Case Report

Pigmented Adrenocortical Carcinoma: Case Report and Review

Jordan L. Geller, MD,1 Paul C. Azer, MD,1 Lawrence M. Weiss, MD,2 and Richard B. Mertens, MD, PHD3

Abstract

Darkly pigmented adrenocortical neoplasms are rare tumors that are often referred to as “black adenomas,” indicative of both their pigmented nature and their invariably benign clinical behavior in previously reported cases. We herein describe an exceptional case of a malignant pigmented adrenocortical neoplasm, with late recurrence and metastasis. At age 53, this female patient was diagnosed with Cushing’s syndrome and underwent a laparoscopic right adrenalectomy, revealing a 3 cm well-circumscribed, darkly pigmented adrenocortical tumor. The tumor exhibited several atypical histologic features and was diagnosed as an atypical pigmented adrenal cortical neoplasm of uncertain malignant potential. Eight years later, the patient developed clinical and biochemical evidence of recurrent Cushing’s syndrome, and imaging studies revealed the presence of several masses in the right retroperitoneum. At subsequent exploratory laparotomy, three separate tumor nodules exhibiting varying degrees of pigmentation and ranging from 2.2 to 3.3 cm maxi- mum dimension were excised. Histologically, the tumor nodules were consistent with local recurrence/metastasis of the patient’s previously excised pigmented adrenocortical neoplasm.

Key Words: Adrenal; pigmented adrenocortical carcinoma; black adenoma; differential diagnosis; late recurrence.

1Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA 90048; 2Division of Pathology, City of Hope National Medical Center, Duarte, CA 91010; and 3Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048.

Address correspondence to Dr. Richard B. Mertens, Cedars-Sinai Medical Center, Department of Pathology and Laboratory Medicine, Room 8746, 8700 Beverly Boulevard, Los Angeles, CA 90048. E-mail: mertensr@cshs.org

Introduction

The vast majority of adrenal cortical neoplasms (both benign and malignant) lack significant pigmentation, aside from their typical yellow to orange coloration related to intracellular lipid content. A few adrenal cortical neoplasms are darkly pig- mented and are sometimes referred to as “black adenomas” [1]. As this name implies, darkly pigmented adrenal cortical neoplasms are generally regarded as benign neoplasms. We report a unique case of an atypical pigmented adrenal cortical neo- plasm associated with Cushing’s syndrome, occurring in a patient who ultimately developed locally recurrent/metastatic

tumor 8 yr following initial adrenalectomy. To our knowledge, this is the first reported case of a pigmented adrenocortical carci- noma in the English language literature.

Case Description

A 61-yr -old Caucasian female presented with 6 mo of weight gain, weakness, and abdominal pain. She also noted bruising and acne. Eight years prior, she was diag- nosed with Cushing’s syndrome; imaging studies at that time revealed a right adre- nal mass, for which she underwent a laparoscopic right adrenalectomy. A diag- nosis of an atypical pigmented adrenal

cortical neoplasm of uncertain malignant potential was made. She remained well during the intervening years until 6 mo before this presentation.

On current evaluation, the patient was hypertensive (BP 154/96 mmHg) and cushingoid (wt 67 kg, ht 155 cm). Signifi- cant laboratory values included a morning cortisol of 34.2 ug/dL (normal 4.3- 22.4 µg/dL) and a 24 h urinary free corti- sol of 385.8 µg (normal 4.0-50 µg/24 h). Plasma ACTH was undetectable. DHEA and serum electrolytes were normal. Abdominal CT scan revealed three mass densities in the right retroperitoneum, ranging in size from 1.8 to 3.3 cm, which were suspicious for recurrence of the adre- nal tumor. The left adrenal gland was nor- mal on CT scan. Subsequently, the patient underwent exploratory laparotomy with resection of three masses, which were located in the right retroperitoneum, right adrenal fossa, and porta hepatis region and which were diagnosed as metastatic and locally recurrent adrenocortical carci- noma, with varying degrees of associated pigmentation.

Postoperatively, the patient did well, and her AM cortisol was 6.0 µg/dL. Because of the indolent and localized nature of the recurrence as well as the utility of cortisol as a marker for tumor recurrence, the decision was made to not treat her with adjunctive medications. Fifteen months following surgery, her morning serum cortisol values have remained within the reference range.

Pathologic Findings

Examination of the initial laparoscopic adrenalectomy specimen revealed a grossly intact adrenal gland measuring 6.0 cm in length and 3.0 cm in maximum width, with variable (scanty to moderate) amounts

of adherent fat. The overall dimensions of the specimen were 8.5 x 5.4x 2.7 cm, with a total weight of 25 g. In the midportion of the gland, a 3.0 x 2.5 x 2.0 cm firm, well-circumscribed, medium brown to dark brown pigmented mass was identi- fied bulging beneath one surface of the gland, with a thin overlying translucent capsule and with scanty yellow cortical tis- sue splayed over its surface; the remainder of the adrenal cortex appeared atrophic (Fig. 1). Microscopically, the cortical tumor exhibited several atypical histologic fea- tures, including high nuclear grade, pre- dominance of eosinophilic cytoplasm, and diffuse architecture; variable amounts of golden brown cytoplasmic pigment were also present within the neoplastic cells (Fig. 2). Although a few scattered mitoses were noted, the mitotic rate was less than 5 per 50 high power fields, and no atypi- cal mitoses were identified. No necrosis was present, and no sinusoidal, venous, or cap- sular invasion was detected. Small aggre- gates of fat cells and/or lymphocytes were focally noted within the neoplasm. The non-neoplastic adrenal cortex exhibited a

Fig. 2. (opposite page) Microscopic appearance of the adrenal cortical neoplasm, demonstrating dif- fuse architecture, predominance of eosinophilic cytoplasm, and nuclear pleomorphism, with vary- ing amounts of cytoplasmic pigment. (Inset: Higher magnification.) Fig. 5. (opposite page) Microscopic appearance of the metastatic tumor nodule from the right retroperitoneum, demonstrating diffuse architec- ture, predominance of eosinophilic cytoplasm, and nuclear pleomorphism. Some of the associated pig- ment is present within the cytoplasm of tumor cells, and some is present within the cytoplasm of inter- mingled macrophages. (Inset: Higher magnification.) Fig. 6. (opposite page) A subpopulation of cells with clear cytoplasm was present in the tumor nod- ules from the right adrenal fossa and porta hepatis regions. Fig. 7. (opposite page) A residual rim of lymph node tissue was focally identified at the periphery of the right retroperitoneal tumor nodule.

Fig. 1. Cross section of right adrenalectomy specimen, demonstrating a grossly intact, well-circumscribed, darkly pigmented cortical neoplasm. The adjacent non-neoplastic adrenal cortex is atrophic. The majority of the adherent periadrenal fat has been removed prior to photography.

Fig. 3. Metastatic tumor nodule from the right retroperitoneum, exhibiting diffuse medium grey pigmentation.

Fig. 4. Locally recurrent tumor from the right adrenal fossa, exhib- iting a variegated yellow-orange to focally tan cut surface. Fig. 2. Fig. 5. Fig. 6. Fig. 7.

moderate degree of atrophy, with reduc- tion in the thickness of the zona fasciculata and zona reticularis but relative preserva- tion of the zona glomerulosa.

The three separate tumor masses resected 8 yr later were each grossly well circum- scribed and included a 3.3 cm tumor nod- ule from the right retroperitoneum, a 2.2 cm tumor nodule from the right adre- nal fossa, and a 2.2 cm tumor nodule from the region of the porta hepatis. The tumor nodule from the right retroperitoneum appeared to be thinly encapsulated and exhibited a medium gray cut surface (Fig. 3), whereas the tumor nodules from the right adrenal fossa and porta hepatis exhibited a variegated yellow-orange to focally tan cut surface (Fig. 4). Histologi- cally, each of the three tumor nodules exhibited histologic features similar to those observed in the primary adrenal tumor, including a mostly diffuse architec- tural pattern, a predominance of eosino- philic cytoplasm, and varying degrees (focally prominent) of nuclear atypia (Fig. 5). The metastatic tumor in the right retroperitoneum was composed nearly entirely of cells with eosinophilic cyto- plasm, whereas a subpopulation (10-30%) of the cells in the tumor nodules from the right adrenal fossa and porta hepatis exhibited clear cytoplasm (Fig. 6). Vary- ing amounts of pigment (present either within tumor cells or within intermingled macrophages) were identified in the three tumor nodules, being most abundant in the tumor from the right retroperitoneum and relatively scant in the tumor from the right adrenal fossa. As in the original pri- mary adrenal tumor, the mitotic rate in each of the three tumor nodules was less than 5 per 50 high power fields, no atypi- cal mitoses were noted, and no large areas of necrosis were present. Small foci of intercellular mucinous degeneration were seen in the tumor nodules from the right

adrenal fossa and porta hepatis. A focal rim of residual lymph node was identified microscopically at the periphery of the right retroperitoneal tumor nodule (Fig. 7), con- sistent with the interpretation that this tumor nodule represented a regional lymph node meta stasis. No lymph node tissue was identified in association with the local recurrence in the right adrenal fossa or the metastasis in the region of the porta hepatis, both of which microscopically were non- encapsulated and demonstrated invasion of adipose tissue at their periphery. In com- parison with the original right adrenal tumor, the locally recurrent/metastatic tumor nodules overall exhibited a lesser degree of nuclear atypia than was observed in the original tumor.

Discussion

Adrenocortical carcinoma is a relatively rare malignancy, with an estimated inci- dence of 0.5 to 2 new cases per million people per year in the United States [2]. Although it is well recognized that adrenal cortical nodules may be darkly pigmented, to our knowledge, pigmented adreno- cortical carcinomas have not been previ- ously described in the English language literature.

The differential diagnosis of primary pigmented tumors of the adrenal gland includes both benign and malignant lesions, the majority of which are benign and arise in the adrenal cortex. Small, incidental pigmented nodules of the adre- nal cortex are not uncommon. In one autopsy study [3], pigmented nodules (ranging from 1 mm to 1.5 cm) were iden- tified in 37 of 100 consecutive autopsies in which both adrenal glands were sec- tioned at 3 mm intervals; in a separate study reported in the same publication [3], pigmented nodules were identified in

104 of 1000 consecutive autopsies in which only random sections of the adre- nal glands were examined. No association of the presence of pigmented adrenal nod- ules with endocrine disturbances, electro- lyte imbalance, or hypertension was established in this study, and the authors concluded that pigmented adrenal corti- cal nodules are generally non-functioning. It is uncertain whether such incidental, small pigmented adrenal nodules represent hyperplastic lesions, neoplasms, or local- ized “condensations” of pigmented cells.

If these relatively frequent incidental, small pigmented cortical nodules are excluded from consideration, diffusely pig- mented (“black”) adrenal cortical neo- plasms are relatively rare [1,4]. Most of the cases reported in the literature have been the subject of individual case reports, and (as described in this case) most have been associated with Cushing’s syndrome [1,4], although rare cases associated with hyper- aldosteronism have been reported [5,6]. The term “black adenoma” has frequently been applied to such neoplasms, reflecting both their dark pigmentation and invari- ably benign behavior in previously pub- lished reports. Such tumors are most frequently diagnosed in the third to fifth decades of life, with a female sex predilec- tion [1]. “Black adenomas” are generally small, usually weighing less than 35 g and measuring 2-3 cm in diameter [1]. The brown or golden brown intracytoplasmic pigment associated with pigmented adre- nal cortical adenomas generally exhibits characteristics consistent with lipofuscin pigment [1], although the presence of neuromelanin pigment has also been reported in a study of incidental pigmented adrenal cortical nodules [7].

Primary pigmented nodular adrenocor- tical disease (PPNAD), a rare condition characterized by the presence of multiple pigmented nodules in the adrenal cortex,

is also often associated with Cushing’s syn- drome and is sometimes a manifestation of Carney’s complex [4,8]. Investigations in recent years have demonstrated the presence of inactivating mutations in PRKAR1A, the gene coding for the regula- tory-subunit type-la (Rla) of cAMP-de- pendent protein kinase A (PKA), in more than half of patients with Carney’s com- plex and/or PPNAD. The resulting dysregulation of the activity of PKA (a key enzyme in the intracellular cAMP signal- ing pathway) is thought to underlie tum- origenesis in these patient with Carney’s complex and/or PPNAD [9].

In addition to pigmented nodules (either hyperplastic or neoplastic) arising from the adrenal cortex, the differential diagnosis of grossly pigmented primary tumors of the adrenal gland also includes rare cases of pigmented pheochromocytoma [10] and primary malignant melanoma of the adre- nal gland [11]. Malignant melanoma may also metastasize to the adrenal gland and must also be considered in the differential diagnosis of pigmented tumors occurring in the adrenal gland. In most cases, the gross and histologic findings in conjunc- tion with the clinical history and pertinent biochemical studies will differentiate between a pigmented adrenal cortical neo- plasm, a pigmented pheochromocytoma, and a malignant melanoma (either primary or metastatic) involving the adrenal gland. In the patient who is the subject of this case report, the presence of clinical and bio- chemical evidence of Cushing’s syndrome, in conjunction with the histologic findings in the primary and recurrent tumor and the clinical/biochemical response to tumor resection, clearly establish the adrenal cor- tical origin of the pigmented tumor which arose in the right adrenal gland. In cases in which the histogenesis of a pigmented adrenal tumor is not clear from the clini- cal presentation, biochemical parameters,

and findings on routine histologic sections, a panel of immunostains (such as chromo- granin, synaptophysin, melan-A, $100 p ro - t e in, H MB - 45, an d inhibin) w i ll b e h e lp f u l in d i s t in gu i s hin g a p i g m e n t e d a d re na l cor - t i c a l n eo pl a s m f ro ma p i g m e n t e d p h eo - c h ro m ocy t o ma or m e l an o ma, w i t ha d re na l cor t i c a l n eo pl a s m s g e n er a ll ye x p ress in g m e l an - A, sy na pt o p h ys in, an d inhibin, b u t n o t c h ro m o g r anin, S 100 p ro t e in, orH MB - 45 [12] . P h eoc h ro m ocy t o ma s, in co n t r a s t, a re t y p i c a ll y imm u n ore a c t i v e f or b o t h sy na pt o p h ys inan d c h ro m o g r aninan d n e g a t i v e f or inhibin; s u s t e n t a c u l a rce ll so f p h eoc h ro m ocy t o ma s a re imm u n ore a c t i v e f or$ 100 protein, and HMB-45 is occa- sionally positive in pheochromocytomas [12]. Malignant melanomas are typically immunoreactive for $100 protein and are usually positive for melan-A and HMB-45 but are negative for synaptophysin, chromogranin, and inhibin.

Despite the generally accepted benign nature of pigmented adrenal cortical nod- ules, cytologic atypia or cytomegaly has frequently been described in such nodules [3,8,13]. As an isolated histologic finding, however, such nuclear atypia or cytomegaly is not diagnostic of malignancy in adrenal cortical neoplasms (either pigmented or nonpigmented).

The histologic distinction between benign adrenal adenomas and adrenocor- tical carcinomas is often difficult; no single histologic criterion reliably discriminates between benign and malignant tumors. To aid in their distinction, several scoring systems (some using purely histologic cri- teria and others using a combination of clinical and histologic criteria) have been devised [14-18], with the most commonly cited and utilized criteria being those of Weiss et al. [17,18]. According to the Weiss system, an adrenal cortical neoplasm is evaluated for the presence or absence of nine histologic criteria, namely, high

nuclear grade, mitotic figures greater than 5 per 50 high power fields, atypical mitotic figures, a predominance (greater than 75%) of tumor cells with eosinophilic cytoplasm, diffuse architecture (present in at least one third of the tumor), necrosis, venous inva- sion, sinusoidal invasion, or capsular inva- sion. Those tumors satisfying three or more of the criteria are considered to be malig- nant (i.e., cortical carcinomas), whereas those exhibiting two or fewer of the criteria are considered to be benign (i.e., adenomas) [18].

The pigmented cortical tumor which is the subject of this case report satisfied three of Weiss’ criteria (high nuclear grade, predominance of eosinophilic cytoplasm, and diffuse pattern) and by the Weiss sys- tem would be classified as an adrenocorti- cal carcinoma. However, there are no published studies regarding the validity of the Weiss system when applied to the evalu- ation of pigmented adrenal cortical neo- plasms. Because pigmented cortical neoplasms generally possess predominantly eosinophilic cytoplasm (accompanied by cytoplasmic pigment) and because focal nuclear atypia is not uncommonly observed in pigmented cortical tumors, such tumors by their very nature may often satisfy at least two of the criteria of Weiss et al. for malignancy. Given the nearly universally benign behavior of pigmented adrenal cor- tical neoplasms, one might therefore sus- pect that the threshold for diagnosing malignancy (in terms of the number of cri- teria of Weiss satisfied by the tumor) might be higher in pigmented cortical tumors in comparison to non-pigmented tumors. Because of these reservations, an unequivo- cal diagnosis of malignancy was not ren- dered on the original adrenalectomy specimen in this case.

The need for use of caution in applying the Weiss system to specific, unusual vari- ants of adrenal cortical tumors is empha-

sized by the observation that the Weiss sys- tem is not reliable for predicting malig- nancy in oncocytic adrenal cortical tumors (which share some histologic features in common with pigmented cortical tumors, including eosinophilic cytoplasm and fre- quent presence of nuclear atypia). Despite exhibiting a diffuse growth pattern, eosi- nophilic cytoplasm, and nuclear atypia, all three adrenocortical oncocytomas described by Sasano et al. [19] behaved in a benign fashion over follow-up intervals ranging from 8 to 27 mo. Similarly, Lin et al. [20] found that five of seven oncocytic tumors satisfying at least three of Weiss’ criteria (including nuclear pleo- morphism, diffuse architecture, and eosi- nophilic cytoplasm) followed a benign clinical course over a follow-up period of up to 99 mo; these authors concluded that a conservative approach should be taken in diagnosing malignancy in oncocytic adrenal tumors in the absence of mitotic activity, necrosis, or invasion, criteria known to be strongly correlated with malignancy. More recently, based on a study of 10 adrenocortical oncocytic tumors, Bisceglia et al. [21] proposed spe- cific criteria (modified from the Weiss sys- tem) for subcategorizing such tumors as benign, malignant, or of uncertain malig- nant potential. By analogy, these studies of oncocytic adrenocortical tumors under- score the need to test the Weiss system on a large series of pigmented adrenal cortical tumors in order to determine whether or not this system is reliable for assessing the malignant potential of such tumors.

In addition to the uniqueness of this reported case as a pigmented adrenocorti- cal carcinoma, the relatively indolent behavior of the tumor, with late recurrence and metastasis, is another unusual feature. The majority of adrenocortical carcinomas behave as aggressive tumors, with a very poor prognosis. A significant number of

patients (30-80%) have distant metastases at presentation [22], and in many reported series, the majority of these patients will not survive beyond 1 yr [23,24]. Overall, more than 50% of patients with adreno- cortical carcinoma will die within 2 yr [22- 24], and the 5-yr survival in most reported series is in the range of 15-40% [23-26]. Despite the generally poor prognosis of adrenocortical carcinoma, occasional tumors (as in the case reported herein) behave in a more indolent fashion, with late recurrence or metastasis and/or long- term survival despite the presence of local recurrence or metastasis [24,27-29]. Of the nine histologic criteria of Weiss, prognosis in adrenocortical carcinoma is most closely related to tumor mitotic activity [18]. The ultimate demonstration of malignant behavior (manifested by local recurrence and metastasis) of the tumor described in this case report after an interval of 8 yr fol- lowing adrenalectomy underscores the need for long-term follow-up of patients diagnosed with adrenocortical carcinoma or an atypical adrenal cortical neoplasm of uncertain malignant potential.

References

1. Lack EE. Tumors of the adrenal gland and extra-adrenal paraganglia. In: Rosai J, ed. Atlas of tumor pathology. Series 3. Fascicle 19. Washington, DC: Armed Forces Institute of Pathology, 1997;102-105.

2. Brennan MF. Adrenocortical carcinoma. CA Cancer J Clin 37:348-365, 1987.

3. Robinson MJ, Pardo V, Rywlin AM. Pig- mented nodules (black adenomas) of the adrenal. An autopsy study of incidence, mor- phology, and function. Hum Pathol 3:317- 325, 1972.

4. Lack EE. Pathology of the adrenal cortex. In: Lechago J, Gould VE, eds. Bloodworth’s endocrine pathology. Baltimore, MD: Will- iams & Wilkins, 1997; 355-415.

5. Caplan RH, Virata RL. Functional black adenoma of the adrenal cortex. A rare cause

of primary aldosteronism. Am J Clin Pathol 62:97-103, 1974.

6. Cohen RJ, Brits R, Phillips JI, et al. Pri- mary hyperaldosteronism due to a func- tional black (pigmented) adenoma of the adrenal cortex. Arch Pathol Lab Med 115:813-815, 1991.

7. Damron TA, Schelper RL, Sorensen L. Cytochemical demonstration of neuromelanin in black pigmented adrenal nodules. Am J Clin Pathol 87:334-341, 1987.

8. 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.

9. Bossis I, Voutetakis A, Bei T, et al. Protein kinase A and its role in human neoplasia: the Carney complex paradigm. Endocr Relat Can- cer 11:265-280, 2004.

10. Belleza G, Giansanti M, Cavaliere A, et al. Pigmented “black” pheochromocytoma of the adrenal gland. A case report and review of the literature. Arch Pathol Lab Med 128:e125- e128, 2004.

11. Lack EE. Tumors of the adrenal gland and extra-adrenal paraganglia. In: Rosai J, ed. Atlas of tumor pathology. Series 3. Fascicle 19. Washington, DC: Armed Forces Institute of Pathology, 1997; 180-182.

12. DeLellis RA, Shin SJ. Immunohistology of endocrine tumors. In: Dabbs DJ, ed. Diag- nostic immunohistochemistry. 2nd ed. Phila- delphia, PA: Elsevier, 2006; 278-283.

13. Feuerstein IM, Tiamson EM. Focal cyto- megaly of the adult adrenal cortex. A rare vari- ant of black adenoma. Arch Pathol Lab Med 109:198-200, 1985.

14. Aubert S, Wacrenier A, Leroy X, et al. Weiss system revisited. A clinicopathologic and immunohistochemical study of 49 adrenocor- tical tumors. Am J Surg Pathol 26:1612-1619, 2002.

15. Hough AJ, Hollifield JW, Page DL, et al. Prognostic factors in adrenal cortical tumors. A mathematical analysis of clinical and mor- phologic data. Am J Clin Pathol 72:390-399, 1979.

16. Van Slooten H, Schaberg A, Smeenk D, et al. Morphologic characteristics of benign and

malignant adrenocortical tumors. Cancer 55:766-773, 1985.

17. Weiss LM. Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Am J Surg Pathol 8:163-169, 1984.

18. Weiss LM, Medeiros LJ, Vickery AL. Patho- logic features of prognostic significance in adrenocortical carcinoma. Am J Surg Pathol 13:202-206, 1989.

19. Sasano H, Suzuki T, Sano T, et al. Adrenal oncocytoma. A true nonfunctioning adreno- cortical tumor. Am J Surg Pathol 15:949-956, 1991.

20. Lin BT-Y, Bonsib SM, Mierau GW, et al. Oncocytic adrenocortical neoplasms. A report of seven cases and review of the literature. Am J Surg Pathol 22:603-614, 1998.

21. Bisceglia M, Ludovico O, Di Mattia A, et al. Adrenocortical oncocytic tumors: report of 10 cases and review of the literature. Int J Surg Pathol 12:231-243, 2004.

22. Luton J-P, Cerdas S, Billaud L, et al. Clinical features of adrenocortical carcinoma, prognos- tic factors, and the effect of mitotane therapy. N Engl J Med 322:1195-1201, 1990.

23. Didolkar MS, Bescher RA, Elias EG, et al. Natural history of adrenal cortical carcinoma: a clinicopathologic study of 42 patients. Cancer 47:2153-2161, 1981.

24. Venkatesh S, Hickey RC, Sellin RV, et al. Adrenal cortical carcinoma. Cancer 64:765- 769, 1989.

25. Allolio B, Hahner S, Weismann D, et al. Management of adrenocortical carcinoma. Clin Endocrinol (Oxf) 60:273-287, 2004.

26. Ng L, Libertino JM. Ad renocortical carci- noma: diagnosis, evaluation, and treatment. J Urol 169:5-11, 2003.

27. Dang C, Mohamed H, Mandal A, et al. Adrenal cortical carcinoma: a case of late pul- monary metastasis. J Natl Med Assoc 93:37- 39,2001.

28. Meyer A, Behrend M. Long-term survival over 28 years of a patient with metastatic adrenal cortical carcinoma - case report. Anticancer Res 24:1901-1904, 2004.

29. Schulick RD, Brennan MF. Long-term sur- vival after complete resection and repeat. resection in patients with adrenocortical car- cinoma. Ann Surg Oncol 6:719-726, 1996.

Quartz 4

Explorer

17308367