Fine-Needle Aspiration of Adrenal Cortical Carcinoma ...

Am J Clin Pathol 2006;126:389-398 389389 DOI: 10.1309/AQFEB5WEMU41N9K1 389

© American Society for Clinical Pathology

Anatomic Pathology / CYTOLOGIC FEATURES OF ADRENAL CORTICAL CARCINOMA

Fine-Needle Aspiration of Adrenal Cortical Carcinoma

Cytologic Spectrum and Diagnostic Challenges

Rulong Ren, MD, Ming Guo, MD, Nour Sneige, MD, Cesar A. Moran, MD, and Yun Gong, MD

Key Words: Adrenal gland; Adrenal cortical carcinoma; Cytology; Fine-needle aspiration; Immunocytochemistry

DOI: 10.1309/AQFEB5WEMU41N9K1

A b s t r a c t

We reviewed the cytologic features of 20 adrenalcortical carcinomas (ACCs; 9 primary and 11metastatic) from 19 patients and highlighted diagnosticpitfalls. The mean size of primary ACCs was 11.9 cm,and that of metastatic ACCs was 3.0 cm. The metastaticsites were liver, lung, lymph node, soft tissue, and bone.Primary and metastatic ACCs were cytologicallysimilar and showed a wide range of features varyingfrom well-differentiated tumor resembling a benigncortical lesion or low-grade neuroendocrine tumor topoorly differentiated pleomorphic tumor mimickingpoorly differentiated carcinoma, melanoma, or high-grade sarcoma. The common cytologic features werehypercellularity (70% of cases), necrotic debris in thebackground (70%), moderate to marked nuclearpleomorphism (80%), mitotic figures (90%), andprominent nucleoli (60%). Twenty percent of casesexhibited all 5 features, 40% exhibited 4 features, and40% exhibited 3 features. Necrosis and/or mitosis werefound in all cases, even in tumors with bland cytologicfeatures. Cytologic, immunophenotypic, andultrastructural findings should be correlated withclinical and radiologic information for achieving aproper cytologic diagnosis.

With the advent of high-resolution imaging techniques,adrenal masses have been detected increasingly during radio-logic staging or follow-up in patients with a history of malig-nancy or workup for unrelated indications.1 Once an adrenallesion is found, it is important to determine whether the lesionis benign or malignant and, if it is malignant, whether it is aprimary adrenal cortical carcinoma (ACC) or a metastasis.

Although imaging studies can provide diagnostic clues, thepathologic diagnosis of an adrenal lesion determines the thera-peutic regimen. A small nonfunctional nodule in an asympto-matic patient without a history of malignancy may only need tobe followed up by radiologic means, whereas for an ACC, com-plete tumor resection with chemotherapy may be indicated.2-4 Inaddition, discovery of a metastasis involving the adrenal glandmay preclude extensive local therapy of the primary tumor whensystemic therapy may be more appropriate. Therefore, a properpreoperative pathologic diagnosis of the nature and extent of thedisease is highly desirable for planning optimal management.Imaging-guided fine-needle aspiration (FNA), which is a safe,simple, and cost-effective procedure, often is used as an initialdiagnostic procedure for this purpose.5-8

ACC is a rare but highly malignant tumor. The incidenceis 1 to 2 per million people per year, which accounts for 0.02%of all malignant neoplasms in humans.3,4,9 Patients with ACCfrequently present at advanced stages. The mean survivalduration is approximately 18 months, and the overall 5-yearsurvival rate after diagnosis is less than 50%.4,9-11 The stage ofACC (defined by tumor size, the presence of adjacent organinvasion, lymph node involvement, and distant metastases)remains the most important prognostic factor.9,11 In a study of253 ACCs, the 5-year survival rates for patients with stages I,II, III, and IV were 66%, 58%, 24%, and 0%, respectively.11

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390 Am J Clin Pathol 2006;126:389-398390 DOI: 10.1309/AQFEB5WEMU41N9K1


Ren et al / CYTOLOGIC FEATURES OF ADRENAL CORTICAL CARCINOMA

Because of the low incidence of ACC, there is relativelylimited literature that details the cytologic characteristics ofthis entity; most published reports have been on small seriesor single cases.5-7,12-19 Familiarity with the cytologic featuresof ACC on FNA samples not only may allow earlier detectionand proper staging of ACC but also may facilitate differentialdiagnosis during workup for an adrenal mass. We reviewedthe cytologic features of 20 ACCs in primary and metastaticsettings and discussed the diagnostic pitfalls.

Materials and Methods

FNA Sample Collection

By using the pathology files of the University of TexasM.D. Anderson Cancer Center, Houston, we retrospectivelyidentified 9 primary and 11 metastatic ACCs diagnosed onFNA samples that had been obtained from 19 patients fromJanuary 1994 through February 2006. In 1 patient, 2 meta-static tumors had been aspirated, and we considered them asseparate cases. Clinical and radiologic information for allpatients was available to us for review. The study was con-ducted with the approval of the M.D. Anderson Cancer CenterInstitutional Review Committee.

Aspirates were obtained using a 20- or 22-gauge biopsyneedle under computed tomographic or ultrasonic guidance.An average of 3 FNA passes was made for each case. Directsmears were air dried for Diff-Quik staining (Stat Lab,Lewisville, TX) or fixed in modified Carnoy fixative (a 6:1ratio of 70% ethanol/glacial acetic acid) for Papanicolaoustaining. Smears were assessed immediately by a cytopathol-ogist for specimen adequacy. Cells obtained from the needlerinses were subjected to centrifugation, and the sediment wasfixed in a 1:1 mixture of 95% ethanol to 10% formalin andembedded in paraffin to make cell blocks. The cell blocks thenwere sectioned and stained with H&E.

The cytologic features of each case were analyzed retro-spectively for background content, cellularity, architecture, cellshape, and cytoplasmic and nuclear features. These cytologicfeatures were compared with pathologic findings from thepatient’s primary and/or metastatic ACC whenever available.

Immunocytochemical Analysis

Immunostaining was performed at the time of cytologicdiagnosis on cell blocks of 13 tumors (6 primary and 7 meta-static), using the EnVision+ system and peroxidase detectionmethods in a DAKO Autostainer (DAKO, Carpinteria, CA).The primary antibodies used were those against pancytokeratin,A103 (Melan-A or MART-1), calretinin, inhibin, vimentin,synaptophysin, chromogranin, S-100, and HMB-45. Thesources and the dilutions of the antibodies are listed in ❚Table 1❚.

Electron Microscopic AnalysisTransmission electron microscopic examination was per-

formed at the time of cytologic diagnosis with 6 primarytumors. A portion of the aspirates was fixed immediately in2% buffered glutaraldehyde, postfixed in 1% osmium tetrox-ide, and embedded in Epon epoxy resin. Specimens were eval-uated by light microscopy using semithin sections stainedwith methenamine blue. After sections were selected from theEpon-embedded blocks, ultrathin sections were cut andstained with uranyl acetate and lead citrate.

Patient Outcome

Overall survival duration (calculated from the time ofdiagnosis of the primary ACC to death or the most recent fol-low-up date) and the 5-year overall survival rate for the 19patients were estimated using the Kaplan-Meier product-limitmethod.

Results

Clinical and Radiologic Findings

The clinical and pathologic characteristics of the 19patients (12 males and 7 females) with primary or metastaticACC are summarized in ❚Table 2❚. The mean age of thepatients at diagnosis of the primary tumor was 52.1 years(range, 34-68 years), and that of patients with metastatictumor was 50.2 years (range, 17-79 years).

The clinical manifestations in the 9 patients with pri-mary ACC were abdominal discomfort or flank pain (n =6), Cushing syndrome (n = 2), lower extremity edema (n =1), ascites (n = 1), and cough and hemoptysis (n = 1). Themean size of the adrenal mass, as measured by computedtomography or ultrasonography, was 11.9 cm (range, 10-14.5 cm). Two patients had a history of malignancy: 1 with

❚Table 1❚Antibody Sources and Dilutions

Antibody Dilution Source

PancytokeratinAE1/AE3 1:500 DAKO, Carpinteria, CACAM5.2 1:50 Becton Dickinson, San Jose, CACytokeratin MNF 116 1:50 DAKOCytokeratins 8 and 18 1:25 Zymed, South San Francisco, CA

A103 1:25 Neomarkers/Lab Vision, Fremont, CA

Calretinin 1:20 ZymedInhibin 1:50 Serotec, Raleigh, NCVimentin 1:600 DAKOSynaptophysin 1:75 BioGenex, San Ramon, CAChromogranin 1:4,000 Chemicon, Temecula, CAS-100 1:40 BioGenexHMB-45 1:50 DAKO

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breast carcinoma (case 8) and 1 with “lung carcinoma” (case9). The latter patient had cough and hemoptysis and was foundto have lung nodules on imaging workup. A diagnosis of“non–small cell lung carcinoma” initially was made based onFNA findings of one of the nodules; shortly thereafter, anadrenal mass was found during imaging staging for the “lungcarcinoma” and was thought to be a metastatic tumor from thelung origin. The adrenal mass was aspirated, and the cytolog-ic features were identical to those of the lung nodule but wereimmunocytochemically consistent with primary ACC. Theadrenal tumor was subsequently removed surgically and con-firmed to be ACC histologically. This case represented anACC with synchronized distant (lung) metastasis. Distantmetastases (predominantly involving liver) were found in 4other patients during imaging staging of their primary ACCs.The cytologic diagnosis of each primary ACC was based on acombination of clinical and radiologic information, cytologicfeatures, immunocytochemical results, and electron micro-scopic findings. Histologic confirmation was available for 3 of9 primary ACCs.

For 11 metastatic ACCs in 10 patients, the sites aspiratedwere lymph node (n = 4; perirenal, mesentery, pelvic, and axil-lary), liver (n = 3), soft tissue (n = 2, thigh and retroperitoneal),lung (n = 1), and femur bone (n = 1). The mean size of themetastatic tumors, as measured by computed tomography or

ultrasonography, was 3.0 cm (range, 0.7-6.0 cm). At the timeof aspiration, 9 of 10 patients had a history of primary ACC (1patient also had a history of prostate carcinoma); most metas-tases were found during imaging follow-up (Table 2), and 1patient (case 11) had virilizing symptoms. One patient (case14) had a history of “renal cell carcinoma” that was diagnosedat a local hospital, based on histologic and gross findings of thepatient’s nephroadrenalectomy specimen that revealed a largemass extensively involving both the adrenal gland and the adja-cent kidney. Four months after nephroadrenalectomy, a newretroperitoneal soft tissue nodule was found and aspirated. Thelesion was cytologically and immunophenotypically consistentwith carcinoma of an adrenal cortical origin. These findings ledto a retrospective review and an immunohistologic workup ofthe original tumor, and the results were consistent with ACCinstead of renal cell carcinoma. For diagnosis of metastaticACCs, a similar approach to that used for diagnosing primaryACC was used. In addition, morphologic comparison of themetastatic tumors with their primary counterparts was attempt-ed in each case. In 2 tumors, a concurrent core biopsy speci-men also was obtained for histologic confirmation.

At the last follow-up date, 6 patients were alive and 13patients had died of ACC. The median overall survival timewas 17 months, and the 5-year overall survival rate was 23%(95% confidence interval, 8%-68%).

Anatomic Pathology / ORIGINAL ARTICLE

❚Table 2❚Clinical and Pathologic Findings of 19 Patients With ACC Diagnosed on FNA Samples

Case No./ History of Site of Site of Tumor Ancillary Tests for Histologic Follow-up Sex/Age (y) Malignancy Manifestations Metastasis* Aspiration Size (cm) FNA Diagnosis Diagnosis (mo) † Outcome

Primary ACC1/M/34 None Cushing syndrome — Adrenal gland 12.5 None — 7 DOD2/M/44 None Abdominal discomfort Liver, rib Adrenal gland 12 EM, ICC — 17 DOD3/M/67 None Abdominal discomfort — Adrenal gland 11.5 EM — 14 DOD4/M/43 None Abdominal discomfort — Adrenal gland 14.5 None — 11 DOD5/M/68 None Flank pain; lower Liver Adrenal gland 10 EM, ICC — 2 DOD

extremity edema6/M/41 None Flank pain; ascites Liver Adrenal gland 10 EM, ICC ACC 9 DOD7/M/40 None Abdominal discomfort — Adrenal gland 14 EM, ICC ACC 4 Alive8/F/66 Breast Ca Cushing syndrome Liver Adrenal gland 12.5 EM, ICC — DOD9/F/66 “Lung Ca” Cough, hemoptysis Lung Adrenal gland 10 ICC ACC 10 Alive

Metastatic ACC10/M/63 ACC Thigh mass NA Soft tissue, thigh 6 None — 99 DOD11/F/47 ACC Virilizing symptoms NA Liver 5 ICC Metastatic ACC 91 DOD12/F/51 ACC Imaging follow-up NA LN, mesentery (A) 3 ICC — 35 DOD

LN, pelvic (B) 3 None —13/F/40 ACC Imaging follow-up NA LN, axillary 2 ICC — 29 DOD14/M/17 “Renal Imaging follow-up NA Soft tissue, 3 ICC — 8 Alive

cell Ca” retroperitoneal15/M/58 ACC Imaging follow-up NA Liver 4 ICC Metastatic ACC 2 DOD16/F/79 ACC Bone pain NA Bone, femur 2.5 ICC — 11 DOD17/M/55 ACC Imaging follow-up NA Lung 0.7 None — 18 Alive18/M/65 ACC, Imaging follow-up NA LN, perirenal 1.3 ICC — 30 Alive

prostate Ca19/F/27 ACC Imaging follow-up NA Liver 2 None — 8 Alive

ACC, adrenal cortical carcinoma; Ca, carcinoma; DOD, died of disease; EM, electron microscopy; FNA, fine-needle aspiration; ICC, immunocytochemical analysis; LN, lymphnode; NA, not available.

* Synchronized metastases at the time of diagnosing primary ACC.† From diagnosis of primary ACC to death or the last follow-up date.

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Cytologic FeaturesThe cytologic features of the 20 ACCs are summarized in

❚Table 3❚. Cytologic features of primary and metastatic ACCwere similar. Most aspiration samples were hypercellular andwere composed of large tumor cells arranged singly or inloose clusters, with focal tissue fragments where tumor cellswere enmeshed in a fibrovascular network. Necrotic debriswas found frequently in the background. Tumor cells weremostly plasmacytoid or polygonal, with well-preserved, mod-erate to abundant, finely granular cytoplasm ❚Image 1❚. Somecells had vacuoles admixed with granular cytoplasm. In 3tumors, perinuclear cytoplasmic condensation was observed(better shown on Diff-Quik smear), giving a globule-likeappearance ❚Image 2❚. Nuclei were mostly eccentricallyplaced and variably enlarged with hyperchromatic and coarsechromatin and prominent nucleoli. Nuclear pleomorphism (ie,anisonucleosis, bizarre-shaped nuclei including binucleationor multinucleation, and spindle-shaped nuclei) was substantialin most tumors. Mitotic figures, occasionally with atypicalforms, were found in all but 2 tumors.

At on-site evaluation, differential diagnosis was broadbecause of the presence of a wide morphologic spectrum.For example, 1 tumor (case 5) exhibited cytologic featuresthat closely simulated those of epithelioid melanoma. Anadrenal cortical origin was supported by immunostainingresults ❚Table 4❚ and ultrastructural findings that demonstrat-ed features of steroid-producing cells (ie, abundant smoothendoplasmic reticulum, numerous mitochondria withtubulovesicular cristae, and lipids). Two primary tumors(cases 6 and 8) were morphologically reminiscent of adrenal

cortical adenoma because the aspirates showed relativelybland cytologic features and were composed of small andrather uniform tumor cells with smooth nuclear outlines,evenly distributed chromatin, inconspicuous nucleoli, and

❚Table 3❚Cytologic Features of 20 Cases of ACC in 19 Patients*

Feature Results

CellularityHigh 14 (70)Moderate 5 (25)Low 1 (5)

ArchitecturePredominantly dyshesive 8 (40)Dyshesive and cohesive 11 (55)Predominantly cohesive 1 (5)

BackgroundNecrotic debris 14 (70)Neutrophils 3 (15)Lipid drops, focal 3 (15)

CytoplasmFinely granular 20 (100)Foamy or vacuolated 6 (30)Stripped off 5 (25)

Nuclear pleomorphismMarked 11 (55)Moderate 5 (25)Mild 4 (20)

Mitotic figuresFrequent 8 (40)Occasional 10 (50)Not found 2 (10)

NucleoliProminent 12 (60)Inconspicuous 8 (40)

* Data are given as number (percentage).

A B

❚Image 1❚ (Case 5) A, Fine-needle aspiration features of a primary adrenal cortical carcinoma showing large polygonal cells withmarked pleomorphism, binucleated cells containing abundant finely granular cytoplasm, irregular eccentrically placed nuclei, andprominent nucleoli, mimicking those of epithelioid melanoma (Diff-Quik, ×400). B, Mitotic figure and necrosis (inset) werecommon findings (Papanicolaou, ×400; inset, Papanicolaou, ×200).

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rare mitotic figures.5,6,20 Focally, tumor cells demonstratedabundant foamy/vacuolated cytoplasm that might bestripped off, resulting in numerous bare nuclei ❚Image 3❚.However, the malignant nature of these 2 tumors was indi-cated by the large size and the presence of synchronized dis-tant metastasis. In addition, occasional mitotic figures andfocal necrosis were identified after careful scrutiny of thesmears. Bland cytologic features also were found in 2metastatic tumors (cases 15 and 16), in which the tumor cellswere plasmacytoid with eccentrically placed uniform nuclei,fine chromatin, and inconspicuous nucleoli, raising a con-cern for metastatic low-grade neuroendocrine tumor from anextra-adrenal origin ❚Image 4❚. Immunoprofiling was, there-fore, performed and the results were consistent with an adre-nal cortical origin (Table 4).

Malignant spindle cells were noted focally in 1 primaryACC (case 4) and diffusely in 1 metastatic ACC (case 13 in


❚Table 4❚Immunocytochemical Results of 6 Cases of Primary and 7 Cases of Metastatic ACC

Case No.

Antibody 2 5 6 7 8 9 11 12A 13 14 15 16 18 Detection Rate*

Pancytokeratin – + – + – – + ND + + – + ND 55 (6/11)A103 ND ND ND ND ND – ND ND ND – + + + 60 (3/5)Calretinin ND – ND ND ND + ND ND ND + ND ND – 50 (2/4)Inhibin ND – ND – ND – ND + + – ND + + 50 (4/8)Vimentin ND ND ND + ND ND ND ND ND + ND – ND 67 (2/3)Synaptophysin ND – ND – ND – ND ND – + ND – + 29 (2/7)Chromogranin – – – – ND – ND ND ND – – – ND 0 (0/8)S-100 ND ND ND – ND – ND ND – – ND ND ND 0 (0/4)HMB-45 ND – ND ND ND ND ND ND – – ND ND ND 0 (0/3)

ND, not done.* Data are given as percentage (number positive/total tested).

A B

❚Image 2❚ Some tumor cells showing globule-like cytoplasmiccondensation (A, Diff-Quik, ×400; B, H&E, ×200).

A B

❚Image 3❚ (Case 8) A, Fine-needle aspiration features of a primary adrenal cortical carcinoma showing small, uniform tumor cellsand numerous bare nuclei arranged singly or in a loosely cohesive pattern (Papanicolaou, ×200). B, Foaming/vacuolatedcytoplasm is best seen on the Diff-Quik–stained slide (×200). These features simulated those of benign cortical adenoma.

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an axillary lymph node). The latter tumor showed abundantsingly arranged or clusters of bizarre spindle cells withmarked nuclear atypia and brisk mitotic figures ❚Image 5❚.These features raised a differential diagnosis that includedsarcomatoid ACC, high-grade sarcoma, and spindle cellmelanoma. The results of immunocytochemical stainingsupported that the tumor had an adrenal cortical origin(Table 4). Histologic material from its primary counterpart

was subsequently obtained for comparison and showed sim-ilar morphologic features.

To evaluate cytologic features that reflected publishedhistologic criteria for ACC,21 5 cytologic amenable criteria (ie,high cellularity, necrosis, moderate to marked nuclear pleo-morphism, mitosis, and prominent nucleoli) were used in eachcase. All 20 cases in our series met at least 3 of these criteria:4 cases (20%) showed all 5 features, 8 (40%) showed 4 fea-tures, and 8 (40%) showed 3 features. Notably, necrosis and/ormitosis were found in each case. Metastatic ACCs generallyshowed a similar frequency of each feature to primary ACCs,except that necrosis was more common in primary ACCs.

Cell-block preparations that contained tumor cells wereobtained in 13 cases and showed features comparable tothose of the direct smears. Tumor cells typically werearranged in diffuse/solid sheets or nests ❚Image 6❚, but a pat-tern of thin trabeculae separated by delicate sinusoidalspaces was observed in 2 tumors ❚Image 7❚. The cellsdemonstrated eosinophilic cytoplasm with variable nuclearatypia, including pleomorphism, hyperchromasia, promi-nent nucleoli, and mitotic figures. Foci of necrosis werenoted frequently.

Immunocytochemical Results

The results of the immunoperoxidase studies of the ACCsare summarized in Table 4. Positive staining for pancytoker-atin was found in 55% (6/11) of the tumors tested, A103 in60% (3/5), calretinin in 50% (2/4), inhibin in 50% (4/8),vimentin in 67% (2/3), and synaptophysin in 29% (2/7). Notumor showed immunoreactivity to chromogranin, S-100, orHMB-45.

A B

❚Image 4❚ (Case 15) Fine-needle aspiration features of a metastatic adrenal cortical carcinoma showing bland tumor cells withminimal nuclear pleomorphism that are plasmacytoid with eccentrically located nuclei, reminiscent of a low-gradeneuroendocrine tumor of an extra-adrenal site (A, Diff-Quik, ×100; B, Papanicolaou, ×100).

❚Image 5❚ (Case 13) Fine-needle aspiration features of ametastatic adrenal cortical carcinoma showing spindle cellfeatures with marked nuclear atypia, raising the possibilityof high-grade sarcoma or spindle cell melanoma(Papanicolaou, ×400).

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Discussion

Our study demonstrated that ACC can show a wide mor-phologic spectrum, which can cause diagnostic confusion. Anadrenal cortical origin of an adrenal mass may be establishedreadily by immunostaining, ultrastructural findings, and clini-cal information. Abnormal endocrine manifestations and/orlaboratory tests are frequent findings because more than halfof ACCs are functional owing to aberrant hormonal secre-tion.4,9 However, distinguishing ACC from adrenal corticaladenoma, a more commonly encountered benign counterpart,may not always be straightforward, even on a histologic basis.

A number of previous studies have tried to establish his-tologic criteria to distinguish between these entities.9,10,21-24

Most of these studies indicated that a high mitotic rate and thepresence of vascular or capsular invasion correlated withmalignant behavior. Currently, the recommended histologiccriteria for ACC are a modified system proposed by Weiss etal21 in which the presence of 3 or more of the following 9 cri-teria is required for diagnosis of ACC: high nuclear grade(Fuhrman criteria), more than 5 mitoses per 50 high-powerfields, atypical mitotic figures, eosinophilic cytoplasm withfewer than 25% of tumor cells being clear cells, diffuse archi-tecture in more than 33% of the tumor, necrosis, venous inva-sion, sinusoidal invasion, and capsular invasion. Unlike histo-logic samples, the ability to diagnose ACC on FNA samples islimited by small samples or insufficient sampling and the lackof an architectural pattern. In addition, macroscopic findingsthat can help predict tumor behavior (ie, tumor weight, intra-tumoral necrosis, hemorrhages, and cystic degenera-tion)3,9,22,24,25 are not available during cytologic diagnosis.

An attempt has been made in the cytology literature todistinguish ACC from adrenal cortical adenoma.5,6,12,14,17

Because assessing vascular and capsular invasion is not possi-ble, the emphasis has been placed on cellularity and individ-ual cell morphologic features. In our study, we found thatACC aspirates were mostly hypercellular with necrotic back-ground. Dyshesive tumor cells often were polygonal or plas-macytoid with well-preserved and granular cytoplasm, moder-ate to marked nuclear pleomorphism, mitosis, and prominentnucleoli. These features were similar to those described in theliterature and usually allowed a distinction from benign corti-cal lesions, in which aspirates typically were of lower cellular-ity with smaller and more uniform cells, a regular nuclearmembrane, fine and evenly distributed chromatin, and incon-spicuous nucleoli.5,6,20 The cells of a benign lesion tend toform cohesive clusters and often have stripped nuclei.Although focal anisonucleosis and mild nuclear atypia may befound, mitosis and necrosis are exceedingly rare in benignlesions.5,8,14 However, benign and malignant cortical tumorsmay show overlapping cytologic features,14 as illustrated bythe 2 primary and the 2 metastatic ACCs in our study thatshowed rather bland cytologic features. Cell-block sections ofACCs also can show a predominantly thin trabecular patternas most benign cortical lesions do.

Because no single specific feature allows a definitivediagnosis of ACC, a defining combination of cytologic fea-tures has been sought. In an attempt to mirror histologic crite-ria, we used 5 cytologically amenable criteria for each case.We found that all 20 cases showed at least 3 of these criteria:20% of the cases met all 5 criteria, 40% met 4 criteria, and40% met 3 criteria. Necrosis and/or mitosis were found in


❚Image 6❚ (Case 16) Cell-block section showing tumor cellsarranged in a solid growth pattern without evident sinusoidalspaces (H&E, ×100).

❚Image 7❚ (Case 15) Cell-block section showing tumor cellsforming thin trabeculae separated by delicate sinusoidalspaces (H&E, ×100).

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each case. The frequency of each feature present in primaryand metastatic ACCs generally was similar, except for necro-sis that was found less easliy in metastatic ACCs, probablybecause of the smaller tumor size. Even in cytologically blandcases, scattered mitoses and/or focal necrosis were detected.Although accurate quantification of these features is not appli-cable in FNA samples, identifying numerous and pronouncedatypical features in multiple fields would enhance the diag-nostic certainty for ACC cytologically. Large tumor size is asupportive feature. Caution should be exercised in tumorsshowing bland cytologic features, especially if the tumors arerelatively small.

Data presented at an international consensus conference3

demonstrated that more than 95% of ACCs were larger than 5cm (mean, 10 cm). Similarly, in a review of 602 ACCs, Ng andLibertino9 found that tumor size ranged from 4 to 25 cm(mean ± SD, 9.8 ± 4.1 cm). In our series, the 9 primary ACCswere all 10 cm or larger (mean, 11.9 cm). In contrast, benignlesions characteristically are smaller than 3.5 cm and rarelyexceed 5 cm.5,6,26 Size overlapping between ACC and corticaladenoma has been reported, mostly within the range of 4.0 to7.0 cm.3,10,27 It has been shown that adrenal cortical tumorslarger than 5 cm likely behave aggressively, even if their mor-phologic features are not evidently malignant.7 Accordingly, acomplete surgical excision of an adrenal mass larger than 5 cmhas been recommended.3

Pheochromocytoma, a primary medullary tumor of theadrenal gland, can mimic an ACC in the growth pattern andcellular morphologic features and, thus, needs to be exclud-ed.28 A systematic approach using clinical, laboratory, radio-logic, cytologic, immunocytochemical, and ultrastructuralfindings can aid in the distinction.21

Because of anatomic proximity, ACC often directlyextends into renal parenchyma.9 Morphologically, ACC andrenal cell carcinoma resemble each other a great deal.7,14,17 Weencountered a primary ACC that initially was diagnosed asrenal cell carcinoma on histologic examination (case 14). Themisinterpretation stemmed from the difficulty in determiningwhere the tumor arose because the large primary tumor exten-sively involved both the adrenal gland and the adjacent kidney.In addition, the morphologic similarity of these 2 tumors con-tributed to the confusion. Morphologic discrimination may bepossible7,16 but unreliable.14 The lack of specific cytologic fea-tures of ACC also is illustrated by case 9, for which metastat-ic ACC in the lung was misinterpreted as primary non–smallcell carcinoma. Furthermore, ACC can simulate melanoma,not only on cytologic features, but also on immunoreactivityto antibody A103.29 Additional immunomarkers such as S-100or HMB-45 should be used to differentiate between ACC andmelanoma. Last, we found a metastatic ACC composed pre-dominantly of malignant spindle cells (case 13), raising thepossibility of spindle melanoma and high-grade sarcoma.

ACCs with spindle features have been reported.7,8,13

Occasionally, they may even show rhabdomyoid, osteogenic,or chondroid differentiation.30-32 In a primary setting, the dif-ferential diagnosis should include spindle cell pheochromocy-toma,13 primary mesenchymal tumor of the adrenal glandsuch as leiomyosarcoma,33 a direct extension of the retroperi-toneal sarcoma or sarcomatoid renal cell carcinoma, andmetastatic spindle cell malignancy such as carcinoma, sarco-ma, and melanoma.

Patients with primary ACC usually present at advancedstages. The most common metastatic sites are liver, lung,retroperitoneal lymph nodes, and bone.9,28,34-36 Similarly, allthe primary ACCs in our study were large (≥10cm), and morethan half of the patients had synchronized distant metastasis (4in liver and 1 in lung) at the time the adrenal masses were aspi-rated. Of the 11 metastatic ACCs aspirated, the liver was themost commonly involved organ. The median overall survivaltime of the 19 patients was 17 months, and the 5-year overallsurvival rate was 23%. These values are within the range ofpreviously reported outcomes.4,9-11

Owing to its rich sinusoidal blood supply, the adrenalgland is the fourth most frequent metastatic site for tumorspread (after the lungs, liver, and bone).9,28 In fact, the inci-dence of metastatic tumor involving the adrenal gland is muchhigher than the incidence of primary adrenal gland tumors.37

The most common primary sites were the lung, kidney, skin(melanoma), stomach, esophagus, breast, pancreas, liver,ovary, and colon.6,20,38,39 As we discussed, a metastatic tumormay be indistinguishable cytologically from primary ACC.Likewise, when an ACC metastasizes to a visceral organ, theprimary malignancy of that organ (especially hepatocellularcarcinoma and renal cell carcinoma)7,14-16,40 needs to be con-sidered. For ACCs metastasizing to lymph node, soft tissue, orbone, the differential diagnosis should include metastatic car-cinoma, sarcoma, and melanoma of other sources. Althoughultrastructural findings showing features of a steroid-produc-ing cell are of great help, an immunoperoxidase study is a sim-ple and fast method to work up difficult cases. Alternatively,comparing morphologic features of the metastatic tumor withthose of previous histologic or cytologic material (obtainedfrom primary ACC or other metastasis in the same patient)may solve the diagnostic dilemma.

Cells of adrenal cortical origin commonly express A103,calretinin, inhibin, and vimentin. The reported detection ratesvaried widely from 50% to 100%,29,41,42 60% to 96%,41,43,44

73% to 100%,41-45 and 67% to 100%,45-47 respectively. In ourstudy, we found that A103 was expressed in 60% of ACCs, cal-retinin in 50%, inhibin in 50%, and vimentin in 67%. We andothers28,48 showed that ACCs variably expressed pancytoker-atin and synaptophysin but not chromogranin. Variable detec-tion rates in these immunomarkers could, in part, result fromdifferences in fixative solution, antigen retrieval technique, and

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antibody used in different studies and insufficient samplingwhen the distribution of positively stained cells is focal andpatchy. These findings highlight the need to include a panel ofimmunomarkers in the diagnostic workup.

FNA cytologic features of ACC are characteristic but notspecific. Identifying at least 3 of the 5 cytologic features wehave proposed, especially necrosis and mitosis, favors a diag-nosis of ACC. Correlation of cytologic, immunophenotypic,and ultrastructural findings with clinical information andknowledge of tumor size are crucial to achieve a proper FNAdiagnosis.

From the Department of Pathology, The University of Texas M.D.Anderson Cancer Center, Houston.

Address correspondence to Dr Gong: Dept of Pathology, Unit53, University of Texas M.D. Anderson Cancer Center, 1515Holcombe Blvd, Houston, TX 77030.

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