J Clin Pathol: first published as 10.1136/jcp.24.9.851 on 1 December 1971. Downloaded from

J. clin. Path, 1971, 24, 851-855

Medullary carcinoma of the with parathyroid and

J. B. MacGILLIVRAY AND C. J. B. ANDERSON From the Department ofPathology, Maryfield Hospital, Dundee, and Arbroath Infirmary

SYNOPSIS A patient with due to a parathyroid adenoma was found to have metastatic medullary carcinoma in lymph nodes close to the thyroid gland. The finding of normal and parathormone concentrations after removal of the adenoma suggested that the parathyroid lesion was not the result of the hypocalcaemic action of calcitonin produced by the tumour in the thyroid. Seventeen other examples of the association between medullary carcinoma and parathyroid enlargement are briefly reviewed. The pathogenesis of the parathyroid lesions is discussed, and it is suggested that some may be caused by the hypocalcaemic action of calcitonin, while others may be part of a syndrome of multiple endocrine adenomatosis.

Medullary carcinoma is a special form of thyroid (normal 2 5-45 mg/100 ml). Inpatient investigation copyright. carcinoma characterized by the presence of amyloid was advised, but the patient, who was by then feeling in the tumour tissue (Williams, Brown, and Doniach, well, declined. 1966) and by the production of calcitonin (Cunliffe, A year later she was seen again having passed Black, Hall, Johnston, Hudgson, Shuster, Gud- further stones. At this time the serum calcium was mundsson, Joplin, Williams, Woodhouse, Galante, 9.4 mg/100 ml and the phosphorus 3-1 mg/100 ml. and Maclntyre, 1968). Medullary carcinoma may be Early in 1970 she began to complain of extreme familial and is sometimes associated with phaeo- lassitude, tiredness, and in backache. Radiographs http://jcp.bmj.com/ chromocytoma and multiple mucosal neuromata June 1970 again showed calcification in both kidneys. (Williams et al, 1966). No definite phalangeal erosions were seen, but the In 17 cases taken from the literature, parathyroid skull showed irregular mottling and multiple trans- adenoma or hyperplasia has been an additional lucent areas. The serum calcium was now 12-9 mg/ feature (Table I) and in six of these there was 100 ml and the phosphorus 2-1 mg/100 ml. A diag- evidence of hypercalcaemia (Table I, cases 12, 13, nosis of hyperparathyroidism was made and the 14, 15, 16, 17). neck was explored. We wish to report a further example of the At operation an enlarged right superior para- on September 30, 2021 by guest. Protected association between medullary carcinoma and para- thyroid was identified and removed. The right lower in a patient who presented with parathyroid was not identified, but the left superior hypercalcaemia and nephrocalcinosis. and left inferior parathyroids were not enlarged. The thyroid was nodular and a circumscribed nodule Case Report found in the lower pole of the left lobe was enucleated. Three small nodules lying close to the A 52-year-old woman was seen in 1967, complaining left lobe of the thyroid were also removed. They were of two episodes of renal pain and the passage of thought to be lymph nodes, but due to the lack of small renal calculi. An intravenous pyelogram frozen section facilities this could not be confirmed. showed calcification in the medullary pyramids. The The postoperative course and convalescence were serum calcium was 11-6 mg/100 ml (normal 8-8- uneventful and six days after operation the serum 10-6 mg/100 ml) and the phosphorus 2-0 mg/100 ml calcium had fallen to 8-9 mg/100 ml. Since that time serum calcium and phosphorus estimations have Received for publication 26 May 1971. always given results within the normal range. 851 J Clin Pathol: first published as 10.1136/jcp.24.9.851 on 1 December 1971. Downloaded from

852 J. B. MacGillivray and C. J. B. Anderson

Case Author Age Medullary Carcinoma Phaeochromo- Parathyroids Comments No. and cytoma Sex

Without Hypercalcaemia I Freeman and Lindsay Adenoma Parathyroid lesion an incidental (1965) finding 2 Ibanez, Cole, Russell, and Adenoma Parathyroid lesion an incidental Clark (1967) finding an 3 Williams (1967) M Hyperplastic Parathyroid lesion incidental 54 Widespread metastases finding 4 Gonzalez-Licea, Hart- Hyperplastic Parathyroid lesion an incidental mann, and Yardley (1968) finding 5 Gonzalez-Licea, Hart- Hyperplastic Parathyroid lesion an incidental mann, and Yardley (1968) finding 6 Sipple (1961) M Nodular enlarge- Lesions all incidental necropsy 33 ment of I gland findings ? adenoma 7 Cushman (1962) M Adenoma Adenoma and phaeochromocytoma 55 Widespread metastases found at necropsy 25 yr after cervical nodes containing medullary carcinoma removed 8 Freeman and Lindsay Adenoma Adenoma an incidental finding (1965) 9 Moorhead, Caldwell, Multiple Also had Cushing's syndrome Kelly, and Morales (1966) Widespread metastases 10 Urbanski (1967) F Adenoma Nodular thyroid containing medul- 32 lary carcinoma found on routine medical; 5 yr later bilateral phaeo- chromocytomas removed 11 Williams, Morales, and F Adenoma Also had Cushing's svndrome Horn (1968) 46 Widespread metastases With Hypercalcaemia 12 Moertel, Beahrs, Woolner, F Probably medullary Adenoma Mass in neck; thyroidectomy per- but no formed; thought to have hyper- and Tyce (1965) 66 carcinoma copyright. amyloid parathyroidism but data incomplete: developed metastases and carcinoid syndrome 13 Steiner, Goodman, and M Chief cell Hyperparathyroidism found on Powers (1968) 17 hyperplasia routine examination; hard nodule in left lobe of thyroid proved to be medullary carcinoma 14 Finegold and Haddad M Two adenomas Hypercalcaemia and nephrocalcino- (1963) 27 Multiple bony sis; bilateral phaeochromocytomas metastases found at necropsy F Three enlarged 1954 bilateral phaeochromocytomas 15 Manning, Molnar, Black, http://jcp.bmj.com/ Priestley, and Woolner 18 due to adenoma removed; 1961 hypercalcaemia and (1963) or chief cell nephrocalcinosis; at parathyroid- hyperplasia ectomy enlarged thyroid also removed 16 Sarosi and Doe (1968) M Twso adenomas Left phaeochromocytoma removed; 54 nodular thyroid noted and thyroid- ectomy performed; serum calcium raised; neck re-explored and adenomas removed 17 Steiner, Goodman, and F Chief cell Bilateral phaeochromocytomas re- Powers (1968) 36 hyperplasia moved; hyperparathyroidism diag- on September 30, 2021 by guest. Protected nosed; medullary carcinoma found when neck explored

Table I Medullary carcinoma, phaeochromocytomna, and parathyroid adenoma or hyperplasia

PATHOLOGY normal parathyroids, it was considered that the The enlarged parathyroid measured 3-5 x 2-5 cm lesion was probably an adenoma. and contained a cyst 1 8 cm diameter. It was made The three nodules were lymph nodes, each about up of chief cells and a smaller number of oxyphil 8 mm in diameter. All of them were extensively cells. There was an abundant oedematous stroma, an replaced by medullary carcinoma containing abun- acinar pattern in many areas, and no sign of any rim dant amyloid which showed characteristic dichroism of normal (Fig. 1). in sections stained with Congo red examined In view of the finding of other macroscopically between crossed polaroids. J Clin Pathol: first published as 10.1136/jcp.24.9.851 on 1 December 1971. Downloaded from

Medullary carcinoma of the thyroid with parathyroid adenoma and hypercalcaemia 853 copyright.

Fig. 1 Parathyroid adenoma with oedematous stroma Fig. 3 Biopsy from left superior parathyroid consisting showing oxyphil cells (above) and chief cells forming ofchief cells, in places forming acini and occasional fat dilated acini (below). Haematoxylin and eosin x 84. spaces. Haematoxylin and eosin x 120. http://jcp.bmj.com/

I VA I %.!% 1.4 -,9 .4 Fig. 2 Medullary carcinoma in left lobe of thyroid.

Amyloid deposits amongst on September 30, 2021 by guest. Protected uniform darkly staining cells and adjacent thyroidfollicles. Haematoxylin and eosin x 120. J Clin Pathol: first published as 10.1136/jcp.24.9.851 on 1 December 1971. Downloaded from

854 J. B. MacGillivray and C. J. B. Anderson The thyroid lesion measured 1 5 cm diameter and The occurrence of two rare lesions in the same was a well circumscribed adenomatous nodule. patient suggests something more than a chance association and two possibilities may be considered. FURTHER INVESTIGATION AND TREATMENT Hypocalcaemia has been reported in patients with The patient did not have any mucosal neuromata. medullary carcinoma (Melvin and Tashjian, 1968; Enquiry revealed a sister who was hypothyroid but McDermott and Hart, 1970). Melvin and Tashjian no other family history of endocrine disorders. The (1968) found that the plasma of their patient con- plasma calcitonin estimated by bioassay was not tained high concentrations of calcitonin and para- raised (Professor I. Maclntyre). The parathormone thormone. These findings, and the reports of para- concentrations estimated by radioimmunoassay thyroid adenoma or hyperplasia in other cases of (Dr R. M. Buckle) in two samples of plasma were medullary carcinoma, suggest that the hypocalcaemic 0 26 and 015 ng/ml (normalO30- <01 ng/ml). Urin- effect of calcitonin produced by the tumour may ary excretion of 5 hydroxyindoles and of vanillyl stimulate parathormone production and cause mandelic acid was not increased. parathyroid enlargement. We concluded that the thyroid was likely to be the The presence of bony secondaries might account site of a medullary carcinoma and that thyroid- for the hypercalcaemia in the case reported by ectomy should be performed. Finegold and Haddad (1963) (Table I, case 14). When the neck was re-explored two months after Calcitonin and parathormone estimations were not the original operation the thyroid could not be performed in the other five patients shown in the identified and removed because of marked induration Table who had hypercalcaemia (Table I, cases 12, 13, in the surrounding tissues due to the previous 15, 16, 17) but the hypercalcaemia may have been , but a further lymph node containing medul- due to the development of an autonomous lesion in a lary carcinoma was excised. Six months later when chronically stimulated gland as sometimes occUIs in the induration had subsided total thyroidectomy was the secondary hyperparathyroidism associated with successfully performed and a biopsy taken from the the malabsorption syndrome and chronic renal failure (Davies, Dent, and Watson, 1968). left superior parathyroid which was not enlarged. copyright. Cushing's syndrome and the carcinoid syndrome PATHOLOGY have been associated with medullary carcinoma The thyroid weighed 30 g. The right lobe contained (Table I, cases 9, 11, 12). Williams, Morales, and an adenomatous nodule 8 mm in diameter. In the Horn (1968) stress the close relationship between centre of the left lobe there was an ill defined, whitish medullary carcinoma, certain thymic tumours, oat area 6 mm in diameter. Microscopy showed this to be cell carcinoma, and carcinoid tumours, all of which a medullary carcinoma containing a mass of amyloid may produce a variety of peptide hormones. in the centre of the tumour (Fig. 2). The biopsy of the Weichert (1970) suggests that cells in these tumours http://jcp.bmj.com/ left superior parathyroid did not show any micro- with the capacity to form peptide hormones have scopic evidence of hyperplasia (Fig. 3). a neural crest origin in common with similar neuro- endocrine cells which migrate into the endocrine Discussion glands. The syndrome of medullary carcinoma of thyroid, Black and Haff (1970) have stressed the difficulty in phaeochromocytoma, and multiple mucosal neuro- to be a distinguishing between parathyroid adenoma and mata is considered by Weichert (1970) on September 30, 2021 by guest. Protected chief cell hyperplasia. In our case the normal dysplasia of neural ectoderm and a type of multiple parathormone and calcium concentrations after the endocrine adenomatosis. This combination of lesions removal of the enlarged gland and the subsequent is, however, thought to be a distinct genetic entity identification of normal parathyroid by light micro- (Schimke, Hartmann, Prout, and Rimoin, 1968; scopy makes it unlikely that more than one abnormal Steiner, Goodman, and Powers, 1968). gland was present. Parathyroid adenoma or chief cell hyperplasia When calcitonin levels have been estimated in may also form part of the syndrome (Steiner et al, patients with clinical evidence of medullary car- 1968; Weichert, 1970). Our finding of a normal cinoma they have almost always been elevated plasma calcitonin level and a normal parathormone (Tashjian, Howland, Melvin, and Hill, 1970; level after removal of the adenoma supports this Galante, 1971). It was surprising to find that in our view. It suggests that the adenoma was not a direct patient the plasma calcitonin was not raised at a result of the presence of the medullary carcinoma, time when medullary carcinoma was present in the unless it is postulated that the tumour at one time thyroid and in a lymph node, and suggests that was producing calcitonin. certain occult tumours may be hormonally inactive. This appears to be the first report of calcitonin J Clin Pathol: first published as 10.1136/jcp.24.9.851 on 1 December 1971. 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Medullary carcinoma of the thyroid with parathyroid adenoma and hypercalcaemia 855 and parathormone concentrations in patients with Moorhead, E. L., Caldwell, J. R., Kelly, A. R., and Morales, A. R. (1966). The diagnosis of . Analysis of 26 hypercalcaemia and medullary carcinoma. Clearly cases. J. Amer. med. Ass., 196, 1107-1113. until further studies are carried out the relation Sarosi, G., and Doe, R. P. (1968). Familial occurrence of parathyroid adenomas, pheochromocytoma and medullary carcinoma of between medullary carcinoma and parathyroid the thyroid with amyloid stroma. (Sipple's syndrome). Ann. adenoma and hyperplasia must remain uncertain. intern. Med., 68, 1305-1309. Schimke, R. N., Hartmann, W. H., Prout, T. E., and Rimoin, D. L. (1968). Syndrome of bilateral pheochromocytoma, medullary We wish to thank Dr R. M. Buckle for determining thyroid carcinoma and multiple neuromas. A possible regulat- the parathormone concentrations and Professor I. ory defect in the differentiation of chromaffin tissue. New Engl. J. Med., 279, 1-7. Maclntyre for performing the calcitonin bioassay. Sipple, J. H. (1961). The association of pheochromocytoma with Our thanks are also due to Professor E. D. Williams carcinoma of the thyroid gland. Amer. J. Med., 31, 163-166. for examining histological material, to Dr C. R. Steiner, A. L., Goodman, A. D., and Powers, S. R. (1968). Study of a kindred with pheochromocytoma, medullary thyroid car- Paterson for advice with the manuscript, and to cinoma, hyperparathyroidism and Cushing's disease: multiple Miss S. Nisbet for the photomicrographs. endocrine neoplasia, type 2. Medicine (Baltimore), 47, 371-409. Tashjian, A. H., Jr., Howland, B. G., Melvin, K. E. W., and Hill, C. S., Jr. (1970). Immunoassay of human calcitonin. Clinical References measurement, relation to serum calcium and studies on patients with medullary carcinoma. New Engl. J. Med., 283, Black, W. C., and Haff, R. C. (1970). The surgical pathology of 890-895. hyperplasia. Amer. J. clin. Path., 53, Urbanski, F. X. (1967). Medullary thyroid carcinoma, parathyroid 565-579. adenoma, and bilateral pheochromocytoma. An unusual triad of endocrine tumors. J. chron. Dis., Cunliffe, W. J., Black, M. M., Hall, R., Johnston, I. D. A., Hudgson, 20, 627-636. P., Shuster, S., Gudmundsson, T. V., Joplin, G. F., Williams, Weichert, R. F., lI. (1970). The neural ectodermal origin of the E. D., Woodhouse, N. J. Y., Galante, L., and Maclntyre, I. peptide secreting endocrine glands: a unifying concept for the (1968). A calcitonin-secreting thyroid carcinoma. Lancet, 2, etiology of multiple endocrine adenomatosis and the inap- 63-66. propriate secretion of peptide hormones by neoendocrine Cushman, P., Jr. (1962). Familial endocrine tumours. Report of two tumors. Amer. J. Med., 49, 232-241. unrelated kindred affected with , one Williams, E. D. (1967). Medullary carcinoma ofthyroid. In Symposium also with multiple thyroid carcinomas. Amer. J. Med., 32, on the Thyroid Gland. J. clin. Path. Suppl. (Ass. Clin. Path.). 352-360. 20, 395-398. Davies, D. R., Dent, C. E., and Watson, L. (1968). Tertiary hyper- Williams, E. D., Brown, C. L., and Doniach, I. (1966). Pathological parathyroidism. Brit. med. J., 3, 395-399. and clinical findings in a series of 67 cases of medullary Finegold, M. J., and Haddad, J. R. (1963). Multiple endocrine carcinoma of the thyroid gland. J. clin. Path., 19, 103-113. tumours. Report of an unusual triad in a family. Arch. Path., Williams, E. D., Morales, A. M., and Horn, R. C. (1968). Thyroid copyright. 76,449-455. carcinoma and Cushing's syndrome: a report of two cases Freeman, D., and Lindsay, S. (1965). Medullary carcinoma of the with a review of the common features of the 'non-endocrine' thyroid gland: a clinicopathological study of 33 patients. Arch. tumours associated with Cushing's syndrome. J. clin. Path., Path., 80, 575-582. 21, 129-135. Galante, L. (1971). Personal communication. Gonzalez-Licea, A., Hartmann, W. H., and Yardley, J. H. (1968). Addendum Medullary carcinoma of the .thyroid. Ultrastructural evidence of its origin from the and its possible rela- tion to carcinoid tumors. Amer. J. clin. Path., 49, 512-520. Since the manuscript was submitted Melvin, Miller, Ibanez, M. L., Cole, V. W., Russell, W. O., and Clark, R. L. (1967). Solid carcinoma of the thyroid gland. Analysis of 53 cases. and Tashjian (1971) have reported 11 members of http://jcp.bmj.com/ Cancer (Philad.), 20, 706-723. a family with medullary carcinoma of the thyroid Manning, P. C., Jr., Molnar, G. D., Black, B. M., Priestley, J. T., and who had raised Woolner, L. B. (1963). Pheochromocytoma, hyperpara- plasma calcitonin levels after cal- thyroidism and thyroid carcinoma occurring coincidentally. cium infusion. Chief cell hyperplasia was found in Report of a case. New Engi. J. Med., 268, 68-72. nine cases. 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