A pleiomorphic GH pituitary adenoma from a Carney complex patient displays universal allelic loss at the protein kinase A regulatory subunit 1A (PRKARIA) locus.

Carney complex (CNC) is a familial multiple endocrine neoplasia syndrome associated with GH-producing pituitary tumours and transmitted as an autosomal dominant trait. Mutations of the PRKAR1A gene are responsible for approximately half the known CNC cases but have never found in sporadic pituitary tumours. Pituitary tissue was obtained from an acromegalic CNC patient heterozygote for a common (PRKARIA)i-inactivating mutation. Both immunohistochemistry and electron microscopy showed a highly pleiomorphic pituitary adenoma. The cell culture population appeared morphologically heterogeneous and remained so after more than 30 passages. The mixture was comprised of cells strongly immunostained for GH, spindle-shaped myofibroblast-like cells, and cuboid cells with large axonal projections (negative for GH). The population appeared to have both epithelial and mesenchymal cells. Both at baseline and at passage 30, cytogenetic analysis indicated the presence of normal 46, XY diploid karyotype, whereas losses of the PRKARIA(i) locus were demonstrated in more than 98% of the cells by fluorescent in situ hybridisation, supporting this gene's involvement in pituitary tumorigenesis. Allelic loss may have occurred in a single precursor cell type that differentiated and clonally expanded into several phenotypes. Epithelial-to-mesenchymal transition may also occur in CNC-associated pleiomorphic pituitary adenomas.

Differences between sporadic pheochromocytoma and pheochromocytoma in multiple endocrime neoplasia, type 2.

We studied the gross and microscopic pathology of the adrenal gland in 69 cases of sporadic phenochromocytoma in order to develop a profile of the neoplasm to compare with that of pheochromocytoma observed in the syndrome of multiple endocrine neoplasia, type 2 (MEN 2). The results showed that sporadic pheochromocytoma was a unicentric (93%), unilateral (100%) neoplasm, which was associated with normal extratumoral adrenal medulla (100%). The findings contrast with those encountered in the adrenal gland in MEN 2, in which the tumor involvement is frequently multicentric, usually bilateral, and associated with extratumoral medullary hyperplasia in cases of early involvement. Therefore, the interpretation of the results of pathologic examination of a pheochromocytoma should be immediately communicated to the surgeon.

Microscopic peliosis of pancreatic islets in a woman with MEN-1 syndrome.

We report herein a case of histologically identified peliosis of pancreatic islets in the surgically removed portion of the pancreas of a 30-year-old woman with multiple endocrine neoplasm, type 1 (MEN-1) syndrome. In addition to microscopic peliosis, the pancreas contained multiple endocrine tumors producing insulin, glucagon, somatostatin, and growth hormone-releasing factor and showed evidence of widespread nesidioblastosis. It is uncertain whether peliosis of pancreatic islets and MEN-1 syndrome were coincidental or whether the two diseases were causally related. Since hormonal factors can result in hepatic peliosis, it is tempting to speculate that the endocrine imbalance secondary to MEN-1 syndrome might have played a role in the genesis of peliosis in this case. Although no direct proof of vascular damage was encountered, it is conceivable that escape of red blood cells from the circulation and their accumulation in tissue spaces was due to abnormal islet blood flow and increased capillary permeability.

Multiple endocrine neoplasia in a dog.

Multiple endocrine neoplasms, including an insulinoma, bilateral adrenocortical adenocarcinomas and an aortic paraganglioma, were diagnosed after euthanasia in a 12-year-old spayed female dog of mixed breed with a history of progressive anorexia, vomiting, diarrhoea, weight loss, polyuria and polydipsia, regenerative anaemia and hypoglycaemia. The clinical, gross pathological, microscopical, immunohistochemical and ultrastructural findings were consistent with the human syndrome of multiple endocrine neoplasia.

[Thymic carcinoid tumors. A clinico-anatomic study of 3 cases]. / Carcinoïdes du thymus. Etude anatomo-clinique de 3 cas.

The carcinoid tumour of the thymus was first detailed by Rosai in 1972. The authors describe three cases of this tumour with particular reference to their histogenesis. It appears to be a tumour predominantly affecting males with an often unfavourable, though slow, progression. Some pathological associations are frequent and characteristic. In one third of cases there is an associated endocrine neoplasia. As a rule the tumour is sited in the anterior mediastinum. The precise diagnosis rests on histochemical criteria (specific granulations). These carcinoids are tumours of the APUD system of endodermal origin. The treatment is surgical.

Neuroendocrine carcinoma in a patient with hairy cell leukemia: a case report.

Second malignancies are common in hairy cell leukemia. We report a case of a neuroendocrine carcinoma arising in a patient who had been diagnosed with hairy cell leukemia 6 years earlier. This case is the first report of these two tumors' occurring together. The pathogenetic basis for the presence of these two uncommon tumors in our patient is discussed.

[Histological and ultrastructural study of intestinal ganglioneuromatosis. The multiple endocrine neoplasms type IIb syndrome]. / Etude histologique et ultrastructurale d'une ganglioneuromatose intestinale. Syndrome de néoplasie endocrine multiple du type IIb.

The syndrome known as the Multiple Endocrine Neoplasia type III or type IIb presents a particular histological intestinal lesion: hyperplasia of the myenteric plexus. The electron microscopic study of the plexus of Auerbach in our observation suggests a disequilibrium of the different types of individual axonal sheaths compared to the descriptions of a normal plexus. The possible role of this anomaly in the genesis of intestinal manifestations in this syndrome is here discussed.

Proliferation of endothelial component of parathyroid gland in multiple endocrine neoplasia type 1. Potential relationship with a mitogenic factor.

The basic fibroblast growth factor-like mitogen detected in the plasma of patients with the multiple endocrine neoplasia type 1 (MEN-1) syndrome was found to have a specific mitogenic effect on parathyroid endothelial cells in vitro. To investigate its pathogenic role in humans, the endothelial component of parathyroid glands was evaluated by ultrastructural morphometry in six MEN-1 patients. The results were compared with those found in six patients with uremic hyperparathyroidism (UHPT) and in three subjects with histologically normal glands. Plasma mitogenic activity was found in all MEN-1 patients but not in those with UHPT or in normal subjects. All morphometric parameters investigated (fractional volume and nuclear density of capillary endothelial cells, volume fraction and number per unit area of capillaries) showed 1.5- to 2-fold higher values in patients with MEN-1 than in those with UHPT (P < 0.05). In contrast, no difference was found between MEN-1 cases and normal subjects. Quantitative evaluation of parathyroid pericytes yielded results similar to those of endothelial cells. These data indicate that the proliferation of parathyroid cells in MEN-1 patients is accompanied by parallel increase in the associated endothelial component that does not occur in patients with UHPT and may support the hypothesis of an in vivo role of the MEN-1 mitogen factor on the endothelial component of parathyroid glands in MEN-1 patients.

Defective organization of actin in cultured skin fibroblasts from patients with inherited adenocarcinoma.

In the cytoplasm of well-spread cultured normal fibroblasts, actin is organized into a network of cables that run the length of the cell just inside the adherent cell membrane. A diffuse matrix replaces the cables in fibroblasts that have become tumorigenic as a result of oncogenic transformation. We have found a similar disruption in actin organization in cultured skin fibroblasts (passage 6-10) obtained by biopsy from patients with the inherited colonic cancer, adenomatosis of the colon and rectum (ACR). Because ACR is inherited as an autosomal dominant trait, about half the children of ACR patients will develop colon cancer, but they typically remain asymptomatic until at least the second decade of life. Actin distribution within cultured cells from children of ACR patients was identical either to that seen in cultured cells from normal persons or to that seen in cultured cells from ACR patients. The two different patterns were independent of age, sex, drug treatment, or infections of the donors. Apparently, this class of colonic carcinoma is accompanied by a systemic aberration in the organization of fibroblast cytoplasm, and this aberration can be detected by immunofluorescent localization of actin within cultured skin fibroblasts, prior to manifestation of any colonic symptoms.

Thyroid medullary carcinoma with thyroglobulin immunoreactivity in sporadic multiple endocrine neoplasia type 2-B.

BACKGROUND: Thyroid carcinomas historically have been divided into two groups according to their presumedly separate embryonic origins: those of neuroectodermal derivation (parafollicular or medullary carcinoma [MCT]) and those of foregut endodermal origin (follicular and papillary carcinomas). The validity of this concept has been questioned by the recognition that some MCT may show immunocytochemical and ultrastructural evidence of follicular components, and display features of follicular function (e.g., organification of iodine, immunoreactivity for thyroglobulin). METHODS: A 14-year-old boy presented with the physical features of multiple endocrine neoplasia type 2-B (MEN 2B) and a thyroid mass. His thyroid lesion was studied by light microscopy; electron microscopy; immunohistochemistry using antisera to calcitonin, thyroglobulin, and other peptides; and in situ hybridization. RESULTS: The tumor was identified as an MCT by light microscopy. It stained positively with calcitonin, thyroglobulin, chromogranin, neuron-specific enolase, and serotonin. At the ultrastructural level, the tumor cells contained numerous neurosecretory granules and showed evidence of follicular differentiation (luminal microvilli, follicle formation, and tight junctions), suggesting a dual neuroendocrine and follicular differentiation. CONCLUSIONS: The morphologic findings suggest that a small number of MCTs arise from a common stem cell (possibly the ultimobranchial body) that may give rise to both MCT and follicular carcinoma. This patient and patients in similar cases documented in the literature challenge the classic concept of separate pathways of embryogenesis for these two cell types.

Islet cell tumor.

A case of islet cell tumor occurring in a patient with the multiple endocrine neoplasia type I syndrome is reported. Immunostaining for insulin was strongly positive in the tumor cells. Numerous dense-core granules of endocrine caliber were identified ultrastructurally. Morphometric analysis of the secretory granules in 20 islet cell tumors gave a granule size of 182 +/- 52 nm (mean +/- standard deviation).

Generation of a panel of somatic cell hybrids containing unselected fragments of human chromosome 10 by X-ray irradiation and cell fusion: application to isolating the MEN2A region in hybrid cells.

We have used X-ray irradiation and cell fusion to generate somatic cell hybrids containing fragments of human chromosome 10. Our experiments were directed towards isolating the region of the MEN2A gene in hybrids and to use those as the source of DNA for cloning and mapping new markers from near the MEN2A locus. A number of hybrid clones containing human sequences that are tightly linked to the MEN2A gene were identified. Some 25% of our hybrids, however, proved to contain more than one human chromosome 10-derived fragment or showed evidence of deletions and/or rearrangements. A detailed analysis of the human content of X-ray irradiation hybrids is required to assess the integrity and number of human fragments retained. Despite retention of multiple human-derived fragments, these hybrids will prove useful as cloning and mapping resources.

CDw60: an antigen expressed in many normal tissues and in some tumours.

CDw60 is a recently described T-cell antigen, which functionally delivers a costimulatory signal in T-cell activation. In addition, CDw60 has been regarded as a melanoma-associated antigen. To date, only limited information exists on the distribution of CDw60 in other normal and pathologically altered tissues in human. In the present study, the expression of CDw60 was analysed immunohistologically in a large panel of formalin-fixed and paraffin-embedded normal and pathological human tissues. The antigen was detected in several normal tissues, such as epithelia of the reproductive system, exocrine and endocrine glands, glial cells and neurons of the central and peripheral nervous systems, and lymphoid cells. These showed different subcellular distribution patterns, i.e. (1) cell surface labelling of peripheral lymphocytes and lymphocytes of the lymph node and thymus, (2) diffuse cytosolic staining in lymphocytes, subpial glial processes, and the outer plexiform layer of the retina, (3) granular cytoplasmic staining associated with the Golgi apparatus in epithelial cells of certain endocrine and exocrine glands, of the ductus epididymis and deferens, neurons of the peripheral and central nervous system, and lymphocytes and megakaryocytes of the bone marrow. In exocrine glands, e.g. of the prostate and uterine corpus, CDw60-positive Golgi fields were located in the juxtaluminal cell compartment, thus reflecting a polarized distribution. In some malignant tumours, the neoplastic cells contained CDw60-immunolabelled Golgi complexes, which were disorderly distributed throughout the cytoplasm, thus reflecting a loss of epithelial polarity. Only in mammary carcinomas was abnormal cell surface labelling detected. A putative de novo expression of CDw60 was observed in pleomorphic adenoma and mucoepidermoid carcinoma of the parotid gland, seminoma, embryonal and teratocarcinoma of the testis, small cell carcinoma of the lung, and malignant melanoma. These results define the CDw60 determinant as a broadly distributed antigen within a large panel of normal human tissues. The antigen is also detectable in some previously undescribed benign and malignant tumours, which may give importance to CDw60 as a possible diagnostic marker.

Three subtypes of gastric argyrophil carcinoid and the gastric neuroendocrine carcinoma: a clinicopathologic study.

BACKGROUND: Enterochromaffinlike (ECL) cell carcinoids recently observed in rats stimulated new interest in gastric endocrine tumors arising in humans. METHODS: Paraffin-embedded sections of 55 endocrine tumor cases were stained with H&E, mucin tests were performed, and immunoperoxidase was used for detecting endocrine markers; 23 cases were also investigated ultrastructurally. RESULTS: Forty-five argyrophil carcinoids, 9 neuroendocrine carcinomas, and 1 gastrinoma were identified. Three clinicopathologic subtypes of carcinoids were characterized: (1) twenty-eight cases, none metastatic, arose in a background of body-fundus atrophic gastritis and hypergastrinemia; (2) seven cases, 2 locally metastatic, were associated with hypertrophic gastropathy and hypergastrinemia due to multiple endocrine neoplasia/Zollinger-Ellison syndrome; and (3) ten were sporadic cases, 7 of which were deeply invasive, 6 metastatic, and 5 histologically atypical. All carcinoids showed histochemical and ultrastructural patterns of ECL cells. The 9 neuroendocrine carcinomas, all deeply invasive and metastatic, were composed of anaplastic, small- to intermediate-sized cells with high mitotic index and focal necrosis. CONCLUSIONS: Gastrin-promoted carcinoids represent a benign or low grade tumor disease, whereas sporadic carcinoids and neuroendocrine carcinomas are life-threatening neoplasms, independent of gastrin promotion.

Multiple nonfunctional pancreatic islet cell tumor in multiple endocrine neoplasia type I. A case report.

A case of multiple nonfunctional pancreatic islet cell tumor in multiple endocrine neoplasia type I (MEN I) is reported. The patient was a 41-year-old woman who had a past history of thyroid cancer (papillary carcinoma) and hyperparathyroidism due to parathyroid adenoma. Later, a nonfunctional pituitary tumor and five nonfunctional pancreatic tumors were found simultaneously and the patient was finally diagnosed as having MEN I. Following surgical enucleation, the pancreatic tumors were histopathologically diagnosed as benign islet cell tumors. One of them (tumor 3) exhibited a solid nodular pattern while the others showed gyriform patterns. They were divided histochemically and immunohistochemically into three types: two (tumors 1 and 2) produced a single hormone (glucagon), one (tumor 3) produced five (insulin, glucagon, somatostatin, gastrin and pancreatic polypeptide) and the remaining two (tumors 4 and 5) produced two (glucagon and pancreatic polypeptide). Electron microscopically, three types of endosecretory granules were found in the tumor cells of tumor 3 but only one type was found in tumor 4. However, in the tumor 4 extract, glucagon, pancreatic polypeptide, C-peptide, somatostatin, vasoactive intestinal peptide and growth hormone releasing factor were detected by radioimmunoassay. These findings suggest that these pancreatic tumors were both multicellular and multihormonal.