The role of Frizzled-4 mutations in familial exudative vitreoretinopathy and Coats disease.

AIM: The aim of this study is to assess the role of Frizzled-4 (FZD4) in familial exudative vitreoretinopathy (FEVR) and Coats disease. METHODS: Tissue samples were collected for DNA extraction and automated DNA sequencing of the two coding exons of FZD4 in both directions. Cases carrying a FZD4 mutation and demonstrating extreme disease severity were selected for direct automated sequencing of all coding exons of LRP5, NDP and TSPAN12. Clinical data were obtained for the purpose of identifying genotype-phenotype correlations. RESULTS: 68 probands were diagnosed as having autosomal dominant or sporadic FEVR. Eleven FZD4 mutations (five missense, three deletions, one insertion, two nonsense) were identified. Six of these mutations are novel, and none were found in 346 control chromosomes. In 16 cases of Coats disease, one polymorphism combination was found in two samples: no mutations were detected. No genotype-phenotype correlation emerged. Three severely affected cases with FZD4 mutations failed to show additional mutations in the three other FEVR genes. CONCLUSION: The authors identified 12 FEVR probands with FZD4 mutations. FZD4 mutation screening can be a useful tool especially in mild or atypical cases of FEVR. Germ-line mutations in FZD4 do not appear to be a common cause of Coats disease.

Primary cutaneous PEComa.

A 48-year-old woman attended a physician because of a solitary cutaneous nodule on the left lower leg. Microscopic examination of the excisional specimen revealed a dermal tumor composed of nests of epithelioid cells exhibiting clear cytoplasm. They had centrally located vesicular nuclei with distinct nucleoli. A rich network of capillaries was present throughout. The tumor showed an infiltrative border. There was no epidermal involvement. Periodic acid-Shif (PAS) and PAS-Diastase stains demonstrated glycogen deposition within the cytoplasm of the clear cells. Immunohistochemical evaluation revealed that the tumor cells were positive for HMB-45 and microftalmia associated transcription factor (MITF). Focal desmin positivity was also seen. The tumor cells were negative for S-100 protein, alfa smooth muscle actin, HHF-35, and various cytokeratins. The case is one of a primary cutaneous pecoma. Pecomas are rare, recently described mesenchymal tumors composed of perivascular epithelioid cells. They constitute a spectrum of lesions in different organs including angiomyolipoma of the kidney and liver, sugar tumor of the lung, lymphangiomatosis, and lymphangiomyoma. Primary cutaneous PEComas are exceptionally rare and have only recently been recognized. To date, these are approximately 22 cases in the English literature. Follow-up data is limited but they appear to behave in a benign fashion. We report an additional case with the goal of alerting dermatopathologists to this distinctive unusual neoplasm.

Detection of tyrosinase mRNA in the sentinel lymph nodes of melanoma patients is not a predictor of short-term disease recurrence.

Sentinel lymph node evaluation has enabled identification of patients with cutaneous melanoma who might benefit from elective regional lymph node dissection. Sentinel nodes are currently assessed by histologic and reverse transcription polymerase chain reaction (RT-PCR) evaluation for melanocyte-specific markers. The clinical significance of positive findings by RT-PCR in the absence of histologic evidence of metastasis (HIS(NEG)/PCR(POS)) remains unclear. Examination of 264 lymph nodes from 139 patients revealed histopathologic positivity in 34 patients (24.5%), in which 26 also demonstrated simultaneous RT-PCR positivity (HIS(POS)/PCR(POS)). Of 35 HIS(NEG)/PCR(POS) patients (25.2%), five also had nodal capsular nevi. In total, capsular nevi were detected in 13 patients (9.4%). A total of 70 patients (50.4%) had negative sentinel nodes by both histopathology and RT-PCR (HIS(NEG)/PCR(NEG)). Over a median follow-up of 25 months, local and/or systemic recurrence developed in 31 patients (22.3%). Recurrence rates were similar among patients with histopathologic evidence of sentinel lymph node metastasis, irrespective of RT-PCR status (HIS(POS)/PCR(POS) 62%; HIS(POS)/PCR(NEG) 75%). In contrast, only 10% of HIS(NEG)/PCR(NEG) patients developed recurrence, significantly less than those in either HIS(POS) group (P<0.0001). Recurrence in the HIS(NEG)/PCR(POS)/CN(NEG) group (7.7%) was comparable to that in HIS(NEG)/PCR(NEG) patients and significantly lower than that in either HIS(POS) group (P<0.0001). The only independent prognostic factors identified by multivariate analysis were the Breslow thickness of the primary tumour and histopathologic positivity of sentinel nodes. Our findings support previous observations that histopathologic evidence of metastatic melanoma in sentinel lymph nodes is an independent predictor of disease recurrence. In contrast, detection of tyrosinase mRNA by RT-PCR alone does not appear to increase the likelihood of short-term disease recurrence.