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PATHOLOGY RESEARCH AND PRACTICE
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Adrenocortical adenoma with rhabdoid features
Pavel Dundra,*, Ctibor Povỳšila, Tomáš Zelinkab, Daniel Tvrdíka, Vanda Ciprováa, Květoslav Novákc
a Department of Pathology, 1st Medical Faculty, Charles University, Studničkova 2, Prague 12800, Czech Republic
bDepartment of Internal Medicine, 1st Medical Faculty, Charles University, Unemocnice 2, Prague 12800, Czech Republic
“Department of Urology, 1st Medical Faculty, Charles University, Ke Karlovu 6, Prague 12800, Czech Republic
Received 2 August 2004; accepted 26 January 2005
Abstract
We report a case of an aldosterone producing adrenocortical adenoma with rhabdoid features in a 16-year-old girl. Grossly, the tumor measured 30 mm in diameter and weighed 24 g. Histologically, the tumor was composed of approximately equal parts of tumor cells with rhabdoid features arranged in a solid and trabecular pattern and cells characterized by compact eosinophilic cytoplasm, solid growth with focal necroses, and increased mitotic activity. The lipid-rich tumor cells with ample clear vacuolized cytoplasm represent a minor component. Immunohistochemically, all the tumor cells showed the same results and were positive for vimentin, synaptophysin, Melan A, and a-inhibin. Cytokeratin CAM 5.2 was positive only focally. Chromogranin A, actin, «-actin, S100 protein, EMA, and cytokeratin AE1/AE3 were negative. Rhabdoid features have been described in many tumors of variable histogenesis; however, to the best of our knowledge, the presence of rhabdoid phenotype has never been described in either adrenocortical adenoma or carcinoma.
C 2006 Elsevier GmbH. All rights reserved.
Keywords: Adrenocortical adenoma; Aldosterone; Rhabdoid features
Introduction
Malignant rhabdoid tumors of the kidney (RTK) and atypical teratoid/ rhabdoid tumors (AT/RTs) of the CNS are rare but distinct neoplasms in infants and young children characterized by clinically aggressive behavior [12]. Tumors with similar features occurred at many other sites in patients of all ages. These neoplasms were considered extra-renal rhabdoid tumors (ERTs). However, increased awareness that many neoplasms of a defined nature could contain cells resembling those of RTK resulted in debates about whether or not ERTs represent specific diagnostic entities or rather other entities with
focal or diffuse expression of cells resembling those of RTK [10]. Recently, all of the malignant RTs, whatever their location, have been related to inactivation of the hSNF5/INI1 gene [3]. Molecular analysis of this gene or immunohistochemical analysis of INI1 protein may be useful in identifying both renal and extra-renal RTs, and in distinguishing these neoplasms from a variety of other tumors with rhabdoid features which may represent phenotypic subsets of various known entities [8]. We report a case of aldosterone producing adrenocortical adenoma with rhabdoid features in a 16-year-old girl.
Case report
A 16-year-old girl with hypertension incidentally detected during a preventive examination by her
*Corresponding author.
E-mail address: pdundr@seznam.cz (P. Dundr).
physician was sent to the General Faculty Hospital for further examination. Her pulse rate was 110 beats/min, and blood pressure was 145/95 mmHg despite treatment with calcium-channel blockers. Laboratory examina- tions revealed marked hypokalemia (3.2 mmol/l, normal values 3.8-5.0 mmol/l), elevated levels of plasma aldos- terone (586 ng/1, normal values 40-160 ng/1), and sup- pressed levels of plasma renin activity (0.65 ul/1/h, normal values 0.7-2.6 ul/1/h) after a 2-h standing and nonsuppressible plasma aldosterone values after the suppression test with intravenous saline load (2 l of 0.9% NaCl infused during 4h), consistent with the diagnosis of primary aldosteronism. Remaining forms of adrenal hypertension were excluded (pheochromocy- toma-normal excretion of urinary-free catecholamines and hypercortisolism-cortisol values within normal range, with circadian variability during the posture study). Ultrasound and CT scans showed a right adrenal mass measuring 3cm in diameter, and laparoscopic adrenalectomy was performed. After the operation, her blood pressure, plasma potassium, aldosterone, and renin activity normalized. Neither recurrence nor metastases were detected on CT scans during the next 16 months of follow-up.
Materials and methods
Sections from formalin-fixed, paraffin-embedded tissue blocks were stained with hematoxylin-eosin.
Immunohistochemical staining was performed using the avidin-biotin-complex method with antibodies directed against the following antigens: synaptophysin (1:25, Dako, Glostrup, Denmark), chromogranin A (1:50, Dako), vimentin (1:300, Bio-Genex, San Ramon, CA, USA), Melan A (1:25, Novocastra, Newcastle, UK), a-inhibin (1:25, Dako), actin (1:100, Dako), x- actin (1:100, Dako), S100 protein (1:400, Dako), cytokeratin CAM 5.2 (1:10, Becton-Dickinson, Moun- tain View, CA, USA), and cytokeratin AE1/AE3 (1:50, Dako). Monoclonal antibody MIB-1 (1:50, Dako) was used for assessing proliferative activity. Electron micro- scopy examination was done on formalin-fixed, paraf- fin-embeded tissue, because glutaraldehyde-fixed material was not available.
Results
Grossly, the resected specimen consisted of the right adrenal gland, with no signs of atrophy, with a well- circumscribed tumor that measured 3 cm in diameter and weighed 24 g. The tumor was bordered by a fibrous capsule, and on part of the surface, there was apparently compressed adrenal cortex. A cross section of the tumor was ochre in color and homogenous.
Histologically, the tumor was composed of approxi- mately equal parts of cells with rhabdoid features (Fig. 1a) and cells without such features, mostly represented by cells with a moderate amount of compact
(a)
(b)
(c)
(d)
eosinophilic cytoplasm (Fig. 1c). The lipid-rich cells with ample clear vacuolated cytoplasm represent less than 10% of tumor cells (Fig. 1b). The cells with rhabdoid features were characterized by eccentric vesicular nuclei with prominent nucleoli and a large amount of cytoplasm with occasionally eosinophilic cytoplasmic inclusions. These cells were arranged in a solid and trabecular pattern. Tumor cells without rhabdoid features demonstrated moderate nuclear pleomorphism and had a moderate amount of compact eosinophilic cytoplasm. These cells were arranged in a solid pattern with focal necroses and showed mitotic activity with up to 19 mitoses per 20 high power fields. The transition among tumor areas composed of cells with rhabdoid features, compact eosinophilic cells, and lipid-rich vacuolated clear cells was sharp; only focally were different tumor cells mixed. On the periphery, the tumor was circumscribed and encapsulated, and there was no evidence of capsular or vascular invasion. In the surrounding adrenal gland, the cortex was histologically normal without any signs of hyperplasia of zona glomerulosa or atrophy of zona fasciculata and reticularis.
Immunohistochemically, all tumor cells were positive for vimentin (Fig. 1d), synaptophysin, Melan A, x-inhibin, and were focally positive for cytokeratin CAM 5.2. In the rhabdoid areas, vimentin and Melan A were positive in the cytoplasmic inclusions, whereas staining for synaptophysin and «-inhibin was rather diffuse. Cytokeratin AE1/AE3, EMA, aktin, «-aktin, chromogranin A, and S100 protein were negative. Examination of the proliferative activity with mono- clonal antibody MIB-1 (Ki-67 index) showed nuclear positivity in less than 3% of both rhabdoid cells and cells with compact eosinophilic cytoplasm. The cells with lipid-rich vacuolated clear cytoplasm were negative.
Electron microscopy of the rhabdoid areas showed cells with large eccentric nuclei and prominent nucleoli in the cytoplasm focally with paranuclear bundles of intermediate filaments and accumulation of organels. However, because of prior paraffin-embedding of the tissue, the morphology was poor.
Discussion
Tumors composed partly or totally of rhabdoid cells are usually highly aggessive neoplasms in infants and young children [12]. The most common locations are in the kidney and CNS. Neoplasms with similar features occurred at many other sites in patients of all ages. These tumors have been considered ERTs. Whereas malignant RTK and AT/RT of the CNS are rare but well-recognized distinct entities, the classification of ERTs is still disputable. Histologically, the tumor cells
are characterized by ample eosinophilic cytoplasm with filamentous inclusions and vesicular nuclei with macro- nucleoli [7]. The occurrence of rhabdoid cells in numerous other neoplasms such as malignant melano- mas [4], carcinomas [1], intraabdominal desmoplastic small cell tumors, endometrial sarcomas [5], hepato- blastomas, adamantinoma [11], and a variety of soft tissue lesions has raised the question of whether ERTs represent distinct entities, or rather other entities with focal or diffuse expressions of cells resembling those of RTK [10,15]. Usually, tumors with rhabdoid features represent highly aggressive neoplasms; however, rhab- doid cytology has been observed in benign tumors occurring in soft tissues or salivary glands [6].
Recently, deletions and mutations of the hSHF5/ INI1 locus in chromosome 22q11.2 have been demon- strated in malignant RTK and extra-renal sites. INI1 is a member of the SWI/ SNF chromatin-remodeling complex and is normally expressed in all tissues [3]. The identification of deletions and mutations of a putative tumor suppressor gene INI1 supports the hypothesis that malignant RTs have a common genetic etiology, regardless of the anatomic site. Molecular analysis or immunohistochemical staining for INI1 protein may be useful in identifying both renal and ERTs and in distinguishing these neoplasms from a variety of other tumors with rhabdoid features which may represent phenotypic subsets of various known entities [8].
In RTKs, polyphenotypic immunohistochemical re- sults are commonly observed, which limits the value of immunostains in establishing this diagnosis. Vimentin is almost always expressed in RTKs, and coexpression of cytokeratin and EMA is also frequently observed. In addition, nonspecific positivity was observed in RTKs for many other epitopes when the positive results were limited to cytoplasmic inclusions or were more diffuse in the cytoplasm, possibly reflecting nonspecific entrap- ment or binding of antibodies in the dense filamentous masses [15].
Adrenal cortical neoplasms (ACNs) in the pediatric population are rare. The annual incidence has been calculated as three per million in children under 20 years of age [9]. In contrast to the adult population, tumors in children more often are hormonally functional, with clinical evidence of virilization, Cushing’s syndrome, mixed endocrine syndromes, and rare instances of feminization or Conn’s syndrome. Only 19 children with aldosterone producing adrenocortical tumors have been reported in the English literature; all of them were classified as adenomas [2].
The differential diagnosis between malignant and benign tumors of the adrenal cortex can be difficult. The definite criteria for malignancy are distant metastases and/or local invasion. In 1984, Weiss proposed a system for evaluating adrenocortical malignancy based on nine histopathological criteria [13,14]. According to this
system, the presence of three or more of the following features is significant for malignant clinical behavior: nuclear grade III or IV, mitotic rate > 5/50 high-power fields, atypical mitoses, clear cells constituting <25%, more than 1/3 diffuse architecture, necrosis, sinusoidal, venous, and capsular invasion. In our case, there were five criteria present so that the tumor should belong to the malignant category. However, the established criteria for distinguishing benign from malignant ACNs in the adult population has not been helpful in predicting the biological behavior of such neoplasms in the pediatric patients. In a study of 83 ACNs presented in the first 2 decades of life, the authors found that 51 of 74 (69%) patients with histologically malignant-appearing tumors had a benign clinical course without recurrence or death from disease [16]. They proposed criteria for malignancy in ACNs in pediatric patients and attempted to separate the clinically benign tumors from those that were clinically malignant based on the number of the following criteria: tumor weight >400 g, tumor size >10.5 cm, extension into periadrenal soft tissues and/or adjacent organs, invasion into the vena cava, venous invasion, capsular invasion, necrosis, mitotic rate >15/20 high-power fields, and atypical mitoses. They proposed a three-part separation: up to two criteria produced a benign long- term clinical outcome; three criteria created an uncertain malignant potential; and four or more criteria repre- sented malignant clinical behavior. This system accu- rately classified 78% of all cases that behave in a clinically malignant fashion; 58% of all cases that behave in a clinically benign fashion; and 22% of patients were placed in an indetermined category, of which 4% behaved in a clinically malignant fashion. However, the authors stressed that these criteria must always be applied on an individual patient basis.
In our case, there were two criteria present (tumor necrosis and >15 mitoses per 20 high-power fields), which placed this tumor into the benign category. The tumor behaved in benign fashion, and neither recurrence nor metastases were detected during the next 16 months of follow-up.
In conclusion, we described an aldosterone-producing adrenocortical adenoma with rhabdoid features in a 16- year-old girl. The presence of cells with ample eosino- philic cytoplasm could be suggestive of oncocytic differentiation, but this was excluded by electron microscopy. To the best of our knowledge, our report represents the first case of adrenocortical neoplasm with such features. We have found only one report describing an RT of the adrenal gland in a 3-year-old boy [17]. However, in this case, the tumor seemed to be a convincing example of ERT, and the patient died of disease soon after the initial diagnosis. The differ- entiation between true ERTs and other neoplasms of different histogenesis which can show rhabdoid
morphology is important, because it may have an impact on the prognosis and treatment of these neoplasms. In cases in which the rhabdoid phenotype is expressed only in part of the tumor, the correct diagnosis may be based on typical tumor areas without rhabdoid morphology. Immunohistochemistry and elec- tron microscopy can be useful in attempts to classify tumors with rhabdoid features into an established morphological category, in particular in cases in which the rhabdoid features are diffuse and obscure the underlying lesion. In cases where the diagnosis of RTs is suspected but the histological features and immuno- phenotype are equivocal, molecular analysis of the hSNF5/INI1 gene or immunostainig for the INI1 gene product may assist in revealing the correct diagnosis.
Acknowledgement
This work was supported by Grant IGA MZ ČR NR 8150-4.
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