MEDULLARY CANCER OF THE THYROID GLAND ASSOCIATED WITH HYPERCORTICISM
ILONA SZIJJ, MD, ZSOLT CSAPÓ, MD, FERENC A. LÁSZLÓ, MD, AND KÁLMÁN KOVÁCS, MD, PHD, DSC.
Rapidly progressing adrenal hypercorticism was observed in a 39-year-old man with a metastasizing medullary carcinoma of the thyroid gland containing amyloid. In the opinion of the authors, the thyroid carcinoma produced a peptide having ACTH activity, and this was responsible for the development of the hypercorticism.
T HYROID CANCER ASSOCIATED WITH HYPER- corticism occurs very rarely. The first case was reported by Dyson5 in 1959. Hökfelt et al .; 10 Riggs and Sprague; 28 Roberts;29, Mirouze et al .; 21 Anderson and Glenn;1 O’Riordan et al.,23 and Goldberg and McNeil8 all have reported one case each. Two cases each have been described by Jensen et al .; 13 Donahower et al.,4 and Williams et al.33 In their mor- phological study on thyroid cancer, Ibanez et al.11 mention another case. Our case, as far as it can be established from the available literature, is the sixteenth case published.
CASE HISTORY
Clinical data. The 39-year-old man was admitted on March 29, 1967 to the Endo- crinological Unit. He said that 6 months pre- viously he suddenly gained weight, his face became round and red, and his skin pigmented brown. He had been impotent for months and complained of dyspnea and edema of the legs. In the course of the last year he had intermittent diarrhea and, during the 4 weeks preceding his admission, he lost 6-8 kg. Previously he had not been ill, and en- docrine disorders had not occurred in his family.
Brown pigmentation of the skin was strik- ing, and slight obesity was localized mainly on the trunk and abdomen. The face was red and a mild cyanosis of the lips and edema of the legs were observed. Abdominal striae were not seen. The blood pressure was 175/ 120 mm Hg, and the pulse rate was 66/min.
From the Departments of Medicine and Pathology, University Medical School, Szeged, Hungary.
Address for reprints: Ilona Szijj, MD., I. Department of Medicine, University Medical School, Szeged, Hun- gary.
The thyroid gland was moderately en- larged and firm. On both sides of the neck, a few mobile lymph nodes the size of a rice grain were palpable. There was a pronounced dorsal kyphosis, and the spine was sensitive to percussion throughout its length. The heart was slightly enlarged and a systolic murmur was heard mainly at the apex. The liver overlapped the right costal margin by 4 finger-breadths-its left lobe was very firm, the edges were sharply defined, and the sur- face was uneven and sensitive to pressure.
The following laboratory observations were made: specific gravity of the urine: 1004, after concentration: 1011; moderate albuminuria, later glycosuria of 4.2-23.4 g/24 hr; sedimen- tation rate: 29-35 mm/hr; erythrocyte count: 4.2 million; leukocyte count: 11-14.000; hemo- globin: 12.8g%; hematocrit: 37%; serum- cholesterol: 291 mg/100 ml; blood sugar: 126 mg/100 ml; serum-bilirubin: indirect 0.48 mg/100 ml; thymol: 2.3 TU; nonprotein nitrogen: 23 mg/100 ml; prothrombin: 80%; endogenous creatinine clearance: 143 ml/ min; tubular phosphate reabsorption: 85%; BSP-retention: 8%; serum-transaminase: 16 U; alkaline phosphatase: 7.3 Bodansky unit; acid phosphatase: 0.3 Bodansky unit; serum- sodium: 155.5 mEq/1; serum-potassium: 3.4 mEq/1; 17-total-ketosteroid excretion: 18.1- 32.5 mg/24 hr; 17-alpha-hydroxycorticoid ex- cretion: 9.1-21.3 mg/24 hr.
Radiographs showed signs of central and peripheral pulmonary congestion. The skull was extensively porotic with the sella turcica: 80 mm.2 Pronounced osteoporosis was observed in the spine, and vertebra D7 showed a wedge- like narrowing towards the front with blurred contours in the middle of its coverplate, and increased density of its anterior portion. Frontal tomography of the adrenal region showed no abnormality. Isotope renography performed with hippuran-131I demonstrated
marked reduction of renal function on the left side. Left ventricle hypertrophy and myo- cardial ischemia of the left ventricle were noted by electrocardiogra
An oral glucose tolerance test produced a diabetic blood sugar curve (fasting: 166 mg/ 100 ml, 30 min: 230 mg/100 ml, 60 min: 286 mg/100 ml, 120 min: 280 mg/100 ml, 180 min: 218 mg/100 ml). Following ACTH adminis- tration, 50 IU daily im, for 3 days, the 17- total-ketosteroid excretion and the 17-alpha- hydroxycorticoid excretion did not change significantly (13.4 - 17.6 mg/24 hr, and 10.6 - 10.8 mg/24 hr). The plasma cortisol level was 80-120 µg%, and it did not increase after ACTH administration.
A considerable muscular weakness devel- oped while the serum postassium level de- creased (3.1 mEq/l.). Electromyographic ex- aminations showed a pronounced weakness of the muscles of the lower extremities. The patient was given digitalis, potassium iodide, and theophylline orally.
On April 19, 1967, pulmonary edema, hypo- tention, and circulatory collapse developed and, a few hours later, he died. Owing to the rapid progression, several examinations (metyrapone test, dexamethasone suppres- sion181I-uptake of thyroid) could not be per- formed.
Autopsy data. The autopsy findings in- cluded kyphoscoliosis, pronounced pulmonary edema, and bilateral bronchopneumonia in the lower lobes. The left kidney was atrophic due to chronic pyelonephritis. The thyroid gland weighed 21.6 g and contained a tumor the size of a hazel-nut with a greyish white cut surface reaching the capsule in the left lobe. Metastatic carcinoma was present in the cervical and mediastinal lymph nodes, lungs, pleurae, and liver. The combined adrenals weighed 24 g, and the cortex was 4-5 mm thick. The pituitary weighed 0.67 g. The bone marrow of the femur and humerus was red and the ribs and vertebrae were porotic and could be cut easily.
Microscopically the cancer of the thyroid gland and its metastases proved to be solid or medullary cancer (Fig. 1). The cancer showed an infiltrative growth and had spread in the perivascular lymphatics. It consisted partly of small cells (Fig. 2, 3). Their nuclei were round or elongated, rich in chromatin, and showed a moderate degree of polymor- phism and polychromasia. In some nests, the tumor cells were larger with broad eosino- philic cytoplasm and a round nucleus con- taining less chromatin (Fig. 4, 5). Mitoses were not frequent. Among the cells, a homo- genous eosinophilic substance could be dem- onstrated here and there in globular foci
or large clusters; this substance with Congo- red proved to be amyloid. The amyloid was often surrounded only by a single row of tumor cells (Fig. 6). The neoplastic cell nests were divided into islets by connective tissue septa. In the amyloid and the connective tissue septa calcium was deposited in fine granules. The metastases in the cervical and mediastinal lymph nodes had a similar struc- ture, but the hepatic metastases were exclu- sively composed of tumor cells containing an ample amount of cytoplasm; amyloid was not detected in them. Microscopic metastatic de- posits were found in the body of the 7th dorsal vertebra and in several pulmonary ves- sels. Chromaffin granules could not be dem- onstrated in the tumor cells by means of diazo reaction, according to Lizon. The adrenal cortex showed considerable hyper- plasia of the zona fasciculata. The zona glo- merulosa was slightly narrower and contained a large amount of lipoids. The outer fascic- ulata was lipoid-poor and, in some parts, completely devoid of lipoid, but here and there a few lipoid-laden cells with foamy cytoplasm could be seen (Fig. 7). The inner fasciculata and the zona reticularis were rich in lipoids. The nuclei of the zona fasciculata showed moderate polymorphism. Neither adenomas nor tumor-metastases were observed in the adrenals. In the anterior pituitary, sev- eral large Crooke cells, with a hyalinized and vacuolated cytoplasm, could be seen (Fig. 8).
DISCUSSION
Brown3 in 1928 was the first to report hy- percorticism associated with extrahypophysial and extraadrenal tumors. His patient suffer- ing from cancer of the lung developed Cush- ing’s syndrome. According to recent publica- tions,7, 14, 15, 17, 22, 26, 30 about 200 cases have been described since then. Hypercorticism oc- curred most frequently in connection with bronchial neoplasms, but it was also associated with tumors of the thymus, pancreas, thyroid, and other organs. The pathogenesis of the endocrine changes was not known till the last few years. Studies performed with modern endocrine methods have revealed that these tumors become able to produce hormone-like substances, including ACTH. For these cases, the name of paraneoplastic endocrine syn- drome, or in the case of ACTH secretion “ectopic ACTH syndrome,” was suggested.16 The fact that these extrahypophysial tumors really produce ACTH has been confirmed by different examinations. ACTH-activity has been demonstrated in the primary tumors and
FIG. 2. (Bottom) Carcinoma of the thyroid gland. This part of the tumor is composed predom- inantly of spindle cells (H and E, x287).
metastases. 6, 8, 16, 18, 19, 25, 26 ACTH content of the pituitary has been found to be abnormally low, whereas that of the blood was consider- ably elevated.16, 18, 19, 25, 29 Following surgical removal of the tumor, or after the administra- tion of cytostatics, the hypercorticism im- proved.6, 17, 19 If the tumor recurred, or me- tastases appeared, Cushing’s syndrome reap- peared. The symptoms of hypercorticism abated after extensive adrenal resection.2, 8, 23 Evidence of the presence of ACTH in the tu- mors has also been furnished by fluorescence antibody technique.12, 26 No differences be- tween the chemical characteristics of the ac- tive material extractable from the tumors and
those of pituitary ACTH have been noted.16
According to previous publications, ectopic ACTH syndrome differs to a certain extent from the classic Cushing’s syndrome origi- nating primarily from the hypophysial-ad- renocortical system. In the case of the ectopic ACTH syndrome, the clinical signs are gen- erally more severe and the progression is more rapid. Muscular weakness is a frequent and prominent symptom. Obesity is usually lack- ing and striae cannot be observed, as the time is too short for them to develop. Skin pigmentation, hypopotassemia, and hypo- chloremic alkalosis occur often. The ACTH content of the blood is high. This is also
different from the classic Cushing’s syndrome having a primary hypophysial-adrenocortical origin as, in the latter, ACTH level of the blood is not, or only slightly, elevated. Fol- lowing administration of metyrapone corti- coid excretion does not increase, and the result of the dexamethasone suppression test is negative, reduction of the corticoid values failing to occur. Administration of ACTH usually does not result in the rise of plasma cortisol, nor does the urinary excretion of ketosteroids and corticoids increase.
Although we did not perform ACTH de- terminations in our case, it seems reasonable to assume that hypercorticism observed in our
patient was due to the medullary cancer of the thyroid gland secreting ACTH. This view is not only supported by the clinical picture and laboratory data characteristic of the ec- topic ACTH syndrome, but also by the his- tologic structure of the thyroid tumor. It is striking that the majority of thyroid neo- plasms producing ACTH-also our own case -proved to be so-called solid or medullary cancers, containing amyloid. This tumor was distinguished by Hazard et al.9 in 1959. Ac- cording to Williams et al.,31, 32 the tumor originates from the parafollicular cells of the thyroid gland. This assumption is also sup- ported by the electron microscopic investi-
gations of Meyer.20 Williams mentions that the cells of the medullary cancer of the thy- roid gland are in close relationship with the argentaffin cells of the initial part of the small intestines. Ibanez et al.11 and Williams et al.33 emphasize that the medullary thyroid cancers are composed of special cells which are also able to produce various biologically active substances: serotonin, bradykinin, ACTH. It is not even necessary that the full human ACTH consisting of 39 amino acids should be produced, for ACTH fragments composed of fewer amino acids are biologi- cally active and stimulate corticoid production in the adrenal cortex.14 The investigations of
Pearse24 are very interesting. He considers the parafollicular or the so-called C-cells of the thyroid gland as a part of the APUD (amine and precursor uptake and decarboxyl- ation) cell system. According to Pearse, these cells can take up and decarboxylate different amines and amine precursors and produce biologically active substances. Lipsett et al.17 and Kracht15 have suggested that anomalous production of hormones by tumors can be explained on the basis of the hypothesis that all cells contain complete genetic informa- tion, some of it repressed. In our case, the parafollicular cells of the thyroid gland con- tain an ACTH gene in a dormant state. If,
FIG. 6. Carcinoma of the thy- roid gland with globoid masses of amyloid (H and E, ×224).
in the course of the tumorous transformation, the cells dedifferentiate and the inhibitory effect of the repressor systems ceases, a new messenger RNA is formed, and the informa- tion present in the DNA molecules results in production of peptides with ACTH activity.
The ACTH excess stimulates the secretion of the corticosteroids, and thus hypercorticism develops. We propose the term for the ACTH-producing tumors originating in the APUD cell system “corticotropin secreting apudoma.”
REFERENCES
1. Anderson, E. E., and Glenn, J. F .: Cushing’s syndrome associated with anaplastic carcinoma of the thyroid gland. J. Urol. 95:1-4, 1966.
2. Brooks, R. V., Dupré, J., Gogate, A. N., Mills, J. H., and Prunty, F. T. G .: Appraisal of adrenocor- tical hyperfunction: patients with Cushing’s syndrome
or “non-endocrine” tumors. J. Clin. Endocr. 23:725- 736, 1963.
3. Brown, W. H .: A case of pluriglandular syndrome: “diabetes of bearded women.” Lancet 2:1022-1023, 1928.
4. Donahower, G., Schumacher, P. O., and Hazard,
J. B .: Two cases of medullary thyroid carcinoma caus- ing Cushing’s syndrome. Clin. Res. 14:430, 1966.
5. Dyson, B. C .: Cushing’s disease: report of a case associated with carcinoma of the thyroid gland and cryptococcosis. New Eng. J. Med. 261:169-172, 1959.
6. Engel, F. E., and Kahana, L .: Cushing’s syndrome with malignant corticotropin-producing tumor. Re- mission and relapse following subtotal adrenalectomy and tumor resection, Amer. J. Med. 34:726-734, 1963.
7. Friedman, M., Marshall-Jones, P., and Ross, E. J .: Cushing’s syndrome: adrenocortical hyperactivity sec- ondary to neoplasma arising outside the pituitary- adrenal system. Quart. J. Med. 35:193-214, 1966.
8. Goldberg, W. M., and McNeil, M. J .: Cushing’s syndrome due to an ACTH producing carcinoma of the thyroid. Canad. Med. Ass. J. 96:1577-1579, 1967.
9. Hazard, J. B., Hawk, W. A., and Crile, G .: Medul- lary (solid) carcinoma of the thyroid-a clinicopatho- logic entity. J. Clin. Endocr. 19:152-161, 1959.
10. Hökfelt, B., Sjögren, B., and Falkheden, T .: Steroid hormone production in a case of Cushing’s syndrome with electrolyte changes simulating primary aldosteronism. Acta Endocr. 31:175-184, 1959.
11. Ibanez, M. L., Cole, V. W., Russell, W. O., and Clark, R. L .: Solid carcinoma of the thyroid gland. Cancer 20:706-723, 1967.
12. Jarett, L., Lacy, P. E., and Kipnis, D. M .: Char- acterisation by immunfluorescence of ACTH-like sub- stance in non-pituitary tumors from patients with hyperadrenocorticism. J. Clin. Endocr. 24:543-549, 1964.
13. Jensen, M. K., Transbol, I., and Olesen, K. H .: Cancer of Cushing’s syndrome. Fem tilfaelde med outale af de specielle klinische og laboratoriemassige fund. Nord. Med. 73:197-202, 1965.
14. Kovács, K .: Die Beziehungen zwischen dem endokrinen System der Geschwülsten der nicht en- dokrinen Organ. Deutsch. Gesundh. 21:1105-1108; 1173-1178, 1966.
15. Kracht, J .: Pathologie der ektopisch hormon- bildenden Geschwülste. Med. Klin. 63:41-46, 1968.
16. Liddle, G. W., Island, D. P., Ney, R. L., Nichol- son, W. E., and Shimizu, N .: Nonpituitary neoplasms and Cushing’s syndrome. Arch. Intern. Med. 111:471- 475, 1963.
17. Lipsett, M. B., Odell, W. D., Rosenberg, L. E., and Waldmann, T. A .: Humoral syndrome associated with nonendocrine tumors. Ann. Intern. Med. 61: 733-756, 1964.
18. Marks, L. J., Rosenbaum, D. L., and Russfield, A. B .: Cushing’s syndrome and corticotropin-secreting carcinoma of the lung. Ann. Intern. Med. 58:143-149, 1963.
19. Meador, C. K., Liddle, G. W., Island, D. P., Nicholson, W. E., Lucas, C. P., Nuckton, J. G., and Luetscher, J. A .: Cause of Cushing’s syndrome in pa-
tients with tumors arising from “non-endocrine” tis- sue. J. Clin. Endocr. 22:693-703, 1962.
20. Meyer, J. S .: Fine structure of two amyloid form- ing medullary carcinomas of thyroid. Cancer 21:406- 425, 1968.
21. Mirouze, J., Jaffiol, C., Badach, L., Saade, F., and Bernard, R .: Syndrome de Cushing avec hypercortiso- lisme pur pseudo-tumoral revelateur d’un cancer thy- roidien latent. Ann. Endocr. (Paris) 26:300-307, 1965.
22. Myers, W. P. L., Tashima, C. K., and Rotschild, E. O .: Endocrine syndromes associated with non-en- docrine neoplasms. Med. Clin. N. Amer. 50:763-778, 1966.
23. O’Riordan, J. L. H., Blanshard, G. P., Maxham, A., and Nabarro, J. D. N .: Corticotropin-secreting carcinomas. Quart. J. Med. 35:137-147, 1966.
24. Pearse, A. G. E .: Common cytochemical and ultrastructural characteristics of cells producing poly- peptide hormones (the APUD series) and their rele- vance to thyroid and ultimobranchial C cells and calcitonin. Proc. Roy. Soc. (Biol). 170:71-80, 1968.
25. Pfohl, R. A., and Doe, R. P .: Adrenal-pituitary studies in a patient with bronchogenic carcinoma and Cushing’s syndrome. Ann. Intern. Med. 58:993-1002, 1963.
26. Pfotenhauer, R., and Kracht, J .: Die extra- hypophysären corticotropen Geschwülste. Endokrino- logie 51:23-53, 1967.
27. Prunty, F. T. G., Brooks, R. V., Dupré, J., Gimlette, T. M. D., Hutchinson, J. S. M., McSwiney, R. R., and Mills, I. H .: Adrenocortical hyperfunction and potassium metabolism in patients with “non- endocrine” tumors and Cushing’s syndrome. J. Clin. Endocr. 23:737-746, 1963.
28. Riggs, B. L. Jr., and Sprague, R. G .: Association of Cushing’s syndrome and neoplastic disease. Arch. Intern. Med. 108:841-849, 1961.
29. Roberts, P. A. L .: Carcinoma of the thyroid, hypoparathyroidism and Cushing’s syndrome. Proc. Roy. Soc. Med. 55:805-808, 1962.
30. Sachs, R. A .: Endocrine disorders produced by non-endocrine malignant tumors. Bull. N.Y. Acad. Med. 41:1069-1086, 1965.
31. Williams, E. D .: Histogenesis of medullary carcinoma of the thyroid. J. Clin. Path. 19:114-118, 1966.
32. , Brown, C. L., and Doniach, I .: Pathologi- cal and clinical findings in a series of 67 cases of medullary carcinoma of the thyroid. J. Clin. Path. 19:103-113, 1966.
33. , Morales, A. M., and Horn, R. C .: Thyroid carcinoma and Cushing’s syndrome. A report of two cases with a review of the common features of the “nonendocrine” tumors associated with Cushing’s syndrome. J. Clin. Path. 21:129-135, 1968.