A Rare Combination Consisting of Primary Hyperaldosteronism and Glucagonoma
Hideki Abe, M.D., Ph.D., Keiichi Kubota, M.D., Ph.D., Tamaki Noie, M.D., Wataru Kimura, M.D., Ph.D., and Masatoshi Makuuchi, M.D., Ph.D.
Second Department of Surgery, Faculty of Medicine, University of Tokyo, Tokyo, Japan
ABSTRACT
A 59-yr-old man with multiple pancreatic tumors is pre- sented. Previously, he had undergone left adrenalectomy for primary hyperaldosteronism and left nephrectomy for renal cell carcinoma at the ages of 39 and 55 yr, respectively. This time, 3 yr after removal of renal cancer, two solid lesions in the pancreas associated with hyperglucagonemia were de- tected. Under a diagnosis of pancreatic metastasis from renal cell carcinoma or islet cell tumor of the pancreas, distal pancreatectomy with splenectomy and enucleation of the tumor in the pancreas head were performed. Microscop- ically, a glucagonoma, measuring 2.3 mm in diameter, was detected among five pancreatic metastases from renal cell carcinoma. Four years after surgery, the patient remains well, without signs of recurrence despite multiple pancreatic metastases. This is the first report of such a rare combination consisting of aldosterone-secreting adrenal adenoma and glucagonoma. (Am J Gastroenterol 1999;94:1397-1401. @ 1999 by Am. Coll. of Gastroenterology)
INTRODUCTION
The combination of primary hyperaldosteronism, i.e., aldo- sterone-secreting adenoma of the adrenal cortex, and other endocrinopathies has rarely been described; to our knowl- edge, only 12 cases have been reported (1-12). With neither pituitary nor parathyroid involvement, the coincidental oc- currence of adrenocortical lesions and pancreatic islet cell tumors is extremely rare, and only one case has been re- ported, which was comprised by a non-symptomatic adrenal adenoma and insulinoma and which was regarded as a case of multiple endocrine neoplasia type 1 (MEN1) (13). Here, we report a first case of an aldosterone-secreting adrenal adenoma and a pancreatic endocrine tumor, as well as a glucagonoma, which was resected together with multiple pancreatic metastases from renal cell carcinoma.
CASE REPORT
A 59-yr-old man was referred to our department for treat- ment of multiple pancreatic tumors. He had undergone surgery twice before. On the first occasion, at 39 yr of age, he was found to have increased systolic and diastolic blood
pressure and hypokalemia. Endocrinological examinations showed an elevated plasma aldosterone level of 21-38 ng/dl (normal range: 5-15), suggesting a diagnosis of primary hyperaldosteronism. Blood samples obtained from the left adrenal vein showed an extremely high aldosterone level. An extensive work-up revealed no signs of hyperfunctional disorders of the parathyroid, thyroid, or pituitary gland. His family history was negative for hereditary disease and en- docrine neoplasia. Under a diagnosis of aldosterone-secret- ing adrenal adenoma, left adrenalectomy was performed, and the lesion was diagnosed pathologically as cortical adenoma. After adrenalectomy, blood pressure returned to the normal range. On the second occasion, at 55 yr of age, follow-up ultrasonography (US) showed a left renal tumor. Under a diagnosis of renal cell carcinoma (RCC), left ne- phrectomy was performed. Two years after this operation, the patient was diagnosed as having chronic hepatitis type C.
This time, follow-up US showed a dilated main pancre- atic duct and two tumors in the pancreatic head and body, measuring 15 and 8 mm in diameter, respectively. Endo- scopic retrograde pancreatography showed that the main pancreatic duct obstruction was in the head. The capillary phase of selective angiography revealed two hypervascular tumors, stained in the head and body (Fig. 1). There were no other signs of RCC recurrence. Although the fasting plasma concentration of immunoreactive glucagon (IRG) was in- creased to 213 pg/ml (normal range: 70-100), fasting levels of immunoreactive insulin (IRI) and gastrin were 78 pmol/l (normal range: 18-90) and 57 pg/ml (normal range: < 200), respectively. Serum carcinoembryonic antigen and carbo- hydrate antigen 19-9 levels remained within the normal ranges. During the oral glucose tolerance test, plasma IRI levels were 60, 384, 762, 894, and 954 pmol/L and blood glucose levels were 6.1, 10.0, 13.3, 13.9, and 11.9 mmol/L at 0, 0.5, 1, 1.5, and 2 h, respectively, after oral adminis- tration of 75 g glucose, indicating a diabetic pattern with marked hyperinsulinemia. Serum creatinine and aspartate aminotransferase levels were 1.3 mg/dl (normal range: 0.7- 1.3) and 24 U/L (normal range: 8-33), respectively, whereas the serum alanine aminotransferase level was slightly elevated to 40 U/L (normal range: 4-33). Under a diagnosis of pancreatic metastases from RCC or multiple
CHA
SPA
endocrine cell tumors including glucagonoma, the patient underwent surgery.
At laparotomy, two bosselated lesions in the pancreatic head and body were palpable. Intraoperative US (7.5 MHz) showed three hypoechoic masses in the pancreas, without infiltration or metastasis to other intra-abdominal organs. Subsequently, distal pancreatectomy including the body and tail with splenectomy and enucleation of the tumor in the head were performed. Serial cross-sections showed five lesions in the resected specimens, which were diagnosed pathologically as metastatic RCC of the left kidney. Micro- scopically, a minute lesion 2.3 mm in diameter was detected in the pancreatic body. This tumor showed a solid alveolar pattern with a thin hyalinized capsule (Fig. 2). Immunohis- tochemically, the lesion was positively stained by Grime- lius’ method for argyrophil granules, showed diffusely pos- itive staining by the peroxidase-antiperoxidase method using antiserum against glucagon, scattered positivity using antiserum against insulin (Fig. 3), and negative staining using antiserum against somatostatin. All antibodies were supplied by Dako (Carpinteria, CA). The patient’s postop- erative course was uneventful. Before discharge from hos- pital, fasting the IRG level was still high at 307 pg/ml. Four years after surgery, the patient has no signs of recurrence and the fasting IRG level is 232 pg/ml.
DISCUSSION
In cases of MEN1, 27-40% have been reported to be associated with adenoma or hyperplasia of the adrenal cor- tex (1, 12, 13), which usually produces no symptoms (12). Since Wermer (15) argued in 1963 that MEN1 must include adenomas of the adrenal cortex, some cases, such as those with adrenocortical lesions and either pituitary tumor (5, 8) or pancreatic islet cell tumor (13), have been reported as possible variants of MEN1. Postmortem studies have shown that the incidence of adrenocortical adenoma, which is gen-
erally a single lesion, is 2-8% (16, 17). As no hormones from the pituitary have been known to stimulate chiefly the zona glomerulosa in the adrenal cortex, hyperfunctional disorders of the zona glomerulosa (where aldosterone is secreted) have been considered attributable to primary neo- plasia. Besides renin-secreting tumor in the kidney, how- ever, secondary hyperaldosteronism without any nodular lesions in the adrenal is often proposed (18).
Although primary hyperaldosteronism is not a rare cause of diagnosis as essential hypertension (19), aldosterone- secreting adrenal lesions are quite rarely associated with other endocrinopathies. Thirteen cases, including the present case, have been reported in the literature (1-12), four of which were diagnosed as MEN1 (Table 1) (1, 4, 10, 12). In seven of the 13 cases, abnormal findings such as hyperplasia, hyperplastic nodules, and microadenomas re- vealed by histology, or hyperplasia shown by scintigraphy, were present in the adrenal cortex other than the main lesions (cases 1, 2, 5, 8, 10-12 in Table 1). Six of the seven cases also showed hyperfunctional disorders of the pituitary. The remaining one patient with bilateral enlarged adrenal cortices who had no pituitary disorder died of gastrointes- tinal bleeding at the age of 15 yr, and her family had been
affected by MEN1 over six generations (case 1) (1). In contrast, in seven of the 13 cases, hyperfunctional disorders of the pituitary were present (cases 2, 4, 5, 8, 10-12 in Table 1), and six of the seven showed abnormal findings in the adrenal cortex other than the main lesions. Nodular hyper- plasia of the adrenal cortex is not always easy to differen- tiate pathologically, from adenoma, especially when hyper- plastic nodules exhibit multifocal or bilateral development. Then, the diagnosis of adrenocortical adenoma is often supported by endocrinological examination, although this may occasionally fail to reveal cases showing autonomic dysfunction. Therefore, in patients with both aldosterone- secreting adrenal lesions and hyperfunctional disorder of the pituitary, the former lesions may develop as secondary ones associated with the hyperfunctional pituitary (18). In the present case, although a glucagonoma of the pancreas was identified, no family history and no signs of hyperfunctional disorders of the parathyroid, thyroid, and pituitary glands were revealed, and an adrenal lesion developed unifocally and unilaterally. Thereby, the adrenal lesion was considered attributable to primary neoplasia.
Glucagonomas have been reported to account for only 1%
of all endocrine cell tumors of the duodenopancreatic area: 99% of them are solitary, 80% are >3 cm in diameter, and 80% of them are malignant (20). Glucagonoma syndrome consists of weight loss, necrolytic migratory erythema, di- abetes mellitus, cheilosis or stomatitis and diarrhea, each of which has been described to be present in 71%, 67%, 38%, 29%, and 29% of patients, respectively (21). In patients with MEN1, glucagonomas are found in <5% of cases (22). Kimura et al. (23) reported that the incidence of endocrine cell tumor of the pancreas was 10% in autopsy cases sub- jected to histological studies of all sections: in six of 18 endocrine cell tumors measuring 517-4351 pm in diameter, glucagon production exceeded that expected for normal Langerhans islets. In the present case, a glucagonoma 2.3 mm in diameter showed diffuse positivity for glucagon and little positivity for insulin immunohistochemically. The cel- lular composition and distribution were clearly different from those of normal surrounding Langerhans islets indi- cating neoplasm, and these were a demonstration that pro- duction of multiple hormones is a very common feature in pancreatic endocrine tumors (24). The plasma IRG level was increased to double the normal level, whereas no clin- ical features of glucagonoma syndrome except for diabetes mellitus were exhibited. After pancreatectomy, the IRG level was still elevated, but did not increase subsequently. This suggested that the hyperglucagonemia before surgery might not have been due to the minute glucagonoma. Al-
though the presence of residual glucagonomas or ectopic enteroglucagon secretion from metastatic RCC (25) was possible, both were unlikely because the patient had no signs of tumor recurrence. The fasting plasma IRG in pa- tients who suffer from adult-onset diabetes mellitus, liver cirrhosis, or chronic renal failure has been reported to in- crease to 118 ± 8, 243 ± 41, and 225 ± 26 pg/ml, respec- tively (26), and adult-onset diabetes mellitus is most likely to have induced the hyperglucagonemia in this patient. Based on these findings, a glucagonoma in the present case was considered to have incidentally developed in the indi- vidual with an aldosterone-secreting adrenal adenoma. Sim- ilarly, Cushing’s syndrome caused by glucocorticoid-secret- ing adrenal adenoma associated with other endocrinopathies has been reported in only a few cases (27).
The pancreas is not a common metastatic site of RCC. Although metastasis to the pancreas was found in 2.8% of 101 patients at the time of diagnosis of RCC, all of the patients had other sites of metastatic spread (28). At au- topsy, the incidence of metastasis only to the pancreas was reported to be 1% of 120 patients who had metastasis in only one organ and died from a cause other than RCC (29). An aggressive surgical approach to metastasis from RCC has been advocated only for solitary lesions in any organs (30), and a long interval from the appearance of a primary RCC to detection of the metastatic focus is known to be a factor associated with favorable survival after removal (31). Ac- cording to a review of 16 patients who underwent surgical resection of pancreatic metastasis from RCC, 12 patients
| Patient | Adrenal Cortex | Pituitary | Parathyroid | Pancreas | Reference |
|---|---|---|---|---|---|
| No./Age at diagnosis/Sex | |||||
| 1*/15/F | enlarged with ballooning cells | | | § | gastrinoma? | 1 |
| 2/501,51/F | adenoma and hyperplastic nodules | hypersomatotropism, solitary tumor | II | none | 2 |
| 3/different for several years/t | solitary tumor | Il | § | none | 3 |
| 4*/metachronous/* | solitary adenoma | hypersomatotropism | § | none | 4 |
| 5/551,58/F | bilateral micronodular hyperplasiaį | PRL-secreting adenoma | | | none | 5 |
| 6/61/F | bilateral multiple adenomas | | | § adenoma | none | 6 |
| 7/27/F | solitary adenoma | Il | § | none | 7 |
| 8/39/F | adenoma and microadenoma | prolactinoma | II | none | 8 |
| 9/42/F | focal tumorous lesion | Il | § adenoma | none | 9 |
| 10*/421,50/F | adenoma and smaller nodulesį | ACTH-secreting adenoma | §adenomaţ | none | 10 |
| 11/55/M | tumor and bilateral hypertrophy | prolactinoma | II | none | 11 |
| 12*/551,62/F | adenoma and ipsilateral nodular hyperplasia | PRL-secreting adenomaţ | § adenoma | elevated PP level | 12 |
| 13/391,59/M | solitary adenomaţ | ǁ | | | adenoma positive for Glu | present case |
* Case of multiple endocrine neoplasia type 1.
* Not described.
¿ Previous incidence.
§ Hyperfunctional.
Not hyperfunctional.
PRL = prolactin; ACTH = adrenocorticotropic hormone; PP = pancreatic polypeptide; Glu = glucagon.
were alive at the time of writing 1-28 months after surgery. In the present case, although five metastases were present 4.5 yr after nephrectomy, 4 yr after distal pancreatectomy, there are no signs of recurrence. Even if RCC metastases to the pancreas are multiple, resection of such lesions is con- sidered to carry a long disease-free interval in cases in which other organs are not involved.
In summary, we have described a case of a primary hyperaldosteronism and a minute glucagonoma among five pancreatic metastases from RCC. This unusual combination is considered to develop incidentally.
Reprint requests and correspondence: Hideki Abe, M.D., Ph.D., Second Department of Surgery, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan. Received Jan. 23, 1998; accepted Aug. 18, 1998.
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