Katty Delbecque

A classification of ductal plate malformations based on distinct pathogenic mechanisms of biliary dysmorphogenesis

Ductal plate malformations (DPMs) are developmental anomalies considered to result from lack of ductal plate remodeling during bile duct morphogenesis. In mice, bile duct development is initiated by the formation of primitive ductal structures lined by two cell types, namely ductal plate cells and hepatoblasts. During ductal plate remodeling, the primitive ductal structures mature to ducts as a result from differentiation of the ductal plate cells and hepatoblasts to cholangiocytes. Here, we report this process is conserved in human fetal liver. These findings prompted us to evaluate how DPMs develop in three mouse models, namely mice with livers deficient in hepatocyte nuclear factor 6 (HNF6), HNF1β, or cystin‐1 (cpk [congenital polycystic kidney] mice). Human liver from a patient with a HNF1B/TCF2 mutation, and from fetuses affected with autosomal recessive polycystic kidney disease (ARPKD) were also analyzed. Despite the epistatic relationship between HNF6, HNF1β, and cystin‐1, the three mouse models displayed distinct morphogenic mechanisms of DPM. They all developed biliary cysts lined by cells with abnormal apicobasal polarity. However, the absence of HNF6 led to an early defect in ductal plate cell differentiation. In HNF1β‐deficient liver, maturation of the primitive ductal structures was impaired. Normal differentiation and maturation but abnormal duct expansion was apparent in cpk mouse livers and in human fetal ARPKD. Conclusion: DPM is the common endpoint of distinct defects initiated at distinct stages of bile duct morphogenesis. Our observations provide a new pathogenic classification of DPM. (HEPATOLOGY 2011;)

Calcifying fibrous tumour of the gastric wall

Sir: Calcifying fibrous tumours (CFTs) are uncommon, tumour-like lesions characterized by the presence of abundant hyalinized collagen with psammomatous or dystrophic calcification and a reactive lymphoplasmocytic infiltrate. These lesions were originally described as soft tissue masses developing in the subcutaneous or deep soft tissues of the extremities, trunk, neck, scrotum, groin or axilla. More recently, several cases have been reported in a subserosal location, involving the pleura or the visceral peritoneum. We report here a case of a CFT of the stomach presenting as a tumour of the gastric wall proper. The lesion was removed from a 63-year-old man with longstanding epigastric pain due to gastroesophagal reflux. A 10–20 mm polypoid lesion of the lesser gastric curvature had been noticed during a gastroscopy 4 years previously. Recent control endoscopies showed that the lesion reached 25 mm in greatest dimension. There was no evidence of mucosal ulceration and the patient reported neither haemorrhage nor increasing pain. An echoendoscopy showed a submucosal lesion with marked central hypoechogenicity. On magnetic resonance imaging examination the lesion appeared as a hyposignal in T2 and a gadolinium-enhanced isosignal in T1; these findings were interpreted as suggestive of a gastrointestinal stromal tumour (GIST) and the patient underwent a partial gastrectomy. The surgical specimen revealed a 20 · 15 · 15 mm well-demarcated but unencapsulated white firm gritty tumour covered by normal mucosa (Figure 1A). On microscopic examination, it consisted of dense eosinophilic collagenous tissue containing sparse spindle cells, numerous psammomatous calcifications and a multifocal lymphoplasmocytic infiltrate (Figure 1B). Immunohistochemically, the cells were positive for vimentin and factor XIII, showed no evidence of smooth muscle differentiation (negative for smooth muscle actin and desmin) and were negative for CD34, CD117 and ALK. The patient is well with no evidence of recurrence 6 months after surgery. About 30 cases of CFTs have been reported in the abdomen. Most cases have occurred in the mesentery, omentum or under the serosal surface of stomach or intestines. To our knowledge only two cases have been described as intrinsic visceral lesions. One case occurred as a large adrenal mass mimicking a neuroblastoma in a 10-year-old girl. The second case was described as a polypoid tumour of the gastric wall in a 49-year-old woman with a history of weight loss and epigastric pain. The case presented here is the first case of CFT of the gastric wall which is clinically, radiologically and histologically well documented. CFTs are usually characterized by benign clinical behaviour. Accordingly, this case showed a slow growth, remained asymptomatic and demonstrated no evidence of recurrence 6 months after surgery. The aetiology and pathogenesis of CFTs are still debated and remain unknown. Based on the location, pathological and immunohistochemical features, an origin from mesenchymal submesothelial cells has been suggested. Some authors have proposed that CFT may represent the end-stage of inflammatory myofibroblastic lesions, a hypothesis not supported by others. Because of the

Distribution of Varicella-Zoster Virus DNA and Gene Products in Tissues of a First-Trimester Varicella-Infected Fetus

Precise information about varicella-zoster virus (VZV) infection in first-trimester fetuses remains sketchy. After varicella infection was diagnosed in a woman, her 12-week-old fetus was aborted and was investigated, by histological examination, virus culturing, polymerase chain reaction, in situ hybridization (ISH), and immunohistochemistry (IHC), for the presence of VZV infection. Only the results of the histological examination suggested the presence of alpha -herpesvirus infection, in the gastrointestinal tract and liver; results of ISH were positive for VZV, and results of IHC staining were positive for intermediate early protein 63 (IE63) but negative for glycoprotein E (gE), in the dorsal root ganglia (DRG), meninges, gastrointestinal tract, pancreas, smooth muscle, liver, and placental trophoblast, indicating the presence of a nonproductive, latency-like VZV infection. Only the gastrointestinal tract and liver exhibited simultaneous staining for IE63 and gE, a result suggesting that active replication of VZV was present. In conclusion, widespread nonproductive VZV infection in the absence of histological clues is an early event in VZV infection in fetuses. The observed gene-expression pattern in most tissues resembles that of latent VZV infection in DRG. Latency-like infection in nonneural cell types may potentially reactivate, leading to multifocal necrosis, fibrosis, and dystrophic calcifications, as observed in advanced congenital varicella syndrome.

Aberrant Promoter Methylation and Expression of UTF1 during Cervical Carcinogenesis

Promoter methylation profiles are proposed as potential prognosis and/or diagnosis biomarkers in cervical cancer. Up to now, little is known about the promoter methylation profile and expression pattern of stem cell (SC) markers during tumor development. In this study, we were interested to identify SC genes methylation profiles during cervical carcinogenesis. A genome-wide promoter methylation screening revealed a strong hypermethylation of Undifferentiated cell Transcription Factor 1 (UTF1) promoter in cervical cancer in comparison with normal ectocervix. By direct bisulfite pyrosequencing of DNA isolated from liquid-based cytological samples, we showed that UTF1 promoter methylation increases with lesion severity, the highest level of methylation being found in carcinoma. This hypermethylation was associated with increased UTF1 mRNA and protein expression. By using quantitative RT-PCR and Western Blot, we showed that both UTF1 mRNA and protein are present in epithelial cancer cell lines, even in the absence of its two main described regulators Oct4A and Sox2. Moreover, by immunofluorescence, we confirmed the nuclear localisation of UTF1 in cell lines. Surprisingly, direct bisulfite pyrosequencing revealed that the inhibition of DNA methyltransferase by 5-aza-2′-deoxycytidine was associated with decreased UTF1 gene methylation and expression in two cervical cancer cell lines of the four tested. These findings strongly suggest that UTF1 promoter methylation profile might be a useful biomarker for cervical cancer diagnosis and raise the questions of its role during epithelial carcinogenesis and of the mechanisms regulating its expression.

Primary mucosa-associated lymphoid tissue lymphoma of the gallbladder: report of a case harboring API2/MALT1 gene fusion.

The genetic alterations underlying extranodal marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue type are heterogeneous and show variation according to the tumor site. Here, we report a case of mucosa-associated lymphoid tissue lymphoma of the gallbladder with genetic characterization. This lymphoma, diagnosed in a 75-year-old woman who underwent cholecystectomy for suspected acute cholecystitis, presented as diffuse thickening of the gallbladder wall. The morphology was typical of mucosa-associated lymphoid tissue lymphoma, and by immunophenotype, the tumor cells were CD20+ CD5- CD10- CD23- CD43- BCL6- BCL2+ IgM+ IgD- lambda+, with moderate nuclear expression of BCL10. Interphase fluorescence in situ hybridization analysis on paraffin sections, using a fusion probe for API2/MALT1, demonstrated 2 fusion signals in most nuclei, bringing the first documentation of a t(11;18)(q21;q21) in this exceptional primary disease location.

Diagnostic pitfall in antenatal manifestations of CPT II deficiency.

Carnitine palmitoyltransferase II (CPT2) deficiency is a rare inborn error of mitochondrial fatty acid metabolism associated with various phenotypes. Whereas most patients present with postnatal signs of energetic failure affecting muscle and liver, a small subset of patients presents antenatal malformations including brain dysgenesis and neuronal migration defects. Here, we report recurrence of severe cerebral dysgenesis with Dandy–Walker malformation in three successive pregnancies and review previously reported antenatal cases. Interestingly, we also report that acylcarnitines profile, tested retrospectively on the amniotic fluid of last pregnancy, was not sensitive enough to allow reliable prenatal diagnosis of CPT2 deficiency. Finally, because fetuses affected by severe cerebral malformations are frequently aborted, CPT2 deficiency may be underestimated and fatty acid oxidation disorders should be considered when faced with a fetus with Dandy–Walker anomaly or another brain dysgenesis.

Histopathological diagnosis of a type vii mucopolysaccharidosis after pregnancy termination.

Type VII mucopolysaccharidosis is a very rare recessive lysosomal storage disease. We diagnosed a type VII MPS in a case of severe fetal hydrops after pregnancy termination at 23 weeks of gestation. The diagnosis was suspected on histopathological examination by the presence of foam cells in many viscera and foamy placental Hofbauer cells. Enzyme assay on cultured amniotic cells showed a markedly deficient β-glucuronidase activity, thus confirming the diagnosis. This report shows the importance of a precise necropsy diagnosis in nonimmune hydrops because of putative implications for genetic counseling and prenatal diagnosis in subsequent pregnancies.

Atypical recurrence of a placental site trophoblastic tumor four years after hysterectomy for benign condition: Case report and review of literature

Highlights • Rare case of PSTT limited to the vagina presenting eight years after last pregnancy and four years after hysterectomy• Differential diagnosis with other vaginal tumors can be challenging but it is critical because behavior and management are different.• Stage-adapted management is proposed and surgery is the mainstay treatment for localized disease.

Hyperacute graft rejection during heart transplantation for giant cell myocarditis: a case report.

We report the case of a patient with giant cell myocarditis who was bridged to transplantation with mechanical circulatory support and developed a fatal perioperative hyperacute rejection. The patient had received abundant transfusions that had raised her anti-HLA antibody titers. The cross-match test was positive. No pre-transplantation immunosuppressive therapy had been administered given concomitant infection. The severity and acuteness of the rejection in this case likely reflect the combined effect of preformed anti-HLA antibodies in the context of an active organ-specific immune process at the time of transplantation. This case raises the questions of the need for intensive immunosuppressive therapy before transplantation in giant cell myocarditis and of the management of patients with positive cross-match in the context of a giant cell myocarditis.

PRIMARY AMYLOIDOSIS (AL) AS A CAUSE OF NEPHROTIC SYNDROME

Abstract AL amyloidosis is a rare systemic disease resulting from tissue accumulation of amyloid fibrils derived from monoclonal immunoglobulin light chains. It can disrupt the tissue architecture and consequently cause organ dysfunction. The prognosis is poor with a median survival of 13 months in untreated patients. By illustrating the case of a patient whose AL amyloidosis was detected after presenting a nephrotic syndrome, the characteristics of the disease are reviewed as well as diagnostic criteria and current available therapeutics.