Novel RET mutations in macedonian patients with medullary thyroid carcinoma: genotype-phenotype correlations.

Medullary thyroid carcinomas (MTCs) are rare neoplasms comprising 2-10% of all thyroid malignnancies. More than 75% are sporadic tumors and the remainder is familial and MEN2 related. Both sporadic and syndromic MTCs frequently show mutations in the RET proto-oncogene. It has been noted that some MTC cases present an indolent, and some an aggressive clinical course. Ki-67 expression is generally low, with documented exceptions, whereas high expression of Bcl-2 has been reported in majority of the cases. Some studies have shown that Ki-67 and Bcl-2 expressions have prognostic value, as well as RET mutational status. We analyzed 20 unrelated MTC cases for Ki-67, Bcl-2 expression and RET mutations and tested their intercorrelations, correlations to the morphologic features and stage of the tumors, as well as their influence on survival. In 13 of the 20 analyzed cases we found 23 sequence changes distributed in exons 8, 10-13 and 16. There were 11 different missense mutations, single nucleotide deletion with frameshift, and 8 different synonymous mutations. Only 4 of the sequence changes have been previously published. Twelve patients (60%) had tumors expressing one or more missense mutations or single nucleotide deletion and 7 of them (35%) had at least one damaging or possibly damaging RET mutation. Most of the tumors had low Ki-67 expression (mean 6.48% of cells) and high Bcl-2 expression (mean 68.3%). Significantly better survival was observed in cases with low Ki-67 (< 6.5%; p < 0.05), high Bcl-2 expression (> 68.3%; p < 0.01) and younger age at diagnosis (< 51 years; p < 0.05).

Histological features, Ki-67 and Bcl-2 immunohistochemical expression and their correlation with the aggressiveness of pheochromocytomas.

Pheochromocytomas and paragangliomas are rare neoplasms. Approximately 10% may present malignant behaviour. There are no reliable morphological signs of malignancy, except for the presence of metastasis. We performed morphological and immunohistochemical analysis on 15 pheochromocytomas and 5 paragangliomas aiming to find correlations between the morphological features of the tumours, immunohistochemical expressions of Ki-67 and Bcl-2, and the biological behaviour of the tumours. According to the biological behaviour of the tumors, the patients were divided into an indolent disease group (ID), and an aggressive disease group (AD). The morphological analysis included the PASS core parameters, greatest tumour diameter and weight, as well as age and gender of the patients, survival and disease-free periods after operation. According to histomorphological parameters, tumours were divided into tumours with "benign-like" morphology and tumours with "malignant-like" appearance. The disease course was neither correlated to the PASS score, nor to the individual parameters comprising it. The rest of the morphological parameters and the immunohistochemical expressions of Ki-67 and Bcl-2 were not able to predict the disease course, although we found significantly higher Ki-67 expression in paragangliomas in comparison to pheochromocytomas (p<0.01). Some of the PASS parameters (vascular invasion and presence of atypical mitoses) were positively correlated to the tumour weight (R=0.75; p<0.01, and R=0.56; p<0.05, respectively). The disease course was in positive correlation to the tumour weight, presence of vascular invasion and atypical mitoses; however there were no statistically significant differences regarding those parameters between the ID and AD groups (p>0.05).

Gastrointestinal malignant lymphomas in Macedonia.

The gastrointestinal tract including oral cavity is the most common location of extranodal lymphomas. In this retrospective study, the histomorphological, immunohistochemical and clinical features of 21 Macedonian cases with diagnosed malignant lymphomas were investigated. The series included 15 males and 6 females, mean age 44 (4-78) years. The most common locations were hard palate (n = 7), gastric site (n = 5), small intestinal wall (n = 2), large intestinal wall (n = 5), and lingual root (n = 2). All cases were B cell lymphomas, 23.8% of them low grade B cell lymphoma of mucosa associated lymphoid tissue, 4.7% mantle cell lymphoma, 47.6% diffuse large cell lymphoma, and 23.8% Burkitt type lymphoma. There was no T cell lymphoma. Most of the cases were positive for CD20 and CD79a. Monoclonality was confirmed by light chain restriction, except for nine cases where it failed due to poor tissue preservation. The fact that eight cases were in the clinically advanced third and fourth stage implied a conclusion that not only primary non-Hodgkin's lymphomas but also secondary lesions could invade the gastrointestinal tract. Immunohistochemical staining was helpful in differentiation between benign and malignant infiltration in low grade lymphomas, and in distinguishing diffuse large cell lymphomas from undifferentiated epithelial neoplasms.

Immunohistochemical and ultrastructural features of Gaucher's cells--five case reports.

Gaucher's disease is an autosomal recessive lysosomal storage disease resulting from glucocerebrosidase deficiency. In this report, five patients with adult Gaucher's disease are described. The clinical course of these patients was characterized by progressive diffuse aseptic necrosis in the large bones, so-called Erlenmeyer's flask deformity, and hepatosplenomegaly. Splenomegaly was accompanied by hypersplenism with anemia and thrombocytopenia, therefore splenectomy was performed. The diagnosis of Gaucher's disease was based on the finding of Gaucher's cells on bone marrow biopsy. Tissue blocks were cut and routinely processed. Slides staining for iron (Peris' blue) and PAS (periodic acid--Schiff) including immunohistochemical staining for CD68 and HLA-DR was performed in all five cases. Gaucher's cells were seen as large cells with granular or fibrillar distended cytoplasm, with the characteristic 'wrinkled tissue paper' appearance, and eccentric nuclei. PAS staining showed strongly positive granular or fibrillar material in the cytoplasm. Immunohistochemical stain for CD68 and HLA-DR helped identify isolated Gaucher's cells, which are hystiocytic in nature. This stain accentuates their fine linear striations. Small pieces were ultrastructurally analyzed.