Pituitary adenomas of the multiple endocrine neoplasia type I syndrome

In a series of 1,500 pituitary adenomas surgically resected at Mayo Clinic, 41 (2.7%) occurred in the setting of multiple endocrine neoplasia, type I (MEN-I). Of the 40 patients (18 males, 22 females), 21 (52%) presented with clinical evidence of a pituitary neoplasm, 13 with hyperparathyroidism, and two with functional islet cell tumor. Of the 41 tumors, 11 (27%) were microadenomas, and 30 (73%) were macroadenomas. Immunocytochemical studies demonstrated the following reactivities: GH (4), GH/PRL (6), GH/PRL/glycoprotein (7), GH/ACTH/glycoprotein (1), PRL (16), PRL/TSH (1), ACTH (3), and null cell adenoma (3). We conclude that, in comparison with pituitary adenomas occurring in the general population, those occurring in association with MEN-I are (1) more often endocrinologically functional, (2) more frequently GH- or PRL-producing, and (3) clinicopathologically similar in terms of the subjects age and sex as well as of tumor size and invasiveness.     

Clonality of endocrine proliferative lesions: A critical reappraisal

The distinction between nodular hyperplasia and benign tumors of the endocrine system is problematical. Although numerous parameters including lesional size, multicentricity and histological features have been suggested as distinguishing criteria, none of these is absolute. Analyses based on X-chromosome inactivation have provided conflicting results with respect to the clonal origins of these lesions, and at least some lesions conventionally classified as hyperplastic nodules appear to be monoclonal. Although clonality has been generally equated with neoplasia, it is likely that clonal expansion of genetically normal cells can occur in the endocrine system as a result of a variety of growth-promoting stimuli. Multiparametric studies employing markers for X-chromosome inactivation together with methods for identification of unique non-X-linked genetic alterations will be required to resolve the many questions relating to the pathogenesis of endocrine proliferative lesions. Presented in part at the 1998 Annual Endocrine Pathology Society Companion Meeting of the United States and Canadian Academy of Pathology, Boston, MA, Feb. 28, 1998.     

Surgical management of pancreatico-duodenal tumors in multiple endocrine neoplasia syndrome type 1

Pancreatico-duodenal tumors are the second most common endocrinopathy in multiple endocrine neoplasia syndrome type 1, and have a pronounced effect on life expectancy as the principal cause of disease-related death. Previous discussions about surgical management have focused mainly on syndromes of hormone excess and, in particular, the management of multiple endocrine neoplasia syndrome type 1-related Zollinger-Ellison syndrome. Since hormonal syndromes tend to occur late and indicate the presence of metastases, screening with biochemical markers and endoscopic ultrasound is recommended for early detection of pancreatico-duodenal tumors, and with early surgery before metastases have developed. Surgery is recommended in patients with or without hormonal syndromes in the absence of disseminated liver metastases. The suggested operation includes distal 80% subtotal pancreatic resection together with enucleation of tumors in the head of the pancreas, and in cases with Zollinger-Ellison syndrome, excision of duodenal gastrinomas together with clearance of regional lymph node metastases. This strategy, with early and aggressive surgery before metastases have developed, is believed to reduce the risks for tumor recurrence and malignant progression.     

Spontaneous proliferative lesions of the adrenal medulla in aging Long-Evans rats. Comparison to PC12 cells, small granule-containing cells, and human adrenal medullary hyperplasia

Aging rats of the Long-Evans strain spontaneously develop diffuse and nodular hyperplasia of the adrenal medulla in association with other abnormalities commonly encountered in human multiple endocrine neoplasia syndromes. The cells which comprise the adrenal nodules resemble those in the parent tumor of the rat PC12 pheochromocytoma cell line in that they show varying degrees of spontaneous or nerve growth factor-induced neurite outgrowth in culture and they contain little or no epinephrine. In addition, cells from at least some of the nodules contain immunoreactive neurotensin and neuropeptide-Y, which are also found in PC12 cells. There are a number of striking resemblances between the cells in adrenal nodules and the small granule-containing cells in the normal rodent adrenal. The findings suggest that spontaneous rat adrenal medullary nodules and PC12 cells might be derived from small granule-containing cells, or that cells within the nodules might regain properties of immature chromaffin cells and acquire characteristics of small granule-containing cells and of PC12 cells in the course of neoplastic progression. They further suggest a possible relationship between proliferative capacity and neurotransmitter phenotype in the adult rat adrenal medulla. By virtue of their sparse epinephrine content and their small granules, the cells in adrenal medullary nodules of Long-Evans rats differ from those in adrenal medullary nodules of humans with multiple endocrine neoplasia syndromes.     

Mixed type Zollinger-Ellison syndrome in a florid case of multiple endocrine neoplasia type I. A case report

An unusual and unreported mixed type Zollinger-Ellison syndrome, including features of a Type I and II syndrome, is presented as a component of a neoplastic profile constituting a highly diverse multiple endocrine neoplasia Type I syndrome.     

A linkage study of multiple endocrine neoplasia type IIa

Members of four families segregating for multiple endocrine neoplasia type IIa (Sipple's syndrome) were typed for 16 segregating blood group, erythrocyte enzyme, and plasma protein loci. Linkage analysis failed to find evidence favoring linkage between the multiple endocrine neoplasia mutation and any segregating marker. The data from this study were combined with the published data to rule out linkage for the HLA, ABO, Rh, or MNS loci at theta less than or equal to 0.25, the ADA, PGMI, AcP, GLOI, or GM loci at theta less than or equal to 0.10, and for GPT, PGD, or HpA at theta less than or equal to 0.05. The pooled data are inconclusive with respect to the previously suggested linkage to the P blood group locus.     

An unusual variant of multiple endocrine neoplasia syndrome: a case report

A case of multiple endocrine neoplasia syndrome (MEN) in a 57-year-old woman with multiple endocrine tumours involving the pancreas, parathyroid and thyroid glands is reported. An unusual feature was the presence of collision tumours in the pituitary and adrenal. In the pituitary there were adenomas and a meningioma whereas in the adrenal there was a carcinoma along with a myelolipoma. Such collision tumours in the pituitary and adrenal as components of MEN syndrome have not been previously described.     

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.     

The parathyroid glands in multiple endocrine neoplasia type 2b.

The histologic features of 21 parathyroid glands obtained from 16 Mayo Clinic patients aged 2 to 52 years who had multiple endocrine neoplasia type 2b (MEN 2b) were evaluated. The findings were correlated with the patients' ages and with the serum concentrations of calcium (15 patients), phosphorus (14 patients), and immunoreactive parathyroid hormone (iPTH) (11 patients), and with the response of serum iPTH to calcium infusion (6 patients). We also studied the histologic features of 13 parathyroid glands obtained from 8 patients not seen at the Mayo Clinic with MEN 2b. The microscopic appearance of the glands was normal in patients under the age of 17; with increased age, the glands did not exhibit normal involution, and an appearance consistent with mild chief-cell hyperplasia was evident. This abnormality was not associated with clinical or laboratory manifestations of hyperparathyroidism. We presently believe that parathyroidectomy for the disorder is not justified.     

Surgical treatment of pancreatic endocrine tumors in multiple endocrine neoplasia type 1

Surgical approaches to pancreatic endocrine tumors associated with multiple endocrine neoplasia type 1 may differ greatly from those applied to sporadic pancreatic endocrine tumors. Presurgical diagnosis of multiple endocrine neoplasia type 1 is therefore crucial to plan a proper intervention. Of note, hyperparathyroidism/multiple endocrine neoplasia type 1 should be surgically treated before pancreatic endocrine tumors/multiple endocrine neoplasia type 1 resection, apart from insulinoma. Non-functioning pancreatic endocrine tumors/multiple endocrine neoplasia type 1 >1 cm have a high risk of malignancy and should be treated by a pancreatic resection associated with lymphadenectomy. The vast majority of patients with gastrinoma/multiple endocrine neoplasia type 1 present with tumor lesions at the duodenum, so the surgery of choice is subtotal or total pancreatoduodenectomy followed by regional lymphadenectomy. The usual surgical treatment for insulinoma/multiple endocrine neoplasia type 1 is distal pancreatectomy up to the mesenteric vein with or without spleen preservation, associated with enucleation of tumor lesions in the pancreatic head. Surgical procedures for glucagonomas, somatostatinomas, and vipomas/ multiple endocrine neoplasia type 1 are similar to those applied to sporadic pancreatic endocrine tumors. Some of these surgical strategies for pancreatic endocrine tumors/multiple endocrine neoplasia type 1 still remain controversial as to their proper extension and timing. Furthermore, surgical resection of single hepatic metastasis secondary to pancreatic endocrine tumors/multiple endocrine neoplasia type 1 may be curative and even in multiple liver metastases surgical resection is possible. Hepatic trans-arterial chemo-embolization is usually associated with surgical resection. Liver transplantation may be needed for select cases. Finally, pre-surgical clinical and genetic diagnosis of multiple endocrine neoplasia type 1 syndrome and localization of multiple endocrine neoplasia type 1 related tumors are crucial for determining the best surgical strategies in each individual case with pancreatic endocrine tumors.     

Pituitary prolactinoma, pancreatic glucagonomas, and aldosterone-producing adrenal cortical adenoma: A suggested variant of multiple endocrine neoplasia type I

A case of a pituitary prolactinoma, pancreatic glucagonoma, and an aldosterone-producing adrenal cortical adenoma coexisting in a 65-year-old man is reported. This case may represent a sporadic variant of the multiple endocrine neoplasia syndrome type I first manifested by hyperaldosteronism.     

Utility of RET mutation analysis in multiple endocrine neoplasia type 2.

OBJECTIVE: To review the role of RET mutation analysis in the diagnosis of multiple endocrine neoplasia type 2 (MEN 2) and in presymptomatic screening for this disorder. DATA SOURCES: Review of the medical literature and current clinical practice. CONCLUSIONS: RET mutation analysis is a sensitive and specific test for MEN 2. It plays a pivotal role in the diagnosis and management of patients and families with MEN 2 and in the individual who presents with an apparently sporadic medullary thyroid carcinoma or pheochromocytoma. These disorders may first come to the attention of either the anatomic or clinical pathologist, who has the opportunity to see that appropriate testing is done. As with any familial disease, professional genetic counseling is an important part of the care of these patients.     

Autopsy case of prostate cancer with multiple endocrine neoplasia 2A

We describe an autopsy case of a 65-year-old man with prostate cancer accompanied by multiple endocrine neoplasia 2A (MEN 2A), including malignant pheochromocytomas, thyroid medullary carcinomas and parathyroid hyperplasia. Metastatic lesions from the prostate primary were identified using immunohistochemistry for prostate specific antigen within both primary and metastatic pheochromocytomas in the liver. To investigate the affinity of prostate cancer for pheochromocytoma cells, immunohistochemistry was carried out using a number of antibodies and both tumors were positive for N-cadherin. Interestingly, pheochromocytomas, thyroid medullary carcinomas and prostate cancer were all positive for the anti-RET antibody. The immunohistochemical results suggest that the cell affinity may, in part, result from cell-cell adhesion via N-cadherin. Although prostate cancer is rarely associated with MEN, RET activation may have participated in the tumorigenesis of this case.     

Cytogenetic studies of individuals from four kindreds with multiple endocrine neoplasia type II syndrome

Multiple endocrine neoplasia type II (MEN-II) syndrome is an autosomal dominant condition characterized by medullary carcinoma of the thyroid, pheochromocytoma, and parathyroid adenoma. A cytogenetic investigation was conducted on 13 MEN-II syndrome patients from four unrelated kindreds and 13 age-matched control subjects for chromosome instability and the chromosome 20 deletion reported in MEN-II syndrome. A significant increase (p less than 0.05) was found in the total number of chromatid and chromosome aberrations in MEN-II cells (12.3%) compared with control cells (6.9%) grown at 96 hours in mitomycin C (20 ng/ml, final concentration). The major difference between the two groups was in chromatid, and not chromosome, aberrations. There was no difference between MEN-II and control individuals in fragile site expression, the number of sister chromatid exchanges or cell kinetics. A blind analysis of high-resolution G-banded chromosomes was performed on blood specimens from 13 MEN-II and seven control individuals. Twelve of 13 MEN-II patients and one of seven control subjects were scored as having a 20p12.2 deletion (chi 2 = 12.6; p less than 0.001). Additional research is needed to determine if this cytogenetic finding is due to a chromosome deletion, inversion, or polymorphism.