Adrenocortical Carcinoma with an Isolated Mineralo- corticoid Excess and Recurrency Fourteen Years after Removal of the Tumor
GORO MIYAZAKI,* NOBUAKI SASANO, + TATSUO TORIKAI; and SOITSU FUKUCHIt
Mishima Social Insurance Hospital, Mishima,* Shizuoka Prefecture and Department of Pathologyt and Department of Internal Medicine,t Tohoku University School of Medicine, Sendai
MIYAZAKI, G., SASANO, N., TORIKAI, T. and FUKUCHI, S. Adrenocortical Carcinoma with an Isolated Mineralocorticoid Excess and Recurrency Fourteen Years after Removal of the Tumor. Tohoku J. exp. Med., 1973, 109 (4), 365-375 -The case of a 31-year-old farmer with primary malignant tumor of the left adrenal cortex, causing pure primary hypermineralocorticism, is reported. The clinical picture consisted of intermittent tetany, periodic muscular weakness, polyuria and polydipsia, hypertension, and edema. This seems to be only the second case of pure hypermineralocorticism caused by adrenocortical carcinoma. Removal of the primary tumor resulted in a complete remission lasting for fourteen years. Thereafter, similar symptoms recurred but disappeared with the removal of the recurrent tumor. The content of aldosterone and cortisol per gram of tissue in the recurrent tumor was very low in comparison with that in the usual adrenocortical adenoma of primary aldosteronism. This case is unique in the following two points; pure mineralocorticoid excess caused by adrenocor- tical carcinoma and the long duration of 14 years for the recurrence after the first surgery. --- carcinoma ; mineralocorticoid; aldosterone
Since the first description of primary aldosteronism by Conn (1955), many cases of this syndrome have been reported. In the majority of cases, either cortical adenoma or hyperplasia has been found in the adrenals at operation. Malignancy is a very rare cause of primary aldosteronism, as defined by Conn et al. (1964). However, several cases of adrenocortical carcinoma manifesting a clinical syndrome caused by the excessive production of aldosterone have been documented.
This report contains the detailed findings of a case of primary aldosteronism caused by left adrenal carcinoma, primary and recurrent after a complete remission lasting for fourteen years. Particularity of malignant aldosteronoma in urinary steroid analysis and tumor histology will be discussed.
CASE HISTORY
A 31-year-old Japanese farmer first visited the Mishima Social Insurance Hospital on April 13, 1956, because of stiffening in both hands and the inability
Received for publication, August 19, 1972.
to handle chopsticks after manual work for the previous two years. In wintertime he complained of fatigue in both legs, which was relieved by rest. He had felt excessive thirst and suffered from polyuria for the previous year but he was un- aware of having hypertension. There was no history of diabetes, and no recent change in weight. The family history was not contributory. He has two sons.
The patient was admitted to the hospital on May 13, 1956. Physical examination revealed an adequately nourished, quite normal-looking man in no acute distress, who did not have the manifestations of a cushingoid appearance such as a moon face, striae etc. (Fig. 1). The thyroid gland was not enlarged, and breath sounds were normal. There was a grade II soft apical systolic murmur, with an accentuated second sound in the aortic orifice. The liver and the spleen were not enlarged. A large mass was palpable, vaguely defined in the depth of the left hypochondric region. Arterial pulsations of all extremities were palpated distinctly. No bruit was heard in the renal area. Neurologic examination was normal. No edema was found.
Blood pressure was 234-180/130-95. The eye fundi showed moderate A-V nicking and generalized diffuse arteriolar narrowing. Urinary volume was 2,000 to 3,000 ml per day with a specific gravity of 1.008-1.011. Ability of the kidney to concentrate urine was decreased, but no other abnormal signs were found. Erythrocyte sedimentation rate was 35 mm per hour. Fasting blood sugar was 79 mg/100 ml. Serum creatinine was 0.8 mg/100 ml. Estimates of serum electro- lytes, urinary catecholamines and steroid hormones were not made at that time. An electrocardiogram showed low T wave in all leads, but U waves were not distinctly recorded. X-ray finding using periadrenal air insufflation revealed a mass 5 by 6 cm above the upper portion of the left kidney.
Left adrenal exploration was performed on June 27, 1956, with a clinical diagnosis of pheochromocytoma. A tumor, well defined and grossly encapsulat- ed, was located adjacent to the upper portion of the left kidney. The tumor, weighing 450 grams, was removed free from the left kidney without injury to the parenchyma (Fig. 2). There was no marked change in the blood pressure through- out the operation.
Histologically, the tumor had undoubtful evidences of adrenocortical carci- noma. The tumor cells, however, were rather small in size and densely arranged in a solid alveolar structure separated by vascular spaces or fine fibrious strands. Areas mainly of relatively uniform clear cells rich in lipid were generally predominant, while some areas were purely composed of compact cells, mostly small and partly medium in size (Figs. 3 and 4). Large nuclei were detected but cellular pleomorphism was slight. Furthermore, signs of infiltrative growth including invasions into capsular veins engorged were occasionally observed (Fig. 5).
The postsurgical course was quite uneventful, daily urinary output decreased to approximately 2,000 ml and the symptoms vanished completely, except for high blood pressure, which remained at 160 mm Hg systolic. The patient left the hospital on July 23, 1956.
The patient was not seen again until November 2, 1970. He had been quite well and working as hard as usual until October 7, 1970. Muscle pain occurred after long walks, and the pain became so bad that the patient was unable to lift up both legs. One week later, hypertension was noticed by a doctor. Paresthesia and paresis in both arms followed. The patient himself noticed that his hands showed symptoms diagnosed as tetany. He had no polydipsia and polyuria. He was admitted to the same hospital on November 3, 1970.
Physical examination revealed a well-nourished man of normal appearance. Body temperature was 36.5℃. Pulse rate was 72 per minute. Blood pressure was 200/80 mm Hg. Abnormal pigmentation of skin was not observed. Cranial nerves were normal. Lymph nodes were not palpable. A chest film showed slight cardiac enlargement, especially of the left ventricle. Breath sounds were normal. The liver and the spleen were not enlarged. Kidneys were not palpable. Discomfort upon pressure was felt in the left hypochondric region. No mass or resistance was palpable in the abdomen. No abnormalities were found in neuro- logical tests in both upper and lower extremities, despite the complaints at that time. No pedal edema was found.
Laboratory tests showed low serum potassium of 2.5 mEq/l. Serum sodium and chloride were 141-144 and 97-99 mEg/l, respectively. Several urine specimens showed a fixed specific gravity in the range of 1.014-1.018. Urinary volume was 2,000 ml per day. Neither proteinuria or glucosuria were detected. Blood urea nitrogen was 2.2 mg/dl. Electrocardiogramdings revealed a slight left ventricular hypertrophy and marked U waves in V2 and V3. A glucose tolerance test showed a slight diabetic curve. Urinary excretion of 17-ketosteroids and
17-hydroxycorticosteroids in 24 hours showed a normal range of 6.3-13.6 and 2.2- 3.0 mg per 24 hours, respectively. X-ray findings with periadrenal air insufflation combined with intravenous pyelogram showed a mass located in the upper portion of the left kidney.
A second laparotomy was performed on December 3, 1970, with the clinical diagnosis of primary aldosteronism caused by left adrenal cortical carcinoma. Both spironolactone and KCI tablets were administered before the operation. A retroperitoneal mass adherent to the upper side of the left kidney as well as to the surrounding tissue had the surface of nodular appearance. The tumor was macroscopically suspected of malignancy and was removed together with the left kidney, stripping off the fascia of the lumbar muscle. The perihilar and para- aortic lymph nodes were not enlarged. No thrombus was found in the lumen of the severed renal vein. Other abdominal viscera had no metastasis at all.
The removed tumor, measuring 10x6x6 cm, was encapsulated with fibrous membrane. The cut surface generally reddish-brown in color had hemorrhagic areas (Fig. 6). In certain limited areas of histologic sections, solid alveolar arrangements of clear cells with foamy cytoplasm suggestive of adrenocortical origin were prevalent (Fig. 7) and this finding was basically identical with that in the previous tumor removed 14 years before. The greater part of the tumor was, however, composed of compact cells in ribbon-like and solid alveolar arrangements separated by vascular spaces or narrow fibrous strands. Nuclear pleomorphism was evident. The stroma was still narrow and the general appearance of the tumor was suggestive of endocrine gland origin but rather undifferentiated and nonspecific (Fig. 8). Tumor cell invasions into the vein were observed in the capsule (Fig. 9).
The postoperative course was uneventful, although no adrenocortical hormone was given. Blood pressure gradually came down to 150/98 mm Hg on the 10th postoperative day and has remained within a normal range ever since. The serum potassium level returned to the normal range of 4.7 mEq/l without special treatment. The slight diabetic curve in the glucose tolerance test, observed before operation, changed to normal on the 15th postoperative day. The Fishberg test showed a urinary specific gravity of 1.020, 1.022 and 1.023 on the 11th postoperative day. 17-ketosteroids and 17-hydroxycorticosteroids excretion in the urine in 24 hours were 6.6 and 2.4 mg, respectively. Ten months after operation the plasma aldosterone measured by radioimmunoassay (Mayes et al. 1970) was 6.2 ng/100 ml. The patient was duly discharged on March 5, 1971, after comple- tion of antineoplastic chemotherapy. Up to February 26, 1973, the patient has been alive and well showing normal ranges of blood pressure and of the serum potassium level.
METHODS AND RESULTS
The detailed functional state of the adrenals was not studied preoperatively, so the corticoid hormones in the adrenals were determined. The adrenal tumor
was frozen at the operating room and sent to the Tohoku University Hospital from the Mishima Social Insurance Hospital, packed in dry ice, 4 months after the operation. The tumor (25 g) was finely chopped and transferred immediately into 50 ml of 80 per cent acetone and allowed to stand 5 hours while being stirred at room temperature. The residue was filtered out and washed with 80 per cent acetone and the acetone solution was concentrated in vacuo below 45℃ to remove the acetone. To the half of the aquous suspension (Fraction A), approximately 10,000 cpm of 3H-aldosterone was added for determining the recovery rate of aldosterone estimation. To the remaining half of the solution (Fraction B) 3H- corticosterone and 3H-hydrocortisone were added for estimating recovery of corti- costerone and hydrocortisone. Both fractions A and B were extracted twice with dichloromethane, which was then dried. The dichloromethane extract was dissolved into 10 ml of dichloromethane, and applied to a silica gel column (8× 30 mm). The column was washed with 5 ml of dichloromethane, then with 5 ml of dichloromethane: methanol 100:2. The sample was eluted with 5 ml dichloro- methane: methanol 100:9. The sample from fraction A was then applied to paper and, after 5 hours of equilibration, was developed on a modified Bush B5 system (hexane: benzene: methanol: water 1 : 9:5:2.5) for 12 hours at 30°C. A strip scanner was used to locate the 1, 2 3H-aldosterone. A section of paper containing the aldosterone was eluted with 5 ml of methanol into a test tube. The aldosterone content of the eluate was measured by the method of radioimmunoas- say reported by Mayes et al. (1970). Fraction B was chromatographed on Zaffaroni’s toluene-propylene glycol system after the silica gel column and finally on the Bush B5 system. Estimation of corticosterone and hydrocortisone was performed by the competitive protein binding radioassay reported by Murphy (1967) using 3H-hydrocortisone and 3H-corticosterone.
The hydrocortisone to corticosterone ratio was described as ratio I and the hydrocortisone to aldosterone ratio as ratio II.
Contents of aldosterone, hydrocortisone and corticosterone in the extirpated mass were 1.28, 276, 184 ng per gram of tissue, respectively. So, ratios I and II were 1.50 and 216, respectively. The recovery rate of this method was 70-80% for aldosterone, and 40-50% for hydrocortisone and corticosterone.
DISCUSSION
The majority of cases of primary aldosteronism have been caused by benign adrenocortical adenomata; most of these patients have been cured by removal of the tumor. Adrenal carcinoma is a very rare cause of primary aldosteronism. The interesting point is that the majority of patients with adrenocortical carci- nomas, who have clinical signs and symptoms of an excess of mineralocorticoids, also have increased glucocorticoid metabolites in the urine, but do not have the clinical signs of excess glucocorticoid production. Therefore, they must be considered to be examples of mixed hypercorticism rather than of pure aldosteron- ism.
When this case was first seen in 1956, pheochromacytoma was suspected before the first surgery. Neither 17-hydroxycorticosteroids, 17-ketosteroids, nor serum potassium were estimated at that time. However, histological findings of the tumor, which was predominantly composed of relatively small cells with spongy or fine granular cytoplasm, fit the definition of malignancy in primary aldosteronism proposed by Symington (1969). Furthermore, findings of cellular atypism and of blood vessel invasions of tumor cells provided undoubtful evidences of malignancy, despite recurrency appeared 14 years later. When the patient was seen for the second time in late 1970, fourteen years later, plasma renin activity and blood aldosterone were also not determined preoperatively. However, excessive excre- tion of 17-hydroxycorticosteroids and 17-ketosteroids was definitely absent and the patient showed no clinical evidence of hypercortisolism or hyperandrogenia. This prompts us to consider that the syndrome was a pure hypermineralocorticism due to adrenocortical carcinoma.
The recurrent tumor measuring 10x6x6 cm showed histologic features of generally nonspecific and in most part consisted of rather undifferentiated carci- noma cells only suspected of endocrine gland origin. The content of aldosterone per gram of tissue in the adrenal tumor was very low in comparison with that in the adrenal adenoma of primary aldosteronism reported previously (Louis and Conn 1958; Fukuchi 1961). However, it is generally accepted that undifferentiated tumor cells in the adrenals produce a relatively small amount of corticosteroid and no symptoms of hypermineralocorticoidism can appear before the development to a large adrenal tumor such as that of the present case. The other possibility exists that the long period to the estimation of the tumor by extirpation might decrease the content of steroids in the tumor. The storage of adrenal glands in a deep freezer over one month is known to cause the decrease in steroid content (Fukuchi 1961). On the other hand, the fact that the concentration of aldosterone in the tumor was about 10 times higher than that of plasma aldosterone, suggests the excess of aldosterone secretion from the tumor. Furthermore, the tumor contained a very small amount of hydrocortisone and corticosterone, which coincides with the results for the excretion of 17-hydroxycorticosteroids. However, the ratio of hydrocortisone to aldosterone in content showed a relatively high value in comparison with the results for adrenal adenoma with primary aldosteronism.
Hypertension and hypokalemic alkalosis, major signs of this case, could be regarded as characteristics for primary aldosteronism but are known to be observed in cases of hypercortisolism without aldosterone hypersecretion. The lack of hypercortisolism in the present case was suggested from the results of tissue steroid analysis of the recurrent tumor. According to Crane and Harris (1966), the hypokalemic alkalosis in patients with adrenocortical malignancies may be caused by an excess of desoxycorticosterone (DOC). Furthermore, a syndrome of hypertension and hypokalemic alkalosis could be also produced by excessive production of DOC and/or corticosterone (B) (Biglieri et al. 1968). This possibility could not be denied in the present case, as secretions or excretions of DOC and B
as well as of aldosterone were not measured. Therefore, the term “syndrome of mineralocorticoid excess” may be applied to this case according to the proposal of Luetscher (1958) as hypertension and hypokalemic alkalosis of the patient cannot be attributed to excessive production of aldosterone.
Alterman et al. (1969), in their case report on primary adrenocortical carcinoma causing aldosteronism, described an excellent review with a list of 11 cases of aldosteronism and/or mineralocorticoid excess syndrome due to primary adrenocor- tical carcinoma. In 9 of 10 cases where urinary steroid studies were performed, excessive excretion of 17-hydroxycorticosteroids and/or 17-ketosteroids was demonstrated without clinical evidences of hypercortisolism or hyperandrogenia. The normal urinary elimination of 17-hydroxycorticosteroids and 17-ketosteroids was established in only one case of mineralocorticoid excess syndrome reported by Santander et al. (1965). Examination of this report, however, reveals that only one measurement of each of these substances was documented and data of aldosterone excretion were missed. The present case is in a similar condition and seems to be only the second reported case of adrenocortical carcinoma producing pure hypermineralocorticism.
X-ray examination supported the clinical diagnosis of hypermineralocorticism of adrenal origin showing a voluminous adrenal mass on the left side. The size of the mass suggested a malignant tumor rather than an adenoma. The lack of signs suggestive of primary tumor in other regions inclined us to think that the adrenal neoplasm was a primary one. Surgical exploration confirmed the diagnosis of a primary carcinoma of the adrenal cortex.
Autopsy records available in 7 of 11 cases in the list of Alterman et al. (1969) revealed that metastasis were most prevalent in the lungs which were followed by the liver and bone.
The time interval for the recurrence after the first surgery was as much as fourteen years. Some cases of primary aldosteronism by adrenocortical carcinoma were reported to have recurred, but they have proved to be fatal in a rather short time. A case reported by Marquezy et al. (1965) was alive and well 18 months after ablation of the tumor. The present case was alive and well 16 years and 7 months after removal of the primary tumor. In this respect, too, this case is unique.
References
1) Alterman, S.L., Dominguez, C., Lopez-Gomez, A. & Lieber, A.L. (1969) Primary adrenocortical carcinoma causing aldosteronism. Cancer, 24, 602-609.
2) Biglieri, E.G., Slaton, P.E., Schambelan, M. & Kronfield, S.J. (1968) Hypermineralo- corticoidism. Amer. J. Med., 45, 170-175.
3) Conn, J.W. (1955) Primary aldosteronism, a new clinical syndrome. J. Lab. clin. Med., 45, 3-17.
4) Conn, J.W., Knopf, R.F. & Nesbit, R.M. (1964) Clinical characteristics of primary aldosteronism from an analysis of 145 cases. Amer. J. Surg., 107, 159-172.
5) Crane, M.G. & Harris, J.J. (1966) Desoxycorticosterone secretion rates in hyper- adrenocorticism. J. clin. Endocr., 26, 1135-1143.
6) Fukuchi, S. (1961) Contents of adrenocortical hormones in adrenal tissues in various endocrine disorders. Tohoku J. exp. Med., 76, 365-373.
7) Louis, L.H. & Conn, J.W. (1958) Content of aldosterone, corticosterone, hydrocor- tisone, and cortisone in adrenal tissue of patients with primary aldosteronism. J. Lab. clin. Med., 52, 923, (abstrect).
8) Luetscher, J.A., Jr. (1958) The syndrome of mineralocorticoid excess. Ann. intern. Med., 48, 1424-1431.
9) Marquezy, R.A., Bricaire, H., Laudat, M.H., Courijacket, J. & Philbert, M. (1965) Adeno-carcinoma de la surrenale avec syndrome d’hyperandrogenie et syndrome d’ hypermineralocorticisme. Ann. endocr. (Paris), 26, 247-266.
10) Mayes, D., Furuyama, S., Kem, D.C. & Nugent, C.A. (1970) A radioimmunoasay for plasma aldosterone. J. clin. Endocr., 30, 682-685.
11) Murphy, B.E.P. (1967) Some studies of the protein-binding of steroids and their application to the routine micro and ultramicro measurement of various steroids in body fluids by competitive protein-binding radioassay. J. clin. Endocr., 27, 973- 990.
12) Santander, S.R., Gonzalez, A. & Suarez, J.A. (1965) Case of probable mineralocor- ticoid excess without hypercortisolism due to a carcinoma of the adrenal cortex. J. clin. Endocr., 25, 1429-1435.
13) Symington, T. (1969) Functional Pathology of the Human Adrenal Gland. E. & S. Livingstone, Edinburgh and London, pp. 145-148.
Fig. 2. The tumor removed on June 27, 1956, was measured as 12x 9x6 cm and weighed 450 gm.
Fig. 3. Portion of the primary tumor composed of clear cells rich in lipid. The finding is faborable for the diagnosis of primary aldosteronism but cells are generally small and irregular in nuclear appearance and arrangements. Hematoxylin and eosin stain, ×100.
Fig. 4. In the dark cell area of the primary tumor, solid and pseudoglandular arrange- ments of small and medium sized compact cells are predominant. Hematoxylin and eosin stain, ×100.
Fig. 5. The capsule of the primary tumor has several veins evidently dilated some of which are invaded by tumor cell at the point of arrow. This finding endorses the diagnosis of malignancy. Hematoxylin and eosin stain, ×120.
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Fig. 6. The recurrent tumor, measuring 10x6x6 cm, removed with the left kidney on December 3, 1970. This photograph was taken after cutting off the tissue for steroid assay.
Fig. 7. Clear cells with spongy cytoplasm are observed in the limited area intermingled occasionally with compact cells. This finding suggests a stimulated endocrine activity. Hematoxylin and eosin stain, x250.
Fig. 8. The predominant pattern of the recurrent tumor is composed of medium-sized compact cells in ribbon-like or alveolar arrnagements with little stroma. Features of nuclear and cellular atypism are evident. Hematoxylin and eosin stain, x250.
Fig. 9. In the capsular region the finding of blood vessel invasion of the tumor cell can be occasionally observed. Hematoxylin and eosin stain, x 120.
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