Clinical Research
Adrenal Cortical Diseases: International Case Conference
Hironobu Sasano, Takashi Suzuki, Junji Irie, Kioko Kawai, Motohiko Aiba, Anne Marie McNicol, and Hiroshi Takami, MD, PHD
Abstract
Six pathologists from Japan and the United Kingdom evaluated four different cases of adrenocortical disorders independently. These adrenocortical disorders included an adrenal tumor in a 45-yr-old female without any endocrine abnormalities, bilateral adrenocorti- cal lesions in a 55-yr-old female with Cushing syndrome, an adrenocortical mass in a 44-yr-old man with hypertension, and an adrenocortical lesion in a 62-yr-old female with chronic hypertension for 30 yr. In this article, we provide a clinical summary, macroscopic and histologic findings, and histologic diagnosis of these four adrenocortical cases. Key Words: Adrenal; adrenal cortex; pathology; hyperaldosteronism; hyperplasia; carci- noma; tumor; adenoma.
Department of Pathology (HS, TS), Tohoku University School of Medicine, Sendai, Japan; Department of Pathology (JI), Nagasaki University School of Medicine, Nagasaki, Japan; Department of Pathology (KK), Nagasaki City Hospital, Nagasaki, Japan; Department of Pathology (MA), Tokyo Women’s College of Medicine, Tokyo, Japan; University Department of Pathology (AMM), Glasgow Royal Infirmary University NHS Trust, Glasgow, UK; and Department of Surgery (HT), Teikyo University School of Medicine, Tokyo, Japan.
Address correspondence to Dr. Hironobu Sasano, Department of Pathology, Tohoku University School of Medicine, 2-1 Seiryou-machi, Sendai, Japan 980-8575.
Endocrine Pathology, vol. 13, no. 2, 141-148, Summer 2002 @ Copyright 2002 by Humana Press Inc. All rights of any nature whatsoever reserved. 1046-3976/02/13:141-148/ $12.00
Case 1: Adrenal Tumor in 45-Yr-Old Female Without Any Endocrine Abnormalities
Clinical Findings
The patient was found to have a right adrenal tumor without any clinical symp- toms or signs. The only endocrinologic or biochemical abnormality was elevated 24-h secretion of 17-ketosteroids (18.8 mg/ d; normal: 2.4-11.0). Adrenocortical car- cinoma was clinically suspected and arte- rial embolization was performed prior to surgery.
Macroscopic Findings
The tumor weighed 250 g and measured 115 x 75 × 45 mm. The cut surface dem- onstrated foci of hemorrhage and necro- sis. There was no evidence of local invasion, and normal adrenal gland was attached to the tumor.
Histologic Findings
The tumor was composed of a mixed population of clear and compact cells arranged in a sheetlike fashion associated with relatively thick fibrous septum (Fig. 1A). Clear tumor cells were predominant with round nuclei and sparsely granulated chro- matin patterns (Fig. 1B). Pleomorphism, confluent necrosis, and atypical mitotic features were not detected. Mitotic activ- ity was low. Embolization material was dis- tinctively detected in some of the vessels. Foci of capsular or venous invasion were not detected, but those of sinusoidal inva- sion were present. Foci of hyalinization and hemorrhage were also detected (Fig. 1C).
Histologic Diagnosis
Five of six pathologists evaluating the lesion made the diagnosis of adrenocorti- cal carcinoma, and one of the pathologists
diagnosed it as “adrenocortical adenoma, follow-up recommended.”
Discussion of Case 1
The distinction between these “well-dif- ferentiated” adrenocortical carcinomas and adenomas may be one of the most diffi- cult differential diagnoses in surgical pathology practice. There is no single his- tologic criterion that can reliably differen- tiate adrenocortical carcinoma from adenoma-like capsular or vascular invasion of thyroid follicular carcinoma. Only the studies that have evaluated multiple histo- logic and/or nonhistologic criteria of the resected cases can provide reliable histologic diagnosis. Three different histologic scor- ing systems have been proposed by vari- ous investigators [1-4], and all are equally useful for predicting clinical outcome of patients with resected adrenocortical neoplasms. Among these criteria, the cri- terion proposed by Weiss and colleagues [3,4] is probably the most widely used because it is relatively easy to use, a good correlation can be detected between results and clinical outcome of the patients, and it requires only tissue slides for evaluation. Cases with more than three of nine crite- ria are considered adrenocortical carci- noma. However, in this case, all of the pathologists who made the diagnosis of adrenocortical carcinoma pointed out two criteria: the presence of architectural abnormalities and sinusoidal invasion. In addition, preoperative embolization made interpretation of this case more difficult. Therefore, the diagnosis of “adrenocortical adenoma” by one patholo- gist is considered justified. In general, how- ever, it is important to combine gross features including those described previ- ously and the histologic scoring system just discussed in order to reach the diagnosis of adrenocortical carcinoma. In this case,
the lesion is large and fibrous bands are present; both of these features are impor- tant in the multifactorial diagnostic systems [1,2]. Additionally, elevated 24-h urinary 17-ketosteroid also suggests malignancy in the criteria of Hough et al. [2]. Therefore, in this case, the diagnosis of adrenocorti- cal carcinoma is considered highly likely; however, this case may require only clini- cal follow-up including adosterol scan but not postoperative chemotherapy employ- ing op’-DDD.
Case 2: Bilateral Adrenocortical Lesions in 55-Yr-Old Female with Cushing Syndrome
Clinical Findings
The patient had been diabetic and hypertensive for the last 8 yr. Physical examination revealed Cushingoid features, and subsequent endocrine examinations revealed elevated cortisol levels with sup- pressed adrenocorticotropic hormone (ACTH) values. Dexamethasone suppres- sion test was not conducted, and there was no circardian rhythm of cortisol. Increased uptake and accumulation of adosterol were detected in both adrenal glands even under dexamethasone suppression of 8 mg.
Macroscopic Findings
The left adrenal gland weighed 12.6 g and the right 8 g. Both showed multiple nodules, golden yellow and black on sec- tion, measuring up to 20 mm in diameter.
Histologic Findings
Right and left adrenals demonstrated similar histologic changes. They were com- posed of multiple nodules of neoplasms of various diameters. The largest lesions were well circumscribed and encapsulated. These lesions were composed of clear and
compact cells (Fig. 2A). Some of the com- pact cells in these largest lesions were associated with abundant eosinophilic cytoplasm containing lipofuscin (Fig. 2B). Lipomyelomatous changes were also detected in some of these lesions (Fig. 2C). The smaller lesions were well circumscribed but not encapsulated and composed pre- dominantly of clear cortical cells (Fig. 2D). The nonneoplastic or nonnodular adrenal cortex was clearly identified in both adrenals. The adrenal cortex was associated with marked cortical atrophy with rela- tively intact zona glomerulosa (Fig. 2E).
Histologic Diagnosis
Three of the pathologists diagnosed the lesion as ACTH-independent macro- nodular hyperplasia (AIMAH), two patholo- gists diagnosed it as bilateral adrenocortical adenomas with cortical nodules, and one pathologist diagnosed it as primary adreno- cortical micronodular dysplasia or primary pigmented nodular adrenocortical disease (PPNAD).
Discussion of Case 2
The presence of bilateral adrenocortical nodules in this patient with ACTH-inde- pendent Cushing syndrome certainly leads to the diagnosis of nonneoplastic Cushing syndrome including AIMAH or PPNAD. However, this case did not have the char- acteristic histologic features of AIMAH, i.e., the specific admixture of clear and compact cells observed in the nodules of the adrenals with AIMAH [5,6]. In addi- tion, nonnodular atrophic adrenal cortex can be detected in AIMAH, but the pres- ence of distinctive nonnodular atrophic cortex, as shown in this case, is extremely rare in AIMAH. The weight was relatively low for adrenals in AIMAH. These find- ings therefore make the diagnosis of
AIMAH rather unlikely. Some of the cor- tical cells in these nodules demonstrated cytologic features of PPNAD such as eosi-
nophilic cytoplasm with pigments [7], but the great majority of other cells in the lesions did not have these cytologic fea-
tures, which makes the diagnosis of PPNAD unlikely because PPNAD affects the adrenals diffusely. In addition, the weight of the adrenals was too high for reported cases of PPNAD [7].
Differentiation between adrenocortical nodules and adenomas can sometimes be quite difficult. However, in this case, the largest lesions in both the right and left adrenals were encapsulated and composed of markedly heterogeneous populations of cortical cells. On the other hand, the smaller lesions were composed of clear cor- tical cells. Adrenal glands with cortical nodules are much more frequently associ- ated with various degrees of atherosclerotic or hypertensive changes in the arteries. These findings also suggest that the non- neoplastic adrenals of adenoma with Cushing syndrome may be associated with adrenocortical nodules. Therefore, this lesion can be interpreted as bilateral adrenocortical adenoma (the encapsulated largest lesion) associated with the presence of adrenocortical nodules (well circum- scribed but not encapsulated smaller cor- tical lesions) in nonneoplastic adrenal glands. However, stimulation of adrenal cortex by unidentified factors is possible, such as food-dependent or gastrointesti- nal inhibitory polypeptide-induced Cushing syndrome [8], and the possibil- ity that this disease may represent a new entity of Cushing syndrome cannot be completely ruled out.
Case 3: Adrenocortical Mass in 44-Yr-Old Man with Hypertension
Clinical Findings
The patient had hypernatremic and hypokalemic hypertension with elevated plasma aldosterone concentration and sup-
pressed plasma renin activity. Abdominal computed tomography (CT) scan revealed a mass in the right adrenal gland. Venous sampling and adosterol scintigraphy dem- onstrated the presence of right adrenocor- tical aldosterone-producing tumor.
Histologic Findings
Foci of confluent necrosis were detected in the tumor (Fig. 3A). The cells were arranged in a sheetlike or trabecular pat- tern, separated by relatively thick fibrous bands (Fig. 3B). The great majority of tumor cells were compact cells with scat- tered foci of clear tumor cells. Nuclear aty- pia was significant (Fig. 3C). Five to seven mitotic figures were seen in 50 high-power fields without apparent foci of atypical mitosis. Vascular invasion was present in the area admixed with organizing throm- bus, and sinusoidal invasion was identified (Fig. 3D). Capsular invasion was not appreciated. The adjacent nonneoplastic adrenal gland was not remarkable.
Histologic Diagnosis
All pathologists diagnosed this lesion as aldosterone-producing adrenocortical carcinoma.
Discussion of Case 3
This case met seven of nine of the crite- ria of Weiss and colleagues [3,4]: sinusoi- dal invasion, increased mitotic activity, venous invasion, confluent necrosis, nuclear grade, architecture, and cytoplasm. Therefore, the histologic diagnosis of adrenocortical carcinoma itself was not difficult. However, adrenocortical carci- noma associated with hyperaldosteronism is relatively rare, although deoxycorticos- terone producing adenocarcinoma has been frequently reported.
Case 4: Adrenocortical Lesion in 62-Yr-Old Female with Hypertension for 30 Yr
Clinical Findings
The patient’s blood pressure on admis- sion to Yokohama Rosai Hospital, Yoko- hama, Japan, was 162/74 mmHg; she was taking antihypertensive medications. Basal corticosteroid concentrations were within normal limits. Plasma renin activity and electrolytes were within nor- mal limits. Rapid ACTH and Lasix stimulation tests revealed hyperresponse of aldosterone secretion. CT and mag- netic resonance imaging images demon-
strated slight enlargement of the left adrenal glands. Selective venous sam- pling of adrenal glands revealed that only aldosterone concentration was different between the right and left adrenal veins (right adrenal vein: 8400 pg/mL; left adrenal vein: 250 pg/mL; femoral vein: 44.0 pg/mL). Other steroid concentra- tions were equivalent between the left and right adrenal veins. Laparoscopic right adrenalectomy was performed, with the clinical diagnosis of primary hyper- aldosteronism. (This case was provided by Dr. Tetsuo Nishawa, Department of Medicine, Yokohama Rosai Hospital, for consultation.)
Macroscopic Findings
Three nodular lesions measuring 0.1- 0.3 cm were found in the adrenal gland.
Histologic Findings
There were multiple microcortical nodules composed of clear cells (Fig. 4A). In addition, there were focal hyperplasia of the zona glomerulosa. The zona fasciculata and zona reticularis were unremarkable.
Histologic Diagnosis
The histologic diagnosis of this lesion was unilateral micronodular hyperplasia or unilateral adrenocortical hyperplasia (three pathologists), idiopathic hyperaldoster- onism (two pathologists), and adrenocor- tical nodularity (one pathologist).
Discussion of Case 4
As discussed, differential diagnosis between adrenocortical nodule and adenoma can be very difficult, and the non- neoplastic adrenal glands of aldosteronoma are well known to be associated with the presence of hyperplasia of the zona glomerulosa, termed paradoxical hyperpla- sia [9,10]. However, these micronodular
lesions can hardly be interpreted as adenoma because of the size and multiple presence of the lesions. Differential diag- nosis of this lesion and separation from idiopathic hyperaldosteronism, especially that with nodular hyperplasia, can be very difficult in this case, although the absence of diffuse hyperplasia of the zona glomerulosa has made the possibility of idiopathic hyperaldosteronism rather unlikely. Immunohistochemistry of 3ß-hydroxy- steroid dehydrogenase (3ß-HSD) can be helpful in the differential diagnosis because the zona glomerulosa can be diffusely posi- tive for this enzyme in the case of idiopathic hyperaldosteronism regardless of the pres- ence or absence of the cortical nodules. Immunohistochemistry of 3-HSD dem- onstrated absence of 30-HSD in the hyperplastic zona glomerulosa, which definitively ruled out the diagnosis of idiopathic hyperaldosteronism. Therefore, this adrenal gland can be diagnosed as uni- lateral micronodular adrenocortical hyper- plasia or unilateral adrenal hyperplasia associated with hyperaldosteronism [11]. Little is known about the etiology, patho- physiology, or other biologic aspects of these unique adrenocortical disorders associated with hyperaldosteronism, and
they await further investigation for clarification.
Acknowledgment
This work was presented in part at the Japan Endocrine Society Meeting, Septem- ber 2001.
References
1. Slooten HV, Schaberg A, Smeenk D, Meelenaar AJ. Morphologic characteristics of benign and malignant adrenocortical tumors. Cancer 55:766-773, 1985.
2. Hough AJ, Hollifield JW, Page DL, Hartmann WH. Prognostic factors in adrenal cortex tumors: a mathematical analysis of clinical and morphological data. Am J Clin Pathol 72:390-399, 1979.
3. Weiss LM. Comparable histologic study of 43 metastasizing and nonmetastasizing adreno- cortical tumors. Am J Surg Pathol 8:163-169, 1984.
4. Weiss LM, Medeiros LJ, Vickery AL. Patho- logic features of prognostic significance in adrenocortical carcinoma. Am J Surg Pathol 13:202-206, 1989.
5. Sasano H, Suzuki T, Nagura H. ACTH-inde- pendent macronodular adrenocortical hyper- plasia: immunohistochemical and in situ hybridization studies of steroidogenic enzymes. Mod Pathol 7:215-219, 1994.
6. Aiba M, Hirayama A, Iri H, et al. Adrenocor- ticotropic hormone-independent bilateral adrenocortical macronodular hyperplasia as a distinct subtype of Cushing’s syndrome. Am J Clin Pathol 96:334-340, 1991.
7. Sasano H, Miyazaki S, Sawai T, et al. Primary pigmented nodular adrenocortical disease (PPNAD): immunohistochemical and in situ hybridization analysis of steroidogenic enzymes in eight cases. Mod Pathol 5:23-29, 1992.
8. Lacroix A, Bolte E, Tremblay J, et al. Gastric inhibitory polypeptide-dependent cortisol hypersecretion-a new cause of Cushing’s syn- drome. N Engl J Med 327(14):974-980, 1992 (see comments).
9. Sasano H. Localization of steroidogenic enzymes in adrenal cortex and its disorders. Endocr J 41:471-482, 1994.
10. Sasano H. New approaches in human adrenocortical pathology: assessment of adrenocortical function in surgical specimen of human adrenal glands. Endocr Pathol 3:4- 13, 1992.
11. Pignatelli D, Falcao H, Coimbra-Peixoto A, Cruz F. Unilateral adrenal hyperplasia. South Med J 87(6):664-667, 1994 (see comments).