ABSTRACT: Multiple endocrine neoplasia type 1 (MEN-1) is a syndrome consisting of tumors of the parathyroids, the enteropancreatic neuroendocrine system, and the anterior pituitary gland. Carcinoid and other tumors occur less commonly. MEN-1 is most often familial, though tumor types can vary within the family. MEN-1 is sometimes a lethal disease, so biochemical and radiological screening for early detection of the associated malignancies may be important. We describe a British Columbia family with MEN-1 and associated pulmonary carcinoids and carcinoid syndrome. We also suggest screening procedures that may be useful in the early detection and follow-up of associated malignancies such as carcinoid tumors in these patients.
Multiple endocrine neoplasia type 1 is a rare but sometimes deadly autosomal dominant disorder. The authors describe a BC family with the disease, discuss the disorder, and suggest screening procedures.
The spectrum of multiple endocrine neoplasia type 1 (MEN-1) extends beyond the defining parathyroid, pancreatic, and pituitary tumors to include duodenal gastrinomas, and, less commonly, carcinoid tumors, thyroid and adrenocortical adenomas, and lipomas. In this British Columbia family with MEN-1 and associated carcinoid tumors and carcinoid syndrome, the syndrome is also variably manifested by parathyroid hyperplasia, pancreatic gastrinomas and insulinomas, pituitary tumors, and lipomas. Although carcinoids are typically slow-growing tumors, in the case discussed, pleural metastases and subsequent recurrence at a thoracotomy incision site occurred, a finding previously unreported.
MEN-1 is quite rare, occurring in approximately 3 to 20 persons of every 100,000. However, because of its potentially lethal nature, widespread screening is usually recommended in affected individuals. Although decreased morbidity has been shown to result from early diagnosis, the effect on mortality is less clear. The additional screening procedures described in the conclusion may be useful in the early detection and follow-up of associated malignancies such as carcinoid tumors in these patients.
The index case is a 52-year-old man with a family history of MEN-1 syndrome who presented in 1976 with hypercalcemia. He was diagnosed with parathyroid hyperplasia and was surgically treated with a subtotal parathyroidectomy. After initial normalization of his serum calcium, he developed recurrent hypercalcemia with development of a renal calculus.
This was asymptomatic and he was not treated. He has also had multiple lipomas requiring surgical excision. In 1995, an asymptomatic 3-cm nodule in the right lower lobe of the lung was identified on a routine chest X-ray, and resection showed a low-grade carcinoid tumor. In February 1997, he developed peptic ulcer disease. Gastrin levels were normal, and no pancreatic or duodenal tumors were detected by computed tomographic (CT) scan.
In January 1998, he presented with flushing, pruritus, and watery diarrhea. Chest X-ray showed no new lesions but a CT scan of the chest revealed local recurrence of a carcinoid tumor in the right lower lobe and pleural metastases, which were unresectable (Figure 1). The CT scan of the abdomen was normal. A 24-hour urine analysis for 5-hydroxyindoleacetic acid (5-HIAA) was elevated at 116 µmol (normal range is 10 to 40 µmol). Octreotide was ineffective for the flushing and diarrhea. In October 1998, he presented with a large 12-by-6-cm lesion at the site of his thoracotomy incision. Resection of this tumor in January 1999 again revealed a carcinoid tumor (Figure 2). He continues to experience symptoms of carcinoid syndrome.
The patient’s mother presented in 1976 with recurrent peptic ulcer disease at age 54. She went on to have a total gastrectomy and distal pancreactectomy for Zollinger-Ellison syndrome due to pancreatic gastrinomas. In 1977, she was diagnosed as having hyperparathyroidism and hypercalcemia and had 3½ parathyroid glands resected. She continued to have elevated serum gastrin and calcium levels. In 1992, she had the remaining half of her parathyroid gland removed and her serum calcium normalized.
In the same year, she developed hemoptysis. Chest X-rays as far back as 1986 revealed a left lung mass. Investigations revealed a low-grade carcinoid tumor of the left lower lobe of the lung. This was associated with elevated 5-HIAA levels and carcinoid syndrome. Her 5-HIAA levels normalized following pneumonectomy. She eventually died of a metastatic transitional cell carcinoma of the ureter at age 71.
The patient’s daughter presented with hypoglycemia due to an insulinoma in 1982 at age 11. In 1983, she had 85% of her pancreas removed. Post-operatively, she continued to have episodes of hypoglycemia. In the same year, a screening CT scan of her head revealed a small nonfunctioning pituitary tumor, which was not treated. In 1988, she had excision of 3½ parathyroid glands for hypercalcemia. In 1989, she had a subtotal pancreatectomy (>95% removed), at which time multiple small tumors were found in the head of the residual pancreas. This resulted in insulin-dependent diabetes mellitus. To date, she has not developed carcinoid tumors.
MEN-1 is an autosomal dominant disorder characterized by tumors of the parathyroids, the pancreas, and the anterior pituitary gland. Less common tumors include skin angiofibromas, thyroid and adrenocortical adenomas, lipomas, and carcinoids.
Parathyroid tumors with hypercalcemia are the first manifestation of MEN-1 in about 90% of patients. In 1998, a review of 130 patients with MEN-1 admitted to the National Institutes of Health showed that 99% of patients had parathyroid tumors. Enteropancreatic neuroendocrine tumors were identified in 66% of the patients. Seventy-one percent of these were gastrinomas, 18% were insulinomas, and 6% were nonfunctioning islet cell tumors.
Rarely, glucagonomas, somatostatinomas, and VIPomas were diagnosed. Pituitary tumors were seen in 47% of patients. Bronchial carcinoid was diagnosed in only 11 patients (8.5%), and gastric carcinoid was detected incidentally on endoscopy in 9 patients (7.7%) who also had gastrinomas. One case (0.7%) of malignant thymic carcinoid was observed.
Carcinoid tumors are usually classified as foregut (lung, thymus, stomach, pancreas, duodenum), midgut (jejunum, ileum, appendix, right colon), or hindgut (left colon, rectum). In 1974, Goodwin analyzed 2837 cases of carcinoid tumors from files at the National Cancer Institute and found most to be in the midgut. However, in 1987, Duh and colleagues reviewed carcinoid tumors in 65 patients who had MEN-1, and found them to be mainly of foregut origin (68%).
These included the bronchus (27%), thymus (24%), duodenum (14%), and stomach (3%). Bronchial carcinoids associated with MEN-1 were more common in women and most (74%) had low-grade features. Pulmonary carcinoids can be classified on a spectrum ranging from a low-grade malignancy (typical carcinoid) to a high-grade malignant small-cell carcinoma. An atypical carcinoid is an intermediate form of tumor. Five-year survival for typical carcinoid tumors ranges from 95% to 100%, and that of an atypical carcinoid tumor from 60% to 80%.[1,9-11]
In terms of biological behavior, only 2% of pulmonary carcinoids are associated with carcinoid syndrome. With gastrointestinal carcinoids, hepatic metastases must be present for the development of carcinoid syndrome, as the secretory products are otherwise metabolically inactivated in the liver. The carcinoid syndrome can be seen without liver metastases when the tumor grows in extraintestinal sites such as the lung, because secretory products can gain direct access to the peripheral circulation.
Carcinoid tumors may metastasize and recur, as shown in our case report. Metastases may spread to liver, bone, and the central nervous system. The present case demonstrates that recurrences can occur at previous incision sites. This is likely due to contiguous extension of residual tumor or cutaneous spread at the time of surgery. It may also be due to blood-borne metastases to sites of inflammation or trauma. Thus, it is important to monitor patients with a previously diagnosed carcinoid tumor who remain at risk of recurrence or of a second primary tumor.
MEN-1 is usually a familial syndrome. In most cases, severity and age of onset is similar in a given family, but this is not always the case. For example, both our index patient and his mother had carcinoid and parathyroid tumors, but clinical presentations and severity of the manifestations of each tumor were clearly different.
Given the evident spectrum of tumors and presentations, if early detection is elected, it may be necessary to screen for a variety of possible tumors. Although there is presently no clear evidence that screening and early diagnosis affects survival from pulmonary carcinoids, it is intuitive that it may. For example, in a retrospective analysis of 59 patients with MEN-1 by Doherty and colleagues in 1998, carcinoid tumors were a cause of death in six patients, a significant attributable mortality.
Possible screening methods for lung carcinoids include biochemical and radiographic testing. Often one modality alone is insufficient. Lung carcinoids can be detected with elevated levels of 5-HIAA, serotonin, calcitonin, or adrenocorticotropic hormone (ACTH) levels.
CT can assess contour and calcification of any masses. Up to 30% of pulmonary carcinoid tumors show some calcification. Routine chest X-ray may be inadequate. If a lesion is detected by radiographic methods, bronchoscopy may also be used, mainly for proximal lesions. However, cytology from brushings is often of low yield because these tumors are covered by a normal mucosa. The main concern of bronchoscopic biopsies is hemorrhage due to the vascularity of the tumors.
Octreotide scintigraphy has also been shown to be useful. Eighty-seven percent of all carcinoid tumors express somatostatin receptors, to which octreotide can bind. CT scanning is often limited to one or two body areas, whereas the whole body is surveyed by the octreotide scan. In 1996, Kwekkeboom and colleagues found that in 19 of 20 patients with histologically proven carcinoids, there was accumulation of octreotide at tumor sites. The combination of scintigraphy, chest X-ray, and ultrasound of the upper abdomen led to the detection of all lesions in all patients.
This case emphasizes the expanded spectrum of MEN-1 beyond the classical parathyroid, pancreatic, and pituitary neoplasms. It stresses the importance of monitoring, both in the individual and in family members. Family counseling is important in such cases. Presently, genetic screening is not well established in MEN-1 as the long-term benefit of early diagnosis is unclear. It may be useful, however, to rule out family members who are not at risk of disease.
In asymptomatic first-degree relatives of patients with carcinoid tumors, we suggest initial biochemical screening with urine 5-HIAA and serotonin. This may be followed by ongoing screening with chest X-ray or CT scan, and preferably scintigraphy. This should be done intermittently (Table 1).
Exclusion of a person as a carrier by genetic testing would clearly obviate additional screening. The frequency of such screening, cost-effectiveness, and impact on clinical outcomes is not yet clear. The age to begin screening is also not known. For follow-up of a known tumor, testing would be advised for several years, until there is no evidence of recurrence. These procedures may lead to decreased morbidity and decreased mortality in those individuals affected with carcinoid tumors and MEN-1.
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Dr Dhalla recently completed her general internal medicine training at UBC and is currently pursuing a master’s degree in epidemiology in Boston. Dr Weinstein is an internal medicine specialist in private practice in Chicago. Dr Holden works as an anatomical pathologist at St Paul’s Hospital in Vancouver. Dr Cleator is a professor of surgery at UBC, head of the Mr and Mrs P.A. Woodword GI clinic, past-president of the Canadian Association of Gastroenterology, past-president of the VMA, and currently a board member of the BCMA.
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