Development of Cushing’s Syndrome and Virilization After Presentation of a Nonfunctioning Adrenocortical Carcinoma
STEVEN M. GRUNBERG, MD
Adrenocortical carcinoma is traditionally divided into functioning and nonfunctioning tumors. However, a case is presented of a 50-year-old woman with a clinically nonfunctioning adrenocortical carcinoma who later developed a Cushingoid appearance and symptoms of virilization with laboratory evidence of marked steroid hormone hypersecretion. The metabolic behavior and the rationale for division of these tumors into two categories (functioning and nonfunctioning) are discussed. It is suggested that such a division may be misleading and may not reflect the true state of the tumors. Cancer 50:815-816, 1982.
A DRENOCORTICAL CARCINOMA is an extremely rare tumor, having an incidence of only two cases per million population and accounting for only 0.2% of can- cer deaths.’ However, its presentation may be dramatic and may be manifested by any of the syndromes of adrenocortical steroid excess. In the large series of func- tioning adrenocortical carcinomas included in the cases collected by Hutter and Kayhoe,2 52% of patients showed Cushing’s syndrome, 35% showed virilization, 12% showed both Cushing’s syndrome and virilization, and 11% showed feminization. Hyperaldosteronism has also been reported.2,3
A distinction between functioning and nonfunction- ing adrenocortical carcinoma has commonly been made. Differences in incidence, sex distribution, and age dis- tribution have been described.3-5 Differences in therapy have been suggested, with o,p’DDD being considered primarily a treatment for functioning tumors. The reap- pearance of elevated hormone levels often precedes re- currence of a functioning tumor after resection.6 How- ever, the development of Cushing’s syndrome and virilization indicating progression of a previously clin- ically nonfunctioning tumor has not been described. Such a case is now reported.
Case Report
In July, 1978, a 50-year-old white woman was hospitalized for chronic depression. Routine urinalysis on admission showed
From the Division of Medical Oncology, Sidney Farber Cancer Institute, Boston, Massachusetts.
Supported in part by NCI Training Grant CA 09172.
Address for reprints: Steven M. Grunberg, M. D., Division of Med- ical Oncology, University of Southern California Comprehensive Can- cer Center, 2025 Zonal Avenue, Los Angeles, CA 90033. Accepted for publication May 26, 1981.
microhematuria. An intravenous pyelogram revealed a left suprarenal mass. Physical examination was unremarkable and urinary 17-hydroxycorticoids and 17-ketosteroids were nor- mal. However, a left lower lobe lung mass was noted and a liver mass was suggested by CT scan. In August 1978, she underwent exploratory laporotomy which revealed an 8 × 15 cm mass replacing the left adrenal gland and extending into the left adrenal vein. Biopsy of this mass revealed a poorly differentiated adrenocortical carcinoma.
The patient was referred to the Sidney Farber Cancer In- stitute where physical examination was again normal. The urinary 17-hydroxycorticoids measured 4.3 mg/24 hours (nor- mal, 1-10 mg/24 hours), the urinary 17-ketosteroids were 17.8 mg/24 hours (normal, 6-15 mg/24 hours), the serum cortisol level was 12.8 ug/dl (normal, 5-20 ug/dl), and the serum testosterone was 120 ng/dl (female normal, 10-130 ng/dl). In September 1978, she underwent another exploratory lapo- rotomy with removal of the left adrenal tumor mass, left ne- phrectomy, splenectomy, and wedge resection of the lung mass. All sites revealed poorly differentiated adrenocortical carci- noma. Liver metastases could not be excised.
In October 1978, the patient was begun on cytoxan and Adriamycin (doxorubicin). However, liver and lung metas- tases increased in size over the next several months. In late December 1978, she developed a Cushingoid appearance. Re- peat studies in January 1979 revealed a urinary 17-hydrox- ycorticoid level of 78.1 mg/24 hours, a urinary 17-ketosteroid level of 107.9 mg/24 hours, and a serum cortisol level of 66 ug/dl. Therapy with o,p’DDD was begun, but the patient could only tolerate low doses of the drug due to marked central nervous system toxicity (somnolence). In February 1979, in- creasing hirsutism was noted. The elevated steroid levels noted in January 1979 were confirmed and a serum testosterone level of 1100 ng/dl was detected. The patient died in early March 1979. Autopsy revealed poorly differentiated adrenocortical carcinoma metastatic to the left and right lung, liver, lymph nodes, and right kidney. The right adrenal gland contained
one small tumor nodule but was reduced in overall size. The right adrenal gland itself was not nodular.
Discussion
Division of cases of adrenocortical carcinoma into functioning and nonfunctioning tumors has been a per- sistent tradition. Tumors tend to be classified at the time of presentation. Serum and urinary steroid levels are monitored in functioning tumors while nonfunc- tioning tumors are expected to recur with signs of a mass lesion only. Bradley6 reported two cases in which nonfunctioning tumors recurred with elevated urinary steroids, while Didolkar et al.7 reported three patients who developed functional syndromes late in their course. However, these cases stand alone in the liter- ature and would be considered the exceptions.
Consideration of the actual functional capabilities of adrenocortical tumors brings this distinction into ques- tion. Adrenal adenomas may indeed be efficient in the production of steroid hormones, so that a small ade- noma may produce a dramatic clinical syndrome. How- ever, even in the cases of greatest steroid production, adrenocortical carcinomas are not hypersecreting on a cellular basis.8 This phenomenon was noted by Seabold and Schteingart’ who measured uptake of 1311-radioio- docholesterol in cortisol-secreting adenomas, adrenal carcinomas, and normal adrenal tissue. They noted as much as a tenfold increase in uptake by adenomas (0.03-0.13% dose/gram tissue) compared to normal tissue (0.01-0.03% dose/gram tissue). However, func- tioning carcinomas (0.0-0.002% dose/gram tissue) showed as much as a tenfold decrease in uptake com- pared to normal tissue.
It should also be noted that functioning adrenocor- tical carcinomas do not produce excess amounts of the normal steroid end-products alone. Excessive produc- tion of tetrahydro-substance S (THS) out of proportion to total cortisol has been noted in cortisol-producing carcinomas, suggesting an additional defect in 11-8- hydroxylase activity in these functioning tumors.8 Tu- mors that are nonfunctioning clinically can still be func- tioning biochemically, since they may produce excessive amounts of metabolites of pregnenelone.4 This implies an early defect in steroid synthesis with shunting of steroid into an alternate metabolic pathway.
Differences in specific activity should be reflected in ease of diagnosis. A hypersecreting tumor might be expected to give evidence of its presence long before a silent nonfunctioning tumor. However, in Macfarlane’s series of adrenocortical carcinomas,1º 70% of both func- tioning and nonfunctioning tumors had palpable masses detected at the time of diagnosis, suggesting a low ef-
ficiency of steroid production relative to growth of tu- mor mass.
Equivalence of therapeutic response has also been noted. Most series of patients treated with o,p’DDD consist of those with functional tumors since these are more easily detected and excessive production of ste- roids provides a parameter of response. However, when the response of functional and nonfunctional adreno- cortical carcinomas in terms of tumor shrinkage has been directly compared, no statistically significant dif- ference in response to this drug has been noted.11
Thus it is suggested that both functioning and non- functioning adrenocortical carcinomas are actually characterized by uncontrolled processing of cholesterol through an inefficient steroidogenic enzyme system and are distinguished only by the site of the prevalent en- zyme defect or by the amount of total tumor mass. The synthetic rate and natural history of a functioning ad- renocortical carcinoma are more similar to those of a nonfunctioning carcinoma than they are to a clinically similar adenoma. Although the division into functioning and nonfunctioning tumors is useful for rapid descrip- tion, it may be misleading and suggests unnecessary and perhaps even inadvisable differences in therapeutic approach. A full screening battery of steroid assays should be used to follow all patients with adrenocortical carcinoma for possible recurrence. It may also be per- fectly valid to include all patients with this tumor in the evaluation of any new therapeutic regimen without dis- tinction on the basis of apparent hormonal function.
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