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Pituitary Adenoma, Multicentric Papillary Thyroid Carcinoma, Bilateral Carotid ... 2a includes C-cell hyperplasia or medullary thyroid car- cinoma, adrenal ...
Case Reports Multiple Endocrine Neoplasia Pituitary Adenoma, Multicentric Papillary Thyroid Carcinoma, Bilateral Carotid Body Paraganglioma, Parathyroid Hyperplasia, Gastric Leiomyoma, and Systemic Amyloidosis OSCAR LARRAZA-HERNANDEZ, M.D., JORGE ALBORES-SAAVEDRA, M.D., GEORGINA BENAVIDES, M.D., LUIS G. KRAUSE, M.D., JUAN CARLOS PEREZ-MERIZALDI, M.D., AND ALEJANDRA GINZO, M.D.

Multiple endocrine neoplasia in a 70-year-old woman are described. The findings include a nonfunctioning pituitary adenoma, a multicentric papillary thyroid carcinoma, bilateral carotid body paragangliomas, parathyroid hyperplasia, gastric leiomyoma and systemic amyloidosis. A study of the kindred revealed that two family members, a daughter and a granddaughter, have clinical' and radiographic evidence of pituitary tumors and bilateral carotid body paragangliomas, suggesting that this may represent a genetically determined syndrome inherited as an autosomal dominant. (Key Words: Multiple endocrine neoplasia syndrome; Pituitary adenoma; Papillary thyroid carcinomas; Carotid body paragangliomas; Parathyroid hyperplasia; Gastric leiomyoma; Amyloidosis) Am J Clin Pathol 1982; 78: 527-532

Department of Pathology, National University of Mexico School of Medicine and Pathology Unit, General Hospital, Mexico, Department of Pathology, University of Miami School of Medicine, Jackson Memorial Medical Center, Miami, Florida and Hospital de Oncologia, IM, S.S., Mexico City, Mexico

coexistance of pituitary adenoma and pheochromocytoma or the association of endocrine pancreatic tumor and pheochromocytoma among other combinations. 6,10,16,17,21,26 Types I and II MEN syndromes are often genetically determined and inherited as an autosomal dominant, whereas most cases of mixed types of MEN syndromes have been sporadic. We recently had the opportunity to study a family in which the propositus had a pituitary adenoma, bilateral carotid body paragangliomas, multicentric papillary thyroid carcinomas, parathyroid hyperplasia, gastric leiomyoma, and generalized amyloidosis. The purpose of this paper is to report this previously undescribed combination of endocrine tumors in the same patient and to discuss their relationship with the other MEN syndromes. The results of the family study are also included.

WITHIN the last three decades, several types of multiple endocrine neoplasia syndromes (MEN) have been wellcharacterized. Type I MEN consists of pituitary adenoma, pancreatic endocrine tumor, usually of G-cell type, hyperplasia or adenoma of the parathyroid glands, and even carcinoids in various anatomic sites.4'24'30,31 The morphologic spectrum of Type 2 MEN also known as Type 2a includes C-cell hyperplasia or medullary thyroid carcinoma, adrenal medullary hyperplasia or pheochromocytoma, and parathyroid hyperplasia or adenoma. 9,28 When ganglioneurofibromatosis of the digestive tract and a Marfanoid phenotype are present, in addition to the thyroid and adrenal neoplasms, the designation of Type 3 or Type 2b. is then applied.8,18,32 Other MEN syndromes include the mixed types with overlapping features of Type 1 and Type 2 such as the

Clinical Summary

Received December 14, 1981; received revised manuscript and accepted for publication February 1, 1982. Address reprint requests to Dr. Larraza-Hernandez: Apartado Postal 7-1023, Mexico 7, D.F.

The propositus, a 70-year-old Mestizo woman, lived in Mexico City for her entire life. She entered the hospital in a near-terminal condition with signs and symptoms of renal and cardiac failure. Nine years before admission to the hospital she began to suffer from constant headaches and blurred vision. Physical examination revealed an obese woman with bilateral temporal hemianopsia and edema of lower extremities. She died shortly after admission. An autopsy was performed.

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tumor cells with the immunoperoxidase technic. Lymph node metastases were not found. Diffuse chief cell hyperplasia with focal collection of oxyphil cells was noted in the four parathyroid glands. The subserosal nodule of the stomach had the histologic structure of an ordinary leiomyoma. In addition, extensive amyloidosis was observed in the spleen, liver, adrenal glands, and kidneys (Fig. 7). Amyloid stains were negative in all the endocrine tumors, that is, the pituitary adenoma, paragangliomas, and papillary carcinomas. Family Study

FIG. 1. Composite photograph showing gross features of three endocrine tumors: a pituitary adenoma (top), two small papillary carcinomas of the right thyroid lobe, and bilateral carotid body paragangliomas. The remaining left papillary carcinomas are not seen on this cut surface of the thyroid.

Pathology The most significant autopsy findings can be summarized as follows: the sella turcica contained a spongy soft tumor that had replaced the entire pituitary gland and had an extrasellar extension. A mass was found at the bifurcation of each carotid artery. The mass located on the left side measured 3.5 cm and was lobulated firm and red; the mass located at the bifurcation of the right carotid artery had similar gross features but measured only 1.8 cm (Fig. 1). Each thyroid lobe had two subcapsular, small, white firm nonencapsulated nodules measuring from 0.3 to 0.5 cm. All four parathyroid glands were uniformly enlarged. A 1.5-cm firm subserosal nodule was found in the midportion of the greater curvature of the stomach. Microscopically, the pituitary neoplasm was composed of cells with eccentric hyperchromatic nuclei and eosinophilic cytoplasm. These cells were arranged around blood vessels or grew in solid sheets or trabeculae (Fig. 2). A rim of normal pituitary gland was still present but appeared compressed by the tumor. The immunoperoxidase technic demonstrated that about 5% of neoplastic cells contained ACTH in their cytoplasm (Fig. 3). Immunohistologic stains for thyroid-stimulating hormone, prolactin, and growth hormone were negative. Microscopically, both tumors located at the bifurcation of the carotid arteries had the usual "zell-ballen" pattern of paragangliomas (Fig. 4). Microscopic examination of the four thyroid nodules revealed nonencapsulated sclerosing papillary carcinomas. Most of the neoplastic cells had ground-glass nuclei, while the stroma was quite sclerotic (Figs. 5 and 6). Calcitonin was not detected in

The pedigree is shown in Figure 8. Two sons of the propositus were normal. A 56-year-old daughter and a 32-year-old granddaughter had clinical symptoms and radiographic abnormalities suggestive of a pituitary tumor. Both patients had slight visual field defects with normal visual acuity. Roentgenograms, including tomograms, revealed an enlarged sella turcica with partial destruction of the posterior clinoid processes. Ultrasound examination showed findings consistent with bilateral paraganglioma of the carotid bodies. A thyroid scintigram, however, did not reveal pathologic changes. Serum determinations of adrenocorticotfopin (ACTH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), growth hormone (GH), and prolactin were within normal range. Thyroid tests, including serum triiodothyronine and thyroxin levels, also were normal. No biochemical or radiographic evidence of hyperparathyroidism was found in any members of the family. Discussion The coexistence of a pituitary adenoma, bilateral carotid paragangliomas, multicentric papillary carcinomas, parathyroid hyperplasia, gastric leiomyoma, and generalized amyloidosis may represent a new MEN syndrome which appears to be genetically determined and inherited as an autosomal dominant. Even though the study of the two affected family members is incomplete, mainly because of lack of histologic confirmation, the results of the clinical, radiographic, and ultrasound examination suggests the presence of a pituitary adenoma and bilateral carotid body paragangliomas in both women. Unfortunately, these patients have refused biopsy and surgical treatment. Since thyroid carcinomas 0.5 cm or less, are often not detected by scintigram'studies, the negative results obtained in the two descendants do not rule out this neoplasm. The bilaterality and multicentricity of the thyroid carcinoma and the carotid body paragangliomas are two features shared by many other endocrine neoplasms that are genetically determined.20 The absence of Cushing's syndrome in the pro-

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•&*•*

FIG. 2 (upper, left). Pituitary adenoma. Perivascular arrangement of tumor cells with round hyperchromatic nuclei and abundant eosinophilic cytoplasm. Hematoxylin and eosin (X275). FIG. 3 (upper, right). Cords of ACTH-containing neoplastic cells from the pituitary adenoma. Peroxidase antiperoxidase technic for ACTH 160X. FIG. 4 (lower, left). Characteristic organoid pattern of carotid body paraganglioma. Hematoxylin and eosin (XI60). FIG. 5 (lower, right). Photomicrograph of one of the papillary thyroid carcinomas. The central portion of the tumor is poorly cellular and sclerotic while the periphery contains papillary structures Hematoxylin and eosin (X80).

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/ FIG. 6 (left). Higher magnification of papillary structures. Neoplastic cells contain characteristic Hematoxylin and eosin (X250).

'ground glass" nuc.

FIG. 7 (right). Extensive amyloid deposition is seen in this glomerulus. Hematoxylin and eosin (X250).

PEDIGREE

Pituitary Adenoma Papillary Carcinoma of Thyroid Bilateral Carotid Body Paraganglioma

H

Normal

O

Not Examined

o

Sex not Stated

FIG. 8. Pedigree of the family.

positus could be explained by the low proportion of the pituitary adenoma cells that contained ACTH or because the target organ was largely replaced by the amyloid deposits. An alternative explanation is that the ACTH-containing cells are in reality entrapped normal cells of the anterior pituitary gland. Unfortunately, it was not possible to determine whether the parathyroid hyperplasia is an integral part of the MEN or whether it was secondary to renal failure due to the amyloidosis. Parathyroid hyperplasia has been reported in all types of MEN syndromes, although its incidence and clinical significance varies with each type. The anatomic distribution of the amyloid substance and its absence in the stroma of the endocrine tumors suggest that it is secondary and systemic and not APUD amyloid. Although systemic amyloidosis is found in about 0.4% of all patients with cancer,19 to our knowledge it has not been demonstrated in any of the known MEN syndromes. The pathogenesis of the amyloid substance in this case is unknown. It is possible, however,

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that the genetic defect responsible for the development of the tumors might have also contributed to the production of the amyloid. Genetically determined amyloidosis such as that associated with the Mediterranean fever has been known for many years." Likewise, systemic amyloidosis has long been described in association with a number of non-endocrine tumors, especially multiple myeloma, renal cell carcinoma, and malignant lymphoma.3152729 The presence of a gastric leiomyoma in our patient is in accordance with what has been observed in all types of MEN, in which the incidence of coexisting non-endocrine tumors tends to be higher than in the general population. Moreover, benign and malignant tumors of the smooth muscle may be found in association with endocrine tumors. For instance, the combination of a gastric leiomyosarcoma, pulmonary chondroma, and extraadrenal paraganglioma is now considered to be a clinico-pathologic syndrome.7 The nonfamilial association of carotid body paragangliomas and papillary carcinomas of the thyroid was first described in 1968.1,2 In order to learn more about this association, we reviewed 162 patients with carotid body paragangliomas, as well as 510 patients with papillary carcinomas of the thyroid seen during the last 20 years. We found that six patients had these two neoplasms. This was statistically significant (P < 0.0001). Paragangliomas also can be associated with other endocrine tumors and be part of MEN syndromes. In our own series, a patient with nonfamilial growth-hormone cell adenoma and bilateral paraganglioma, and another patient who had unilateral carotid body paraganglioma and parathyroid adenoma were found. A case of carotid body paraganglioma has been reported in association with an endocrine tumor of the pancreas.12 A patient with paraganglioma of the organ of Zuckerkandl and a papillary carcinoma of the thyroid was previously reported.1'2 Although sporadic carotid body paragangliomas are associated with high altitude and chronic hypoxia,25 they can also be genetically determined. In fact, it has been estimated that carotid body paragangliomas are familial in at least 9.5% of all cases,13 an incidence, which in our experience, is too high. These genetically determined carotid body paragangliomas are usually bilateral and have no sex predilection, which suggests an autosomal mode of genetic transmission.1314 In contrast to this, in our 162 patients with sporadic carotid body paragangliomas, the female-male ratio was 11:1. It is possible that patients having carotid body paraganglioma and papillary carcinomas of the thyroid, as well as those with carotid body paraganglioma and pituitary adenoma, represent instances of partial clinical expressions of this new MEN syndrome. Two patients with three coexisting endocrine lesions

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similar to those present in our case have been reported previously. The first one was a young woman with multiple paragangliomas in the cervical, thoracic, and abdominal regions, but none in the carotid bodies, a pituitary adenoma, and parathyroid hyperplasia.10 The second patient had carotid body paraganglioma, pituitary adenoma, parathyroid hyperplasia, and G-cell hyperplasia of the gastric antrum and duodenum.5 However, these two cases differ from ours in that they did not have papillary thyroid carcinoma, gastric leiomyoma, and systemic amyloidosis, and genetic transmission of the disease was not documented. Recently, a familial form of papillary thyroid carcinoma not associated to Gardner's syndrome, has been described.21 As expected, early onset and bilateral involvement of the thyroid gland have been reported in some cases.23 The histologic features of the familial papillary carcinomas are similar to those of sporadic cases, but a comparative study of the biologic behavior of the two tumor types remains to be done. Of interest is the fact that cells which give rise to the tumors of this new MEN syndrome do not have a common embryologic origin. Some are derived from the endoderm (papillary thyroid carcinoma), others from mesenchyme (leiomyoma), and still others appear to be of ectodermal (pituitary adenoma) or neuroectodermal origin (paraganglioma). The two cell mutation events that have been postulated for the development of the MEN syndromes and other hereditary tumors20 may be applicable to our case. It should be noted, however, that an early age of onset was not demonstrated in the propositus, and the multiple tumors did not arise from histologically similar tissues. Addendum: After this manuscript was submitted for publication, a paper by Parry and associates (Carotid body tumors in humans; Genetics and epidemiology. JNCI 1982; 68:573-578) describes an excess of thyroid cancer in patients with carotid body tumors.

References 1. Albores-Saavedra J, Duran ME: Association of thyroid carcinoma and chemodectoma. Am J Surg 1968; 116:887-890 2. Albores-Saavedra J, Cuevas A, Luna-Olivares A, Brandt H, Rodriguez-Cuevas H: Sindromes carcinoma papilar-quimiodectoma y carcinoma-rnedular-feocromocitoma. Estudio comparative Prensa Med Mex 1969; 34:334-342 3. Azzopardi JG, Lehnen T: Systemic amyloidosis and malignant disease. J Clin Pathol 1966; 19:539-548 4. Ballard HS, Frame B, Hartsock BJ: Familial multiple endocrine adenoma-peptic ulcer complex. Medicine 1964; 433:481-516 5. Berg B, Biorklund A, Grimelius L, etal: A new pattern of multiple endocrine adenomatosis. Acta Med Scand 1976; 200:321-326 6. Boden G, Owen DE: Familial hyperglucagonemia—an autosomal dominant disorder. N Engl J Med 1977; 100:495-498 7. Carney JA: The triad of gastric epithelioid leiomyosarcoma, functioning extra adrenal paraganglioma and pulmonary chondroma. Cancer 1979; 43:374-382 8. Carney JA, Sizemore GW, Hayles AB: C-cell disease of the thyroid gland in multiple endocrine neoplasia Type 2 B. Cancer 1979; 44:2173-2183

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9. Chong GC, Beahrs OH, Sizemore GW, Woolner LH: Medullary thyroid carcinoma of the thyroid gland. Cancer 1975; 35:695704 10. Farhi F, Dikman SH, Lawson W, Cobin RH, Zak FG: Paragangliomatosis associated with multiple endocrine adenomas. Arch Pathol Lab Med 1976; 100:495-498 11. Glenner GG, Ignaczak TF, Page DL: The inherited systemic amyloidosis and localized amyloid deposits. Metabolic basis of inherited disease. Fourth edition. Edited by JB Stanbury, JB Wyngarden, DF Frederickson. New York, McGraw-Hill, 1978, pp. 1308-1339 12. Goodof II, Lischer CE: Tumor of the carotid body and pancreas. Arch Pathol 1943; 35:906-911 13. Grufferman S, Gillman MW, Pasternak R, Peterson CL, Young WG: Familial carotid body tumors. Case report and epidemiologic review. Cancer 1980; 46:2116-2122 14. Lack EE, Cubilla A, Woodruff JM, Farr HW: Paragangliomas of the head and neck region. A pathologic study of tumors from 71 patients. Hum Pathol 1979; 10:191-218 15. Lichtenstein HL, Lee JCK: Amyloidosis associated with metastasizing basal cell carcinoma. 1980; 46:2693-2696 16. Kadowaki S, Baba Y, Kakita T, et al: A case of acromegaly associated with pheochromocytoma. Saishin Igaku 1976; 31:1402— 1409 17. Kahn MT, Mullen DA: Pheochromocytoma without hypertension. Report of a case with acromegaly. JAMA 1964; 188:7475 18. Khairi MRA, Dexter RN, Burzynski NJ, Johnston CC Jr: Mucosal neuroma pheochromocytoma and medullary thyroid carcinoma: multiple endocrine neoplasia type 3. Medicine 1975; 54:89-112 19. Kimball KH: Amyloidosis in association with neoplastic disease. Ann Intern Med 1961; 55:958-962 20. Knudson AG, Strong LC: Mutation and cancer: neuroblastoma and pheochromocytoma. Am J Hum Genet 1972; 24:514-532

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21. Lote K, Andersen K, Nordal E, Brennhord OI: Familial occurrence of papillary thyroid carcinoma. Cancer 1980; 46:12911297 22. Miller GL, Wynn J: Acromegaly, pheochromocytoma, toxic goiter, diabetes mellitus and endometriosis. Arch Intern Med 1971; 127:299-303 23. Phade VR, Lawrence WR, Max MH: Familial papillary carcinoma. Arch Surg 1981; 116:836-837 24. Rosai J, Higa E, Davie J: Mediastinal endocrine neoplasm in patients with multiple endocrine adenomatosis: a previously unrecognized association. Cancer 1972; 29:1075-1083 25. Saldana MJ, Salem LE, Travezan R: High altitude hypoxia and chemodectomas. Hum Pathol 1973; 4:251-263 26. Somer T, Teppo L: Hypernephroma and amyloidoiss, Amyloidosis. Edited by O Wegelins, A Pasternack. New York, Academic Press, 1976, pp. 455-470 27. Steiner AL, Goodman AD, Powers SR: Study of a kindred with pheochromocytoma medullary thyroid carcinoma, hyperparathyroidism and Cushing's disease. Multiple endocrine neoplasia, Type 2. Medicine 1968; 47:371-409 28. Tateishi R, Wada A, Ishiguro S, et al: Coexistance of bilateral pheochromocytoma and pancreatic islet cell tumor. Report of a case and review of the literature. Cancer 1978; 42:2928-2934 29. Tschang TP: Nodular malignant lymphoma and amyloidosis: a case report. Cancer 1976; 38:2192-2196 30. Wermer P: Endocrine adenomatosis and peptic ulcer in a large kindred. Inherited multiple tumors and mosaic pleiotropism in man. Am J Med 1963; 35:205-212 31. Williams ED, Celestin LR: The association of bronchial carcinoid and pluriglandular adenomatosis. Thorax 1962; 17:120-127 32. Williams ED, Pollock DJ: Multiple mucosal neuromata with endocrine tumors: a syndrome allied to von Recklinghausen's disease. J Pathol Bacteriol 1966; 91:71-80

Meningeal Myeloma LUAN D. TRUONG, M.D., HAN-SEOB KIM, M.D., AND ROLANDO ESTRADA, M.D.

A case of leptomeningeal myeloma is described and a brief review of the reported cases is made. Afflicted patients may be neurologically asymptomatic or may present with a clinical picture similar to carcinomatous and lymphomatous meningitis. Atypical plasma cells and monoclonal immunoglobulin in the cerebrospinal fluid (CSF) are the two most important findings for the diagnosis of leptomeningeal involvement in a patient with multiple myeloma. (Key words: Multiple myeloma; Leptomeningeal myeloma) Am J Clin Pathol 1982; 78: 532535 A L T H O U G H THE NEUROLOGIC COMPLICATIONS may be seen in 40% of patients with multiple myeloma, 1 2 leptomeningeal involvement without involvement of contiguous bone is rare; only eight cases Received November 9, 1981; received revised manuscript and accepted for publication January 14, 1982. Address reprint requests to Dr. Truong: Department of Pathology, Baylor College of Medicine, 1200 Moursund Avenue, Houston, Texas 77030.

Department of Pathology, Baylor College of Medicine and the Ben Taub General Hospital, Houston, Texas

have been reported.''2'6'7"13'15 In this paper, we describe another case and review the related literature. The significance of cytologic and electrophoretic studies of CSF is emphasized. Report of a Case A previously healthy 58-year-old white man presented with an 8month history of pain in lower extremities and right shoulder. He also complained of a 30-lb weight loss in 7 weeks and multiple, slowly enlarging masses on the chest wall. Three subcutaneous nontender, firm nodules on the chest wall and a 10-cm right testicular mass were seen during physical examination. Abnormal laboratory findings included a bone survey showing several lytic lesions in the right fibula, tibia, and humerus, serum total proteins 9.7 g/dL with normal IgG and IgM concentrations, and monoclonal IgA of 3,200 mg/dL (normal: 39-358 mg/dL). Except for mild megakaryo-erythrocytic hyper-

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