Clinical Findings

Many patients with pancreatic endocrine tumors present with signs and symptoms of excess hormone secretion. Clinical manifestations of the most common endocrine tumor, an insulinoma, are profound hypoglycemia with diaphoresis, confusion, and syncope. Classically, gastrinomas are the second most common tumor of islet-cell origin, and they present with peptic ulcer disease. Other common symptoms include diarrhea and esophagitis.

VIPomas are associated with a syndrome of watery diarrhea, hypokale-mia, and achlorhydria (WDHA). Glucagonomas may present with diabetes, depression, deep-vein thrombosis, and dermatitis (necrolytic migratory erythema). Presenting symptoms of the rare somatostatinomas include cholelithiasis, diabetes, steatorrhea, diarrhea, weight loss, and abdominal pain.

Although the majority of these tumors present in a sporadic manner, it is important to identify those patients in whom the endocrine tumors occur in the setting of a hereditary syndrome, such as MEN 1 or VHL disease.

25.13.1 Multiple Endocrine Neoplasia Type 1 (MEN 1)

MEN 1 is characterized by neoplasia of the pancreatic islet cells, parathyroid glands, and anterior pituitary gland. In 1954, Wermer60 first described this syndrome, with its autosomal dominant mode of inheritance, in a family. In 1988, Larsson et al.61 were able to link the MEN 1 gene to Chromosome 11q13. The MEN 1 gene was subsequently identified by positional cloning about 10 years later.62,63 This tumor suppressor gene consists of 10 exons, spans over 9 kb, and encodes for menin, a 610-amino acid protein, which appears to function as a nuclear factor interacting with the transcription factor JunD, an inhibitor of cell growth.64

The usual criteria for the clinical diagnosis of MEN 1 consists of an individual with involvement of at least two of the most commonly affected endocrine glands (parathyroid, pituitary, and pancreatic islet cells) along with a first-degree relative having at least one of the neoplastic lesions seen in MEN 1 or, within established kindreds, an individual with one of the major neoplastic lesions and concordance of an affected first-degree relative.65,66 Multiple studies suggest a mean age at diagnosis ranging from 29 to 41,66 and penetrance at age of 50 ranges from 82 to 100%.66 These studies also demonstrate a range in the prevalence of islet cell tumors from 36 to 75%.

Gastrinomas are the most common functional tumor type followed by insulinomas.66 Importantly, the malignant potential of MEN 1 gastrinomas ranges from 15 to 60%.66 One report suggests that certain truncating mutations of the MEN 1 gene have a greater potential for metastasis.67 Insulinomas are commonly multiple and have a lower malignancy rate of 8% as compared to gastrinomas.66,68 Although the other three endocrine tumor types have been seen with MEN 1, the third most common pancreatic lesion is a nonfunctional islet cell tumor.66

A comprehensive study by Carty et al.69 of the penetrance and spectrum of manifestations of MEN 1 patients from western Pennsylvania and Ohio found that 13 of 34 (38%) patients presented initially with islet cell tumors. Noteworthy is that only 3 of these patients were diagnosed at the same time with primary hyperparathyroidism. The prevalence of MEN 1 islet cell tumors in these 34 patients was 71% and consisted of 16 gastrinomas, 3 insulinomas, 3 nonfunctional tumors, and 2 glucagonomas. Five of the 6 MEN 1 related deaths in this study occurred from metastatic islet cell tumors. The etiology and natural history of these deaths are consistent with results from a report from Doherty et al. who determined that pancreatic endocrine tumors were the most common cause of death in MEN 1 family members.70 They found that 46% of deaths were at a median age of 47 years and were related to endocrine tumors.

These results suggest the importance of screening for pancreatic endocrine tumors. It is essential that a successful screening approach find small tumors. This is based on results of a study by Cadiot et al.71 who found that 36% of patients with tumors greater than 3 cm had liver metastases as compared to 6% of patients with tumors that were less than 3 cm. One suggested screening method searches for hormonal evidence of endocrine tumors by measuring serum levels of gastrin, glucose, insulin, proinsulin, and pancreatic polypeptide.72 Another screening approach could utilize imaging techniques such as computed tomography, magnetic resonance imaging, somatostatin receptor scintigraphy, and endoscopic ultrasound (EUS). This latter imaging modality has been shown to be the most sensitive technique available for the detection of small sporadic pancreatic endocrine tumors.73 Indeed, a small retrospective study by Gauger et al.72 found EUS to be useful for detecting endocrine tumors in asymptomatic patients with MEN 1.

25.13.2 Insulinomas

Bartsch et al.74 note that the role molecular mechanisms play in contributing to the tumorigenesis of insulinomas remains elusive. They note, however, that inactivation of the plffNK4a tumor suppressor gene predisposes to gastrinomas and nonfunctioning endocrine pancreatic carcinomas. These authors studied the role of pi&NK4a in the tumorigenesis of insulinomas. Findings showed that the pl&NK4a tumor suppressor gene contributed to tumorigenesis in only a small set of insulinomas.

We believe that a reasonable pancreatic endocrine surveillance program should include both biochemical tests and imaging studies including computed tomography (CT) and EUS. CT scanning is recommended because of its ability to visualize other organs such as the liver and adrenal glands, whereas EUS is felt to be the best imaging modality for the pancreas.

25.13.3 VHL Disease

VHL disease is an autosomal dominant multisystem cancer syndrome characterized by the development of hemangioblastoma of the central nervous system, retinal angioma, renal cell carcinoma or cysts, pheo-chromocytoma, endolymphatic sac tumors, pancreatic cysts and neuroendocrine tumors. This highly penetrant syndrome results from a mutation in the VHL gene.75,76 VHL is a tumor suppressor gene found on the short arm of Chromosome 3. The gene encodes for a 213-amino acid protein that is localized in the nucleus or cytoplasm. Loss of normal VHL protein function appears to effect ubiquitin-mediated degradation of large cellular proteins.

Pancreatic involvement in VHL consists of pancreatic cysts, serous cystadenomas, or neuroendocrine tumors.75,77 Pancreatic neuroendocrine tumors arise in 12 to 17% of VHL patients.77,78

The association of endocrine tumors with VHL was first reported in 1979 in a family in which all four siblings developed lesions associated with VHL disease, and two of these siblings developed endocrine tumors.79 Pancreatic neuroendocrine tumors appear to occur at a significantly younger age, namely a mean of 35 years80 in VHL patients as compared to a mean age of 58 years for sporadic patients. Unlike MEN 1 patients, the pancreatic endocrine tumors are usually clinically nonfunctional and the majority did not appear to express pancreatic or gastrointestinal hormones by immun-ostaining.80 A distinguishing histologic feature in the majority of these endocrine tumors in VHL patients was clear-cell morphology.80

Because renal cell carcinomas are the major malignancy in VHL, CT scan has been suggested as the imaging study of choice. One experienced group suggests starting screening for abdominal lesions at the age of 12 years using annual CT scanning.81 Using this approach, they were able to identify 44 patients with a neuroendocrine tumor of the pancreas. Five of these patients were not candidates for resection based on the presence of metastatic disease. Twenty-five patients fulfilled their criteria for resection:

■ No evidence of metastatic disease

■ Lesion greater than 3 cm in the body or tail of the pancreas or greater than 2 cm in the head

■ If the patient was undergoing a laparotomy for the resection of a kidney or adrenal lesion (another pathologic manifestation of VHL)

None of these 25 patients had developed metastatic disease with a median follow-up time of 32 months. Additionally, none of the patients with lesions or clinical scenarios that did not fulfill the above-mentioned criteria and were just followed with serial abdominal CT scans, developed met-astatic disease.

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