gene for the enteric phenotype on the background of a monogenic trait. METHODS: The syndromic HSCR entities studied were congenital central hypoventilation (CCHS) and Mowat-Wilson syndrome (MWS), caused by PHOX2B and ZFHX1B gene mutations, respectively. The RET locus was genotyped in 143 CCHS patients, among whom 44 had HSCR, and in 30 MWS patients, among whom 20 had HSCR. The distribution of alleles, genotypes, and haplotypes was compared within the different groups. To test the interaction in vivo, heterozygous mice were bred for a null allele of Phox2b and Ret genes. RESULTS: RET was shown to act as a modifier gene for the HSCR phenotype in patients with CCHS but not with MWS. The intestine of double heterozygote mice was indistinguishable from their littermates. A loss of over 50% of each gene function seemed necessary in the mouse model for an enteric phenotype to occur. CONCLUSIONS: In CCHS patients, the weak predisposing haplotype of the RET gene can be regarded as a quantitative trait, being a risk factor for the HSCR phenotype, while in MWS, for which the HSCR penetrance is high, the role of the RET predisposing haplotype is not significant. It seems likely that there are both RET dependent and RET independent HSCR cases.

Unité(s) : U781, Anatomo-Pathologie

Contiguous Gene Deletion within Chromosome Arm 10q Is Associated with Juvenile Polyposis of Infancy, Reflecting Cooperation between the BMPR1A and PTEN Tumor-Suppressor Genes

DELNATTE C, SANLAVILLE D, MOUGENOT JF, VERMEESCH JR, HOUDAYER C, BLOIS MC, GENEVIEVE D, GOULET O, FRYNS JP, JAUBERT F, VEKEMANS M, LYONNET S, ROMANA S, ENG C, STOPPA-LYONNET D

2006 - Amer. J. Hum. Genet. 78(6):1066-1074

We describe four unrelated children who were referred to two tertiary referral medical genetics units between 1991 and 2005 and who are affected with juvenile polyposis of infancy. We show that these children are heterozygous for a germline deletion encompassing two contiguous genes, PTEN and BMPR1A. We hypothesize that juvenile polyposis of infancy is caused by the deletion of these two genes and that the severity of the disease reflects cooperation between these two tumor-suppressor genes.

Unité(s) : Anatomo-Pathologie, Département de Pédiatrie, E 0210, Génétique Médicale Pédiatrique

High-grade glioma in children under 5 years of age: A chemotherapy only approach with the BBSFOP protocol

DUFOUR C, GRILL J, LELLOUCH-TUBIANA A, PUGET S, CHASTAGNER P, FRAPPAZ D, DOZ F, PICHON F, PLANTAZ D, GENTET JC, RAQUIN MA, KALIFA C

2006 - Eur. J. Cancer 42(17):2939-2945

The aim of this study was to evaluate a chemotherapy strategy that avoids radiotherapy in first-line treatment of young children with high-grade glioma. A total of 21 children under 5 years of age received the BBSFOP protocol, comprising seven cycles of three drug pairs (carboplatin/procarbazine, cisplatin/etoposide and vincristine/cyclophosphamide) administered over a 16 month period. Radiotherapy was performed in case of recurrence/progression. Median age at diagnosis was 23 months. Histology was classified as World Health Organisation (WHO) grade III in 13 and grade IV in 8. Of the 13 children with a residual tumour, chemotherapy induced 2 partial responses (PR), 1 minor response (MR) and 1 stable disease (SD) with no recurrent disease. Five-year progression-free survival was 35% and 5-year overall survival was 59%, with a median follow-up of 5.2 years. At the last update, 12 children were alive (10 without radiotherapy). In conclusion, this study shows that an adjuvant chemotherapy first approach is safe and allows radiotherapy to be avoided in selected children.

Unité(s) : Anatomo-Pathologie, Neurochirurgie Pédiatrique

Neuronal Intranuclear Inclusion Disease Presenting as Chronic Intestinal Pseudo-Obstruction in the Neonatal Period in the Absence of Neurologic Symptoms

EL-RIFAI N, DAOUD N, TAYYARAH K, BAYDOUN A, JAUBERT F

2006 - J. Pediat. Gastroenterol. Nutr. 42(3):321-323

Unité(s) : Anatomo-Pathologie

A clonogenic bone marrow progenitor specific for macrophages and dendritic cells

FOGG DK, SIBON C, MILED C, JUNG S, AUCOUTURIER P, LITTMAN DR, CUMANO A, GEISSMANN F

2006 - Science 311(5757):83-87

Macrophages and dendritic cells (DCs) are crucial for immune and inflammatory responses and belong to a network of cells that has been termed the mononuclear phagocyte system (MPS). However, the origin and lineage of these cells remain poorly understood. Here, we describe the isolation and clonal analysis of a mouse bone marrow progenitor that is specific for monocytes, several macrophage subsets, and resident spleen DCs in vivo. It was also possible to recapitulate this differentiation in vitro by using treatment with the cytokines macrophage colony-stimulating factor and granulocyte-macrophage colony-stimulating factor. Thus, macrophages and DCs appear to renew from a common progenitor, providing a cellular and molecular basis for the concept of the MPS.

Unité(s) : IRNEM, Anatomo-Pathologie, Avenir

p53 Pathway dysfunction in primary childhood ependymomas

GASPAR N, GRILL J, GEOERGER B, LELLOUCH-TUBIANA A, MICHALOWSKI MB, VASSAL G

2006 - Pediatr. Blood Cancer 46(5):604-613

BACKGROUND: Childhood ependymoma remains a major therapeutic challenge despite surgery, chemotherapy, and irradiation. We hypothesized that p53 function might be abrogated in ependymomas and implicated in their resistance to anti-cancer therapy. PROCEDURE: Primary ependymomas at diagnosis or relapse from 24 children were analyzed for p53 pathway, using a functional assay in yeast, RT-PCR, Western blot analysis, and/or immunohistochemistry for TP53 mutation, p14(ARF) deletion and promoter hypermethylation, MDM2 and PAX5 expression, respectively. p53-mediated response to radiation-induced DNA damage was evaluated using Western blot and flow cytometry analysis in two ependymoma xenograft models, IGREP37 and IGREP83, derived from primary anaplastic childhood ependymomas. RESULTS: No TP53, MDM2, p14(ARF), PAX5 gene abnormalities were detected in the primary ependymomas tumors and xenografts tested. Interestingly, despite the lack of these abnormalities, p53 induced p21-mediated G(1) growth arrest in response to irradiation was altered in the IGREP37 xenograft tumors. Although irradiation induced necrosis and apoptotic cell death, IGREP37 tumors were moderately sensitive to radiation therapy in vivo. In contrast, irradiation yielded significant tumor growth delays and tumor regressions in the p53 functional IGREP83 xenografts. CONCLUSION: Alterations in p53-mediated growth arrest in ependymomas might be implicated in the radio-resistance of these tumors and demand further evaluation.

Unité(s) : Anatomo-Pathologie

The Class 6 Semaphorin SEMA6A Is Induced by Interferon-{gamma} and Defines an Activation Status of Langerhans Cells Observed in Pathological Situations

GAUTIER G, DE SAINT-VIS B, SENECHAL B, PIN JJ, BATES EE, CAUX C, GEISSMANN F, GARRONE P

2006 - Amer. J. Pathol. 168(2):453-465

Originally implicated in axon guidance, semaphorins represent a large family of molecules that are now known to be expressed in the immune system. Among different semaphorins tested by reverse transcriptase-polymerase chain reaction in human immune cells, the expression of class 6 transmembrane semaphorin SEMA6A was restricted to dendritic cells (DCs). Using in-house generated monoclonal antibodies, SEMA6A expression appeared further restricted to Langerhans cells (LCs). In vivo, SEMA6A mRNA was expressed in freshly isolated skin LCs but SEMA6A protein was not detectable on normal skin and tonsillar epithelium. Of interest, SEMA6A protein was strongly expressed on skin and bone LCs and on LCs in draining lymph nodes from patients with LC histiocytosis or dermatopathic lymphadenitis, respectively, representing two inflammatory conditions in which LCs display an immature DC-LAMP(low), CD83(low), and CCR7(+) phenotype. SEMA6A expression was low in resting LCs generated in vitro and was enhanced by interferon (IFN)-gamma but not by interleukin-4, interleukin-10, IFN-alpha/beta, or lipopolysaccharide. Most IFN-gamma-induced SEMA6A-positive cells remained immature with low CD83 and DC-LAMP/CD208 expression, but they expressed CCR7 and responded to macrophage inflammatory protein-3beta (MIP-3beta/CCL19). The expression of SEMA6A, for which the ligand and function remain unknown, may therefore identify an alternative IFN-gamma-dependent activation status of LCs in vivo.

Unité(s) : IRNEM, Anatomo-Pathologie, Avenir

Fas ligand-mediated lethal hepatitis after rapid lysis of a localized natural killer cell lymphoma

GHEZ D, DAMOTTE D, PERRINE SP, FALLER DV, CANIONI D, BROUSSE N, LEFRERE F, VARET B, HERMINE O

2006 - Clin. Lymphoma Myeloma 6(5):417-419

Natural killer (NK) cell malignancies have been associated with neutropenia and disturbances of liver function tests, thought to be related to high levels of soluble Fas ligand (FasL) in the circulation. We report a case of fulminant hepatitis occurring 3 weeks after the initiation of salvage therapy by arginine butyrate and ganciclovir for refractory Epstein-Barr virus-positive NK cell lymphoma. Pathologic examination revealed disappearance of the NK tumor and massive liver injury caused by apoptosis of virtually all hepatocytes. Immunohistochemistry revealed an intense staining for FasL. To our knowledge, this is the first description of the occurence of FasL-mediated lethal hepatitis after lysis of a NK cell lymphoma.

Unité(s) : Anatomo-Pathologie, Hématologie Adulte

Omenn syndrome in an infant with IL7RA gene mutation

GILIANI S, BONFIM C, DE SAINT-BASILE G, LANZI G, BROUSSE N, KOLISKI A, MALVEZZI M, FISCHER A, NOTARANGELO LD, LE DEIST F

2006 - J. Pediat. 148(2):272-274

Omenn syndrome (OS) is a rare combined immunodeficiency characterized by erythroderma, lymphadenopathy, and autoimmune manifestations. Most cases are due to mutations in the RAG genes. We report a case of OS due to mutations of IL7RA, thus defining Omenn syndrome as a genetically heterogeneous condition.

Unité(s) : Anatomo-Pathologie, U768

Molecular Mechanisms of Neonatal Hyperinsulinism

GIURGEA I, BELLANNE-CHANTELOT C, RIBEIRO M, HUBERT L, SEMPOUX C, ROBERT JJ, BLANKENSTEIN O, HUSSAIN K, BRUNELLE F, NIHOUL-FEKETE C, RAHIER J, JAUBERT F, DE LONLAY P

2006 - Horm. Res. 66(6):289-296

Congenital hyperinsulinism (CHI), characterized by profound hypoglycaemia related to inappropriate insulin secretion, may be associated histologically with either diffuse insulin hypersecretion or focal adenomatous hyperplasia, which share a similar clinical presentation, but result from different molecular mechanisms. Whereas diffuse CHI is of autosomal recessive, or less frequently of autosomal dominant, inheritance, focal CHI is sporadic. The most common mechanism underlying CHI is dysfunction of the pancreatic ATP-sensitive potassium channel (K(+)(ATP)). The two subunits of the K(+)(ATP) channel are encoded by the sulfonylurea receptor gene (SUR1 or ABCC8) and the inward-rectifying potassium channel gene (KIR6.2 or KCNJ11), both located in the 11p15.1 region. Germ-line, paternally inherited, mutations of the SUR1 or KIR6.2 genes, together with somatic maternal haplo-insufficiency for 11p15.5, were shown to result in focal CHI. Diffuse CHI results from germ-line mutations in the SUR1 or KIR6.2 genes, but also from mutations in several other genes, namely glutamate dehydrogenase (with associated hyperammonaemia), glucokinase, short-chain L-3-hydroxyacyl-CoA dehydrogenase, and insulin receptor gene. Hyperinsulinaemic hypoglycaemia may be observed in several overlapping syndromes, such as Beckwith-Wiedemann syndrome (BWS), Perlman syndrome, and, more rarely, Sotos syndrome. Mosaic genome-wide paternal isodisomy has recently been reported in patients with clinical signs of BWS and CHI. The primary causes of CHI are genetically heterogeneous and have not yet been completely unveiled. However, secondary causes of hyperinsulinism have to be considered such as fatty acid oxidation deficiency, congenital disorders of glycosylation and factitious hypoglycaemia secondary to Munchausen by proxy syndrome. Copyright (c) 2006 S. Karger AG, Basel.

Unité(s) : Anatomo-Pathologie, Chirurgie Pédiatrique, Département de Pédiatrie, Radiologie Pédiatrique

Congenital hyperinsulinism and mosaic abnormalities of the ploidy

GIURGEA I, SANLAVILLE D, FOURNET JC, SEMPOUX C, BELLANNE-CHANTELOT C, TOUATI G, HUBERT L, GROOS MS, BRUNELLE F, RAHIER J, HENQUIN JC, DUNNE MJ, JAUBERT F, ROBERT JJ, NIHOUL-FEKETE C, VEKEMANS M, JUNIEN C, DE LONLAY P

2006 - J. Med. Genet. 43(3):248-254

BACKGROUND: Congenital hyperinsulinism and Beckwith-Wiedemann syndrome both lead to beta islet hyperplasia and neonatal hypoglycaemia. They may be related to complex genetic/epigenetic abnormalities of the imprinted 11p15 region. The possibility of common pathophysiological determinants has not been thoroughly investigated. OBJECTIVE: To report abnormalities of the ploidy in two unrelated patients with congenital hyperinsulinism. METHODS: Two patients with severe congenital hyperinsulinism, one overlapping with Beckwith-Wiedemann syndrome, had pancreatic histology, ex vivo potassium channel electrophysiological studies, and mutation detection of the encoding genes. The parental genetic contribution was explored using genome-wide polymorphism, fluorescent in situ hybridisation (FISH), and blood group typing studies. RESULTS: Histological findings diverged from those described in focal congenital hyperinsulinism or Beckwith-Wiedemann syndrome. No potassium channel dysfunction and no mutation of its encoding genes (SUR1, KIR6.2) were detected. In patient 1 with congenital hyperinsulinism and Beckwith-Wiedemann syndrome, paternal isodisomy for the whole haploid set was homogeneous in the pancreatic lesion, and mosaic in the leucocytes and skin fibroblasts (hemihypertrophic segment). Blood group typing confirmed the presence of two erythroid populations (bi-parental v paternal only contribution). Patient 2 had two pancreatic lesions, both revealing triploidy with paternal heterodisomy. Karyotype and FISH analyses done on the fibroblasts and leucocytes of both patients were unremarkable (diploidy). CONCLUSIONS: Diploid (biparental/paternal-only) mosaicism and diploid/triploid mosaicism were present in two distinct patients with congenital hyperinsulinism. These chromosomal abnormalities led to paternal disomy for the whole haploid set in pancreatic lesions (with isodisomy or heterodisomy), thereby extending the range and complexity of the mechanisms underlying congenital hyperinsulinism, associated or not with Beckwith-Wiedemann syndrome.

Unité(s) : Anatomo-Pathologie, Chirurgie Pédiatrique, Département de Pédiatrie, Génétique Médicale Pédiatrique,

Anti-LFA-1 antibody postpones T-cell receptor triggering while preserving generation of regulatory T cells in T-cell receptor anti-HY transgenic mice

GO S, FLEISCHMANN A, LANTZ O, CRETOLLE C, BROUSSE N, CERF-BENSUSSAN N, SARNACKI S

2006 - Transplantation 82(1):119-126

BACKGROUND: Anti-LFA-1 (CD11a) antibody increases allograft survival and/or induces tolerance in murine models, but its mechanisms of action remain to be elucidated. METHODS: Rag-2-/- H-2b recipient mice, bearing a transgenic T-cell receptor specific for the male antigen HY presented by MHC class II molecule, were transplanted with a C57BL/6 (H-2b) male heart with or without administration of anti-LFA-1 antibody from days -1 to 9. RESULTS: Treatment prevented the transient episode of acute graft rejection observed in nontreated mice and maintained a naive phenotype and proliferative characteristics comparable to that of naive transgenic lymphocytes on day 7 during treatment, with decreased IFN-gamma mRNA and increased IL-4 mRNA. On day 14, phenotype and proliferative response of lymphocytes in treated mice was comparable to those of untreated animals. Furthermore, treatment did not interfere with the generation of CD4+Vbeta6+CD25+ (Foxp3) cells that were observed in long-term nontreated tolerant mice. CONCLUSIONS: This in vivo model demonstrates that anti-LFA-1 treatment induced a transient blockade of antigen recognition, which inhibited and postponed induction of signal 1 via the TCR and decreased the intensity of the Th1 response. Importantly, LFA-1 blockade did not disturb spontaneous generation of regulatory mechanism. This treatment would be compatible in clinical settings with other therapeutics inducing regulatory mechanisms.

Unité(s) : Anatomo-Pathologie, Chirurgie Pédiatrique, U793

Vulvar lichen planus in children

HATUEL H, FRAITAG S, THIBAUD E, HAMEL D

2006 - Ann. Dermatol. Vénéréolog. 133(10):802-803

BACKGROUND: Lichen planus is less common in children about in adults and mostly affects the skin.CASE REPORT: A 9-year-old girl was referred for a purplish blue and violaceous, unilateral and asymptomatic vulvar lesion noted 4 months earlier and stable. Histopathologic examination showed typical features of lichen planus. She responded well and rapidly with topical steroids.DISCUSSION: We report the first case of vulvar lichen planus in a little girl. Mucosal involvement is uncommon in children with lichen planus and genital localisation is extremely rare. Vulvar lichen sclerosis is the principal differential diagnosis. The risk of vulvar synechia and development of vulvar carcinomas warrants regular long-term follow-up.

Unité(s) : Dermatologie, Anatomo-Pathologie, Métabolisme-Neurologie

Sporadic bilateral kidney tumour: practical approach and place of conservative surgery

HINTZY MC, HUPERTAN V, LAROUSSERIE F, CHRETIEN Y, THIOUNN N, DUFOUR B, MEJEAN A

2006 - Prog. Urol. 16(2):134-138

OBJECTIVE: To study the specific features of the sporadic form of bilateral renal cell carcinoma (RCC). MATERIAL AND METHOD: Twenty-six patients presented bilateral RCC among a total of 759 patients operated for RCC in our institution between 1985 and 1998. The mean follow-up for 23 patients (3