Immunohistochemical analysis of small cell tumors of the thyroid gland: an Eastern Cooperative Oncology Group study.

The majority of small cell anaplastic tumors of the thyroid gland are generally believed to be non-Hodgkin's lymphomas, including most of those formerly classified as small cell carcinomas. Using a panel of antibodies capable of detecting epithelial, neuroendocrine, and B and T cells in paraffin-embedded tissue sections, we studied 68 thyroid neoplasms in which the original diagnosis was small cell carcinoma or lymphoma. Sixty-three of the tumors were identified as lymphomas of B-cell origin on the basis of L26 reactivity used in conjunction with light chain restriction and MB2 immunostaining. Two additional tumors were classified as lymphomas of indeterminate phenotype. Immunophenotyping indicated an epithelial origin in the remaining three tumors. No cases of medullary carcinoma were detected by immunostaining. Histologic review revealed a predominance of large cell and immunoblastic lymphomas, with low-grade lymphomas of mucosa-associated lymphoid tissue histology accounting for only five cases. Our findings indicate that the majority of small cell anaplastic tumors of the thyroid are B-cell lymphomas. Although primary small cell carcinoma of the thyroid may rarely occur, this diagnosis should not be made without immunohistologic confirmation.     

Immunohistochemical localization of metallothionein in human thyroid tumors.

High levels of metallothionein (MT) are present in the developing mammalian liver; however, a remarkable decrease is observed during postnatal life after weaning. This developmental profile is similar to that of certain oncofetal gene products such as alpha-fetoprotein, which is used as a tumor marker. This study deals with the reexpression of MT genes in thyroid tumors. With an immunohistochemical method, the presence of MT was investigated in tissue sections of normal and neoplastic human thyroid glands. Tissue sections of 34 thyroid tumors and 10 normal human thyroid glands were studied by means of the peroxidase-antiperoxidase method. MT was localized in 31 of the thyroid gland tumors. MT was also present in two of the normal thyroid glands. These findings indicate that although high levels of MT are mainly found in the fetal liver, it may also be expressed actively in certain human thyroid neoplastic tissues, and occasionally in normal thyroid tissue.     

Expression of intermediate filament proteins in thyroid gland and thyroid tumors

The presence of intermediate filament proteins of cytokeratin/prekeratin type and vimentin type was evaluated in non-neoplastic thyroid glands and in different types of thyroid neoplasms. Follicular epithelium of both normal and goitrous thyroids showed a strong reaction with anticytokeratin antibodies that widely cross-react with various simple epithelia. On the other hand, in normal thyroid, there were only occasionally (in one of 12 cases) solitary cells reacting with antibodies to epidermal prekeratin. In nodular goiters, such cells were often seen (eight of 18), especially among the lining cells of cysts, and in chronic thyroiditis in all (12 of 12) cases. Only the stromal cells and intraluminal macrophages reacted with antibodies to vimentin. Neoplastic cells of papillary carcinomas showed a positive staining reaction both with antibodies to cytokeratins and to epidermal prekeratin. Follicular carcinoma cells, although positive for cytokeratins, could generally not be stained with antibodies to epidermal prekeratin. Medullary carcinoma cells also showed cytokeratin positivity and, only occasionally, positivity for epidermal prekeratin. Anaplastic carcinomas were also reactive with antibodies to cytokeratin but, for the most part, were negative for epidermal prekeratin. Interestingly, some neoplastic cells of all types of thyroid carcinomas also appeared to contain vimentin, as shown with both polyclonal and monoclonal antivimentin antibodies. In contrast to carcinomas, the intermediate filaments of thyroid sarcomas and lymphomas were only of vimentin type. Furthermore, it was found that the papillary structures in benign goiters were only reactive with cytokeratin antibodies and lacked, in contrast to papillary carcinomas, epidermal prekeratin-like immunoreactivity. Hence, the analysis of intermediate filament proteins of thyroid tumors can be utilized to differentiate between papillary and follicular carcinomas and between benign and malignant papillary lesions as well as between anaplastic thyroid carcinomas and sarcomas or lymphomas.     

Immunohistochemical characterization of basal cell adenomas of the salivary gland

Seven cases of basal cell adenomas of the salivary gland were analyzed by immunohistochemical methods with a broad panel of routinely used antibodies. Histologically the epithelial elements were classified as tubuloglandular, trabecular and solid patterns. The authors' results indicated the following: 1) The duct lining cells of tubuloglandular and trabecular patterns have distinct epithelial features with cytokeratins (KL 1, PKK 1, *PKK 2 and PKK 3), alpha-one-antichymotrypsin (alpha 1-ACT), carcinoembryonic antigen (CEA) and S-100 alpha subunit positivity. 2) The basaloid cells in the trabecular and solid patterns expressed two immunophenotypes: one had actin, neuron-specific enolase (NSE), S-100 protein and S-100 beta subunit patterns typical of myoepithelial cells in normal glands. The other basaloid cells had vimentin and S-100 protein patterns. The former cell type could be found in 4 of 7 cases and the latter was found in 7 cases. This represents a minor participation of the myoepithelial cells in the basal cell adenoma. 3) The basement membrane and stromal connective tissue around the neoplastic cells were positive for alpha-one-antitrypsin (alpha 1-AT). This antibody is a good marker in identifying the basement membrane-like material.     

Immunohistochemical localization of metal binding proteins in thyroid tissues and tumors

Positive immunohistochemical staining for three metal binding proteins, ceruloplasmin, lactoferrin, and transferrin, has been suggested to be a reliable diagnostic marker of malignant but not benign thyroid neoplasms. We tested this hypothesis on a series of 9 nodular hyperplasias, 17 follicular adenomas, 54 papillary carcinomas, 20 follicular carcinomas, and 3 anaplastic carcinomas of thyroid using formalin-fixed paraffin-embedded tissues. We found focal staining for ceruloplasmin and lactoferrin in approximately 25% of follicular adenomas examined; focal ceruloplasmin positivity was also seen in nonneoplastic tissues surrounding thyroid neoplasms. No staining for these markers was found in malignant neoplasms or hyperplasias. Transferrin was found in 55% of papillary carcinomas, but more follicular adenomas (20%) than follicular carcinomas (11%) were positive using this antiserum. These findings show that immunostaining for these antigens is not a reliable method to distinguish benign from malignant thyroid lesions of follicular cell origin.     

Immunohistochemical localization of keratin, vimentin and myosin in salivary gland tumors

An immunohistochemical study on keratin, vimentin, and myosin was performed in 117 specimens of human salivary gland under normal and several neoplastic conditions. In normal glands, positive immunostaining for keratin was observed in the inner cells of all ductal systems, whereas myosin and vimentin were the cytoskeletal components of myoepithelial cells. In pleomorphic adenoma, the inner cells showing a tubular pattern demonstrated positive immunostaining for keratin, and the outer cells as well as the neoplastic cells with a solid and myxoid pattern exhibited positive immunostaining for all antibodies. Monomorphic tubular and trabecular adenoma, and adenolymphoma showed positive immunostaining for keratin, although one case of tubular adenoma exhibited positive immunostaining for all antibodies. Squamous cell carcinoma, adenosquamous carcinoma, and mucoepidermoid tumor showed positive immunostaining only for keratin, but one case of adenocarcinoma, two cases of adenoid cystic carcinoma, and clear cell tumor disclosed positive immunostaining for keratin and vimentin.     

Immunohistochemical characterization of pancreatic tumors induced by dimethylbenzanthracene in rats

Dimethylbenzanthracene (DMBA) induces pancreatic adenocarcinomas in rats 9 months after carcinogen exposure, with precursor lesions (tubular complexes) developing 1 month after initiation of treatment. Because previous studies have suggested an acinar cell of origin for these tumors, we investigated the expression pattern of ductal, acinar, and islet cell markers in these cancers to gain insight into their phenotype and cell of origin. Pancreatic neoplasms were induced in rats by implantation of DMBA into the head of the pancreas. Lesions studied included 10 early tubular complexes (DMBA for 2 weeks), 8 tubular complexes (DMBA for 1 month), and 10 adenocarcinomas (DMBA for 9 months). Normal rat pancreas served as a control. For comparison, 5 human ductal adenocarcinomas were also evaluated. Immunohistochemistry with ductal (keratin, cytokeratin 19, cytokeratin 20), acinar (chymotrypsin), and islet (chromogranin A) cell markers was performed to analyze the tissues. Rat tubular complexes and adenocarcinomas revealed strong expression of keratin, cytokeratin 19, and cytokeratin 20 in the cytoplasm of all neoplastic cells, absence of chymotrypsin, and rare immunoreactivity to chromogranin A. Human adenocarcinomas showed strong expression of keratin and cytokeratin 19 in all neoplastic cells, expression of cytokeratin 20 in 5-20% of cells, and absence of chymotrypsin and chromogranin A. Pancreatic adenocarcinomas induced by DMBA in rats express markers consistent with a ductal phenotype, as observed in human tumors. Ductal marker expression in early tumor stages suggests a ductal cell of origin.     

Immunohistochemical expression of cytokeratins 7 and 20 in malignant salivary gland tumors.

On the basis of the heterogeneity of cytokeratins 7 and 20 expression in malignant epithelial tumors, the cytokeratin 7/20 immunophenotype has served as a useful diagnostic tool for discrimination of primary and/or metastatic carcinomas of unknown origin. However, the expression pattern of these cytokeratins in malignant salivary gland tumors has not been thoroughly studied. Our study material was composed of 84 malignant tumors of primary major or minor salivary gland origin. Nine histologic types of carcinoma were represented, including mucoepidermoid (26 cases), adenoid cystic (25), polymorphous low grade (11), salivary duct (8), acinic cell (4), ex mixed tumor (3), not otherwise specified (3), clear cell (2), and basal cell (2). In all, 13 cases of primary skin or mucosal squamous cell carcinoma with secondary salivary gland involvement were also examined. Immunoreactivity for cytokeratin 7 was evident in all malignant salivary gland tumors; the staining pattern was diffuse and strong in 62 cases, and focal and strong in 22 cases. In contrast, 78 cases were negative for cytokeratin 20, whereas only six cases (two mucoepidermoid, one adenoid cystic, and three salivary duct) displayed focal weak positivity. Overall, 92.9% of malignant salivary gland tumors were characterized by a cytokeratin 7 positive/20 negative immunoprofile, the remaining 7.1% of cases being positive for both cytokeratins. The latter phenotype was more common in salivary duct carcinomas (P< or =0.05). On the other hand, most squamous cell carcinomas (69%) were negative for both cytokeratins, while the remaining cases (31%) were negative for cytokeratin 20 and focally weakly positive for cytokeratin 7. We suggest that assessment of cytokeratin 7/20 immunoprofile may facilitate the differential diagnosis of (a) primary malignant salivary gland tumors from metastatic tumors, (b) metastatic salivary gland tumors, (c) primary salivary gland tumors, especially mucoepidermoid carcinomas, from squamous cell carcinomas, and (d) salivary duct carcinomas from other malignant salivary gland tumors.     

Immunohistochemical detection of acid cysteine proteinase inhibitors in lymphatic infiltrates of the thyroid gland

Thyroid tissues containing lymphoid secondary follicles were studied immunohistochemically for the presence of acid cysteine proteinase inhibitor (ACPI). Reticulum cells in the lymphoid secondary follicles, mainly dendritic reticulum cells, exhibited a positive reaction. In addition, in 2 cases a positive reaction could be detected in some of the thyroid epithelial cells, adjacent to the lymphoid secondary follicles. The possible function of ACPI generally and its role in the function of those cells containing it, is discussed.     

Immunohistochemical study in differential diagnosis of benign and malignant lesions of the thyroid gland

The paper is devoted to immunohistochemical (IHC) investigation of various benign and malignant proliferating lesions in the thyroid with a special focus on borderline lesions--atypical adenomas (AA) and focal adenomatous areas (FAA). All papillary carcinomas (PC) and FAA in Hashimoto thyroiditis demonstrated strong immunoreactivity for CK-19. More than 50% of PCNA-positive cells were detected in most of the investigated carcinomas; in FAA, and in AA PCNA expression was not so prominent but higher than in other adenomas and nodular goiters. Strong expression of vimentin by follicular epithelium was detected in PC. In FC, AA and FAA it was focal from moderate to strong. In other cases immunoreactivity to vimentin was weak or absent. Thus, it is worth to form on the basis of histological and IHC results the group of thyroid proliferating processes with possible malignant transformation. AA and FAA with more than 10% PCNA-immunoreactive cells and vimentin expression from moderate to strong should be included in this group. Further observation of our patients will enable to assess malignant potential of this processes. Besides, CK-19 expression is an additional criterion for the diagnosis of early PC.     

Immunohistochemical characterization of ovarian borderline tumors of intestinal and mullerian types.

A panel of monoclonal antibodies (MAbs) including MOv2, MOv8, anti-CA 19-9, and anti-carcinoembryonic antigen (CEA), and a polyclonal antibody against CEA, was applied to three types of ovarian borderline tumors. The tumors included 19 intestinal-type mucinous borderline tumors (IMBTs), 22 endocervical-like mucinous borderline tumors (EMBTs), and 23 mixed-epithelial borderline tumors (MEBTs); the latter two tumors are of mullerian type. Statistically significant differences in the percentage of positive IMBTs compared to the mullerian tumors were seen for anti-CEA and MOv8; strikingly different staining patterns were also seen. IMBTs were more often and more diffusely CEA-positive than were the mullerian tumors; within the mullerian tumors, only one type of cell, the indifferent eosinophilic cell, was consistently CEA positive. The MAbs MOv2, MOv8, and anti-CA 19-9 showed more extensive positivity in the mullerian tumors than in the IMBTs. This study highlights the differences in cell types between IMBTs and these two types of mullerian borderline tumors.