An Overview: Clinical Management for MEN I Patients

Johannes D. Veldhuis

University of Virginia School of Medicine Charlottesville, Virginia 22908


    Introduction
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 Introduction
 References
 
THE ACCOMPANYING discussions by two expert academic teams, namely, J.A. Norton and S.A. Wells, Jr. from the Washington University School of Medicine (see below) and A.L. Vinik and R.R. Perry from the Eastern Virginia Medical School (see below)), highlight some of the interesting, significant, and at times controversial issues in clinical management of patients with multiple endocrine neoplasia Type I (MEN I). By way of background, MEN I was recognized by Erdheim in his autopsy examination of an electrician with acromegaly and a pituitary tumor (1). Other endocrine lesions were identified in this individual, raising the question by Erdheim of predisposition to multiple endocrine neoplasia. Since then a broad definition of MEN I has emerged as an array of endocrine tumors typically involving the pituitary gland, parathyroid glands, and islet cells of the pancreas (hence three P’s), sometimes with carcinoid tumors as well (2, 3, 4). A fourth feature is typically autosomal dominant inheritance, often with high penetrance (hence four P’s) (2, 4, 5, 6). Of major clinical significance, individual patients and kindreds exhibit a broad diversity of initial and subsequent clinical manifestations, including presentation with parathyroid disease, pituitary tumors, spells (hypoglycemia associated with insulinoma), gastrointestinal ulcers (gastrinoma), watery diarrhea (VIPoma), necrolytic migratory erythema (glucagonoma). Indeed large kindreds have been identified with one or more of the foregoing as the initial presenting disorder (3, 5). Most recently, a presumptively causal tumor-suppressor gene has been mapped to the long arm of chromosome 11 (locus 11q13), thereby identifying a genetic predisposition in approximately 50% of relevant offspring (7, 8). With this historical background, the issues of medical and surgical management of patients with the potential for multiple endocrine tumors are highlighted elegantly and quite comprehensively by the two accompanying papers.

Points of consensus are that the primary hyperparathyroidism is very common in MEN I kindreds, and it reflects multigland hyperplasia and/or multiple parathyroid adenomas (2, 9). Thus, there is an attendant high risk of postoperative recurrence if surgical removal of only a single parathyroid gland, rather than a 3 1/2 or 4-gland parathyroidectomy, is used as primary therapy. However, surgically induced hypoparathyroidism is not a trivial disease, and no controlled studies have explored the relative long-term merits of 3 1/2- vs. 4-gland parathyroidectomy with heterotopic autotransplantation. Thus, some surgical uncertainties remain. Other patients who are poor surgical candidates should be followed in accordance with the sensible consensus recommendations applicable to primary hyperparathyroidism in general (see Ref. 7 in Vinik and Perry).

Many additional issues remain to be addressed in primary hyperparathyroidism associated with MEN I, such as the exact sensitivity and specificity of dual-isotopic scans (sestamibi/pertechnetate); the roles, if any, of estrogen treatment (as suggested by Vinik and Perry) in postmenopausal patients with hypercalcemia; or the advisability of oral phosphate therapy, as the latter carries the potential danger of inducing progressive renal failure. Moreover, glucocorticoid treatment (although mentioned by Vinik and Perry) is rarely helpful in primary parathyroid-hormone excess. Similarly, far more information will be required to assign the relative risk-to-benefit ratio of iatrogenically infarcting a parathyroid tumor in MEN I individuals, i.e. what is the success rate, recurrence risk, and feasibility of this strategy as a second invasive procedure? Thus, a number of cautions and queries remain, despite the general view that surgery is appropriate primary therapy in parathormone-dependent hypercalcemia associated with MEN I.

The second most common tissue site of clinical involvement in MEN I is the pancreatic islet, typically presenting with excess gastrin secretion and resultant clinical symptoms caused by hyperchlorhydria and its sequelae. Here, the exact role of surgery is more difficult to establish. Vinik and Perry argue that primary management may be medical using available potent proton-pump inhibitors, such as omeprazole, with or without H-2 receptor antagonists, recognizing that gastrin-secreting cell clusters are often diffuse, and sometimes malignant and difficult to localize. The exact malignancy rate is not definitively established, but ranges between 7 and 47%. Vinik and Perry emphasize that, in two recent series, surgical cure was not possible in 16 of 17 patients and in 28 of 29. Such observations clearly raise the consideration of either endorsing primary medical treatment and/or defining conditions for more effective earlier surgical intervention. Indeed, the latter contention is thoughtfully posed by Norton and Wells. Citing the experience that gastrinomas are often small, multiple, and located within the duodenum as well as the pancreas, and that 50% of patients may have lymph node metastases identified when surgery is undertaken, these authors acknowledge the expected difficulty in carrying out primary surgery for such presentations. As importantly, the presence of liver metastases appears to point to a more baleful prognosis. Consequently, an important unresolved issue is when to intervene in such patients (i.e. possibly before tumors reach known metastatic distribution), how to identify such at-risk individuals, and how to prevent metastases, medically or surgically. In addition, the definition of "cure" after gastrinoma or other endocrine-tumor resection is also important and probably at least requires provocative testing and careful long-term followup. Possible novel avenues for therapy may ultimately include somatostatin-receptor-directed cytotoxic treatment, although this is not in the immediate offing.

A second important islet cell tumor observed in MEN I is insulinoma, which is largely a pancreatic lesion without extrapancreatic primary lesions (unlike gastrinoma, above). Vinik and Perry argue that such tumors are easier to identify and localize via angiography and stimulation tests; e.g. calcium infusion (10) or secretin injection, thus prompting a greater role for surgery with the expectation that cure is possible in most patients. Here, the specter of islet cell malignancy is greatly reduced. Consequently, surgery is often indicated for insulinoma, given the assertion by the experienced Norton and Wells team that 85% are benign, 80% are detected by angiography with or without calcium stimulation, and 90% are surgically curable. Moreover, even some patients with liver metastases may merit surgical exploration, as prolonged survival is possible after partial tumor removal.

Although not discussed in this particular controversy, pituitary neoplasms occur in approximately 15% (3–50%) of MEN I patients (3, 4, 5, 11). Limited available histopathological data have not demonstrated a possibly expected diffuse pituitary-cell hyperplasia in such individuals with prolactinoma or acromegaly or in those with clinically nonsecretory pituitary tumors (3), although these considerations cannot be absolutely ruled out. In general, I believe that the present recommendations for management of sporadic pituitary tumors remain largely appropriate in MEN I patients with pituitary tumors. For example, dopamine-2 receptor agonists are useful to suppress hyperprolactinemia, especially in patients with drug-responsive, surgically bulky adenomas and in patients who desire to preserve fertility and residual pituitary function. On the other hand, transsphenoidal pituitary microadenomecty remains appropriate in most acromegalic individuals. Relevant postoperative endocrine and neurosurgical followup remains important, as espoused for the general pituitary-tumor patient population, namely monitoring tumoral hormone over-secretion, evaluating associated endocrine deficits, and following the patient for mass-lesion effects (e.g. headache, visual field deficits, etc.).

A clinical mystery that remains is the basis for the patient-to-patient phenotypic variability in MEN I kindreds. Vinik and Perry present a good intuitive construct in this regard, but ultimately the exact molecular and biochemical bases for any particular individual’s or family’s single or multi-glandular involvement, given his/her genetic background and environment, will be important to establish.

Important issues that I believe remain unresolved include the exact cost-to-benefit ratio of screening individual new patients, and their families, in whom just a single endocrine tumor is the presenting feature. In addition, at what age should screening begin for children, and under what conditions should surgical or medical treatment in young individuals be first initiated? What preventive measures will become valuable in patients (within known MEN I families) who are carrying a relevant gene defect but remain asymptomatic? When should secretagogue tests first be employed in kindreds, and how may the results be used to predicate more timely surgical intervention? What are the mechanisms underlying the variable clinical expressitivity of these highly penetrant genes? Moreover, why are so many disparate islet-cell peptides and nonpeptide products secreted by pancreatic tumors, including insulin, grastrin, glucagon, VIP, GnRH, and GHRH? Perhaps most importantly, developing novel medical treatments for gastrinomas that are malignant and show multiple metastatic deposits remains an immediate need.

Overall, the MEN I constellation is a fascinating and clinically important entity, for which therapeutic controversy is valuable to trigger further appropriately controlled studies. Such investigations should clarify short-term management options as well as long-term novel molecular and biochemically based treatment interventions in increasingly well-defined subsets of MEN I patients.


    Footnotes
 
Address all correspondence regarding these controversies and requests for reprints to: Dr. Johannes D. Veldhuis, Department of Medicine/ Endocrinology & Metabolism, University of Virginia School of Medicine, Box 202, Charlottesville, Virginia 22908.

Accepted October 22, 1996.


    References
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 Introduction
 References
 

  1. Erdheim J. 1903 Zur normalen und pathologischen histologie der glandula thyreoidaea, parathyreoidaea, und hypophysis. Beitr Pathol Anat. 33:158–236.
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  10. Brunt LM, Veldhuis JD, Dilley WG, et al. 1986 Stimulation of insulin secretion by a rapid intravenous calcium infusion in patients with beta cell neoplasms of the pancreas. J Clin Endocrinol Metab. 62:210–216.[Abstract]
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