Mixed medullary and follicular cell thyroid carcinoma in a dog.

A 12-y-old, castrated male Weimaraner dog was presented for a wellness examination. A 7-cm, firm mass was palpated on the left, ventral, mid-lateral neck. The neck mass was removed surgically and submitted for histopathology. A thyroid carcinoma was diagnosed based on microscopic examination. Immunohistochemistry for chromogranin-A, calcitonin, and thyroglobulin identified dual immunoreactivity of the latter two, and a final diagnosis was of a well-differentiated, compact, mixed medullary and follicular cell thyroid carcinoma. These neoplasms are rare in humans and have not been reported in dogs, to our knowledge.

Fine needle aspiration cytology of mixed medullary-follicular thyroid carcinoma: a case report.

BACKGROUND: Mixed medullary-follicular thyroid carcinoma (MMFTC) is a rare tumor that has been regarded as a clinicopathologic variant of medullary thyroid carcinoma. MMFTC represents a diagnostic challenge by fine needle aspiration cytology (FNAC). CASE: A 77-year-old woman had a palpable mass on the left side of the neck. It was diagnosed as follicular neoplasm by FNAC; she underwent total thyroidectomy. Pathology revealed follicular carcinoma. Radioactive iodine was administered. An enlarging mass was present in the left mandible later. FNAC showed suspicious follicular neoplasm with predominance of oncocytic cells. Pathology revealed follicular carcinoma with parafollicular cell differentiation. Immunohistochemical analysis demonstrated positive status for thyroglobulin and calcitonin. Simultaneous expression of thyroglobulin and calcitonin within the same neoplastic cell was considered. She underwent several courses of radioactive iodine therapy without significant effect. Interestingly, her serum calcitonin level was not elevated. CONCLUSION: Coexpression of thyroglobulin and calcitonin in the same cell is very rare. The component of medullary carcinoma should be considered when encountering an atypical thyroid carcinoma with predominance of cells showing oncocytic changes on FNAC and with clinically poor response to conventional treatment. Immunohistochemistry and pathologic analyses are helpful to confirm the diagnosis, especially in the absence of elevated serum calcitonin level.

Renal medullary carcinoma: ultrastructural studies may benefit diagnosis.

Renal medullary carcinoma is a recently described highly aggressive malignancy that in most instances exhibits a constellation of clinical and light microscopic features sufficiently distinctive to enable a quick and confident diagnosis. Presented are three examples where, because of unusual elements in the clinical presentation, electron microscopic examination proved beneficial in establishing the diagnosis.

[A familial form of medullary carcinoma of the thyroid gland]. / Semeinaia forma medulliarnogo raka shchitovidnoi zhelezy.

A case of a family form of medullary thyroid cancer is reported. Histological, immunohistochemical and ultrastructural data are presented and problems of etiology, pathogenesis and diagnosis are discussed.

Fine needle aspiration biopsy of mixed medullary-follicular thyroid carcinoma. A report of two cases.

BACKGROUND: Mixed differentiated thyroid carcinomas are rare tumors, difficult to recognize on fine needle aspiration biopsy (FNAB). Most cases are diagnosed only after histologic investigation. CASES: The cases entailed two cytologic samples and a thyroidectomy specimen. Two FNAB thyroidectomy specimens from a 60-year-old man presenting with a solitary thyroid nodule (case 1) were investigated. Both cytologic samples were referred as atypical, with a mixture of features indicating a proliferating follicular lesion but also containing some characteristics of medullary carcinoma. The serum calcitonin level was borderline. Surgery was recommended because of a suspicion of malignancy. The diagnosis of mixed medullary follicular carcinoma was established after a complex histologic investigation. The tumor was encapsulated, with partly microfollicular architecture. Immunohistochemistry was positive for both calcitonin and thyreoglobulin. Electron microscopy from the formol-paraffin block found neurosecretory granules in many cells. The patient was well one year after the operation. One FNAB and thyroidectomy specimen from a 47-year-old woman with long-treated lymphoplasmocellular thyroiditis (case 2) was investigated. The tumor in case 2 was diagnosed on FNAB as medullary carcinoma. Only after histologic and immunohistochemical investigation was mixed differentiation proven. CONCLUSION: Mixed differentiated thyroid tumors are a diagnostic challenge on fine needle aspiration. Irrespective of their rarity, they can be suspected if combined features are present. FNAB recognition of the medullary component in both cases was of crucial importance. Nevertheless, definitive diagnosis remains a histologic problem due to the necessity for topographic information.

[Ultrastructural characteristics of thyroid medullary carcinoma]. / Ul'trastrukturnye osobennosti medulliarnogo raka shchitovidnoi zhelezy.

17 thyroid medullary carcinomas (TMC) were studied electron microscopically (EM). Two cell groups were revealed regardless of their histological structure: EM differentiated (with signs of C-cell differentiation) and non-differentiated (without these signs). There is no correlation between histological structure of the tumor and the degree of its EM differentiation. In patients who lived 5 years maximum after the diagnosis there were different histological types but EM the tumors had relatively monomorphous structure with domination of non-differentiated cells (more than 70%), high content of dark cells (50% and more) and low content of desmosomes (less than 30%). The prognosis is more favourable the higher is content of EM differentiated cells, the better desmosomes are developed and the lower is content of dark cells. The scope of surgery and local metastases do not influence the prognosis while distant metastases (stage IV) deteriorate the prognosis.

Differential characteristics of two new tumorigenic cell lines of human breast carcinoma origin.

Permanent human tumor cell lines are an important tool for the study of breast cancer. Two new breast cancer cell lines (BrCa-MZ-01 and BrCa-MZ-02) were isolated from a solid tumor and a pleural effusion, respectively. One cell line was established from a medullary carcinoma, the other from a ductal carcinoma. These cells exhibit ultrastructural and immunohistochemical features of epithelial cells of mammary origin. Intermediate filament and cytokeratin typing showed a clear predominance of the simple-epithelial cytokeratins CK 8, CK 18 and CK 19, although the expression was reduced in comparison to the hormone receptor-positive reference cell lines MCF-7 and ZR-75-1. Both cell lines produced slow-growing tumors after subcutaneous (s.c.) transplantation of 1 x 10(7) viable tumor cells into nude mice. The cell line BrCa-MZ-01 expresses the estrogen and progesterone receptor, whereas the cell line BrCa-MZ-02 remains negative. Both cell lines are positive for secretion of platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta), whereas interleukin-6 (IL-6) is only secreted by the cell line BrCa-MZ-02.

Expression of v-Ha-ras driven by the calcitonin/calcitonin gene-related peptide promoter: a novel transgenic murine model for medullary thyroid carcinoma.

v-Ha-ras has been demonstrated previously to induce neuroendocrine differentiation of medullary thyroid carcinoma (MTC, malignant C cell tumor) cell lines. The potential role of ras mediated signaling in neuroendocrine cells in vivo has been investigated by expressing v-Ha-ras under control of the neural/neuroendocrine specific calcitonin/calcitonin gene-related peptide (CGRP) promoter. Five independent mouse lineages were derived following germ line insertion of the transgene. Four of the five lineages consistently express the transgene; neuroendocrine expression is found in three of the five lineages as both spliced and full length messages. Phenotypically, the mice expressing rascal have shortened lifespans primarily due to the high incidence of MTCs between 6 months to a year of age. C-cell hyperplasia is demonstrated in several mice in the absence of gross evidence of tumor formation. Histopathological and ultrastructural analyses demonstrate typical features of MTCs including prominent immunohistochemical staining for calcitonin and dense-core neurosecretory-type granules. In addition, four of 22 tumors co-express thyroglobulin (a non-neuroendocrine follicular epithelial cell marker) and calcitonin (a neuroendocrine marker) in a subset of the tumor cells. The rascal transgenic mouse provides a unique model for investigating the sequential pathogenesis of MTC and possibly also for elucidating the relationship between MTC and mixed medullary-follicular carcinomas.

Medullary carcinoma of the breast: an ultrastructural morphometric study of nine cases.

Ultrastructural and morphometric features of 10 medullary carcinomas of the breast (MC) were investigated. Cases with a long follow-up were selected by applying stringent histologic criteria. All tumors had a homogeneous appearance by light microscopy. Under transmission electron microscopy, they showed occasional intracellular lumen formation or keratinization. In one tumor squamous differentiation was prominent and diffuse. Tumors with lymph node metastases possessed over 40% more desmosomes than nonmetastatic tumors. The number of cells with three or more nucleoli per nuclear section was significantly higher in metastatic than in nonmetastatic tumors (p = .02). Classic cases of MC of the breast display a relatively uniform appearance. However, subtle differences can be identified between metastatic and nonmetastatic tumors by ultrastructural morphometry. Although these differences are not associated with changes in the outcome of patients in this study, they seem to bear some relationship to the peculiar behavior of MC.

Amphicrine medullary carcinoma of the thyroid with luminal differentiation: report of an immunohistochemical and ultrastructural study.

A case of amphicrine medullary carcinoma of the thyroid is presented. The patient was an 18-year-old female with nonhereditary MEN IIb, submucosal neuromas in the oral cavity, and a thyroid tumor that metastasized to regional lymph nodes. Histologically the thyroid tumor was composed of polygonal cells arranged in a solid/trabecular pattern admixed with mucus-producing goblet cells and displaying focal cytoplasmic lumen formation. Immunohistochemical stains were positive for calcitonin, carcinoembryonic antigen, and chromogranin. Electron microscopy demonstrated C-cells containing neurosecretory granules as well as intestinal-type microlumina. The presence of goblet cells and intestinal-type microlumina in medullary carcinoma of the thyroid is reminiscent of amphicrine tumors of the gastrointestinal tract and supports the hypothesis that the parafollicular C-cells of the thyroid may be of endodermal derivation.

Cáncer tiroídeo tipo intermedio folicular-medular; una forma inhabitual, particular y agresiva: comunicación de tres casos / Mixed medullary and follicular carcinoma of the thyroid: report of three cases

Mixed medullary and follicular carcinomas of the thyroid shares secretory and immunohistochemical features of both follicular and parafollicular thyroidal cells. We report three women, aged 34, 63 and 61 old with this type of tumor. Its diagnosis must be bore in mind in patients with thyroidal tumors and a histological appearance of a medullary or undifferentiated carcinomas. An early diagnosis of a mixed medullary and follicular carcinomas of the thyroid is important, considering its special treatment and negative prognosis

Immunoelectron microscopic demonstration of regulated pathway for calcitonin and constitutive pathway for carcinoembryonic antigen in the same cells of human medullary carcinomas of thyroid glands.

The human medullary carcinomas are well known to secrete calcitonin (CT) as a neuroendocrine peptide and carcinoembryonic antigen (CEA) as a serum protein that is integrated into the cell membrane. This ultrastructural study is designed to elucidate whether CT and CEA are secreted via two different intracellular secretory pathways, a regulated pathway and a constitutive pathway. The immunoelectron microscopic postembedding method, performed on four cases of the human medullary carcinomas of the thyroid using plastic embedding material, disclosed two distinct different localization patterns for CT and CEA. CT was localized exclusively in dense cored secretory granules. CEA was present in the cell membrane and in the secretory vesicles. The secretory granules were completely negative for CEA. The trans-Golgi networks were also positive for CT and CEA. Electron microscopic double staining confirmed these localization in the same carcinoma cells. These observations suggest the presence of two distinct pathways in the endocrine cancer cells, i.e., the regulated pathway for CT and the constitutive pathway for CEA.

[Thyroid neoplasm of mid follicular-medullary type; an uncommon, particular and aggressive form: report of 3 cases]. / Cáncer tiroídeo tipo intermedio folicular-medular; una forma inhabitual, particular y agresiva. Comunicación de tres casos.

Mixed medullary and follicular carcinoma of the thyroid shares secretory and immunohistochemical features of both follicular and parafollicular thyroidal cells. We report three women, aged 34, 63 and 61 old with this type of tumor. Its diagnosis must be bore in mind in patients with thyroidal tumors and a histological appearance of a medullary or undifferentiated carcinoma. An early diagnosis of a mixed medullary and follicular carcinoma of the thyroid is important, considering its special treatment and negative prognosis.

Mixed medullary-follicular carcinoma of the thyroid gland: a clinicopathologic variant of medullary thyroid carcinoma.

A rare case of mixed medullary-follicular carcinoma of the thyroid gland, which occurred in a 44-year-old man, is reported. The thyroid tumor was composed of solid nests of polygonal cells, with an admixture of many evenly distributed thyroid follicles that contained colloid. The lymph node metastases were the same composition as the primary, with follicle formations that contained colloid. Immunohistochemically, in both the primary and metastatic lesions, calcitonin and carcinoembryonic antigen were present in the predominant solid areas of medullary carcinoma, whereas thyroglobulin was demonstrated in the follicular structures. At the ultrastructural level, most of the tumor cells contained numerous neurosecretory granules, but some showed follicular cell differentiation. These findings fulfilled the criteria of mixed medullary-follicular carcinoma of the thyroid according to the World Health Organization classification and also suggested dual neuroendocrine and follicular differentiation of this type of thyroid carcinoma. We reviewed the literature on mixed medullary-follicular carcinoma of the thyroid and concluded that it might constitute another clinicopathologic entity different from conventional medullary thyroid carcinoma; it occurs predominantly in younger males and is associated with a more favorable clinical course than the usual medullary thyroid carcinoma.

Multiple endocrine neoplasia type two B. A case report with light and electron microscopic and immunohistochemical correlation.

PURPOSE: To describe a case of multiple endocrine neoplasia type two B (MEN IIB) where ocular and systemic clinicopathological findings are correlated, in association with light and electron microscopic and immunohistochemical findings. METHODS: A 23-year-old man presented with mucosal neuromas of the lips, tongue and eyelids, a Marfanoid habitus and prominent corneal nerves. These findings led to the diagnosis of multiple endocrine neoplasia type two B. The patient subsequently developed phaeochromocytoma and metastatic medullary thyroid carcinoma (MTC) which led to his demise. Correlation of light and electron microscopic and immunohistochemical findings with the systemic and ocular findings is presented to emphasise the aggressiveness of MTC in MEN IIB. Clinicopathological correlation was obtained by examining the eyes post mortem. RESULTS AND CONCLUSIONS: Three new findings in MEN IIB have been established by this study. The enlarged corneal nerves can now be regarded as ganglioneuromas. Medullary thyroid carcinoma metastases were found in the choroid. Light and electron microscopic examination of the eye showed ganglioneuromas of the nerves in the limbus, trabecular meshwork, uveal tract and posterior ciliary nerves; this finding may account for the glaucoma occasionally seen in patients with MEN IIB.

Fine needle aspiration of medullary carcinoma of the thyroid. Cytomorphology, immunocytochemistry and electron microscopy.

OBJECTIVE: To analyze of medullary carcinoma of the thyroid (MCT) diagnosed by fine needle aspiration (FNA) utilizing cytomorphologic features and ancillary studies. STUDY DESIGN: Nine cases of MCT were collected, and the cytomorphologic findings were reviewed. Additionally, immunocytochemistry, immunoelectron microscopy and ultrastructural examination results were reviewed for selected cases. RESULTS: In five cases, loose groups predominated over single cells, whereas single cells predominated in three cases. One case showed only highly cohesive groups of cells. Most cells were round to oval, and every case had some degree of plasmacytoid morphology. Spindle-shaped cells were predominant in one case and were occasionally noted as a subpopulation in the other cases. Binucleation was noted in seven cases, and scattered, abnormally large nuclei were identified in five cases. The cytoplasm was moderate to abundant and delicate in all cases. Routine immunocytochemical staining for calcitonin and chromogranin was positive in three of four cases, and staining positive for the markers was detected by immunoelectron microscopy in two cases. In four cases, electron microscopy revealed neurosecretory granules. CONCLUSION: The cytomorphologic appearance of medullary thyroid carcinoma is highly distinctive, and the diagnosis can be corroborated by appropriate ancillary studies.

A metastasizing composite carcinoma of the thyroid with distinct medullary and papillary components.

Thyroid tumors with differentiation of both parafollicular and follicular epithelial cells are rare. The majority of those reported have been composed of a single cell population with combined features of the two cell types. We describe a 48-year-old man with a thyroid tumor composed of two discrete cell populations: thyroglobulin-positive papillary carcinoma intermixed with calcitonin-containing medullary carcinoma. The tumor metastasized to regional lymph nodes and maintained this composite differentiation. We propose that such tumors with two discrete intermingled cell populations be called composite thyroid carcinomas, as opposed to mixed thyroid tumors, which describes tumors with a single cell population that exhibits features of two cell types. Dual differentiation in thyroid neoplasms has been interpreted as indicative of a common stem cell origin. In this case, the presence of two mature, highly differentiated elements may suggest a proliferative response of two distinct cell populations to a common tumorigenic stimulus.

Transforming growth factor-beta 1 induces growth inhibition of a human medullary thyroid carcinoma cell line despite an increase in steady state c-myc messenger ribonucleic acid levels.

Medullary thyroid cancer (MTC) is an endocrine tumor of the thyroid C-cells which provides an important experimental model for studies of tumor differentiation and progression. We investigated the effects of transforming growth factor-beta 1 (TGF beta 1) on the growth and functional characteristics of a human medullary thyroid carcinoma cell line (TT). Because the c-myc protooncogene may play an important role in the growth inhibition induced by TGF beta 1, we also assessed steady state c-myc messenger RNA (mRNA) levels in these cells. A 6-day exposure of TT cells to TGF beta 1 resulted in a dose-dependent inhibition of cell proliferation. In addition, TGF beta 1 exposure led to a 3-fold increase in nonadherent floating TT cells in the culture supernatants. The floating cells exhibited ultrastructural features of dying or apoptotic cells, including chromatin condensation, cytoplasmic and nuclear vesicularization, and DNA degradation with evidence of internucleosomal DNA "laddering." Despite inhibition of cell proliferation, steady state c-myc mRNA levels were 3.6 +/- 0.6-fold higher in cells exposed to TGF beta 1 compared to those in control cells (P < 0.001). Exposure of cells to a 15-base antisense c-myc oligonucleotide (10 microM) resulted in an attenuation of the TGF beta 1-induced growth inhibition and induction of cell death. TGF beta 1 also resulted in an approximately 3-fold decrease in steady state calcitonin and calcitonin gene-related peptide mRNA levels. Finally, using a sensitive bioassay for TGF beta, TT cells were shown to produce and activate significant amounts of TGF beta, particularly under conditions of serum deprivation. Our data thus indicate that TGF beta 1 has multiple effects on TT cell growth and function. It induces growth inhibition in the presence of an increase in steady state mRNA levels of the c-myc protooncogene, which is usually associated with cell proliferation. In addition, TGF beta 1 accelerates apoptosis in TT cells.

Hybridocytochemical and immuno-ultrastructural study of calcitonin gene expression in cultured medullary carcinoma cells.

The study was aimed at a morphological demonstration of calcitonin (CT) gene expression in cultured TT cells, or, more specifically, hybridocytochemical detection of CT mRNA and calcitonin gene-related peptide (CGRP) mRNA and ultrastructural localization of the two hormones. The TT cells originated from medullary carcinoma of human thyroid gland. Ultrastructural studies of TT cells demonstrated a well-developed rough endoplasmic reticulum, large Golgi apparatus and low number of secretory granules. Hybridocytochemical studies showed the presence of mRNAs for CT and CGRP in all TT cells. At the ultrastructural level, double immunolabelling demonstrated that the two hormones were always expressed together in the same secretory granules. Our results provide a significant addition to the biochemical studies performed up to now and indicate that all TT cells produce both mRNAs and both hormones in parallel.

Medullary carcinoma of the thyroid gland with sustentacular cell-like cells in a patient with multiple endocrine neoplasia, type IIA. Report of a case with ultrastructural and immunohistochemical studies.

We report a case of a medullary carcinoma of the left lobe of the thyroid gland that occurred in a 57-year-old woman. The patient had undergone surgery for treatment of a bilateral-functioning pheochromocytoma when she was 39 years old. A medullary carcinoma of the thyroid gland and/or a pheochromocytoma had also been diagnosed in other family members. The tumor was composed of cells arranged in nests and large sheets separated by fibrous stroma that contained amyloid deposits. Elongated cells with thin, branched cytoplasmic projections that were strongly reminiscent of sustentacular cells usually found in paragangliomas were seen among the neoplastic cells. Immunohistochemical study showed a diffuse positive reaction for calcitonin and low-weight keratins (CAM 5.2) in neoplastic cells, whereas the sustentacular cell-like cells were positive for S100 protein. The reaction for thyroglobulin was negative. Electron microscopy disclosed large numbers of typical neurosecretory granules in the cytoplasm of tumor cells. The sustentacular cell-like cells showed elongated cytoplasmic processes and lacked neurosecretory granules. We concluded that the finding of sustentacular cell-like cells in a medullary carcinoma of the thyroid gland made its differential diagnosis from paraganglioma more problematic.