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Differentiation between primary colonic adenocarcinoma arising in flat mucosa and carcinoma metastatic to the colon is often difficult. Examination of the mucosa adjacent to the tumor, the so-called transitional mucosa (TM), may be helpful. The morphologic, ultrastructural, and histochemical characteristics of the TM have been reported previously in detail. In this study the morphologic and immunohistochemical characteristics of the TM have been compared in 18 cases of primary colonic adenocarcinoma and 13 cases of metastasis to the colon. Five immunophenotypic markers were used: carcinoembryonic antigen (CEA), Lewis (x) and (y) blood group antigens, ras oncogene p21, and tumor-associated glycoprotein (TAG-72). Neoplastic transformation of colonic epithelium is associated with altered expression of these antigens. The morphologic and immunohistochemical profile of the TM was similar in both primary colonic adenocarcinomas and metastases to the colon. In some cases the TM adjacent to colonic metastases stained with one or more antibodies while the metastatic tumor was negative. Therefore, in cases where differentiation between primary colonic adenocarcinoma arising in flat mucosa and metastasis is difficult, the use of these reagents, particularly CEA, TAG-72, or ras oncogene p21, may be helpful. The similar immunohistochemical staining pattern of the TM in both primary and metastatic colon lesions supports a reactive, non-neoplastic origin of the TM. Furthermore, expression of these antigens is not limited to neoplastic epithelial cells.

Two encapsulated medullary carcinomas of the thyroid gland exhibiting an organoid and trabecular pattern with hyalinized stroma and composed of polyhedral to spindled tumor cells with hyaline-appearing cytoplasm are described and compared with three histologically indistinguishable adenomas of follicular cell derivation. Positive immunocytochemical staining for calcitonin and negative staining for thyroglobulin confirms the diagnosis of medullary carcinoma in these tumors, while positive staining for thyroglobulin confirms the follicular cell nature of the adenomas. The distinction between these tumor types is a crucial one, given the prognostic and potential genetic implications of medullary carcinoma.

In kindreds with familial medullary thyroid carcinoma (MTC), individuals are often detected whose peripheral plasma calcitonin (CT) levels are undetectable in the basal state but increase minimally following provocative testing. The proper management of such patients has been uncertain, but most investigators have advocated repeat testing and evaluation after an interval of several months. The present study was conducted to evaluate the diagnostic implications of these modest increases in plasma calcitonin. In 25 kindred members at direct risk for familial medullary thyroid carcinoma (MTC), basal peripheral plasma calcitonin (CT) levels were less than 240 pg/ml. Following provocative testing with intravenous calcium or pentagastrin or both, calcitonin values remained below 240 pg/ml in eight subjects (Group A), however, they were mildly elevated (260-580 pg/ml) in 12 subjects (Group B) and moderately elevated (700-940 pg/ml) in five subjects (Group C). Following the transfemoral placement of a catheter into the inferior thyroid vein (ITV), provocative testing was repeated, and ITV and peripheral blood samples were collected simultaneously. Basal ITV plasma CT levels were below 240 pg/ml in all patients in Group A, however, they were mildly elevated (500 pg/ml) in one of the 12 patients in Group B and moderately elevated (800 pg/ml, 1400 pg/ml) in two of the five patients in Group C. Following provocation, ITV plasma CT levels became markedly elevated in one patient in Group A and in all of the patients in Groups B(2520+/-635 pg/ml) and C (6322+/-2598 pg/ml). Thyroidectomy was performed in patients whose ITV plasma CT level was elevated following provocative testing. Medullary thyroid carcinoma of C-cell hyperplasia were evident either on microscopic (1/1 patient in Group A;9/12 patients in Group B; and 2/5 patients in Group C), or gross (3/12 patients in Group B;3/5 patients in Group C) examination of thyroidectomy specimens. In only one of 14 patients was metastatic MTC noted on histologic examination of resected cervical lymph nodes. Postoperative peripheral plasma CT levels were unchanged from basal and less than 240 pg/ml following provocative testing in all but one patient. The present study then provides definitive evidence that patients at direct risk for familial MTC who have even minimally abnormal responses in peripheral plasma CT following provocative testing generally harbor some stage of a C-cell proliferative disorder. Identification of such individuals with early disease is important because thyroidectomy offers an extremely high cure rate.

Clinical, biochemical, and morphologic parameters in 72 patients with familial medullary thyroid carcinoma (MTC) associated with multiple endocrine neoplasia IIA (MEN IIA) were reviewed. Sixty-nine patients had undergone total thyroid resection. In 27 patients (Group I) the thyroid tumors were smaller than 0.7 cm in diameter; five of these patients had C-cell hyperplasia alone. In 19 patients (Group II) tumors ranged from 0.7 to 1.5 cm, and in 26 patients (Group III) they were larger than 1.5 cm. The mean ages at surgery were 19.6 years (Group I), 33.7 years (Group II), and 32.2 years (Group III). Regional lymph node metastases occurred less often in patients of Group I, 4/20 (20%) and Group II, 4/13 (30%) than in those of Group III, 14/17 (82%) [p = 0.0001]. Elevated postoperative plasma calcitonin levels, indicative of residual MTC, were observed less frequently in patients in Group I, 6/27 (22%) and Group II, 6/15 (50%) than in Group III, 11/15 (73%) [p = 0.005]. All of the patients in Group I and Group II are alive (mean follow-up of 3.5 years and 6.0 years following surgery), whereas 6/26 (23%) Group III patients have died of metastatic MTC, three within 2 years of initial diagnosis. Histologic features varied with tumor diameter. All tumors from patients in Group III contained amyloid, while the majority of those from patients in Group I had an infiltrative configuration and 9/22 tumors lacked amyloid. Among neoplasms from patients in Group III, mitotic figures correlated with distant metastases or death from tumor. Only 1/16 patients who died from MTC had a distinctive tumor morphology, namely a prominent component of small cell anaplastic carcinoma. Early detection of minimal MTC in MEN IIA family members offers the best chance of curing patients with this potentially fatal lesion.

We evaluated the cellular distribution of calcitonin (CT), L-dopa decarboxylase (DDC), and histaminase [diamine oxidase (DAO)] in 33 patients with medullary thyroid carcinoma (MTC). CT immunostaining was uniform (greater than 90% of the cells) and intense (4+) in lesions from 7 patients with C-cell hyperplasia and 6 with microscopic MTC: conversely, patchy CT staining (less than 40% of the cells) and diminished intensity (1+) were found in metastases from 8 patients who died of virulent disease. In 17 patients who underwent thyroidectomy for macroscopic cervical MTC with no evidence distant metastases, CT staining was intense (3-4+) and homogeneous (greater than 90%) in 11 subjects who were well 0.5-16 yr postoperatively. Six patients with similar clinical presentations had heterogeneous staining for CT in primary tumor (less than 40% of the cells; 1-2+ intensity); 5 died of disseminated MTC 0.5-5 yr postoperatively (P less than 0.001). Biochemical studies of distant metastases revealed an inverse relationship between the distribution of CT and that of both relationship between the distribution of CT and that of both DDC (r = 0.71; P less than 0.01) and DAO (r = 0.81; P less than 0.001). We conclude that cellular heterogeneity in MTC tissue is associated with a distinct biochemical pattern, and its presence, whether in a primary or metastatic lesion, indicates a virulent neoplasm associated with a grave prognosis.

Three unusual cases of anaplastic medullary thyroid crcinoma, two having small cell characteristics and one having the features of an anaplastic giant-cell carcinoma, were encountered during a review of 110 cases of familial and sporadic medullary carcinoma. Immunoperoxidase demonstration of calcitonin within tumor cells in these three cases enabled differentiation of the two small cell variants from lymphoma or other small cell carcinomas, and differentiation of the anaplastic giant-cell variant from other giant cell carcinomas of the thyroid. Although the existence of small cell carcinomas of the thyroid gland has been questioned, this study shows that small cell carcinomas of the thyroid gland do exist and that at least some are variants of medullary carcinoma. Whereas previous immunohistochemical studies have been successfully employed in defining the spectrum of C-cell proliferative disorders and in understanding the evolution of medullary thyroid carcinoma, this study demonstrates the value of these techniques in diagnostic pathology. Immunoperoxidase staining can be successfully used in differentiating unusual variants of medullary carcinoma from other thyroid tumors.

We used an unique model, human medullary thyroid carcinoma (MTC) in culture (the TT line), to study features of neuroendocrine-related biochemistry in relationship to growth, differentiation, and tumor progression. Tumor tissues from patients with virulent MTC contain a very heterogeneous distribution of cells staining for calcitonin (CT) and have a high ratio of intracellular L-dopa decarboxylase activity (DDC) to CT. We found, in a culture line of MTC derived from a patient with virulent disease, that the degree of the inverse relationship between DDC and CT and the heterogeneous cellular distribution of CT probably relate to the rate of cellular growth and the biochemical set of individual cell clones. During exponential growth of the parent TT cell line, intracellular DDC and CT varied. DDC increased by 70% and CT decreased by 40%. Single time-point measurements in 54 cell clones or highly enriched cell populations revealed a more dramatic variability for CT (15-fold) than for DDC (5-fold). During growth of the clones having the highest and lowest CT measurements, respectively, inverse dynamics between DDC and CT were again found. However, each clone maintained a distinct range of CT during the entire growth curve, with a 2- to 4-fold difference in CT between the two clones throughout. In the low producing CT clone, ratios between DDC and CT rose to greater than 1.0 during growth, a very high value found before this study only in MTC tissues from patients with virulent disease. Immunohistochemical staining for CT of parent cells and clones grown on embryonic chick skin revealed increased cellular heterogeneity for CT distribution during growth. The TT line provides a powerful tool to study neuroendocrine related biochemical events in relationship to growth, differentiation, and tumor progression in MTC. Our in vitro findings in the TT line well explain observations made previously in patients. We conclude that: (1) DDC, a neural property of MTC, is an early differentiation marker as compared to CT and that the differentiation status of MTC cells varies inversely with cell growth rate; and (2) in patients with MTC, the virulence of the tumor probably varies inversely with differentiation status. The inverse ratio of DDC to CT is probably determined in MTC by the proportion of rapidly growing cells and numbers of cell clones which have a poor ability for maturation.

The distribution of carcinoembryonic antigen (CEA) and its relationship to calcitonin in early, localized, and disseminated (virulent) medullary thyroid carcinoma (MTC) have been studied using immunoperoxidase methods. Carcinoembryonic antigen can be demonstrated within C-cells through all stages of progression of MTC. In early disease (C-cell hyperplasia and microscopic carcinoma), CEA, and calcitonin have a similar distribution, being present in virtually every cell. Likewise, calcitonin and CEA have a similar, homogeneous distribution among cells in gross medullary carcinoma confined to the thyroid region. In both primary and metastatic tumors from patients with virulent, disseminated disease there is an inverse relationship between calcitonin and CEA distribution such that CEA expression is retained and frequently present in the greatest amounts in cells which have poor or absent staining for calcitonin, and present in the least amounts where cellular staining for calcitonin is greatest. It is postulated that in MTC expression of CEA (a marker for early epithelial differentiation), in the face of loss of calcitonin (a marker for terminal differentiation/cellular maturity), may reflect a degree of maturation block in tumors from patients with aggressive disease.

We identified a system, the TT human medullary thyroid carcinoma cell line which contained 74.5 +/- 26.0 ng (mean +/- SD) immunoreactive SRIH/mg protein, for studying the products of SRIH gene expression. The close homology between man and rat for the entire proSRIH and complete homology for a portion of the amino terminus (proSRIH-NTP) permitted the application of a RIA directed toward the amino terminus of rat proSRIH. Immunohistochemical studies of the human TT cell line showed that SRIH and proSRIH-NTP immunoreactivities were present in the same cells. RIA of gel filtration fractions showed that the major cellular proSRIH-NTP-containing species lack SRIH and had an apparent mol wt of 8000. A 10,000-dalton SRIH-containing species coeluting with proSRIH-NTP immunoreactivity, putative proSRIH, also was found. Similar species were found in culture medium. The major cellular and secreted form of SRIH immunoreactivity had a mol wt of 1600 (SRIH). High pressure liquid chromatography revealed that both cellular and secreted 8000-dalton proSRIH-NTP-containing material consisted of a major and several minor species. None of the species contained SRIH. The precise structure of these proSRIH-NTP-containing species and their physiological roles are not known. The fact that proSRIH-NTP-containing species are secreted suggests that they may be functional. Since the processing of proSRIH and consequently the final products appear to be tissue specific, alterations in the relative presence of different forms might reflect specific pathological processes.