Carcinoma of the Adrenal Cortex Causing Primary Hyperaldosteronism
A Case Report and Review of the Literature
PETER H. TH. J. SLEE, MD, AART SCHABERG, MD, AND PETER VAN BRUMMELEN, MD
A male patient presenting with primary hyperaldosteronism after a three-year delay, was found to have an aldosterone producing adrenocortical carcinoma. Evidence is presented that aldosterone was the only steroid produced in excess. Only six other patients with adrenocortical carcinoma and isolated primary hyperaldosteronism could be traced in the literature. The relation between histology and endocrine functions of the tumor cells is discussed.
Cancer 51:2341-2345, 1983.
C ARCINOMA of the adrenal cortex is a rare tumor, accounting for 0.023% of all malignancies. The reported incidence is two per million population per year. The mean age at diagnosis is in the fourth decade. Two thirds of reported patients are female. The prog- nosis is poor: most large series report a five-year mor- tality between 75 and 90%.1.2 On the basis of endocrine syndromes or biochemical findings, the tumor may be defined as “functioning” or “nonfunctioning.” Func- tioning neoplasms of the adrenal cortex may cause Cushing’s syndrome, the adrenogenital syndrome (vi- rilization or feminization), precocious puberty, the syn- drome of primary hyperaldosteronism, or mixed syn- dromes. Some patients only demonstrate excess precur- sor steroids in the absence of endocrine syndromes.
Nonfunctioning carcinomas are only diagnosed when they reach considerable size and cause local symptoms (pain in the abdomen and flank) or general symptoms (malaise, weight loss, and fever). Because neither the slowly developing endocrine syndromes nor the vague local symptoms initially suggest a malignancy, often the correct diagnosis is delayed.
The vast majority of patients with primary hyperal- dosteronism suffer from benign lesions (adrenocortical
adenoma or hyperplasia). For instance in the series re- ported by Conn et al.,3 only one patient of 145 was diagnosed as adrenocortical carcinoma. The patient pre- sented in this study demonstrated the clinical picture of primary hyperaldosteronism as the initial manifestation of adrenocortical carcinoma.
Case Report
A 41-year-old man suffered from insulin-dependent diabetes mellitus since 1967. In 1974 his blood pressure was 150/90 mmHg and hypokalemia (serum K+ 3.0 mmol/l) was noticed. One year later, polyuria was found despite satisfactory control of the diabetes mellitus. The blood pressure was 160/110 mmHg. In the face of a serum K+ of 2.6 mmol/l, the urinary excretion of K+ was above 80 mmol per day and metabolic alkalosis was found. Without further investigations, treatment with spironolactone 100 mg per day was started, which re- turned the blood pressure and serum potassium to normal values.
In August 1977, the patient was admitted to the nephrology department of the Leiden University Hospital for further in- vestigations. Spironolactone therapy was discontinued. He complained of periodic aches in the left lumbar region, which had been present for several years. There was no weight loss. fever, or malaise. On physical examination a mass was pal- pated in the left upper abdomen, which was tender on pal- pation. The blood pressure was 160/110 mmHg. Laboratory data: ESR. (Westergren, 1 h) 36 mm; hemoglobin, 7.3 mmol/ 1; Na+, 140 mmol/l; K+, 2.6 mmol/l; serum creatinine, 116 umol/l; pH, 7.44; pCO2, 6.7 pKa; HCO3 , 29 mmol/l; base excess, +4.5 mmol/l. Liver function studies were normal. In-
Address for reprints: Peter H. Th. J. Slee, MD, St. Jozef Ziekenhuis. Graaf Florisweg 77, 2805 AH Gouda.
travenous urography revealed a mass in the region of the left adrenal. Selective arteriography showed that the mass was hy- povascular, and on ultrasound examination, a solid mass of 10 × 7 × 5 cm was found (Fig. 1).
| Sodium intake | Normal range | ||
|---|---|---|---|
| Normal | Low | ||
| Plasma renin activity* | |||
| supine | 0.15 | 0.08 | 0.3-3.5 ng/ml/hr |
| ambulant | 0.22 | 0.52 | 0.8-5.5 ng/ml/hr |
| Plasma aldosterone | |||
| supine | 0.84 | 0.67 | <0.33 nmol/l |
| ambulant | 3.17 | 3.17 | <0.45 nmol/l |
| Plasma cortisol | |||
| 08.00 am | 0.4 | <0.5 μmol/I | |
| 24.00 pm | 0.2 | ||
| Urinary 17-hydroxysteroidst | 64.2 | 28-76 umol/24 hr | |
| 52.4 | |||
| Urinary 17-ketosteroids | 22.6 | 14-90 umol/24 hr | |
| 18.8 | |||
* Renin-activity, aldosterone and cortisol were measured by radioimmu- noassay.
+ 17-hydroxysteroids and 17-ketosteroids were measured colorimetrically.
Special Studies
Supine plasma renin-activity (PRA) was extremely low during a free sodium intake and after seven days of sodium restriction (50 mmol Na/day). There was a slight increase in PRA after 1 hour ambulation. Supine plasma aldosterone was elevated. It was not influenced by so- dium restriction, but increased further after ambulation (Table 1). Plasma cortisol showed normal values over the day and the excretion of 17-hydroxysteroids and 17- ketosteroids was in the normal range. Gas-liquid-chro- matography of the 24-hour urine, according to the method described by Moolenaar and van Seters,4 did not show excess excretion of any steroid. Indeed, normal values were found for pregnanediol, pregnanetriol and dihydroxyepiandrosterone, which are usually elevated in cases of adrenocortical carcinoma. However, excre- tion of tetra-hydro-11-desoxycortisol (THS) was not measured.
On the basis of hypertension, hypokalemia, and met- abolic alkalosis, together with low levels for plasma renin-activity and elevated levels for plasma aldosterone, a diagnosis of primary hyperaldosteronism was made.
FIGS. 3A-3C. (A, top left) Area of the tumor showing zona fas- ciculata type cells (×400). (B, right) Area showing “hybrid cells”: these cells have a clear cytoplasma, contain lipids, but are smaller in size than fasciculata cells (×400). (C, bottom left) Area showing glomerulosa type cells, which form solid areas and trabeculae and have little cytoplasm (×160).
The finding of a mass in the left adrenal region, by far surpassing the usual size of a benign adenoma, suggested the presence of a cortical carcinoma.
Clinical Course
During admission, the patient’s insulin requirement increased and his serum amylase was elevated, suggest- ing involvement of the pancreas by the tumor. After the selective arteriography, pain in the lumbar region in- creased, the temperature rose and serum transaminases were transiently elevated. No further endocrine evalu- ation was undertaken so as not to unduly delay surgical therapy. The preoperative diagnosis was aldosterone producing tumor of the left adrenal, most probably an adenocarcinoma.
At laparatomy, November 1977, a large tumor was found in the left suprarenal region, invading the tail of the pancreas. No metastases were apparent. The tumor, together with the left kidney, the tail of the pancreas, and the spleen, was resected en bloc. Postoperatively, blood pressure and serum potassium normalized and
plasma renin activity was within a normal range. These findings strongly suggest that the syndrome of primary hyperaldosteronism indeed was caused by the tumor. A subphrenic abscess necessitated a second laparotomy in December 1977, at which time liver metastases were diagnosed. Consequently systemic treatment with 1,1- dichloro-2-(O-chlorophenyl)-2-(p-chlorophenyl)-ethane (o,p’DDD) was started. In spite of adequate serum levels of o,p’DDD no response was observed and the clinical condition of the patient deteriorated rapidly. He died in March 1978. Autopsy was not performed.
Pathologic Findings
The tumor measured 12 × 5 X 7 cm, was lobulated, yellow, and was surrounded by a thin capsule. The cut surface was grey-yellow with dark-yellow areas. Normal adrenal tissue was not observed.
Microscopically the tumor consisted of epithelial cells which penetrated the capsule, the vascular walls (Fig. 2) and the adhering pancreatic tissue. Scattered necrotic areas were present. Mitoses were fairly numerous with
| Reference | No. | Endocrine studies | |
|---|---|---|---|
| Blood | Urine 24 hours | ||
| Conn et al .. 3 1964 | 1 | aldosterone, 17-ketosteroids 17-hydroxysteroids | |
| Santander et al.,"3 1965 | 1 | 17-ketosteroids. 17-hydroxysteroids | |
| Salassa et al.,14 1974 (Case 3, 5, and 6) | 3 | renin | 17-ketosteroids, 17-ketogenic steroids, tetrahydro-11-deoxycortisol, aldosterone |
| Revach et al., 16 1977 | 1 | renin and aldosterone | 17-ketosteroids, 17-hydroxysteroids |
| Slee et al., 1983 | 1 | renin and aldosterone | 17-ketosteroids, 17-hydroxysteroids, gas-liquid-chromatography |
a moderate polymorphism of the nuclei locally. The cells showed a trabecular or aveolar arrangement, in some areas lying in long cords separated by connective tissue and vascular spaces. Three cell-types could be detected: (1) cells which in size, nuclear/cytoplasmic ratio and high lipid content resembled the clear cells of the zona fasciculata of the normal gland (Fig. 3A); (2) cells re- sembling clear cells in their high lipid content, but smaller in size with a vesicular nucleus and a nuclear/ cytoplasmic ratio closer to the cells of the zona glom- erulosa, the so-called “hybrid cells” (Fig. 3B); and (3) cells of the zona glomerulosa type, which form solid trabeculae (Fig. 3C). No hormonal assay of tumor tissue was done.
Discussion
The patient presented here fulfilled all criteria for pri- mary aldosteronism, i.e., hypertension, hypokalemia, and metabolic alkalosis, together with elevated aldoste- rone and suppressed renin levels. This syndrome is al- most exclusively caused by benign lesions of the adrenal gland including cortical adenomas and hyperplasia of the zona glomerulosa. In few instances, however, pri- mary aldosteronism has been described in connection with adrenocortical carcinoma.3,5-12 Differentiation be- tween these entities influences management since sur- gery is the treatment of choice for adenoma and carci- noma, whereas patients with bilateral hyperplasia are preferably treated with the aldosterone antagonist spi- ronolactone.12 In the case of adrenocortical carcinoma, only early recognition of the disease with prompt sur- gical excision of the tumor will give the patient a chance for definite cure. Due to the delay in diagnosing adre- nocortical carcinoma in our patient, the tumor had reached considerable size at the time of investigation and only a palliative surgical procedure could be car- ried out.
An interesting feature of our patient’s disease is the finding of hyperaldosteronism as the only endocrine manifestation of an adrenocortical carcinoma. Plasma cortisol levels were not elevated and the urinary excre- tion of 17-hydroxysteroids and 17-ketosteroids was re- peatedly in the normal range. Furthermore gas-liquid- chromatography of the urine did not reveal excess ex- cretion of any steroid. In most cases of adrenocortical carcinoma and the clinical picture of hyperaldosteron- ism, hypersecretion of other steroids is also found.3,5-12 Only six cases of apparently pure hyperaldosteronism could be traced in the literature, these are summarized in Table 2.3.14-16
Pathology
In adrenocortical adenomas with primary hyperal- dosteronism, four different cell types have been de- scribed: clear cells resembling zona fasciculata cells; hy- brid cells resembling fasciculata cells in their high con- tent of cytoplasmic lipids, but smaller in size; cells similar to those found in the zona glomerulosa; and compact cells indistinguishable from zona reticularis cells. Any or all four cell types may be present in one tumor, but hybrid cells are nearly always found.5
The histologic pattern of malignant adrenocortical tumors with primary aldosteronism varies from case to case and, to some extent, between different parts of the same tumor.5.7,8 Only two of the authors mentioned in Table 2 reported the histologic features of the tumor. Well-differentiated cells resembling those found in the normal zona glomerulosa were described by Revach et al.16 Santander et al.14 described trabecular structures resembling the fascicular layer in some areas and the reticular layer in others. In the tumor from our patient clear cells, hybrid cells and glomerulosa-like cells were found. This is consistent with other reports in the lit- erature.
Is it possible to attribute the aldosterone production to one of these cell types? It appears that the hybrid cells are more or less characteristic for aldosterone producing tumors. However, one should be circumspect in attrib- uting specific endocrine activity to a particular cell type on purely morphological grounds as the same cells may also be found in adrenal tumors showing other or no hormonal activity.
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