— AN AUTOPSY CASE —

A diagnosis of the heritable disorder Sipple's syndrome was made in a Japanese male aged 28 years. The coexistence of bilateral pheochromocytomas, bilateral medullary thyroid carcinomas and secondary hyperplasia of parathyroid was confirmed at the time of autopsy. Pancreatic islets were hyperplastic with marked proliferation of A and D cells. Transition of the ductal cell to the islet, i.e. 'nesidioblatosis' was observed. There was no proliferation of B cells, but a retention of B cell granules, a manifestation of suppressed secretion of insulin attributed to the overproduction of catecholamines was evident. In the stomach, numerous petechial hemorrhages and proliferation of gastrin cells were found. The pathogenesis of changes in the pancreatic islets and stomach is discussed from the viewpoint of hormonal disorders induced by pheochromocytoma and medullary thyroid carcinoma such as are found in Sipple's syndrome. ACTA PATH. JAP. 27: 739˜748,1977.     

Ultrastructural study of thyroid medullary carcinoma.

This study deals with 11 cases of thyroid medullary carcinoma of which 7 were familial cases including 3 cases of Sipple's syndrome and 4 cases of sporadic cases. There were also 2 cases of Cushing's syndrome. In addition to the previously described English literatures about human medullary carcinoma of the thyroid, the rod-shaped body with cristae and an abundant glycogen particles in the cytoplasm, nuclear inclusion bodies of cytoplasmic invagination and microvilli at the surface membrane of gland formation were found in our cases. The mean and mode diameters of secretory granules of all familial cases with only calcitonin secretion were larger than those of the sporadic cases with ectopic ACTH and beta-MSH in addition to calcitonin secretion. Ultrastructural study on non-cancerous follicles of grossly normal thyroid of two cases of early familial medullary carcinoma disclosed apparently increased C-cells which were not intrathyroidal metastases. It is supposed that the increased C-cells in the thyroid of the familial cases are multicentric C-cell hyperplasia.     

Immunohistochemical localization of amylin in human pancreas, thyroid, pituitary and their tumors

The aim of the present study was to investigate immunohistochemically expression of amylin, a 37 amino acid peptide, cosecreted with insulin by beta cells in pancreatic islets in 12 non-tumorous pancreatic tissues, 22 pancreatic islet tumors, 14 non-tumorous thyroids, 14 medullary carcinomas of the thyroid, 10 non-tumorous pituitaries and 50 pituitary adenomas including 10 amyloid-forming prolactin-cell adenomas using the streptavidin-biotin-peroxidase complex method. Amylin was expressed in non-tumorous pancreatic islets but not in non-tumorous thyroids and pituitaries. Since amylin plays an important role in amyloid formation in pancreatic islets, those tumor types were selected to study which may produce amyloid. Amylin was widely expressed in one insulin producing beta cell tumor. Few tumor cells were immunopositive in 8 islet-cell tumors and in 5 medullary thyroid carcinomas. Immunostaining was not found in pituitary adenomas, including those which produced amyloid. It can be concluded that amylin is not a satisfactory immunohistochemical marker to identify pancreatic islet tumors, medullary thyroid carcinomas and pituitary adenomas.     

ULTRASTRUCTURAL STUDY OF THYROID MEDULLARY CARCINOMA

This study deals with 11 cases of thyroid medullary carcinoma of which 7 were familial cases including 3 cases of Sipple's syndrome and 4 cases of sporadic cases. There were also 2 cases of Cushing's syndrome. In addition to the previously described English literatures about human medullary carcinoma of the thyroid, the rod-shaped body with cristae and an abundant glycogen particles in the cytoplasm, nuclear inclusion bodies of cytoplasmic invagination and microvilli at the surface membrane of gland formation were found in our cases. The mean and mode diameters of secretory granules of all familial cases with only calcitonin secretion were larger than those of the sporadic cases with ectopic AGTH and beta-MSH in addition to calcitonin secretion. Ultrastructural study on non-cancerous follicles of grossly normal thyroid of two cases of early familial medullary carcinoma disclosed apparently increased C-cells which were not intrathyroidal metastases. It is supposed that the increased C-cells in the thyroid of the familial cases are multicentric C-cell hyperplasia. ACTA PATH. JAP. 27: 605˜622, 1977.     

Ovarian strumal carcinoid in association with multiple endocrine neoplasia, type IIA.

Strumal carcinoid is an unusual form of monodermal ovarian teratoma with thyroid-like follicles admixed with typical carcinoid tumor patterns. We encountered a case of this neoplasm in a patient with multiple endocrine neoplasia, type IIA (Sipple's syndrome), including a medullary thyroid carcinoma diagnosed 24 years previously. During evaluation of bilateral adrenal pheochromocytomas, a unilateral left ovarian strumal carcinoid was discovered. Subsequently, the patient had a parathyroid adenoma excised. The ovarian tumor was immunohistochemically reactive for neuron-specific enolase, chromogranin, synaptophysin, and serotonin, but did not stain for calcitonin. The follicular structures stained for thyroglobulin. This unusual case shows that ovarian strumal carcinoid, like carcinoid tumors at other sites, may arise in association with multiple endocrine neoplasia.     

Immunohistochemical comparison of chromogranins A and B and secretogranin II with calcitonin and calcitonin gene-related peptide expression in normal, hyperplastic and neoplastic C-cells of the human thyroid

Normal and hyperplastic thyroid C-cells and 14 cases of medullary thyroid carcinoma were investigated immunohistochemically with antibodies against chromogranins A and B, secretogranin II, calcitonin and calcitonin gene-related peptide (CGRP). Normal and hyperplastic C-cells showed strong calcitonin and chromogranin A immunoreactivity whereas CGRP, chromogranin B and secretogranin II expression was less intense. Strong calcitonin and chromogranin A immunoreactivity was also found in the majority of tumour cells in medullary thyroid carcinoma. The CGRP, chromogranin B and secretogranin II staining observed was present in variable patterns. In some cases CGRP, chromogranin B and secretogranin II could only be demonstrated in isolated tumour cells with elongated processes suggestive of neuronal differentiation of these cells. The biological function(s) of the chromogranins/secretogranins remain(s) still unclear. There is evidence that these proteins are pro-peptides which give rise to functionally active compounds. Studies on normal C-cells and medullary thyroid carcinoma may elucidate the role of chromogranins/secretogranins in endocrine and neuronal cells.     

Hereditary and familial thyroid tumours

The worldwide incidence of thyroid malignancies has been increasing rapidly. Sensitive imaging modalities and early detection of thyroid lesions have made thyroid cancers the most rapidly increasing cancers in the USA in 2017 (SEER Cancer Facts, 2017). Clinical awareness of potential risk factors, such as inherited thyroid cancers, has allowed earlier recognition of more vulnerable population clusters. Hereditary thyroid neoplasms arising from calcitonin‐producing C cells are known as familial medullary thyroid carcinomas (FMTCs), and include well‐documented syndromes such as multiple endocrine neoplasia IIA or IIB, and pure familial medullary thyroid carcinoma syndrome. Familial thyroid cancers arising from follicular cells are referred to as familial non‐medullary thyroid carcinoma (FNMTC), or familial follicular cell‐derived carcinoma. Clinicopathological correlations have resulted in the further subclassification of FNMTCs into two groups. Among the first group are found syndromes characterised by a predominance of non‐thyroidal tumours, including familial adenomatous polyposis, Cowden syndrome, Werner syndrome, Carney complex, and Pendred syndrome. The second group encompasses a spectrum of familial syndromes characterised by a predominance of non‐medullary thyroid tumours, such as pure familial papillary thyroid carcinoma with or without oxyphilia, familial papillary thyroid carcinoma with papillary renal cell carcinoma, and familial papillary carcinoma with multinodular goitre. Most familial thyroid cancers have been described as being more aggressive than sporadic thyroid cancers, with a predisposition for lymph node metastasis, extrathyroidal invasion, and a younger age of onset. The distinct thyroid pathology in some of these syndromes should alert the pathologist to a possible familial cancer syndrome.     

Immunohistologic localization of corticotrophin-releasing hormone in human tumors

The authors investigated formalin-fixed, paraffin-embedded human tissues for the presence of corticotrophin-releasing hormone (CRH) using the avidin-biotin-peroxidase technic. Immunopositivity was demonstrated in nontumorous hypothalami, 1 of 8 hypothalamic gangliocytomas, 3 of 9 bronchial endocrine tumors, 1 of 30 small cell lung carcinomas, 1 of 8 ileal endocrine neoplasms, 2 of 20 pancreatic endocrine tumors, 2 of 10 medullary thyroid carcinomas, and 1 of 3 small cell prostate carcinomas. Of the tumors containing immunoreactivity, most were associated with Cushing's syndrome; the ileal and thyroid tumors were not. Adrenocorticotrophic hormone was immunohistochemically localized in two bronchial and one pancreatic tumor, which contained CRH-like immunoreactivity. No CRH was detected in nontumorous extrahypothalamic tissues from which the CRH-containing tumors derived, two mediastinal endocrine carcinomas, six endocrine tumors of the stomach/duodenum/appendix, eight pheochromocytomas, one Merkel cell tumor, and 32 squamous and adenocarcinomas of the lung/gut. CRH-like immunoreactivity may be found in tumors composed of peptide-hormone-producing endocrine cells; hypersecretion of CRH by those neoplasms may be significant in the development of Cushing's syndrome.     

Von Recklinghausen's Disease Associated with Somatostatin-rich Duodenal Carcinoid (Somatostatinoma), Medullary Thyroid Carcinoma and Diffuse Adrenal Medullary Hyperplasia

This report describes the concomitant occurrence of a somatostatin-rich duodenal carcinoid, a medullary thyroid carcinoma and a diffuse adrenal medullary hyperplasia in a patient with von Recklinghausen's disease. A 50-year-old Japanese man died from lung metastasis of a malignant schwannoma. In addition to extensive viscero-cutaneous neurofibromatosis, two different types of neuroendocrine tumors were found in the duodenum and thyroid gland at autopsy. The duodenal tumor, which was located in the second portion, showed the histologic appearance of a carcinoid tumor with glandular differentiation and psammoma-bodies. Immunohistochemically the tumor cells were intensely positive for somatostatin. The thyroid tumor was composed of nests of tumor cells arranged in an endocrine pattern, and showed immunoreactivity for calcitonin. A review of the literature revealed no previously reported case of concomitant occurrence of duodenal somatostatinoma and medullary thyroid carcinoma in a single patient with von Recklinghausen's disease. Morphometric analysis of adrenal glands disclosed the presence of diffuse medullary hyperplasia. Thus, the present case exhibited a similarity in some respects with multiple endocrine neoplasia (MEN) syndrome, Type Ila or IIb.     

von Recklinghausen's disease associated with somatostatin-rich duodenal carcinoid (somatostatinoma), medullary thyroid carcinoma and diffuse adrenal medullary hyperplasia.

This report describes the concomitant occurrence of a somatostatin-rich duodenal carcinoid, a medullary thyroid carcinoma and a diffuse adrenal medullary hyperplasia in a patient with von Recklinghausen's disease. A 50-year-old Japanese man died from lung metastasis of a malignant schwannoma. In addition to extensive viscero-cutaneous neurofibromatosis, two different types of neuroendocrine tumors were found in the duodenum and thyroid gland at autopsy. The duodenal tumor, which was located in the second portion, showed the histologic appearance of a carcinoid tumor with glandular differentiation and psammoma-bodies. Immunohistochemically the tumor cells were intensely positive for somatostatin. The thyroid tumor was composed of nests of tumor cells arranged in an endocrine pattern, and showed immunoreactivity for calcitonin. A review of the literature revealed no previously reported case of concomitant occurrence of duodenal somatostatinoma and medullary thyroid carcinoma in a single patient with von Recklinghausen's disease. Morphometric analysis of adrenal glands disclosed the presence of diffuse medullary hyperplasia. Thus, the present case exhibited a similarity in some respects with multiple endocrine neoplasia (MEN) syndrome, Type IIa or IIb.     

Cholecystitis, cholelithiasis, and ganglioneuromatosis of the gall bladder: an unusual presentation of MEN type 2b.

A 40 year old man with multiple endocrine neoplasia type 2b (MEN 2b) presented with cholecystitis caused by gall stones. Twenty four years earlier, he had had a partial thyroidectomy for a cold nodule. At his initial presentation MEN 2b with medullary carcinoma of the thyroid had not been made. This was diagnosed while investigating his gall bladder symptoms and he was found to have asymptomatic residual medullary thyroid carcinoma and bilateral adrenal phaeochromocytomas. The cholecystectomy specimen contained several mixed calculi and extensive ganglioneuromatosis with large, prominent nerves containing ganglion cells in the gall bladder wall.     

High resolution chromosome and DNA analysis in multiple endocrine neoplasia type II syndrome

Multiple endocrine neoplasia type II (MEN-II or Sipple's syndrome) is an autosomal dominant disorder characterized by medullary thyroid cancers, pheochromocytomas, and parathyroid adenomas. A blind analysis of high resolution G-banded chromosomes was performed on blood specimens from eight MEN-II individuals from three unrelated families and six control subjects. Seven of eight MEN-II patients and one of six control subjects were determined to have a deletion at 20p12.2. These findings support the hypothesis that MEN-II patients have a 20p12.2 deletion (chi 2 = 6.99; p less than 0.01). Genomic DNA from seven of the eight MEN-II patients was studied using the DNA probe, D20S5, localized by in situ hybridization to 20p12. The probe binding site is not deleted in some MEN-II patients, as demonstrated by the presence of two alleles detected as restriction fragment length polymorphisms. Thus, D20S5 does not hybridize to DNA sequences that are deleted based on cytogenetic analysis in MEN-II patients.     

Genotype-phenotype correlation in multiple endocrine neoplasia type 2

Multiple endocrine neoplasia type 2 is an autosomal-dominant hereditary cancer syndrome caused by missense gain-of-function mutations of the rearranged during transfection proto-oncogene, which encodes the receptor tyrosine kinase, on chromosome 10. It has a strong penetrance of medullary thyroid carcinomas and can be associated with bilateral pheochromocytoma and primary hyperparathyroidism. Multiple endocrine neoplasia type 2 is divided into three varieties depending on its clinical features: multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, and familial medullary thyroid carcinoma. The specific rearranged during transfection mutation may suggest a predilection toward a particular phenotype and clinical course of medullary thyroid carcinoma, with strong genotype-phenotype correlations. Offering rearranged during transfection testing is the best practice for the clinical management of patients at risk of developing multiple endocrine neoplasia type 2, and multiple endocrine neoplasia type 2 has become a classic model for the integration of molecular medicine into patient care. Recommendations on the timing of prophylactic thyroidectomy and extent of surgery are based on the classification of rearranged during transfection mutations into risk levels according to genotype-phenotype correlations. Earlier identification of patients with hereditary medullary thyroid carcinoma can change the presentation from clinical tumor to preclinical disease, resulting in a high cure rate of affected patients and a much better prognoses.     

Thyroid carcinoma and Cushing''s syndrome: A report of two cases with a review of the common features of the `non-endocrine'' tumours associated with Cushing''s syndrome

Two cases of thyroid carcinoma and Cushing's syndrome are reported. Nine other previously published cases of this association are reviewed: in one the thyroid tumour was described as medullary, in two as papillary, and in the other six as anaplastic, undifferentiated, atypical, or solid carcinoma. Both of our own cases were medullary carcinomas of the thyroid, and on reviewing the histology of five of the other cases all proved to be medullary carcinoma with identifiable amyloid in the stroma. A consideration of the temporal relationships of the development of the carcinoma and of Cushing's syndrome suggested that in the two cases with papillary carcinoma these conditions could have been unrelated, but that in eight of the nine cases with medullary carcinoma there was evidence that thyroid carcinoma was present at the time of diagnosis of Cushing's syndrome.The other main groups of the so-called ;non-endocrine' tumours associated with Cushing's syndrome are briefly reviewed, and evidence that a surprising number of these cases are related to carcinoid tumours is put forward. Medullary carcinoma of the thyroid is also probably related to this group of tumours. It is suggested that the great majority of the tumours associated with Cushing's syndrome are derived from cells of foregut origin which are endocrine in nature. In neoplasms derived from these cells the polypeptide hormone may well be imperfectly formed, and possess an amino-acid sequence in common with ACTH or other biologically active polypeptides.     

Characterization of gene expression induced by RET with MEN2A or MEN2B mutation

Germ-line point mutations of the RET gene are responsible for multiple endocrine neoplasia (MEN) type 2A and 2B that develop medullary thyroid carcinoma and pheochromocytoma. We performed a differential display analysis of gene expression using NIH 3T3 cells expressing the RET-MEN2A or RET-MEN2B mutant proteins. As a consequence, we identified 10 genes induced by both mutant proteins and eight genes repressed by them. The inducible genes include cyclin D1, cathepsins B and L, and cofilin genes that are known to be involved in cell growth, tumor progression, and invasion. In contrast, the repressed genes include type I collagen, lysyl oxidase, annexin I, and tissue inhibitor of matrix metalloproteinase 3 (TIMP3) genes that have been implicated in tumor suppression. In addition, six RET-MEN2A- and five RET-MEN2B-inducible genes were identified. Among 21 genes induced by RET-MEN2A and/or RET-MEN2B, six genes including cyclin D1, cathepsin B, cofilin, ring finger protein 11 (RNF11), integrin-alpha6, and stanniocalcin 1 (STC1) genes were also induced in TGW human neuroblastoma cells in response to glial cell line-derived neurotrophic factor stimulation. Because the STC1 gene was found to be highly induced by both RET-MEN2B and glial cell line-derived neurotrophic factor stimulation, and the expression of its product was detected in medullary thyroid carcinoma with the MEN2B mutation by immunohistochemistry, this may suggest a possible role for STC1 in the development of MEN 2B phenotype.     

Metastasizing islet cell carcinoma of the pancreas in a 10-year-old girl (author's transl)]

A medullary islet cell carcinoma of the pancreas with liver and peritoneal metastases was found at autopsy of a 10-year-old girl. Ultrastructurally, the carcinoma cells showed typical secretion granules resembling prevailingly A1 (D) cell granules in pancreatic islets. Silver impregnation according to Hellerstr?m and Hellman (1960) for demonstration of A1 islet cells was moderately positive in the tumor cells. Therefore, it is suggested that the presented metastasizing islet cell carcinoma may have derived from A1 islet cells.     

Adrenal medullary hyperplasia. A morphometric analysis in patients with familial medullary thyroid carcinoma.

The syndrome of familial medullary thyroid carcinoma (MTC), pheochromocytoma, and parathyroid hyperplasia is inherited as an autosomal dominant trait, and is characterized by development of bilateral and multicentric thyroidal and adrenal medullary tumors. One of the earliest manifestations of adrenal medullary hyperfunction in patients with this syndrome is an increased ratio of epinephrine to norepinephrine in urine. In order to define the morphologic correlates of these early catecholamine abnormalities in a large kindred with familial MTC, a morphometric analysis based on a point-counting system to asses adrenal medullary volume was undertaken. These studies clearly revealed adrenal medullary hyperplasia as reflected by a two- to three-fold increase in medullary volume and weight as compared to age- and sex-matched controls. The increase in total medullary mass resulted from diffuse and multifocal modular proliferations of adrenal medullary cells primarily within the head and body regions of the glands. These results support the hypothesis that the pheochromocytomas in patients with familial MTC may, in fact, represent extreme degrees of nodular hyperplasia of the medulla.     

FAMILIAL MEDULLARY CARCINOMA OF THE THYROID THROUGH 3 GENERATIONS

A family with high genetic penetrance of medullary carcinoma of the thyroid was reported. Seven proven (6 patients and one autopsy case) and 2 probable cases of medullary carcinoma were present in 25 members through 3 generations. An endogamy had intervened in the prior generation of these cases. Preliminary results in clinicopathological examinations of 7 proven cases were as follows; clinically, all of the cases showed B type blood group. Glycosuria was found in 2 cases, and diarrhea in one case. Serum thyrocalcitonin being estimated In two cases showed high levels. The autopsy cases coexisted with medullary carcinoma of the thyroid and pheo-chromocytoma of the right adrenal. Pathologically, the majority of tumors occurred in both thyroid lobes, and were present from the middle to upper portion of the thyroid. The tumor showed a variety of histological features even in the same tumor. In the tumor cell, numerous membrane-limited granules were seen with an electron microscope. Amyloid was demonstrated only In the tumor tissue.     

Expression of the chemokine receptor CXCR2 in normal and neoplastic neuroendocrine cells

BACKGROUND: Chemokines effect their proinflammatory and growth regulatory roles through interaction with serpentine receptors. One such receptor, CXCR2, binds multiple CXC chemokines, including interleukin 8, GRO-alpha, GRO-beta, GRO-gamma, and NAP-2. We have previously identified CXCR2 expression on myeloid cells, notably mature granulocytes, and projection neurons. OBJECTIVE: To determine the expression of CXCR2 by cells of the neuroendocrine system. DESIGN: Archival specimens from normal neuroendocrine tissues and their malignant counterparts were analyzed by immunohistochemistry with monoclonal antibodies specific for CXCR1 and CXCR2. RESULTS: Immunohistochemical analysis revealed high-level expression of CXCR2 by cells in the pituitary, adrenal medulla, pancreatic islets, thyroid C cells, scattered Kulchitsky cells in the bronchi, and counterpart neuroendocrine cells in the stomach, small bowel, colon, and appendix. Neuroendocrine neoplasms that demonstrated high-level CXCR2 expression included (1) primary carcinoids localized to the stomach, small bowel, colon, appendix, fallopian tube, ovary, and lung; (2) atypical carcinoids of the lung; (3) metastatic carcinoids; (4) pituitary adenomas; (5) pheochromocytomas; and (6) medullary carcinomas of the thyroid. Small cell lung carcinomas, large cell neuroendocrine carcinomas of the lung, small cell carcinoma of the cervix, Merkel cell carcinomas, neuroblastomas, and malignant melanomas lacked evidence of CXCR2 expression. CONCLUSIONS: The expression of CXCR2 by normal neuroendocrine cells and neoplastic counterparts that have retained phenotypic features of this differentiation program suggests that chemokines may play an important role in functions that are characteristic of this cell type. In addition, this raises the possibility that chemokines may modulate secretion of biologically active products of these cells and their neoplastic counterparts.