Melanocytic tumors express connexin 43 but not 26: immunohistochemical analysis with potential significance in melanocytic oncogenesis.

Connexins (Cx) are structural proteins that form gap junctions, which are vital to cell-cell communication and help to regulate cell division. The purpose of this study was to evaluate if there are diagnostically important differences in immunostaining for connexins 43 (Cx43) and 26 (Cx26) in melanoma compared with nevi. Formalin-fixed paraffin-embedded sections of 34 histologically well-characterized melanocytic lesions, 17 primary malignant melanomas (MM), and 17 nevi were stained with a polyclonal antibody to Cx43 and a polyclonal antibody to Cx26. Immunoreactivity in tumor cells was evaluated semiquantitatively based on extent (1%-100%) and intensity (0-3) of reactivity. A score of 0-300 was generated by the product of the extent and intensity readings in each case. Significantly higher Cx43 immunoreactivity was detected in MM (mean intensity score = 253.5; 95% confidence interval, 227.9-279.2; P = 0.002) compared with nevi (mean intensity score = 152.4; 95% confidence interval, 104.9-199.8). In contrast, Cx26 immunoreactivity was less than 5% or entirely absent in all melanocytic tumors (n = 34). The significantly higher Cx43 staining in MM when compared with nevi suggests an oncogenic role for this protein in melanocytic tumor progression. Consequently, the evaluation of immunohistochemical staining for Cx43 in conjunction with other ancillary stains and tumor histology may be helpful in distinguishing MM from nevi, although positive Cx26 reactivity suggests that a cutaneous neoplasm is of nonmelanocytic origin.

Clinicopathologic correlation of cutaneous metastases: experience from a cancer center.

OBJECTIVE: To analyze the clinical, histopathologic, and immunohistochemical characteristics of skin metastases. DESIGN: Retrospective analysis (January 1, 1990, to December 31, 2005). SETTING: Comprehensive cancer center. PATIENTS: Fifty-one patients (21 men and 30 women) with biopsy-proven skin metastases and correlative clinical data. INTERVENTIONS: Four dermatopathologists reviewed a random mixture of metastases and primary skin tumors. Immunohistochemical studies for 12 markers were performed on the metastases, with skin adnexal tumors as controls. MAIN OUTCOME MEASURES: Clinical characteristics of cutaneous lesions, clinical outcomes, histologic features, and immunohistochemical markers. RESULTS: Eighty-six percent (43 of 50) of the patients had known stage IV cancer, and skin metastasis was the presenting sign in 12% (6 of 50). In 45% (21 of 47) of the biopsies, the lesions were not suspected of being metastases owing to unusual clinical presentations. Seventy-six percent of the patients died of disease (median survival, 5 months). On pathologic review, many metastases from adenocarcinomas were either recognized or suspected, but the primary site was not easily identified based on histologic findings alone. Metastases from small cell carcinomas and sarcomas were histologically misinterpreted as primary skin tumors. Immunohistochemical analysis using a panel including p63, B72.3, calretinin, and CK5/6 differentiated metastatic carcinoma from primary skin adnexal tumors. CONCLUSIONS: Cutaneous metastases can have variable clinical appearances and can mimic benign skin lesions. They are usually seen in patients with advanced disease, but they can be the presenting lesion. Although many metastatic adenocarcinomas can be recognized based on histologic findings alone, immunohistochemical analysis is an important diagnostic adjunct in some cases.

Detection and diagnostic utilization of placental alkaline phosphatase in muscular tissue and tumors with myogenic differentiation.

Placental alkaline phosphatase (PLAP) is normally produced by primordial germ cells and syncytiotrophoblasts, and the detection of its expression has been useful in the diagnosis of germ cell tumors. We have recently observed PLAP immunoreactivity in normal human adult and fetal muscle tissue. Based on this observation, we explored the possible role of PLAP in the diagnosis of soft tissue tumors. A total of 271 tumors were studied. These included tumors with myogenic, neural, fibrous, myofibroblastic, lipomatous, neuroepithelial, perivascular, and epithelial differentiation. A formalin-fixed, paraffin-embedded section from each tumor was stained with PLAP monoclonal antibody using standard immunohistochemical methods preceded by antigen retrieval. In addition, western blotting with PLAP monoclonal antibodies was performed on fresh samples from a uterine leiomyoma, grossly normal myometrium, and placenta. Also, formalin-fixed sections of fetal skeletal muscle were labeled with double immunohistochemistry techniques using antibodies to myogenin and PLAP. Cytoplasmic PLAP reactivity was detected in all leiomyomas and rhabdomyosarcomas (100%), 7 of 15 (46%) leiomyosarcomas, 15 of 19 (79%) desmoplastic small round cell tumors, 2 of 15 (13%) gastrointestinal stromal tumors, 1 of 8 (13%) Wilms' tumors, 1 of 9 synovial sarcomas (9%), and 2 of 7 (29%) myofibroblastic tumors. No PLAP reactivity was detected in hyperplastic scars, nodular fasciitis, or the other remaining soft tissue and epithelial tumors. Double immunohistochemistry studies showed coexpression of myogenin and PLAP in fetal skeletal muscle cells, and western blot analysis showed a 70-kDa band in samples derived from grossly normal placenta, benign myometrium, and a uterine leiomyoma. PLAP immunoreactivity is detected in soft tissue tumors with known myogenic differentiation. PLAP immunoreactivity seems to relate to the degree of myogenic differentiation in soft tissue tumors and is more frequently expressed in cells with skeletal muscle differentiation and least in those with myofibroblastic features. The biologic function of PLAP in muscle and tumors with myogenic differentiation is unknown and merits further investigation. In addition to its role as a germ cell marker, PLAP may also be used as a myogenic marker in the diagnosis of soft tissue tumors.

Fibrillin and other matrix proteins in mitral valve prolapse syndrome.

BACKGROUND: Unlike myxomatous degeneration in Marfan syndrome, which has been reported to result from a mutation in the gene that codes for the extracellular structural protein fibrillin, no specific molecular abnormality has been documented to be the underlying cause of myxomatous degeneration in mitral valve prolapse syndrome (MVPS). The present study examined the distribution of fibrillin and other extracellular matrix proteins in patients with isolated MVPS. METHODS: Mitral valve leaflets from 7 MVPS patients and 5 rheumatic heart disease (RHD) patients were characterized immunohistochemically for fibrillin, elastin, collagen I, and collagen III distribution, and compared with five normal mitral valves. RESULTS: In normal mitral valve leaflets immunostaining for fibrillin, elastin, collagen I, and collagen III revealed a fibrillary and laminar pattern in the atrialis and the spongiosa. In addition, both the collagens were present in the ventricularis, and the coarse bundles in the fibrosa exhibited alternating bandlike collagen I immunoreactivity. The staining patterns of fibrillin, elastin, and collagens I and III revealed distinctly different distribution in MVPS relative to the normal and RHD leaflets. MVPS leaflets in areas of myxoid degeneration displayed a more diffuse, weaker, and nonlaminar pattern of staining for fibrillin. Similar, but less severe abnormality of elastin, collagen I, and collagen III was also observed. Unlike diffuse abnormality in MVPS, the disruption of extracellular proteins in RHD only occurred at the site of the inflammatory damage, but the overall architecture was preserved. CONCLUSIONS: The results of the current study suggest a primary role for abnormal fibrillin and other matrix proteins in producing myxoid degeneration of mitral valve leaflets in MVPS.

Expression of neurotrophin receptor Trk-C in nevi and melanomas.

BACKGROUND: Neurotrophins (NTs) are growth factors for neurons and other neural crest-derived cells. Their functions are mediated by 75-kDa low-affinity glycoprotein receptor (p75) NT receptor and a family of tyrosine kinase receptors (Trks) that includes Trk-A, -B, and -C. Signal transduction through the Trk receptors has been shown to regulate growth and apoptosis of tumors of neuronal origin. In addition, Trk oncogenes have been shown to be rearranged in some non-neuronal neoplasms. Recently, immunoexpression of NT-3 has been shown to be significantly higher in melanomas than in banal nevi on cryostat tissue. METHODS: Since the biologic function of NT-3 is mediated primarily through Trk-C, we investigated Trk-C immunoexpression on paraffin sections of 10 compound nevi and 63 melanomas. RESULTS: The expression of Trk-C was relatively low in compound nevi (30%). Trk-C expression was overall 62% in melanomas of various stages. Our data show that the expression of Trk-C increased as melanoma progressed from in situ (58%) to papillary dermal invasion (91%), and then declined in deeper (57%) and metastatic melanomas (31%). CONCLUSION: These findings suggest a possible role of Trk-C in the progression of early stages of melanoma.