Case Keport

PARATHY ROlD CARCINOMA OCCURRING IN MULTIPLE ENDOCRINE NEOPLASIA TYPE I

Kurt S. Kodrofi M.D. EA.C.E.,l Claude Lieber, M.D., EA.C.S.,2 and Lester D. R. Thompson, M.D3

ABSTRACT INTRODUCTION

Objective: To describe a patient with multiple The multiple endocrine neoplasia type I (MEN-I) syn- endocrine neoplasia type I (MEN-I) in whom parathyroid drome is characterized by neoplasms of the parathyroid, carcinoma developed. anterior pituitary, and pancreatic islet cells (1,2) as well as Methods: A case report is presented, including tumors in several other tissues, such as bronchial, thymic, detailed history, laboratory findings, and pathologic and gastric carcinoids, adrenocortical tumors, lipomas, features. and, possibly, thyroid tumors (3). Hyperparathyroidism is Results: A 49-year-old man with a known history of the most common feature to manifest in patients with this MEN-I syndrome had hypercalcemia and profoundly disorder, reaching a prevalence of almost 100% by age 40 increased parathyroid hormone levels. Seven years earlier, years; it is usually due to chief cell hyperplasia or adeno- he had been diagnosed with a gastrinoma, prolactinoma, ma (1). The recommended initial treatment for this cause and primary hyperparathyroidism. A neck exploration at of primary hyperparathyroidism is surgical intewention- that time consisted of resection of a right inferior parathy- a subtotal parathyroidectomy or total parathyroidectomy roid gland and parathyroid tissue in the thyroid gland as in conjunction with autotransplantation, primarily because well as biopsies of two left-sided glands, after which of the high rate of recurrences with lesser procedures microscopic examination revealed parathyroid hyperpla- (4,5). Recurrences usually result from continued growth sia and his serum calcium levels normalized. On reexplo- of residual hyperplastic tissue in patients who undergo less ration of the neck, resection revealed pathologic f~ndings than total parathyroidectomy (4,5). consistent with parathyroid carcinoma. Herein we describe a patient with MEN-I who had Conclusion: Parathyroid carcinoma has rarely been documented gastrinoma, prolactinoma, and hyperparathy- reported in the setting of MEN-I. This case illustrates the roidism, in whom hypercalcemia recurred because of a need for near-complete resection of parathyroid tissue in parathyroid carcinoma. The carcinoma was discovered in the patient with MEN-I. Subtotal or total parathyroidecto- the neck of the patient, who had previously been operated my in conjunction with forearm autotransplantation on for benign parathyroid hyperplasia. should be performed, not simply to prevent recurrence of benign disease but also to prevent the potential develop- CASE REPORT ment of carcinoma over time. (Endocr Pract. 1999; 5347-349) A 49-year-old man came to the Wilrnington Veterans Affairs ~&icalCenter because of nephGlithiasis. His serum calcium concentration was 12.8 mg/dL. The patient had been well until he was 34 years old, when he had passed a kidney stone. At age 43 years, he had a recurrence of kidney stones and was found to have a serum calcium concentration of 13.3 mn/dL and an increased intact parathyroid hormone (PTH) level (310 Submitted for publication October 7,1998 pg/mL). During further evaluation, he was found to have Accepted for publication March 3,1999 a fasting serum gastrin of 1,196 pg/mL (normal, 400) and From the l~e~artmentof Medicine and 2~epartmentof Surgery, Wilmington Veterans Affairs Medical Center, Wilmington, Delaware, and a serum gastrin after secretin stimulation of 2,005 pg/mL. 3~epartmentof Endocrine and Otorhinolaryngologic-Head & Neck Magnetic resonance imaging of his pituitary gland Pathology, Armed Forces Institute of Pathology, Washington, DC. revealed an 8-rnm sellar mass. A serum prolactin level at The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of that time was 76 ng/mL (normal, 45). the US Department of the Navy or the Department of Defense. Surgical exploration of the patient's neck revealed an Address correspondence and reprint requests to Dr. K. S. Kodroff, Division enlarged right inferior parathyroid gland (1.0 by 0.5 cm). of Endocrinology, Bronx-Lebanon Hospital Center, 1650 Grand Concourse The right superior parathyroid gland was not found despite Avenue, Bronx, NY 10457. 0 1999 AACE. a thorough search. A palpated nodule in the right upper

ENDOCRINE PRACTlCE Vol. 5 No. 6 NovemberIDecember 1999 347 348 MEN Type I and Parathyroid Carcinoma, Kodroff et al. lobe of the thyroid gland was excised (and later deter- (normal, 1.5 to 9.3), follicle-stimulating hormone 4.7 mined to be parathyroid tissue by histologic examination). mIU/mL (normal, 1.4 to 18.I), vasoactive intestinal pep- Exploration of the left side of the neck revealed normal- tide acromegaly. Visual fields were level declined to 9.7 mg/dL in association with a serum intact to confrontation. The thyroid gland was difficult to albumin concentration of 3.5 g/dL and an intact PTH level palpate because of obesity. No neck masses were felt. The of 60.7 pg/mL. At 12 weeks postoperatively, the PTH abdomen was soft; no abdominal masses and no level was 61.2 pg/mL, the serum calcium concentration hepatomegaly were detected. The testicles were 5 cm in was 10.1 mgIdL, and the serum albumin was 3.7 g/dL. At length bilaterally and of normal consistency. Gyneco- 20 weeks, the intact PTH was 68.4 pgImL, and the serum mastia, striae, peripheral edema, and rashes were not calcium was 10.5 mg/dL. present. Laboratory studies revealed the following: semm cal- DISCUSSION cium 12.3 mg/dL (normal, 8.4 to 1~0.2),phosphorus 2.8 mg/dL (normal, 2.5 to 4.9, intact PTH (imrnunoradiomet- Parathyroid carcinoma in the setting of MEN-I is ric assay) 243 pg1mL (normal, 12 to 72), plasma glucose extremely rare. Our review of the literature (MEDLINE, 1 15 mg/dL (normal, 75 to 1 lo), creatinine 0.8 mg/dL (nor- 1966 through 1997) revealed only three cases with this mal, 0.8 to 1.5), serum sodium 143 mEq/L (normal, 137 to possible association. One case in 1974 was in a 43-year- 145), prolactin 539 ng/mL (normal, <15), growth hormone old man with a family history of familial hyperparathy- <0.1 ng/mL (normal, 0.1 to 5), testosterone 31 1 ng/dL roidism, but the index case did not have evidence of (normal, 241 to 827), luteinizing hormone 3.9 mIUlmL pancreatic or pituitary tumors (8). In 1985, parathyroid MEN Type I and Parathyroid Carcinoma, Kodroff et al. 349

Fig. 1. High-power photomicrographic appearance of parathy- Fig. 2. Area of vascular invasion was identified just beyond cap- roid carcinoma. Tumor cells demonstrate an increased nuclear to sule and dense fibrous connective tissue of parathyroid carcino- cytoplasmic ratio, nuclear contour irregularities, and prominent ma. (Hematoxylin-eosin; x150.) nucleoli. Note mitotic figure. (Hematoxylin-eosin; x300.) carcinoma was reported to exist in a large kindred in complete resection of parathyroid tissue in the patient with Tasmania affected with MEN-I (9). One additional case MEN-I by subtotal or total parathyroidectomy in conjunc- reported in 1992 documented the presence of a nonfunc- tion with forearm autotransplantation-not just to prevent tioning pituitary adenoma in a 42-year-old man, in whom recurrence of benign disease but also to prevent the a parathyroid carcinoma subsequently developed development of carcinoma over time. (although it was not established that the man had the MEN-I syndrome) (10). Our patient, because of preexist- REFERENCES ing gastrinoma, prolactinoma, and parathyroid hyperpla- sia, clearly had the MEN-I syndrome. 1. DeLellis RA. Multiple endocrine neoplasia syndromes Exactly how hyperplastic parathyroid tissue becomes revisited: clinical, morphologic, and molecular features. malignant is not entirely clear. Parathyroid carcinoma has Lab Invest. 1995;72:494-505. been reported coexisting in the same gland as parathyroid 2. Teh BT. Recent advances in multiple endocrine neoplasia hyperplasia (1 1), as well as in a kindred in which affected type I. Curr Opin Endocrinol Diabetes. 1998;5:35-39. 3. Marx S, Spiegel AM, Skarulis MC, Doppman JL, family members had pathologic features ranging from Collins FS, Liotta LA. Multiple endocrine neoplasia type parathyroid hyperplasia to carcinoma (12). 1: clinical and genetic topics. Ann Intern Med. 1998;129: No histologic features are pathognomonic for the 484-494. diagnosis of parathyroid carcinoma (6,7,13). Instead, an 4. Baumann DS, Wells SA Jr. Parathyroid autotransplanta- aggregate of features are used to determine the diagnosis, tion. Surgery. 1993;113:130-133. including adherence to surrounding soft tissue or thyroid 5. Metz DC, Jensen RT, Bale AE, et al. Multiple endocrine neoplasia type I: clinical features and management. In: gland, vascular invasion, capsular invasion, dense, acellu- Bilezikian JP, Marcus R, Levine MA, eds. The lar fibrous connective tissue bands, increased mitotic fig- Parathyroids: Basic and Clinical Concepts. New York: ures, trabecular growth pattern, cellular spindling, necro- Raven Press, 1994: 591-646. sis and apoptosis, increased nuclear to cytoplasmic ratio, 6. Schantz A, Castlemen B. Parathyroid carcinoma: a study nuclear pleomorphism and atypia, and prominent of 70 cases. Cancer. 1973;31:600-605. eosinophilic irregular nucleoli (6,7,13). The histopatho- 7. Wynne AG, van Heerden J, Carney JA, Fitzpatrick LA. logic findings in the current case furfled most of these Parathyroid carcinoma: clinical and pathologic features in 43 patients. Medicine (Baltimore). 1992;71:197-205. criteria and are consistent with parathyroid carcinoma. 8. Mallette LE, Bilezikian JP, Ketcham AS, Aurbach GD. Whereas recurrence of hypercalcemia is common after Parathyroid carcinoma in familial hyperparathyroidism. parathyroidectomy, especially in patients with the MEN-I Am J Med. 1974;57:642-648. syndrome, the cause is usually growth of residual hyper- 9. Shepherd JJ. Latent familial multiple endocrine neopla- plastic tissue after the initial operation (5) and not a sia in Tasmania. Med JAust. 1985;142:395-397. parathyroid carcinoma. 10. Wu CW, Huang CI, Tsai ST, Chiang H, Lui WY, P'eng FK. Parathyroid carcinoma in a patient with non- secretory pituitary tumor: a variant of multiple endocrine CONCLUSION neoplasia type-I? Eur J Surg Oncol. 1992;18:517-520. 11. Desch CE, Arsensis G, Woolf PD, May AG, Amatruda In this report, we describe a man with MEN-I who JM. Parathyroid hyperplasia and carcinoma within one underwent a neck exploration that revealed parathyroid gland. Am J Med. 1984;77:131-134. hyperplasia. On subsequent recurrence of hypercalcemia, 12. Streeten EA, Weinstein LS, Norton JA, et al. Studies in a kindred with parathyroid carcinoma. J Clin Endocrinol repeated neck exploration disclosed parathyroid carcino- Metab. 1992:75:362-366. ma. This case is important because it clearly documents 13. Cohn K, Silverman M, Corrado J, Sedgewick C. the existence of parathyroid carcinoma in the setting of Parathyroid carcinoma: the Lahey Clinic experience. MEN-I. Furthermore, it underscores the need for near- Surgery. 1985;98:1095-1 100.