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CLINICAL CASE SEMINAR |
Departments of Medicine (M.B., P.J.S.) and Pathology and Laboratory Medicine (V.A.L.), University of Pennsylvania, Philadelphia, Pennsylvania 19104-6149; Department of Laboratory Medicine and Pathobiology (S.L.A.), University of Toronto, Toronto, Ontario, Canada M5G 2M9; and Christiana Hospital (V.A.W.), Newark, Delaware 19713
Address all correspondence and requests for reprints to: Peter J. Snyder, M.D., 778 Clinical Research Building, 415 Curie Boulevard, Philadelphia, Pennsylvania 19104-6149.
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Abstract |
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Introduction |
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Most types of pituitary tumors have been reported to be associated with MEN1. Lactotroph adenomas have been reported most commonly, but somatotroph, corticotroph, thyrotroph, and clinically nonfunctioning adenomas have also been reported (2, 3, 4, 5, 6, 7). Only two gonadotroph tumors have been reported in association with MEN1, and only by immunohistochemical staining (7); none has been recognized clinically.
We report here a patient who had a clearly documented gonadotroph tumor associated with MEN1. The gonadotroph tumor presented first; it was suspected by ovarian hyperstimulation, typical biochemical features, and a sellar mass and confirmed by immunocytochemistry of excised pituitary tumor tissue. Hyperparathyroidism developed next, and she was found to have three hypercellular parathyroid glands. The diagnosis of MEN1 was confirmed by finding a mutation of the second exon of the MEN1 gene that predicts a stop codon.
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Case Report |
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-subunit (23.3 µg/ml; normal range, 0.1–1.0 µg/liter) concentrations, elevated FSH (17.8 mIU/ml; normal range, 5.4–12.4 mIU/ml), suppressed LH (0.7 mIU/ml; normal range, 1.7–7.7 mIU/ml), and increased LHß-subunit response to TRH, which together suggested the diagnosis of a gonadotroph adenoma causing ovarian hyperstimulation, the first time this presentation of a gonadotroph tumor was documented (8). She had transsphenoidal surgery again later in 1993, and by immunohistochemical staining, the excised tissue was strongly positive for -subunit and focally positive for FSHß-subunit. She was treated by 
-knife radiation in January 1994.
Later in 1994, when she was age 40, a routine biochemical profile showed an elevated calcium concentration. She was then found to have an elevated serum parathyroid hormone concentration and elevated 24-h urine calcium excretion (Table 1
). Because she had no symptoms or signs of primary hyperparathyroidism, no specific treatment was advised at that time. In 1998, however, plain radiographs of the abdomen showed bilateral renal calculi, confirmed by abdominal ultrasound. Serum calcium and parathyroid hormone concentrations were still elevated (Table 1) and serum creatinine normal. At neck exploration in December 1998, the right and left upper parathyroid glands appeared to be enlarged and were completely excised. The right inferior parathyroid appeared normal in size and was biopsied. The left inferior parathyroid was not identified. By histological examination, all three glands were hypercellular (Fig. 1). Postoperatively, serum calcium and parathyroid hormone concentrations remained elevated (Table 1). Also in 1998, a lipoma measuring 5 cm in diameter was excised from her right thigh; the diagnosis was confirmed histologically.
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), and by immunohistochemical staining, it was positive for the neuroendocrine marker synaptophysin as well as steroidogenic factor-1 (Fig. 2), indicating gonadotroph differentiation, but the tumor was negative for -, LHß-, and FSHß-subunits.
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Genetic testing
After genetic counseling, she gave written informed consent to genetic testing for MEN1. Genomic DNA obtained on a buccal swab sample was screened for all coding exons (2, 3, 4, 5, 6, 7, 8, 9, 10) of the MEN1 gene by bidirectional sequence analysis at GeneDx, Inc. (Gaithersburg, MD). PCR was used to amplify exons 2–10 of the MEN1 gene and the corresponding intron/exon boundaries. Sequence analysis was performed to confirm the presence of a mutation in the gene.
Morphological evaluation
Excised tissues were fixed in 10% neutral buffered formalin and embedded in paraffin. Parathyroid and temporal lobe sections were stained with hematoxylin and eosin. Sections of temporal lobe tissue were evaluated immunohistochemically using the streptavidin-biotin-peroxidase complex technique and antibodies to synaptophysin, FSHß, LHß, glycoprotein -subunit, chromogranin, and steroidogenic factor-1 (9).
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Results |
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Sequence analysis revealed the presence of a heterozygous deletion of a single base (C) in exon 2 of the MEN1 gene, which is denoted as c.307delC (GTCGACCTGTC). This deletion affects codon Leu 103, causing a shift in the reading frame and a premature truncation codon 15 codons downstream. The mutation was confirmed by sequence analysis of exon 2 on a second aliquot of DNA from the same sample. The c.307delC deletion mutation is predicted to cause premature truncation of the resulting menin protein 15 codons downstream from the deletion (p.Leu103fsX15).
Parathyroid tissue
The left superior parathyroid gland weighed 4.6 grams and measured 3.0 x 1.5 x 0.6 cm; the right superior gland weighed 3.2 grams and measured 1.5 x 1.0 x 0.2 cm; the biopsied piece of the right inferior gland weighed less than 0.1 grams and measured 0.2 x 0.1 x 0.1 cm.
By histological examination, all three parathyroid glands were entirely cellular. No rim of normal tissue was seen, even from the two upper glands that had been removed in their entirety. The two upper glands exhibited several cell types, including chief cells in a nodular pattern, oncocytes, and water-clear cells (Fig. 1
). The right lower gland showed chief cells with follicle formation.
Temporal lobe tissue
Microscopic examination of the temporal lobe tumor tissue showed an epithelioid tumor composed of closely apposed elongated cells with pale acidophilic cytoplasm and distinct polarity, forming pseudorosettes around vascular channels. A few small clusters of small round cells with chromophobic cytoplasm were identified (Fig. 2). Immunocytochemistry showed that tumor cells stained positively in the nuclei for synaptophysin and steroidogenic factor 1 (Fig. 2) but were negative for chromogranin and -, FSHß-, and LHß-subunits.
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Discussion |
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This patient met the clinical criteria for MEN1 because she had two of the three main endocrine features of MEN1 (1), a pituitary tumor and primary hyperparathyroidism. She also manifested two nonendocrine features of MEN1, a lipoma and an angiofibroma. Because she does not have a first degree relative known to have any of the main endocrine features of MEN1, she is considered to be a sporadic case.
The first manifestation of MEN1 was the gonadotroph tumor, the first case described that presented as ovarian hyperstimulation (8). The diagnosis was confirmed by finding nonsuppressed serum FSH, markedly elevated -subunit, and suppressed LH concentrations, and a large pituitary tumor that stained immunohistochemically for - and FSHß-subunits. The gonadotroph tumor was initially considered an adenoma because most pituitary tumors, including most gonadotroph tumors, are adenomas. However, the subsequent finding of a temporal lobe lesion that was histologically similar to the intrasellar lesion and that stained for steroidogenic factor-1, a gonadotroph cell marker (9), suggests that the gonadotroph tumor was a gonadotroph carcinoma that metastasized to the temporal lobe. That the temporal lobe tissue stained only for steroidogenic factor-1 and not for gonadotropin subunits likely indicates that the metastasis was less well differentiated than the primary pituitary lesion.
Pituitary carcinomas are rare, accounting for only 0.1–0.2% of all pituitary tumors. Carcinomas of most pituitary cell types have been described, and most are endocrinologically active. Gonadotroph carcinomas are unusual even among pituitary carcinomas, accounting for only approximately 5% of pituitary carcinomas (10); this is the ninth case reported (11, 12, 13, 14, 15, 16, 17), and the first associated with MEN1. In some gonadotroph carcinomas, the metastatic tissue retained immunostaining for gonadotropins (15, 17), and in others, it did not.
The second manifestation of MEN1 was primary hyperparathyroidism, as documented by high-normal to high serum calcium and parathyroid hormone concentrations and three hypercellular parathyroid glands. The hyperparathyroidism of MEN1 is thought to be the result of multiple, independent, clonal parathyroid adenomas, rather than parathyroid hyperplasia (1). The presence of multiple enlarged glands with cellular nodules is consistent with this process even in the absence of a rim of normal tissue.
The diagnosis of MEN1 was confirmed by finding a deletion mutation (c.307delC) in the MEN1 gene, a tumor suppressor gene that has been mapped to the long arm of chromosome 11. This mutation is predicted to cause premature truncation of the resulting menin protein (p.Leu103fsX15). This specific mutation has not previously been reported, but many other mutations that predict premature truncation have been (4, 18).
The type of pituitary tumor most commonly associated with MEN1 is the lactotroph adenoma, but somatotroph, corticotroph, thyrotroph, and nonfunctioning pituitary adenomas have also been reported (2, 3, 4, 5, 6, 7). In an analysis of 324 patients with documented MEN1 that focused on pituitary adenomas (7), pituitary adenomas were found in 136 patients, and of these, 85 were lactotroph, 12 somatotroph, six corticotroph, 13 cosecreting, and 20 nonsecreting. However, when 15 of the 20 nonsecreting adenomas were examined by immunocytochemistry, two stained for LH and FSH, suggesting that they were gonadotroph adenomas. None, apparently, had been recognized as such in vivo. Adenomas categorized as nonfunctioning have also been reported in other series of patients with MEN1 (4, 6), and it is well recognized that most clinically nonfunctioning adenomas are composed of cells with variable gonadotropic differentiation (19). When the characteristics of these pituitary adenomas in 136 patients with MEN 1 were compared with those of pituitary adenomas in 110 patients without MEN 1 and matched for age, year of diagnosis, and duration of observation, adenomas associated with MEN 1 were larger and more aggressive (7).
The significance of this case is that gonadotroph tumors, like other pituitary tumors, may be part of MEN1 and may be malignant. Presumably, loss of menin functions in the gonadotroph cell predisposes to tumorigenesis in the gonadotroph cell, just as loss of menin functions in other pituitary cells predisposes to tumorigenesis in those cells. The clinical implications of this finding are that other manifestations of MEN1 should be considered in patients who have gonadotroph tumors and that the clinical and biochemical features of gonadotroph tumors should be considered in patients who are being evaluated for MEN1.
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Acknowledgments |
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Footnotes |
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Abbreviation: MEN1, Multiple endocrine neoplasia type 1.
Received July 15, 2004.
Accepted September 28, 2004.
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