Ricardo V. Lloyd

Minor salivary gland tumors. A histologic and immunohistochemical study

Clinical, histologic, and immunohistochemical data were reviewed and evaluated on 238 oral minor salivary gland tumors. Benign neoplasms accounted for 65% of the total. Pleomorphic adenomas were the most common of all neoplasms, and mucoepidermoid carcinomas were the most frequently encountered malignancies. Pleomorphic adenomas and adenoid cystic carcinomas stained positive for S‐100 protein. Immunohistochemistry was believed to be of potential assistance in diagnosis of salivary gland tumors and in prediction of histogenesis.

Ultrastructural localization of chromogranin: a potential marker for the electron microscopical recognition of endocrine cell secretory granules

SummaryUsing a monoclonal antibody (LK2H10) directed against human chromogranin, we have been able to localize this soluble glycoprotein to the matrix of secretory granules from a wide variety of endocrine cells. In the gut, enterochromaffin, enteroglucagon, glucose-dependent insulinotropic peptide, gastrin, and neurotensin-containing cells exhibit chromogranin immunoreactivity. In our system, chromogranin-immunoreactive material was restricted to the halo of human pancreatic glucagon-containing secretory granules within A-cells. Chromogranin immunoreactivity was also localized to secretory granules in phaeochromocytomas, gastrinomas, medullary carcinomas of the thyroid and a carotid body tumour (chemodectoma). Chromogranin is proposed as a potential marker for the ultrastructural recognition of endocrine cell secretory granules.

Malignant phaeochromocytoma: clinical, biochemical and scintigraphic characterization.

We have evaluated thirty patients with malignant metastatic phaeochromocytoma with regard to clinical features, indices of catecholamine secretion, histology of lesions and a number of imaging procedures including scintigraphy with the recently developed sympathetic tissue‐seeking radiopharmaceutical 131I‐metaiodobenzylguanidine (131I‐MIBG). The primary tumour was extraadrenal in 13 cases. The commonest site of metastases was the axial skeleton (20 cases), followed by liver (four cases), lymph nodes (four cases), peritoneum (two cases) and lung (three cases). The malignancies were indolent, the mean time following the initial diagnosis was 9·18 years (range 0 to 33 years) and the mean duration of known metastases 3·71 years (range 0 to 18 years). There was a wide range of abnormalities in plasma and urinary catecholamines which did not correlate with the extent of tumour spread, histological pattern (mitotic index, Zellballen pattern, capsular or vascular invasion pleomorphism or necrosis) or 131I‐MIBG uptake by tumour deposits. 131I‐MIBG scintigraphy was found to be a useful technique for determining the extent of metastatic disease in most cases (26 of 30) and in some patients (16 of 30) was more sensitive than other radiological procedures. No false positive scans were encountered.

Ectopic pituitary adenomas with normal anterior pituitary glands

Two patients with ectopic pituitary adenomas and biopsy-proven normal anterior pituitaries are described. Both tumors were located in the sphenoid sinus. One tumor produced prolactin, and the other one was a plurihormonal adenoma that produced predominantly adrenocorticotropin and to a lesser extent thyroid stimulating hormone and alpha subunit. The patient with the plurihormonal tumor, who had Cushings disease, was cured by surgery while the patient with the prolactinoma was treated by surgery and medical therapy. A review of these two cases and an additional nine cases from the literature of ectopic pituitary adenomas in patients with normal intrasellar anterior pituitaries indicate that these uncommon tumors are capable of secretory function and may be the only cause of excessive pituitary hormone production.

Calcitonin, carcinoembryonic antigen and neuron‐specific enolase in medullary thyroid carcinoma. An immunohistochemical study

Calcitonin, carcinoembryonic antigen (CEA) and neuron specific enolase (NSE) were studied in the thyroid glands of patients with multiple endocrine neoplasia (MEN) type 2a, 2b, and with sporadic thyroid carcinomas (MTC). Calcitonin, CEA and NSE were localized in normal C‐cells, hyperplastic C‐cells, and in MTC. While the distribution of calcitonin and CEA was quite similar in most cases, a smaller proportion of cases were positive for NSE. C‐cell hyperplasia was identified in all nine patients with MEN 2a and in four of six patients with MEN 2b. None of the four patients with sporadic MTC had C‐cell hyperplasia. These results indicate that C‐cell hyperplasia is present in patients with MEN 2a and 2b and that NSE in addition to calcitonin and CEA is a useful marker for the thyroid C‐cells.

Reversible transdifferentiation: interconversion of somatotrophs and lactotrophs in pituitary hyperplasia.

Previous studies conclusively demonstrated transformation of somatotrophs into bihormonal mammosomatotrophs in gestational lactotroph hyperplasia during pregnancy. Similar transdifferentiation of somatotrophs into thyrotrophs through bihormonal intermediate thryrosomatotrophs was documented during thyrotroph hyperplasia in both rodent and human pituitaries in hypothyroidism. The cessation of the stimulation resulted in reversal of the process in both conditions. The conversion of lactotrophs into somatotrophs was suggested but not documented previously in the human gland. The present study was undertaken to investigate cases of somatotroph hyperplasia by transmission electron microscopy, immunoelectron microscopy using double immunogold labeling for growth hormone and prolactin, as well as combined immunocytochemistry and in situ hybridization. Adenohypophysial tissue was removed from a 38-year-old man and a 29-year-old woman with longstanding acromegaly due to ectopic overproduction of growth hormone–releasing hormone (GRH) by bronchial carcinoid tumors. For comparison, two pituitary biopsies were studied: one from a 38-year old woman with idiopathic lactotroph hyperplasia and one from a 14-year-old boy with secondary lactotroph hyperplasia due to a suprasellar craniopharyngioma. In the patients with somatotroph hyperplasia, the prevailing cell type was the hyperplastic somatotroph joined by mammosomatotroph deriving from lactotrophs, whereas monohormonal lactotrophs were rare. The predominance of mammosomatotrophs and active lactotrophs was documented in the patient with idiopathic lactotroph hyperplasia, whereas the case of the patient with secondary lactotroph hyperplasia was characterized by monohormonal lactotrophs and somatotrophs, but mammosomatotrophs were rare. That finding in the pituitary of the boy suggests that participation of mammosomatotrophs in lactotroph hyperplasia is not unconditional. Our findings conclusively demonstrate conversion of lactotrophs into mammosomatotrophs during somatotroph hyperplasia, providing further evidence for the potential of reversible transdifferentiation between somatotrophs and lactotrophs in response to functional demand.

Silent subtype 3 pituitary adenoma: a clinicopathologic analysis of the Mayo Clinic experience

Background  Macroadenomas represent 50% of pituitary tumours and are often (30%) nonfunctioning. Their immunophenotype suggests differentiation toward a specific pituitary cell line. A substantial proportion of tumours with particularly aggressive behaviour are so called ‘silent subtype 3 adenoma’. Its diagnosis requires ultrastructural confirmation. Although once included among silent corticotroph adenomas, this aggressive, morphologically distinctive tumour is now recognized as a major form of plurihormonal adenoma and, in fact, some patients might present with clinical hormonal excess. The cytogenesis and pathobiology of silent subtype 3 adenomas is unsettled.

Congenital gingival granular cell tumor with smooth muscle cytodifferentiation.

Congenital epulis of the newborn is a rare benign congenital gingival granular cell tumor (GGCT) of unknown histogenesis which occurs most commonly on the gingiva of the anterior maxillary alveolar ridge in girls. The granular cells in this entity are histologically indistinguishable from those in extragingival granular cell tumors, known historically as granular cell myoblastoma (GCM), which occur at any age and appear to be of Schwann cell origin. Ultrastructural, histochemical, and immunohistochemical features of three GGCT were examined and compared to three GCM and a granular cell ameloblastoma. This is the first instance in which the ultrastructure of granular cells in a congenital epulis showed evidence of smooth muscle differentiation. Carcinoembryonic antigen-like immunoreactivity was localized in granular cells from all granular cell tumors studied, but S-100 protein was present only in GCM. The smooth muscle ultrastructural features and the lack of S-100 protein in GGCT strongly suggest a different histogenesis from that of GCM. The GGCT is likely derived from a primitive gingival perivascular mesenchymal cell with the potential for smooth muscle cytodifferentiation.

Carcinoid (Neuroendocrine Carcinoma) of the Larynx

Carcinoid of the larynx is a rare aggressive malignancy with few long-term survivors. Three cases of laryngeal carcinoid treated at the University of Michigan and 23 cases reported previously are reviewed. The clinical behavior, patterns of metastasis, and response to therapy were analyzed to determine optimal therapeutic evaluation and treatment strategies. Patient survival did not correlate with clinically evident regional adenopathy, length of symptoms, extent of laryngeal surgery, or retrospective staging according to American Joint Committee guidelines on cancer of the larynx (AJC-1980). Distant metastatic spread occurred frequently and was the most common cause of death. Surgical therapy is currently the only effective treatment for primary or recurrent disease. Future treatment regimens must address distant spread of tumor.

In situ hybridization study of pro-opiomelanocortin (POMC) gene expression in human pituitary corticotrophs and their adenomas

Pro-opiomelanocortin (POMC) mRNA was detected on paraffin sections by in situ hybridization (ISH) in corticotrophs of 12 nontumorous pituitaries, 11 functioning corticotroph, and 11 silent pituitary adenomas. ISH combined with immunocytochemistry for adrenocorticotrophic hormone (ACTH), a POMC-derived peptide, was also performed. ACTH immunoreactive cells of the anterior lobes and those invading the posterior lobe showed a high or moderate level of POMC mRNA that was not correlated with the intensity of ACTH immunoreactivity. Variable levels of POMC gene expression were present in Crookes cells, corticotrophs suppressed by glucocorticoid excess. Most functioning corticotroph adenomas and silent subtype 1 adenomas had an intense hybridization signal and ACTH immunoreactivity. In silent subtype 2 and 3 adenomas, POMC mRNA had a diffuse low level or was absent; in these adenomas ACTH immunoreactivity was diffuse, restricted to some cells, or negative. The results indicate that POMC gene is expressed in both normal and suppressed nontumorous corticotrophs. Intense signals for POMC mRNA are found in most functioning corticotroph adenomas. The difference between POMC gene expression in silent 1 and silent 2 and 3 adenomas suggests that different mechanisms are responsible for the lack of endocrine activity.