K. Weingärtnerª E.W. Gerharza A. Bittingerb J. Rosaid R. Leppekc H. Riedmillera
Departments of
a Urology (Chairman: Prof. H. Riedmiller),
b Pathology (Chairman: Prof. C. Thomas), and
· Radiology (Chairman: Prof. K .- J. Klose), Philipps University Medical School, Marburg, Germany;
d Department of Pathology, (Chairman: Prof. J. Rosai), Memorial Sloan-Kettering Cancer Center, New York, N.Y., USA
Key Words
Adrenocortical carcinoma Primary aldosteronism Diagnosis and treatment Review of the literature
Isolated Clinical Syndrome of Primary Aldosteronism in a Patient with Adrenocortical Carcinoma
Case Report and Review of the Literature
Abstract
Primary carcinoma of the adrenal cortex is an extremely rare neoplasm, accounting for an estimated 0.05-0.2% of all malignancies. Hormonally func- tioning tumors occur in about 50% of patients with Cushing’s syndrome (50%), virilism (30%) and feminization (12%) being the most common clinical manifestations. Isolated aldosteronism caused by adrenocortical carcinoma is found in about 1-3% in patients with the clinical signs of Conn’s syndrome. The only preoperative feature suggesting malignancy is a size of more than 5 cm in computed tomography. We report a rare case of a 29-year-old man with biochemically proven primary aldosteronism as the unique manifesta- tion of a carcinoma of the right adrenal cortex.
Introduction
Adrenal cortical carcinoma (ACC) is an uncommon, highly aggressive malignancy with a calculated frequency of 1-2 cases per million population per year and account- ing for an estimated 0.2% of all cancers [1-4]. Only 50% are candidates for curative resection [4]. Half of them are functioning and half are hormonally inactive [2]. The prognosis for such tumors is poor, with median survival reported being less than 2 years [1]. ACC that produce only excessive amounts of mineralocorticoids are ex- tremely rare. Because of the rarity of this disease, few cli- nicians can claim an extensive experience in its diagnosis and treatment. The literature consists mainly of isolated case reports of functional tumors with only a few studies involving a significant number of patients. Today there is no biochemical or radiological marker than can reliably distinguish benign from malignant tumors. We present a
case in which severe primary aldosteronism was the unique clinical feature expressed by an ACC which was mistaken for an adenoma until the histopathological stud- ies were completed.
Case Report
A 29-year-old Caucasian male was admitted to the hospital for re-adjustment of his medical treatment for a long-standing epilepsia due to encephalitis in early childhood. His past medical history was otherwise unremarkable. After a recent syncope for the first time, persistently elevated blood pressures (180/120 mm Hg) were mea- sured on both arms. His physical examination was completely nor- mal except for ocular findings of grade II hypertensive changes. ECG showed a left axis deviation and changes of hypokalemia; echocardi- ography revealed a concentric hypertrophy of the left ventricle. Abdominal ultrasonography and computerized tomographic (CT) scanning disclosed a 3-cm right adrenal mass without calcifications (fig. 1). No signs for liver or kidney involvement and no retroperito-
Received: February 13, 1995
Accepted: April 3, 1995
Karl Weingärtner, MD Department of Urology
Philipps University Marburg Medical School
@ 1995 S. Karger AG, Basel 0042-1138/95/0554-0232 $8.00/0
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neal lymphadenopathic condition. RBC, WBC and blood chemistry including thyroid hormones were within normal limits except for potassium (2.4 mmol/l) and sodium (152 mmol/l). Adrenaline, nor- adrenaline, dopamine and plasma cortisol were normal, plasma aldo- sterone was markedly elevated (>1,000 pg/ml; reference 20-120 pg/ ml), plasma-renin activity (in supine position) 3.3 ng/l was under the normal limit. Vanillin mandelic acid in 24-hour urine collection (4.77 mg/dl) and urinary free cortisol (105 pg/l) were normal (urine volume 3,100 ml/24 h). Urinalysis was unremarkable; urine was ster- ile on culture. Excretory urography (IVP), sonography of the thyroid gland, chest X-ray were normal and renal angiogram disclosed a nor- mal vasculature. Presumed diagnosis was adenoma of the adrenal gland.
Adrenalectomy was performed and regional lymph nodes were removed. Pathologic examination of the specimens revealed a carci- noma of the adrenal cortex G2 (fig. 2-4), stage I according to Nader et al. [5]. Diagnosis was confirmed by immunohistochemical meth-
ods. A reference pathologist (J.R.) confirmed the initial diagnosis. Postoperative recovery was uncomplicated; potassium and aldoste- rone were normal, but arterial hypertension persisted.
Discussion
In 1955, Jerome Conn [6] described the syndrome of primary hyperaldosteronism. In the same year, Foye and Feichtmeier [7] reported the first case of ACC solely pro- ducing mineralocorticoid effect, which up to date appears to be a rare phenomenon [8]. The most frequent cause of this endocrinopathy is solitary adenoma of the adrenal cortex (up to 72%) and bilateral adrenocortical hyperpla-
sia [3, 6, 9-11]. In sharp contrast to the abundance of cor- tical adenomas, ACC is a rare disorder with an annual incidence from cancer registries that has varied from 0.006 to 0.00017% [12]. ACC is most frequently seen in patients older than 40 years of age, with no male-to- female preponderance. Most of the patients less than 40 years of age are female and have functioning tumors. They usually cause Cushing’s syndrome, the adrenogeni- tal syndrome and precocious puberty [3, 11]. Although pure primary aldosteronism most often results from be- nign adrenocortical adenoma or bilateral hyperplasia, it may also indicate the presence of an ACC: 1-3% of ACC produce excessive amounts of mineralocorticoids, as in our case. Compared to other patients with primary aldo- steronism, patients with carcinoma have lower serum potassium levels [3]. Calcifications and a tumor size of more than 5 cm are suggestive of a malignant adrenal neo- plasm [3]. Compared to the mean size of adrenal cancers of at least 12 cm, the tumor in our patient was rather small (Ø3 cm) [4].
Histologically it is extremely difficult to distinguish between adenomas and carcinomas in certain cases [13]. Whereas Newsome [8] comments that ‘in the absence of metastases or local recurrence there is no clinical or histo- logical criterion that can prove the malignant nature of the lesion’, other authors state that multiple mitotic fig- ures, pleomorphic nuclei or cytoplasm, hemorrhages and/ or necrosis are always evidence of malignancy. The ACC presented in our report fulfills at least four of the criteria for malignancy in this organ that were laid down by Weiss [13]: presence of numerous mitoses, atypical mitoses, paucity of clear cells, and high nuclear grade. Because both adrenal adenomas and carcinomas may contain abnormal DNA stemlines, ploidy alone is not a reliable discriminator in individual cases.
The most common presenting symptoms of ACC in- clude abdominal pain, fatigue, weight loss and symptoms referable to steroid excess, such as acne, oligomenorrhea and easy bruisability [2, 4]. Our patient became symp- tomatic due to epilepsia caused by a hypertensive crisis. The mean duration of initial symptoms is often 6 months or longer. Typical findings on physical examination are hypertension (28%) and a palpable abdominal mass [2,4].
Once the diagnosis of an adrenal neoplasm is sus- pected, usually a wide battery of biochemical and localiz- ing investigations is carried out; but as the study of Her- rera et al. [12] demonstrates, it is completely sufficient to screen the patient with a 24-hour urine metanephrine determination, serum potassium level and a 1-mg over-
night dexamethasone suppression test to screen for func- tioning tumors. Approximately equal numbers of func- tional and nonfunctional tumors are found; functional tumors are more often encountered in women and chil- dren [2, 4].
Imaging of the adrenal gland has improved dramatical- ly during the last decade: with the advent of CT scanning, ultrasonography and magnetic resonance imaging (MRI), masses as small as 1 cm (so-called ‘incidentalomas’) may be readily detected in the adrenal gland. CT and MRI pro- vide useful information in terms of localization, extent of local invasion and presence of metastatic disease. But no valid criteria could be found to differentiate adenomas from carcinomas.
Complete surgical excision of the tumor and resection of regional lymph nodes is the only effective form of ther- apy for patients with this disease. In patients with ACC the immunologic system may be compromised, being responsible for complications like wound infection or pneumonia. Henley et al. [4] report a significantly high morbidity rate of 18% (hemorrhage, thrombosis, pulmo- nary embolism, etc.). Another severe problem may be the development of an Addison crisis in the postoperative period, which can be prevented effectively by prophylac- tic administration of 100 mg cortisol, given intraopera- tively plus additionally 100 mg cortisol within 24 h. Fur- ther therapy depends on the kind of tumor and surgical procedure. The mortality rate of about 2% is comparable to other surgical procedures [14].
The only factor influencing patient survival is the pres- ence of localized disease at initial diagnosis. Bodie et al. [2] reviewed 82 patients with ACC, 48.8% presented with a hormonally functioning tumor. More than half of the patients had regional or distant tumor spread when the diagnosis was established. This finding presumably re- flects the anatomical location of the adrenal gland deep in the retroperitoneum, which renders it inaccessible to physical examination. ACC remain silent until symptoms are produced from advanced malignancy or hormonal excess. Complete surgical removal of all gross tumor was achieved in 49 patients. Overall 3- and 5-year survival rate in this series were 37.5 and 25.1%, respectively. The overall 5-year survival rate in a retrospective analysis of the Mayo Clinic data was 16%. Fifty-one patients died of carcinoma after a mean survival time of 19 months [4]. No significant differences in survival times are seen in terms of tumor size, function and grade or patient’s sex, and no difference was seen in survival times between patients less than 39 years of age and those 40 years of age and older.
Isolated Clinical Syndrome of Primary Aldosteronism in a Patient with Adrenocortical Carcinoma
In our patient the ACC was small and confined to the adrenal gland. After complete removal of the neoplasm he received no further therapy. At the moment, 1 year after surgery, the patient is free of disease. All clinical signs of primary aldosteronism have resolved, except the patient’s hypertension. This observation has been reported by oth- ers: even if patients show normal values for blood pres- sure postoperatively, in about one third hypertension will recur [15].
The most common sites of metastases were liver, lungs, pleura and peritoneal surfaces and regional lymph nodes. Tumor thrombus extending into adrenal vein, renal vein or inferior vena cava were described [4]. The success of adjunctive therapy has largely been disappointing. In patients with metastatic ACC, survival was not affected
by chemotherapy (e.g. op’DDD) or radiation therapy [2]. In a retrospective nonrandomized study, Jensen et al. [1] compared patients with first recurrence of adrenocortical cancer treated either by surgical resection and chemother- apy or chemotherapy alone. Only one third of patients who underwent surgical resection of the recurrence in combination with adjuvant chemotherapy (mitotane) showed a benefit from combined treatment [1].
Irrespective of the size, all hormonally active adrenal masses should be surgically removed. The treatment of nonfunctioning adrenal tumors (incidentalomas) remains a controversial issue. Reliable criteria to differentiate benign from malignant lesions are still lacking. Therefore, ACC continues to be a diagnostic and therapeutic chal- lenge.
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