Non-functioning Adrenocortical Carcinoma Arising in an Adrenal Rest: Immunohistochemical Study of an Adult Patient
Hiroshi Yokoyama,1 Tomotaro Adachi,1 Kazuna Tsubouchi,1 Masatoshi Tanaka1 and Hironobu Sasano2
1Department of Urology, Faculty of Medicine, Fukuoka University, Fukuoka City, Fukuoka, Japan
2Department of Pathology, Tohoku University School of Medicine, Sendai City, Miyagi, Japan
Adrenal rest is uncommon in adults, and usually represents a small lesion incidentally detected during surgery or autopsy. The adrenal rest can be detected anywhere along the path of embryonic migration of adrenal cortex, including celiac axis, genitals and broad ligament, and may be formed with the separation of cortical fragments by the migration of medullary elements from the sympathochromaffin tissue into the preformed cortical primordium. In addition, even primary adrenocortical carcinoma is a rare tumor with incidence 0.5-2 per million annually; therefore, adrenocortical carcinoma arising in adrenal rests is extremely rare. We encountered a patient with non-functioning ectopic adrenocortical carcinoma in retroperitoneum. A 34-year-old female presented with an incidentally discovered retroperitoneal mass revealed by abdominal ultrasound in her regular health examinations. She did not have any clinical abnormalities and underwent hand-assisted laparoscopic resection of the tumor. A dark-brown tumor, measuring 65×56×45 mm, was identified in the retroperitoneal space between lower pole of right kidney and inferior vena cava. Histologically, the tumor was predominantly composed of compact eosinophilic cells forming nest-like arrangements and diffusely positive for the steroidogenic factor-1. The tumor met four of the criteria of Weiss used in histological diagnosis of adrenocortical carcinoma (eosinophillic cytoplasm, nuclear atypia, atypical mitosis, and sinusoidal invasion). The tumor cells were immunohistochemically positive for 17a-hydroxylase, dehydroepiandrosterone sulfotransferase and 36-hydroxysteroid dehydrogenase, each of which is involved in the synthesis of adrenocortical steroids. Therefore, based on these findings, we diagnosed this tumor as ectopic adrenocortical carcinoma arising in adrenal rest of retroperitoneum.
Keywords: adrenal rest; adrenocortical carcinoma; immunohistochemistry; pathology; steroidogenesis Tohoku J. Exp. Med., 2013 April, 229 (4), 267-270. @ 2013 Tohoku University Medical Press
Introduction
Adrenal rests have been postulated to be formed by the separation of cortical fragments displaced by the migration of medullary elements from the sympathochromaffin tissue into the preformed cortical primordium (Goren et al. 1991). The incidence of adrenal rests could be as high as 50% in children, but the lesion generally disappears within a few years of birth (Goren et al. 1991).
Adrenal rests tumor are further uncommon and the great majority of clinically detected adrenal rest tumors are reported to be functioning (Goren et al. 1991). Non- functioning adrenal rest tumors are less frequent and were discovered incidentally (Goren et al. 1991). In addition, adrenocortical carcinoma is a rare tumor with incidence 0.5-2 per million population annually, and also an aggres- sive cancer with a poor prognosis with 32-45% 5-year over-
all survival (Icard et al. 2001). Therefore, adrenocortical carcinoma presumed to be arising in adrenal rest is extremely rare (Goren et al. 1991; Arai et al. 2000; Akishima-Fukasawa et al. 2011).
In this study, we herein report clinical aspects in the patient with non-functioning ectopic adrenocortical carci- noma arising in adrenal rest and its histopahtological find- ings including immunohistochemical evaluation.
Clinical Report
A 34-year-old female was presented to our institution with incidentally discovered retroperitoneal tumor follow- ing abdominal ultrasound in her regular health evaluation. An abdominal ultrasound imaging revealed a 6.5 cm right retroperitoneal mass between right kidney and inferior vena cava. Computed tomography scans of abdomen identified normal bilateral adrenal glands at normal location.
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Laboratory evaluation of the patient’s blood and 24-hours urine samples revealed normal adrenal functions.
A hand assisted laparoscopic resection of right retro- peritoneal tumor was performed. The tumor was not adhered to right kidney and surrounding tissue and com- pletely removed without any further complications. The dark-brown tumor, measuring 65×56×45 mm, weighing 71 g, was well encapsulated and did not show foci of hemor- rhage and necrosis (Fig. 1).
Light microscopically, the tumor was composed pre- dominantly of eosinophilic compact cells with nest-like for- mation (Fig. 2). There were not any areas simulating the non-pathological adrenal glands. The tumor was sur- rounded by a relatively dense fibrous capsule, and myeloli- pomatous changes were also detected in the tumor. These findings were histopathologically consistent with those of adrenocortical neoplasm. Among the criteria of Weiss for adrenocortical malignancy (Weiss 1984), factors on eosin- ophillic cytoplasm, nuclear atypia, atypical mitosis and sinusoidal invasion were met in the tumor, but those on capsular invasion, venous invasion, confluent necrosis, mitosis and architecture were not detected.
Immunohistochemically, almost all of the tumor cells were diffusely and strongly positive for steroidogenic fac- tor-1 (SF-1) suggesting that these cells had the characteris- tic of adrenocortical cells (Fig. 3A). Based on the criteria of Weiss and the results of SF-1 immunohistochemistry, this lesion was diagnosed as adrenocortical carcinoma aris- ing in ectopic adrenal gland located in the retroperitoneum. In addition, positive immunoreactivity for the three types of steroidogenic enzymes was detected in those cells. The rel- ative immunointensity of these steroidogenic enzymes var- ied among tumor cells. Immunoreactivity for 17a- hydroxylase (P450c17) was mostly detected in the tumor cells (Fig. 3B), and immunoreactivity for dehydroepian- drosterone sulfotransferase (DHEA-ST) was partially detected in those (Fig. 3C). However, immunoreactivity for
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3ß-hydroxysteroid dehydrogenase (3B-HSD) was rarely detected in these tumor cells (Fig. 3D). The control sec- tions for negative immunostaining were performed using normal rabbit IgG or 0.01 M PBS instead of primary anti- bodies, and no specific immunoreactivity was detected in these sections (data not shown). Ki67 labeling index as a cellular marker to determine for proliferation was less than 1%.
The postoperative course was unremarkable, and the patient has been clinically free from the disease after ten years of follow-up.
Discussion
Adrenal rest is uncommon in adults, and usually repre- sents a minute lesion incidentally detected during surgery or autopsy (Goren et al. 1991; Arai et al. 2000). The rest may be detected anywhere along the path of embryonic migration including celiac axis, genitals and broad liga- ment, but the adrenal rest tumor is rare even in these areas (Arai et al. 2000).
In our patient, the tumor demonstrated light micro- scopic histopathological features similar to those of primary adrenocortical tumor. Weiss’s criteria are generally used in distinguishing adrenocortical malignancy from benign tumors (Weiss 1984). The Ki67 labeling index represents an immunohistochemical marker for proliferation, and the mutations in the p53 tumor suppressor gene were also reported as another approach to differentiate between benign and malignant adrenocortical neoplasms (Arola et al. 2000). Although Ki67 labeling index in our patient was low with less than 1%, the tumor had four positive points of Weiss’s criteria. Therefore we considered this tumor as adrenocortical carcimona. However it is important to point out that due to the rarity of adrenocortical tumor arising in
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adrenal rest or ectopic adrenal, the validity of applying the criteria of Weiss in these tumors has not been established at this juncture.
SF-1 is a universal regulator of steroidogenic P450 gene transcription and constantly expressed not only in the normal adrenal cortex but also in its hyperplasia or neo- plasm (Arai et al. 2000). However, SF-1 can also be detected in the gonads, pituitary glands and placenta (Arai et al. 2000). P450c17 is involved in the synthesis of gluco- corticoid and sex hormones, and is expressed only in the adrenal cortex and gonads (Arai et al. 2000). Immunoreactivity of DHEA-ST is detected in the adrenal cortex but not in the gonads (Arai et al. 2000). In our patient, SF-1 immunoreactivity was detected markedly in almost all of the tumor cells, and that for DHEA-ST was partially detected. These results all indicated that the tumor had characteristic of adrenocortical neoplasm. In addition, 3B-HSD is involved in the adrenal pathway of corticoste- roid synthesis (Sasano et al. 1990). In our patient, the 3B-HSD immunoreactivity was rarely detected in the tumor cells. Therefore, results of immunohistochemical evalua- tion of these steroidogenic enzymes suggest that the tumor could produce adrenal androgens but not cortisol or aldoste- rone. This is also consistent with the patterns of disorga-
nized steroidogenesis, characteristic of adrenocortical carci- noma (Sasano et al. 1993).
Malignant transformation of adrenal rest is extremely rare, as an especially non-functioning incidentally discov- ered (Goren et al. 1991; Arai et al. 2000). To the best of our knowledge, only several reports of ectopic adrenocortical carcinoma including the renal hilus, spinal region and testis, have been published in the literature (Goren et al. 1991; Bani-Hani 2003; Jain et al. 2008; Rodriguez et al. 2009; Akishima-Fukasawa et al. 2011). However, the detailed histopathological evaluations have been done only in one report (Akishima-Fukasawa et al. 2011) that presented Cushing’s syndrome as usual. On the other hand, our patient had non-functioning tumor arising in the adrenal rest. The diagnosis of adrenocortical carcinoma arising from the adrenal rest is difficult because we do not know whether we could apply the criteria used in the primary adrenocortical neoplasms, and further investigations are required for clarification.
Conflict of Interest
All authors have no conflict of interest.
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