Lymphomatoid papulosis in children: a series of 25 cases.

BACKGROUND: Lymphomatoid papulosis (LyP) is an uncommon cutaneous T-cell lymphoproliferative disorder (CTLPD) rarely encountered in children. OBJECTIVES: To specify characteristics of paediatric LyP and to describe both diagnostic difficulties and the course of the disease with the experience of 10 years' follow-up. METHODS: This was a retrospective, single-centre study of 25 children diagnosed with LyP according to the 2008 World Health Organization guidelines, and a clinical and pathological correlation by two experts. RESULTS: The mean age at onset was 7·5 years. The lesions were mostly papulonodular with frequent pruritus (40%). Mucosal involvement was sometimes observed. A single ulcerative nodule was initially suggestive of a primary cutaneous anaplastic large-cell lymphoma (C-ALCL). Pityriasis lichenoides was associated in 36% of cases, atopic dermatitis in 28% and nonspecific infections in 28%. Complete remission was observed in 44% of cases. Through the mean follow-up of 10 years, none of our patients have experienced lymphoma occurrence. Histopathological subtype A clearly predominated (82%). A marked eosinophilic infiltrate was present in 44% of cases and a cutaneous T-gamma clone in 40%. No correlation was observed between histopathological subtype, cutaneous clone or LyP clinical course. CONCLUSIONS: Paediatric LyP belongs to the group of CD30-positive CTLPDs including C-ALCL. Children have to be carefully followed up lifelong, even if the prognosis appears good. The high frequencies of an associated viral infection, atopic dermatitis, marked eosinophilic infiltrate and a good outcome suggest that paediatric LyP could be considered a reactional disease rather than a malignant disorder.

[Histopathology of coeliac disease]. / Le diagnostic histologique de la maladie cœliaque.

Coeliac disease is a common disease, affecting 1% of the population. Clinical manifestations are multiple. The diagnosis requires serologic testing and a duodenal biopsy that shows the characteristic findings of intraepithelial lymphocytosis, crypt hyperplasia and villous atrophy, and a positive response to a gluten-free diet. In most patients, the histological diagnosis is easily established. Pitfalls in the pathological diagnosis include a poorly orientated biopsy specimen, either an inadequate biopsy sampling in patients with patchy villous atrophy and the other causes of villous atrophy. A non-response to the gluten-free diet needs to reassess first, the initial diagnosis, second to be sure of the gluten-free diet adherence, and third, to exclude malignant complications such as refractory celiac disease or enteropathy-associated T-cell lymphoma.

Rituximab induction immunotherapy for first-line low-tumor-burden follicular lymphoma: survival analyses with 7-year follow-up.

BACKGROUND: The purpose of this study was to report long-term results of rituximab induction monotherapy in patients with low-tumor-burden follicular lymphoma (LTBFL). PATIENTS AND METHODS: Of 49 first-line LTBFL patients who received weekly doses of rituximab (375 mg/m(2)), 46 have been followed with a long-term analysis of clinical and molecular responses. RESULTS: Best clinical response (at any staging within a year following treatment) was 80%, 24 (52%) patients had complete or unconfirmed complete response, 13 (28%) had partial response and 9 (20%) had stable or progressive disease. Of 31 patients having a positive bcl2-JH rearrangement, 15 (48%) became negative following treatment. After 83.9 months of follow-up (95% confidence interval 6.4-92.8 months), the median progression-free survival is 23.5 months and overall survival (OS) is 91.7%. Five patients died (one progression, one myelodysplasia, one diffuse large B-cell lymphoma and two solid tumors). Seven patients (15%) are progression-free including five who are bcl2 informative. No unexpected long-term adverse event has been observed. CONCLUSION: A significant proportion of patients remain progression-free 7 years after a single 4-dose rituximab treatment in first-line LTBFL. The 7-year overall survivalOS is very high in this selected population of patients.

Normal oxidative phosphorylation in intestinal smooth muscle of childhood chronic intestinal pseudo-obstruction.

BACKGROUND: Chronic intestinal pseudo-obstruction (CIPO) is a severe disease of the digestive tract motility. In pediatric population, CIPO remains of unknown origin for most patients. Chronic intestinal pseudo-obstruction is also a common feature in the course of mitochondrial oxidative phosphorylation disorders related for some patients to mutations in TYMP, POLG1, mtDNA tRNA(leu(UUR)) or tRNA(lys) genes. We hypothesized that CIPOs could be the presenting symptom of respiratory chain enzyme deficiency and thus we investigated oxidative phosphorylation in small bowel and/or colon smooth muscle of primary CIPO children. METHODS: We studied eight children with CIPO and 12 pediatric controls. We collected clinical, radiological and pathological data and measured respiratory chain enzymatic activity in isolated smooth muscle of the small bowel and/or the colon. We also sequenced TYMP, POLG, mtDNA tRNA(leu(UUR)) and tRNA(lys) genes. KEY RESULTS: Neither pathological nor radiological data were in favor of a mitochondrial dysfunction. No respiratory chain enzyme deficiency was detected in CIPO children. In myogenic CIPO, respiratory enzymes and citrate synthase activities were increased in small bowel and/or colon whereas no abnormality was noted in neurogenic and unclassified CIPO. Levels of enzyme activities were higher in control small bowel than in control colon muscle. Sequencing of TYMP, POLG, mtDNA tRNA(leu(UUR)) and tRNA(lys) genes and POLG gene did not reveal mutation for any of the patients. CONCLUSIONS & INFERENCES: The normal enzymatic activities as the lack of radiological and genetic abnormalities indicate that, at variance with adult patients, oxidative phosphorylation deficiency is not a common cause of childhood CIPO.

Enteropathy-associated T-cell lymphoma: a review on clinical presentation, diagnosis, therapeutic strategies and perspectives.

INTRODUCTION: Enteropathy-associated T-cell lymphoma (EATL) is a rare complication of celiac disease (<1% of lymphomas) and has a poor prognosis. METHODS: International literature review with PubMed search (up to January 2009) of pathophysiological, clinical and therapeutic data. RESULTS: EATL is found in patients with a mean age of 59 years, often with a complication that signals its diagnosis. Refractory celiac disease (RCD), equivalent to low-grade intraepithelial T-cell lymphoma, could be an intermediary between celiac disease and high-grade invasive T-cell lymphoma. The median survival is 7 months, with no significant difference between stages; the cumulative 5-year survival is less than 20%. The poor prognosis is determined by disease that has often spread before it is diagnosed (50%), multifocal involvement of the small bowel (50%), poor general health status and undernutrition, and recurrence of complications (infections, perforations, gastrointestinal haemorrhages, occlusions), thus delaying the chemotherapy and contributing to frequent chemotherapy resistance. There is currently no effective and consensual treatment: preventive surgery for complications is controversial, and the results of chemotherapy are disappointing. The classic CHOP protocol (combination of doxorubicin-cyclophosphamide-vincristine-prednisone) does not have satisfactory results and survival remains poor, especially in patients with underlying RCD. High-dose chemotherapy with autotransplantion seems to only improve the prognosis in localised forms. Allogeneic bone marrow transplantation was not evaluated. In all, 1/3 of patients, being unfit for treatment, die before 3 months and half of treated patients stop chemotherapy prematurely due to inefficacy, intolerance and/or complications. CONCLUSION: Improvement of the prognosis requires collaboration in order to compose a national cohort, to evaluate new diagnostic and therapeutic strategies and to define prognostic factors.

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

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.

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

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.

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

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.

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

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 children; 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.

[Nodular fasciitis of childhood: a clinicopathological analysis of 10 cases]. / Etude anatomoclinique de dix cas de fasciite nodulaire de l'enfant.

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.

Evaluation of c4d deposition and circulating antibody in small bowel transplantation.

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.

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

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.

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

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.

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

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.

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

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.

Variable expression of Epstein-Barr virus-induced gene 3 during normal B-cell differentiation and among B-cell lymphomas.

Epstein-Barr virus (EBV)-induced gene 3 (EBI3) is expressed by tumour cells in several EBV-associated malignancies. EBI3 was recently found to associate with a novel peptide, p28, to form a new heterodimeric cytokine, called interleukin-27. In this study, we investigated EBI3 and p28 expression in normal human B lymphocytes and in non-EBV-associated B-cell lymphomas. Low levels of EBI3 were detected in purified tonsillar B cells and expression was upregulated upon anti-CD40 or anti-micro stimulation via NF-kappaB activation. In non-neoplastic tissues, EBI3 expression by lymphocytes was largely restricted to a subset of germinal centre (GC) B cells located at the margin of the light zone, in close contact with CD3+ T lymphocytes. Over 50% of EBI3+ GC B cells were engaged in cell proliferation as assessed by Ki67 expression, and 10-30% expressed MUM1, an early marker of plasma cell differentiation expressed by late centrocytes. Many EBI3+ GC B cells had downregulated bcl-6 expression, which further suggests that these cells correspond to late CD40-activated centrocytes. Immunohistochemical analysis of 64 B-cell lymphomas showed that the highest EBI3 levels were detected in follicular lymphomas and in diffuse large B-cell lymphomas of both GC B-cell-like or non-GC B-cell-like types. No or rare p28 expression was detected in normal or tumour B cells. This constitutive expression of EBI3 by neoplastic B cells may be involved in lymphomagenesis, and may be a useful marker for lymphoma diagnosis.

Breast inflammatory gigantomastia in a context of immune-mediated diseases.

CONTEXT: Localized breast lesions have been described in lupic or diabetic patients. However, the description of breast gigantomastia in women presenting with autoimmune diseases has not been reported. SETTING: The study took place within the Department of Endocrinology and Reproductive Medicine, Necker Hospital, Paris, France. PATIENTS: We describe eight patients with inflammatory gigantomastia, occurring in a context of immune-mediated diseases: myasthenia, chronic arthritis, or thyroiditis. MAIN OUTCOME MEASURES: Together with hormonal, immunological, and breast magnetic resonance imaging (MRI) evaluation, breast histology enabled us to perform immunocytochemical and indirect immunofluorescence studies. Control sera were obtained from patients with (n = 10) and without (n = 7) antinuclear antibodies. RESULTS: Six of the eight patients developed gigantomastia either at puberty or during pregnancy. Neither a hormonal oversecretion nor a specific immunological pattern was observed. All patients except one presented antinuclear antibodies. Histological study revealed a diffuse, stromal hyperplasia and a severe atrophy of the lobules. A rarefaction of adipocytes was also noted, as previously suggested on MRI. There was a perilobular lymphocytic infiltrate made of CD3+ lymphocytes. Study of sera from five of six cases of gigantomastia showed a nuclear immunofluorescence pattern in normal mammary ductal and lobular glandular epithelium, as well as in kidney and intestine epithelial cells. In control sera, a nuclear signal was observed only when antinuclear antibodies were present. CONCLUSIONS: We suggest that breast tissue may be a target tissue in autoimmune diseases, this process being favored by the hormonal milieu. However, the precise mechanism of such association is not individualized. The fact that stromal hyperplasia is the main histological feature justifies the search for the involvement of growth factors in such a process.