X inactivation, DNA deletion, and microsatellite instability in common acquired melanocytic nevi.

We have investigated several molecular characteristics of common acquired melanocytic nevi to clarify their relationship to malignant melanoma, which is characterized by clonality and the progressive accumulation of DNA deletions. Twenty-four common acquired nevi were subjected to analysis for loss of heterozygosity at four loci on chromosome 9p and six loci on 10q that are commonly deleted in melanoma, but no deletions were seen. X inactivation analysis was performed in lesions from females, using the methylation-sensitive restriction HpaII site in the CAG microsatellite repeat (HUMARA) in exon 1 of the androgen receptor (AR) gene. In 14 melanomas, 11 (92%) were confirmed to have skewed X inactivation, consistent with monoclonality, as were 16 (80%) of 20 benign nevi. One nevus (5%) and 4 (33%) of 12 melanomas also showed loss of heterozygosity at HUMARA. One nevus showed an additional allele, consistent with low level microsatellite instability, at one of the 11 loci that were examined. Common melanocytic nevi, therefore, arise by apparently clonal proliferation, but they do not share chromosomal deletions that are characteristic of melanoma. However, skewed X inactivation patterns were seen in some samples of adjacent microdissected normal epidermis.

CDKN2A mutation and deletion status in thin and thick primary melanoma.

Human melanoma cell lines and tumor tissue from familial and sporadic melanomas have frequent, nonrandom chromosomal breaks and deletions on chromosome 9p21, a region that includes the tumor suppressor gene CDKN2A/p16INK4A. Germ-line mutations within this gene have been observed in some familial melanoma kindreds, but somatic mutation in sporadic primary melanoma is infrequent. Thirty-nine archival, paraffin-embedded, sporadic, primary cutaneous malignant melanomas (20 >3-mm-thick and 19 <0.75-mm-thick cases) were examined for mutations of the CDKN2A gene using single-strand conformational polymorphism analysis and direct sequencing. No mutations were detected. Loss of heterozygosity for the 9p21 microsatellite marker D9S942 was detected in 6 of 17 informative thick lesions (35%) but 0 of 18 thin lesions (P = 0.006). These results support other studies indicating that intragenic mutation is an infrequent mechanism of CDKN2A inactivation in primary melanoma. The finding of loss of heterozygosity for the 9p21 microsatellite D9S942 in thick but not thin primary melanoma suggests that deletion or inactivation of CDKN2A or other tumor suppressor gene(s) at this locus is involved in the progression rather than initiation of sporadic malignant melanoma.

A large-animal model to evaluate the clinical potential of fetal pig pancreas fragment transplantation.

The long-term goal of this study is to assess the feasibility of using fetal pig pancreas fragment (FPPF) transplantation to treat patients with type I diabetes. Using the highly inbred Westran Pigs, our initial aim was to establish a rejection-free transplant model of FPPF grafted into sibling recipient pigs without immunosuppression. FPPFs were isolated from 80-100-day-old fetuses of either Westran Pigs or outbred pigs and transplanted into the thymus, spleen, liver, or kidney of the recipient Westran pig. Biopsies were taken from each transplant site at set time points and assessed histologically for islet viability, rejection, and endocrine function. Fifty-eight fetal donors were used to transplant 16 recipient pigs. A nonspecific inflammation was seen for both outbred and inbred FPPF donor tissue at day 3 and was considered a response to ischemic necrosis. However, all the transplanted outbred FPPF donor tissue was acutely rejected and lost by day 10-14. In contrast, inbred FPPF tissue showed little evidence of graft necrosis after 3 days, and growth and formation of epithelial islet cell nest-like structures were seen to 28 days after transplantation. With time after transplantation, increasing amounts of insulin immunoperoxidase staining was seen together with chromogranin and somatostatin staining. In summary, this study confirms the potential of the Westran pig to answer the unproven ability of fetal pancreatic tissue to reverse type I diabetes in a large animal model.

Subungual malignant melanoma with cartilaginous differentiation.

A case of subungual malignant melanoma with cartilaginous differentiation is presented and the phenomenon of sarcomatoid differentiation in malignant melanoma reviewed. Osseous and/or cartilaginous (osteocartilaginous) differentiation of malignant melanoma is rare. Only 14 cases have previously been reported. This small number of cases and the subject of this Case Report have several features in common, including acral (particularly subungual) location, high Breslow thickness, presence of a lentiginous radial growth phase component, and predominance of epithelioid melanocytes with amelanotic cytoplasm. Melanoma with osteocartilaginous differentiation may therefore represent a subgroup of melanoma with distinctive clinical and pathologic features. Further study is required to establish whether any unique molecular or genetic features are also present.

Leiomyoma of the thyroid gland.

Primary smooth muscle tumors of the thyroid gland are very rare neoplasms, leiomyosarcomas comprising the majority of these. Only three cases of primary leiomyoma have been reported to date, all of which have occurred in females of varying ages. We present the morphological, immunohistochemical and ultrastructural features of a fourth case of leiomyoma of the thyroid gland, occurring in a post-menopausal woman with a history of uterine leiomyomas.

Composite mantle-cell lymphoma and plasmacytoma.

We report a case of a composite lymphoma comprising both mande cell lymphoma and a plasmacytoma. The two components were morphologically and immunohistochemically quite distinct. These properties, coupled with both direct and indirect molecular genetic evidence, suggest that these were two separate tumours occurring together by chance or by unknown oncogenic mechanisms, rather than clonally linked lymphomas.

Primary intracerebral small lymphocytic non-Hodgkin's lymphoma with plasmacytoid differentiation, associated with prominent extracellular proteinaceous deposits.

A case of primary intracerebral non-Hodgkin's lymphoma in a 67-yr-old immunocompetent female is presented. The histopathological diagnosis was supported by immunohistochemical, flow cytometric and electron microscopic findings, and by clinical staging. This tumor is unusual in its morphological features of a low grade, small lymphocytic lymphoma with plasmacytoid differentiation (Working Formulation Classification), and its association with extensive, local, extracellular, proteinaceous deposits. Primary central nervous system non-Hodgkin's lymphomas are briefly discussed and it is postulated that the extracellular proteinaceous deposits in this case originated from immunoglobulins secreted by the neoplastic cells. To our knowledge the massive degree of local immunoglobulin deposition present in this primary central nervous system lymphoma has not been previously reported in the literature.