Case Report
ECTOPIC CORTISOL AND ANDROGEN-PRODUCING
ADRENOCORTICAL CARCINOMA ARISING FROM ADRENAL REST
TISSUE IN A KIDNEY: CASE REPORT AND LITERATURE REVIEW
Grace Y. Kim, MD1; Helen Anaedo, MD1; Sahar Nozad, MD2;
Tipu Nazeer, MD2; Hassan Shawa, MD1
ABSTRACT
Objective: To present a case of an aggressive adre-
nocortical carcinoma producing both ectopic cortisol and
androgens and to provide an extensive literature review of
similar cases.
Methods: A case presentation is provided that illus-
trates clinical, biochemical, radiologic, and pathologic
findings. We also conducted a PubMed search for similar
cases and summarize 15 other cases of malignant adrenal
rest tissue.
Results: A 50-year-old woman presented with symp-
toms of Cushing syndrome and virilization. Urine free
cortisol and serum adrenal androgens were significantly
elevated. Computed tomography of the abdomen revealed
a 12-cm mass within the right kidney. Subsequently, the
patient underwent right radical nephro-adrenalectomy.
The tumor showed a high-grade neoplasm centered in
the kidney with polymorphism, highly atypical nuclei,
abundant mitotic activity, and necrosis. The Ki-67 prolif-
eration index was 25 to 30%. Immunohistochemical stain-
ing of the neoplastic cells favored an adrenal origin. The
native adrenal gland was atrophic and free of the tumor.
Postoperatively, cortisol and adrenal androgen levels
Submitted for publication March 4, 2018
Accepted for publication April 23, 2018
From the 1Division of Endocrinology and Metabolism, and 2Department of
Pathology and Laboratory Medicine, Albany Medical Center, Albany, New
York.
Address correspondence to Dr. Hassan Shawa, Albany Medical Center,
Division of Endocrinology and Metabolism, 25 Hackett Boulevard, MC 141,
Albany, NY 12208.
E-mail: ShawaH@amc.edu.
DOI:10.4158/ACCR-2018-0110
To purchase reprints of this article, please visit: www.aace.com/reprints.
Copyright © 2018 AACE.
Copyright © 2018 AACE AACE CLINICAL CASE REPORTS Vol 4 No. 6 November/December 2018 e447
became undetectable. However, her disease unfortunate-
ly recurred 5 months later with innumerable peritoneal,
mesenteric, omental, and serosal implants within the abdo-
men and pelvis. She was started on mitotane and mifepris-
tone but unfortunately expired within a few days from a
septic shock secondary to Pseudomonas aeruginosa pneu-
monia.
Conclusion: We present an unusual case of a function-
al adrenocortical carcinoma arising in adrenal rest tissue
in a kidney resulting in Cushing syndrome and virilization
with very aggressive biology. To the best of our knowl-
edge, no similar case has been reported thus far. (AACE
Clinical Case Rep. 2018;4:e447-e452)
Abbreviations:
ACC = adrenocortical carcinoma; CT = computed
tomography
INTRODUCTION
Adrenal rest tissue is seen in almost 50% of newborns,
but rarely persists in adults as it usually undergoes atrophy
and disappears within a few years of birth (1). Adrenal rest
tissue can be found anywhere along the path of embryonic
migration from the urogenital ridge. It has been described
within the celiac axis, the broad ligament, the testis, the
spermatic cord, the kidney, and the retroperitoneum (2).
Primary (eutopic) adrenocortical carcinoma (ACC) is
a rare tumor with incidence of 0.5 to 2 per million annu-
ally (3). Tumoral transformation can happen in adrenal
rest tissue, but malignant transformation is extremely rare
(4). We present an unusual case of functional ACC aris-
ing in adrenal rest tissue in a kidney resulting in Cushing
syndrome and virilization with very aggressive biology.
To the best of our knowledge, no similar case has been
reported thus far. In light of this, our aim is to describe
e448 Ectopic Adrenocortical Carcinoma, AACE Clinical Case Rep. 2018;4(No. 6) Copyright © 2018 AACE

the first case observed in our practice and compare it with
other ectopic ACCs reported in the literature as well as the
known data about eutopic ACCs.
CASE REPORT
A 50-year-old woman presented to our institution
with hypertensive emergency associated with mild confu-
sion. Her medical history was remarkable for systolic heart
failure (ejection fraction of 25%) diagnosed 2 years prior
and was attributed to nonischemic cardiomyopathy. The
patient reported that she had excessive facial hair growth
since her mid-20s, which had progressively worsened over
the last 3 years. She also reported rapidly worsening proxi-
mal muscle weakness to a point where she became wheel-
chair bound in the last few weeks. There was no weight
gain. Her systolic blood pressures upon admission ranged
from 177 to 194 mm Hg with diastolic pressures of 112
to 122 mm Hg. Physical examination showed an obese
woman weighing 220 pounds with moon faces, plethora,
substantial supraclavicular and dorsocervical fat accumu-
lations, excessively dark and coarse hair on the face and
chest, significant proximal muscle weakness of both upper
and lower extremities, extensive ecchymoses, and central
obesity. Her biochemical profile was consistent with adre-
nocorticotropic hormone-independent Cushing syndrome
with severe hyperandrogenism (Table 1). Computed
tomography (CT) scan of the abdomen and pelvis revealed
a 12 × 10 × 12-cm exophytic mass in the right upper pole
kidney (Fig. 1). CT scan of the chest and head were other-
wise unremarkable. Subsequently, the patient underwent
open right nephro-adrenalectomy.
Grossly, the mass was irregular measuring 12.8 × 11.4
× 10.0 cm centered in the kidney. The tumor invaded the
perirenal fat but not beyond the Gerota fascia. The margins
were not involved although the tumor was extremely close

Table 1
Patient’s Biochemical Profile over Time
Immediately 5 months
Biomarker (normal range) At presentation after surgery after surgery
Serum cortisol (4.3-22.4 µg/dL) 47.9 2.4 143
24-hour urine cortisol (0-50 µg/24 hours) 441 <3 -
DHEA-S (26-200 µg/dL) 645 <15 133
Androstenedione (<10-93 ng/dL) 453 27 -
Testosterone (10-75 ng/dL) 94 <10 103
17-hydroxyprogesterone (0.2-1.7 ng/mL) 10 0.5 -
ACTH (0-46 pg/mL) <10 - <10
Abbreviations: DHEA-S = dehydroepiandrosterone sulfate; ACTH = adrenocorticotropic
hormone.

Fig. 1. Coronal section of the abdomen by computed tomography angiography revealed a large mass (arrow)
arising from the right upper pole of the kidney. The right adrenal gland is atrophic (circled).
Copyright © 2018 AACE Ectopic Adrenocortical Carcinoma, AACE Clinical Case Rep. 2018;4(No. 6) e449

to the margin. The native adrenal gland appeared to be
atrophic and uninvolved by the tumor (Fig. 2 B). The TNM
stage was pT3aNxMx.
Histologically, the tumor had a prominent diffuse solid
growth pattern with extensive necrosis. It was composed of
highly atypical, pleomorphic cells with abundant eosino-
philic and clear cytoplasm, enlarged nuclei, and prominent
nucleoli. The mitotic index reached 8 per 10 high-power
fields (Fig. 2 A) and Ki-67 demonstrated a proliferation
index of approximately 25 to 30%. The modified Weiss
system score of the tissue was 5: 2 × 1 for mitotic activi-
ties, 2 × 1 for clear cells less than 25%, and 1 for necrosis.
Immunohistochemical analysis of the tumor cells demon-
strated positive immunostaining for calretinin, inhibin,
melanoma antigen recognized by T cells-1, synaptophysin,
and vimentin (Fig. 3 A through E). The neoplastic cells
were negative for cytokeratin AE1/AE3, CK7, CD10, S100
protein, SOX-10, actin, and desmin.
Postoperatively, the patient became adrenally insuffi-
cient and adrenal androgen normalized or became unde-
tectable (Table 1). She was started on hydrocortisone
replacement and was able to lose more than 50 pounds
in 2 months. CT scan of the chest, abdomen, and pelvis 2
months after the surgery was negative for local recurrence
or metastatic disease. Shortly after, the patient started to
gain weight. Biochemical workup revealed rising corti-

A B

Fig. 2. Histology slides revealed a (A) large, high-grade neoplasm centered in the kidney with polymorphism, highly atypical nuclei, abundant mitotic
activity, and necrosis. (B) The native adrenal gland is tumor free.

A B C

D E

Fig. 3. Immunohistochemistry staining images taken at 10× for (A) calretinin, (B) inhibin, (C) melanoma antigen recognized by T cells-1, (D) synaptophy-
sin, and (E) vimentin.
e450 Ectopic Adrenocortical Carcinoma, AACE Clinical Case Rep. 2018;4(No. 6) Copyright © 2018 AACE

sol and androgens again (Table 1). Repeat CT scan of the
abdomen and pelvis 5 months after the surgery unfortu-
nately showed innumerable peritoneal, mesenteric, omen-
tal, and serosal implants within the abdomen and pelvis
with an atrophic left adrenal gland. None of the metastatic
lesions were biopsied because it was felt to be redundant
in the setting of a recent history of ACC and elevated
cortisol and adrenal androgens with an atrophic contra-
lateral adrenal gland. She was started on mitotane and
mifepristone in the hospital; however, the patient expired
within a few days due to a septic shock after Pseudomonas
aeruginosa pneumonia.

Table 2
Summary of All Reported Malignant Adrenal Rest Tumors Including Our Index Case
Reference, Age, Functional Mitotic
country sex Tumor site Tumor size status rate Therapy Follow-up data
Laparotomic left Tumor free
1, Israel 50, F Left kidney hilum 8 × 4 × 5 cm None N/A
radical nephrectomy 1 year later
Intradural,
5 in 10 HPF, Recurrence in
8, USA 0.5, F extramedullary at 6 × 1.5 cm None Total resection
Ki-67 23% 6 months
the lumbar spine
Resection then Metastasis and
9, USA 3.5, M Left testis 9 × 6 × 6 cm Cortisol N/A
radiotherapy death in 1 year
Patient became
comatose and died on
Laparotomic
PO day 6. On autopsy,
resection of
10, Japan 57, M Left scrotum 5 × 5 × 4 cm Cortisol N/A he was found to have
abdominal
primary tumor in
metastases
scrotum with a lung
metastasis.
Left radical Metastasis and
11, USA 65, M Testes 8.5 × 6.5 × 6.5 cm Cortisol N/A
inguinal orchiectomy death 5 months PO
Cortisol and No surgery, findings Died 7th day post
17, USA 23, F Right lobe of liver 18 × 15 × 15 cm High
androgens based on autopsy arteriography
Thoracophreno-
Cortisol and Disease free
12, Chile 21, F Right lobe of liver 12 cm N/A laparotomy then
androgens 9 months PO
chemotherapy
Laparotomic Cushing syndrome
13, USA 59, M Retroperitoneum 6.5 × 7.5 cm Cortisol Infrequent
resection resolved
Laparotomic
Cortisol and Tumor free
14, Germany 26, F Retroperitoneum 15 cm Extensive resection followed
androgens 15 months PO
by irradiation
Laparotomic Tumor free
4, Jordan 52, M Retroperitoneum 19 × 15 × 9 cm None 3 in 50 HPF
resection 25 months PO
Metastatic disease in
lungs, bone, ovaries,
Cortisol and
16, Japan 31, F Retroperitoneum 25 × 16 × 12 cm Ki-67 10% Chemotherapy liver, left adrenal,
androgens
and pericardium.
Died 16 months PO.
Laparoscopic Tumor free
15, Japan 34, F Retroperitoneum 6.5 × 6.6 × 4.5 cm None Ki-67 <1%
resection 10 years PO
Laparotomic
resection followed Tumor free
19, USA 68, M Retroperitoneum 4.1 ×  4.0 × 3.8 cm None Ki-67 30%
by radiation therapy 2 years PO
and mitotane
Liver segmentectomy
18, Republic 1-2 in 50 Tumor free
75, M Liver 6.0 × 4.5 cm None with
of Korea HPF 2 years PO
cholecystectomy
Cortisol and Died day 2 PO due to
5, Algeria 34, F Right ovary 14.5 × 13.7 cm N/A Ovarian resection
androgens pulmonary embolism
Died 5 months
8 in 10 HPF,
Present case, Cortisol and Laparatomic right PO because of
50, F Right kidney 12.8 × 11.4 × 10.0 cm Ki-67
USA androgens radical resection diffuse metastasis
25-30%
and septic shock
Abbreviations: HPF = high-power field; NA = not available; PO = post operation.
Copyright © 2018 AACE Ectopic Adrenocortical Carcinoma, AACE Clinical Case Rep. 2018;4(No. 6) e451
DISCUSSION
We herein present a case of cortisol- and androgen-
producing ACC arising from the adrenal rest tissue in a
kidney with very aggressive biology. To our knowledge,
no similar case has been reported in the literature. Tumors
arising from adrenal remnants are usually scarce. They
are often benign and non-functioning (5). Primary ACC is
also rare with an incidence of 0.5 to 2 per million annu-
ally (3). Malignant transformation in adrenal rest tissue
is extremely rare and those secreting cortisol or andro-
gens are even rarer (5). The incidence and follow-up are
totally unknown.
The criteria proposed by Weiss et al (6) is currently
the most widely employed to distinguish between benign
and malignant primary adrenocortical tumors. It could
be speculated that the same criteria could be applied on
adrenal rest tumors. Our patient’s tumor size was very
large with extrarenal invasion. Histologically, it showed
polymorphism, highly atypical nuclei, abundant mitotic
activity, and necrosis. All of the above is consistent with
the malignant nature of this tumor. Immunohistochemical
studies confirmed the tumor cells’ steroidogenic capabil-
ity as they were immunopositive for calretinin, inhibin,
vimentin, melanoma antigen recognized by T cells-1, and
synaptophysin (5,7). Immunohistochemical studies were
also useful to differentiate the tumor from renal cell carci-
noma as the tumor was immunonegative for cytokeratin
and CD 10, markers that are found in renal cell carcino-
ma (7). In addition, the native adrenal gland was atrophic
and free of the tumor which strongly supports that the
malignant tumor cells arose from the adrenal rest tissue in
the kidney.
Searching PubMed and Google Scholar, we found only
15 ectopic ACC cases (1,4,5,8-19). The demographic, clini-
cal, pathologic, and follow-up data of these cases as well as
our index case are summarized in Table 2. Intrarenal local-
ization seems to be exceptional. Goren et al (1) reported an
adrenal rest carcinoma in the hilum of a kidney. However,
the diagnosis of malignancy was based only on the tumor’s
size and weight. The tumor had a uniformly innocuous
histological appearance without mitotic activity. In addi-
tion, the tumor was nonfunctional. On the other hand, our
case was clearly consistent with malignancy based on the
histologic features as well as the mitotic rate and biologi-
cal behavior. Furthermore, it was functional which makes
our case the first to be reported with this combination.
Similarly, the diagnosis of malignancy was made only by
tumor size and weight in 2 other cases (4,12). Jain et al (11)
stated that the possibility of a malignant Leydig cell tumor
with ectopic cortisol production could not be fully ruled
out. Immunohistochemical studies are indeed necessary to
distinguish the adrenocortical origin of these tumors.
Nine of the reported cases were functional (cortisol
or androgen producing). Six of them developed diffusely
metastatic disease and ended with death within a few days
to months. Our case followed the same course. Cortisol
hypersecretion has been recognized as a poor prognostic
factor in eutopic ACC due to infections and coagulopa-
thy (20). We speculate that will hold true in ectopic ACC
as well.
The treatment of ectopic ACC does not seem to differ
from that of eutopic tumors (5). Surgery is the cornerstone.
Adjuvant mitotane use (alone, without chemotherapy) is
recommended for patients with eutopic ACC at the high-
est risk of recurrence who have histologically high-grade
disease (e.g., Ki-67 staining of >10 % of tumor cells or >20
mitotic figures per 50 in a high-power field regardless of
tumor size), intraoperative tumor spillage or fracture, and
some large tumors that are low grade but have vascular or
capsular invasion (21,22).
In our patient, adjuvant mitotane was not initiated
after the surgery due to the sparse data available in the
literature on the biology of ectopic ACC. At the time, given
the margin-free resection of the tumor with complete post-
surgical biochemical remission, it was felt that course was
a reasonable approach. However, reviewing the outcome
of our patient, we would recommend the same approach
for ectopic ACC. It is possible that our patient’s recur-
rence-free and overall survival could have been improved
if mitotane was used postoperatively given the tumor size
and the high mitotic rate.
CONCLUSION
We present an unusual case of functional ACC aris-
ing from adrenal rest tissue in a kidney resulting in
Cushing syndrome and virilization with very aggres-
sive biology. Immunohistochemical studies are neces-
sary to diagnose adrenal rest tumors and to confirm their
steroidogenic capability.
DISCLOSURE
The authors have no multiplicity of interest to disclose.
REFERENCES
1. Goren E, Engelberg IS, Eidelman A. Adrenal rest carcinoma in
hilum of kidney. Urology. 1991;38:187-190.
2. Ayala AR, Basaria S, Udelsman R, Westra WH, Wand GS.
Corticotropin-independent Cushing’s syndrome caused by an
ectopic adrenal adenoma. J Clin Endocrinol Metab. 2000;85:
2903-2906.
3. Allolio B, Fassnacht M. Clinical review: adrenocortical carcino-
ma: clinical update. J Clin Endocrinol Metab. 2006;91:2027-2037.
4. Bani-Hani KE. Primary non-functional extra-adrenal adrenocorti-
cal carcinoma. Saudi Med J. 2003;24:301-304.
5. Chentli F, Terki N, Azzoug S. Ectopic adrenocortical carcinoma
located in the ovary. Eur J Endocrinol. 2016;175:K17-K23.
6. Weiss LM, Medeiros LJ, Vickery AL Jr. Pathologic features of
prognostic significance in adrenocortical carcinoma. Am J Surg
Pathol. 1989;13:202-206.
e452 Ectopic Adrenocortical Carcinoma, AACE Clinical Case Rep. 2018;4(No. 6)
7. Mondal SK, Dasgupta S, Mandal PK, Sinha MG. Cytodiagnosis
of myxoid adrenocortical carcinoma and role of immunocyto-
chemistry to differentiate it from renal cell carcinoma. J Cytol.
2014;31:111-113.
8. Rodriguez FJ, Scheithauer BW, Erickson LA, Jenkins RB,
Giannini C. Ectopic low-grade adrenocortical carcinoma in the
spinal region: immunohistochemical and molecular cytogenetic
study of a pediatric case. Am J Surg Pathol. 2009;33:142-148.
9. Engel FL, McPherson HT, Fetter BF, et al. Clinical, morpho-
logical and biochemical studies on a malignant testicular tumor. J
Clin Endocrinol Metab. 1964;24:528-542.
10. Morimoto Y, Hiwada K, Nanahoshi M, et al. Cushing’s syndrome
caused by malignant tumor in the scrotum: clinical, pathologic and
biochemical studies. J Clin Endocrinol Metab. 1971;32:201-210.
11. Jain SH, Sadow PM, Nosé V, Dluhy RG. A patient with ectopic
cortisol production derived from malignant testicular masses. Nat
Clin Pract Endocrinol Metab. 2008;4:695-700.
12. Contreras P, Altieri E, Liberman C, et al. Adrenal rest tumor
of the liver causing Cushing’s syndrome: treatment with keto-
conazole preceding an apparent surgical cure. J Clin Endocrinol
Metab. 1985;60:21-28.
13. Ney RL, Hammond W, Wright L, Davis WW, Acker J, Bartter
FC. Studies in a patient with an ectopic adrenocortical tumor. J
Clin Endocrinol Metab. 1966;26:299-304.
14. Raith L, Karl HJ. Pregnancy in ectopic adrenal carcinoma. Horm
Metab Res. 1969;1:149-150.
15. Yokoyama H, Adachi T, Tsubouchi K, Tanaka M, Sasano H.
Non-functioning adrenocortical carcinoma arising in an adrenal
Copyright © 2018 AACE
rest: immunohistochemical study of an adult patient. Tohoku J Exp
Med. 2013;229:267-270.
16. Akishima-Fukasawa Y, Yoshihara A, Ishikawa Y, et al.
Malignant adrenal rest tumor of the retroperitoneum producing
adrenocortical steroids. Endocr Pathol. 2011;22:112-117.
17. Wallace EZ, Leonidas JR, Stanek AE, Avramides A. Endocrine
studies in a patient with functioning adrenal rest tumor of the liver.
Am J Med. 1981;70:1122-1125.
18. Park WY, Seo HI, Choi KU, et al. Three cases of adrenocortical
tumors mistaken for hepatocellular carcinomas/diagnostic pitfalls
and differential diagnosis. Ann Diagn Pathol. 2017;31:9-13.
19. Wright JP, Montgomery KW, Tierney J, Gilbert J, Solórzano
CC, Idrees K. Ectopic, retroperitoneal adrenocortical carcinoma
in the setting of Lynch syndrome. Fam Cancer. 2018;17:381-385.
20. Abiven G, Coste J, Groussin L, et al. Clinical and biological
features in the prognosis of adrenocortical cancer: poor outcome
of cortisol-secreting tumors in a series of 202 consecutive patients.
J Clin Endocrinol Metab. 2006;91:2650-2655.
21. Miller BS, Gauger PG, Hammer GD, Giordano TJ, Doherty
GM. Proposal for modification of the ENSAT staging system for
adrenocortical carcinoma using tumor grade. Langenbecks Arch
Surg. 2010;395:955-961.
22. Giordano TJ. The argument for mitotic rate-based grading for the
prognostication of adrenocortical carcinoma. Am J Surg Pathol.
2011;35:471-473.