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
Abstract
We reviewed the cytologic features of 20 adrenal cortical carcinomas (ACCs; 9 primary and 11 metastatic) from 19 patients and highlighted diagnostic pitfalls. The mean size of primary ACCs was 11.9 cm, and that of metastatic ACCs was 3.0 cm. The metastatic sites were liver, lung, lymph node, soft tissue, and bone. Primary and metastatic ACCs were cytologically similar and showed a wide range of features varying from well-differentiated tumor resembling a benign cortical lesion or low-grade neuroendocrine tumor to poorly differentiated pleomorphic tumor mimicking poorly differentiated carcinoma, melanoma, or high- grade sarcoma. The common cytologic features were hypercellularity (70% of cases), necrotic debris in the background (70%), moderate to marked nuclear pleomorphism (80%), mitotic figures (90%), and prominent nucleoli (60%). Twenty percent of cases exhibited all 5 features, 40% exhibited 4 features, and 40% exhibited 3 features. Necrosis and/or mitosis were found in all cases, even in tumors with bland cytologic features. Cytologic, immunophenotypic, and ultrastructural findings should be correlated with clinical and radiologic information for achieving a proper 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 adrenal lesion is found, it is important to determine whether the lesion is benign or malignant and, if it is malignant, whether it is a primary adrenal cortical carcinoma (ACC) or a metastasis.
Although imaging studies can provide diagnostic clues, the pathologic 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 to be followed up by radiologic means, whereas for an ACC, com- plete tumor resection with chemotherapy may be indicated.2-4 In addition, discovery of a metastasis involving the adrenal gland may preclude extensive local therapy of the primary tumor when systemic therapy may be more appropriate. Therefore, a proper preoperative pathologic diagnosis of the nature and extent of the disease 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 initial diagnostic procedure for this purpose.5-8
ACC is a rare but highly malignant tumor. The incidence is 1 to 2 per million people per year, which accounts for 0.02% of all malignant neoplasms in humans.3,4,9 Patients with ACC frequently present at advanced stages. The mean survival duration is approximately 18 months, and the overall 5-year survival rate after diagnosis is less than 50%.4,9-11 The stage of ACC (defined by tumor size, the presence of adjacent organ invasion, lymph node involvement, and distant metastases) remains the most important prognostic factor.9,11 In a study of 253 ACCs, the 5-year survival rates for patients with stages I, II, III, and IV were 66%, 58%, 24%, and 0%, respectively.11
Because of the low incidence of ACC, there is relatively limited literature that details the cytologic characteristics of this entity; most published reports have been on small series or single cases.5-7,12-19 Familiarity with the cytologic features of ACC on FNA samples not only may allow earlier detection and proper staging of ACC but also may facilitate differential diagnosis during workup for an adrenal mass. We reviewed the cytologic features of 20 ACCs in primary and metastatic settings and discussed the diagnostic pitfalls.
Materials and Methods
FNA Sample Collection
By using the pathology files of the University of Texas M.D. Anderson Cancer Center, Houston, we retrospectively identified 9 primary and 11 metastatic ACCs diagnosed on FNA samples that had been obtained from 19 patients from January 1994 through February 2006. In 1 patient, 2 meta- static tumors had been aspirated, and we considered them as separate cases. Clinical and radiologic information for all patients was available to us for review. The study was con- ducted with the approval of the M.D. Anderson Cancer Center Institutional Review Committee.
Aspirates were obtained using a 20- or 22-gauge biopsy needle under computed tomographic or ultrasonic guidance. An average of 3 FNA passes was made for each case. Direct smears were air dried for Diff-Quik staining (Stat Lab, Lewisville, TX) or fixed in modified Carnoy fixative (a 6:1 ratio of 70% ethanol/glacial acetic acid) for Papanicolaou staining. Smears were assessed immediately by a cytopathol- ogist for specimen adequacy. Cells obtained from the needle rinses were subjected to centrifugation, and the sediment was fixed in a 1:1 mixture of 95% ethanol to 10% formalin and embedded in paraffin to make cell blocks. The cell blocks then were sectioned and stained with H&E.
The cytologic features of each case were analyzed retro- spectively for background content, cellularity, architecture, cell shape, and cytoplasmic and nuclear features. These cytologic features were compared with pathologic findings from the patient’s primary and/or metastatic ACC whenever available.
Immunocytochemical Analysis
Immunostaining was performed at the time of cytologic diagnosis on cell blocks of 13 tumors (6 primary and 7 meta- static), using the EnVision+ system and peroxidase detection methods 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. The sources and the dilutions of the antibodies are listed in Table 11.
Electron Microscopic Analysis
Transmission electron microscopic examination was per- formed at the time of cytologic diagnosis with 6 primary tumors. A portion of the aspirates was fixed immediately in 2% buffered glutaraldehyde, postfixed in 1% osmium tetrox- ide, and embedded in Epon epoxy resin. Specimens were eval- uated by light microscopy using semithin sections stained with methenamine blue. After sections were selected from the Epon-embedded blocks, ultrathin sections were cut and stained with uranyl acetate and lead citrate.
Patient Outcome
Overall survival duration (calculated from the time of diagnosis of the primary ACC to death or the most recent fol- low-up date) and the 5-year overall survival rate for the 19 patients were estimated using the Kaplan-Meier product-limit method.
Results
Clinical and Radiologic Findings
The clinical and pathologic characteristics of the 19 patients (12 males and 7 females) with primary or metastatic ACC are summarized in Table 21. The mean age of the patients at diagnosis of the primary tumor was 52.1 years (range, 34-68 years), and that of patients with metastatic tumor 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). The mean size of the adrenal mass, as measured by computed tomography or ultrasonography, was 11.9 cm (range, 10- 14.5 cm). Two patients had a history of malignancy: 1 with
| Antibody | Dilution | Source |
|---|---|---|
| Pancytokeratin | ||
| AE1/AE3 | 1:500 | DAKO, Carpinteria, CA |
| CAM5.2 | 1:50 | Becton Dickinson, San Jose, CA |
| Cytokeratin MNF 116 | 1:50 | DAKO |
| Cytokeratins 8 and 18 | 1:25 | Zymed, South San Francisco, CA |
| A103 | 1:25 | Neomarkers/Lab Vision, Fremont, CA |
| Calretinin | 1:20 | Zymed |
| Inhibin | 1:50 | Serotec, Raleigh, NC |
| Vimentin | 1:600 | DAKO |
| Synaptophysin | 1:75 | BioGenex, San Ramon, CA |
| Chromogranin | 1:4,000 | Chemicon, Temecula, CA |
| S-100 | 1:40 | BioGenex |
| HMB-45 | 1:50 | DAKO |
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ITable 2 Clinical and Pathologic Findings of 19 Patients With ACC Diagnosed on FNA Samples
| Case No./ Sex/Age (y) | History of Malignancy | Manifestations | Site of Metastasis* | Site of Aspiration | Tumor Size (cm) | Ancillary Tests FNA Diagnosis | for | Histologic Diagnosis | Follow-up (mo) * | Outcome | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary ACC | ||||||||||||
| 1/M/34 | None | Cushing syndrome | — | Adrenal gland | 12.5 | None | — | 7 | DOD | |||
| 2/M/44 | None | Abdominal discomfort | Liver, rib | Adrenal gland | 12 | EM, ICC | — | 17 | DOD | |||
| 3/M/67 | None | Abdominal discomfort | — | Adrenal gland | 11.5 | EM | — | 14 | DOD | |||
| 4/M/43 | None | Abdominal discomfort | — | Adrenal gland | 14.5 | None | — | 11 | DOD | |||
| 5/M/68 | None | Flank pain; lower | Liver | Adrenal gland | 10 | EM, ICC | — | 2 | DOD | |||
| extremity edema | ||||||||||||
| 6/M/41 | None | Flank pain; ascites | Liver | Adrenal gland | 10 | EM, ICC | ACC | 9 | DOD | |||
| 7/M/40 | None | Abdominal discomfort | — | Adrenal gland | 14 | EM, ICC | ACC | 4 | Alive | |||
| 8/F/66 | Breast Ca | Cushing syndrome | Liver | Adrenal gland | 12.5 | EM, ICC | — | DOD | ||||
| 9/F/66 | "Lung Ca' | Cough, hemoptysis | Lung | Adrenal gland | 10 | ICC ACC | 10 | Alive | ||||
| Metastatic ACC | ||||||||||||
| 10/M/63 | ACC | Thigh mass | NA | Soft tissue, thigh | 6 | None | — | 99 | DOD | |||
| 11/F/47 | ACC | Virilizing symptoms | NA | Liver | 5 | ICC | Metastatic | ACC 91 | DOD | |||
| 12/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 | DOD | ||||
| 14/M/17 | "Renal | Imaging follow-up | NA | Soft tissue, | 3 | ICC | — | 8 | Alive | |||
| cell Ca" | retroperitoneal | |||||||||||
| 15/M/58 | ACC | Imaging follow-up | NA | Liver | 4 | ICC | Metastatic | ACC 2 | DOD | |||
| 16/F/79 | ACC | Bone pain | NA | Bone, femur | 2.5 | ICC | — | 11 | DOD | |||
| 17/M/55 | ACC | Imaging follow-up | NA | Lung | 0.7 | None | — | 18 | Alive | |||
| 18/M/65 | ACC, | Imaging follow-up | NA | LN, perirenal | 1.3 | ICC | — | 30 | Alive | |||
| prostate Ca | ||||||||||||
| 19/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, lymph node; 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.
breast carcinoma (case 8) and 1 with “lung carcinoma” (case 9). The latter patient had cough and hemoptysis and was found to have lung nodules on imaging workup. A diagnosis of “non-small cell lung carcinoma” initially was made based on FNA findings of one of the nodules; shortly thereafter, an adrenal mass was found during imaging staging for the “lung carcinoma” and was thought to be a metastatic tumor from the lung origin. The adrenal mass was aspirated, and the cytolog- ic features were identical to those of the lung nodule but were immunocytochemically consistent with primary ACC. The adrenal tumor was subsequently removed surgically and con- firmed to be ACC histologically. This case represented an ACC with synchronized distant (lung) metastasis. Distant metastases (predominantly involving liver) were found in 4 other patients during imaging staging of their primary ACCs. The cytologic diagnosis of each primary ACC was based on a combination of clinical and radiologic information, cytologic features, immunocytochemical results, and electron micro- scopic findings. Histologic confirmation was available for 3 of 9 primary ACCs.
For 11 metastatic ACCs in 10 patients, the sites aspirated were 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 the metastatic tumors, as measured by computed tomography or
ultrasonography, was 3.0 cm (range, 0.7-6.0 cm). At the time of aspiration, 9 of 10 patients had a history of primary ACC (1 patient also had a history of prostate carcinoma); most metas- tases were found during imaging follow-up (Table 2), and 1 patient (case 11) had virilizing symptoms. One patient (case 14) had a history of “renal cell carcinoma” that was diagnosed at a local hospital, based on histologic and gross findings of the patient’s nephroadrenalectomy specimen that revealed a large mass extensively involving both the adrenal gland and the adja- cent kidney. Four months after nephroadrenalectomy, a new retroperitoneal soft tissue nodule was found and aspirated. The lesion was cytologically and immunophenotypically consistent with carcinoma of an adrenal cortical origin. These findings led to a retrospective review and an immunohistologic workup of the original tumor, and the results were consistent with ACC instead of renal cell carcinoma. For diagnosis of metastatic ACCs, a similar approach to that used for diagnosing primary ACC was used. In addition, morphologic comparison of the metastatic 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 13 patients had died of ACC. The median overall survival time was 17 months, and the 5-year overall survival rate was 23% (95% confidence interval, 8%-68%).
Cytologic Features
The cytologic features of the 20 ACCs are summarized in ITable 31. Cytologic features of primary and metastatic ACC were similar. Most aspiration samples were hypercellular and were composed of large tumor cells arranged singly or in loose clusters, with focal tissue fragments where tumor cells were enmeshed in a fibrovascular network. Necrotic debris was found frequently in the background. Tumor cells were mostly plasmacytoid or polygonal, with well-preserved, mod- erate to abundant, finely granular cytoplasm IImage 11. Some cells had vacuoles admixed with granular cytoplasm. In 3 tumors, perinuclear cytoplasmic condensation was observed (better shown on Diff-Quik smear), giving a globule-like appearance Image 21. Nuclei were mostly eccentrically placed and variably enlarged with hyperchromatic and coarse chromatin and prominent nucleoli. Nuclear pleomorphism (ie, anisonucleosis, bizarre-shaped nuclei including binucleation or multinucleation, and spindle-shaped nuclei) was substantial in most tumors. Mitotic figures, occasionally with atypical forms, were found in all but 2 tumors.
At on-site evaluation, differential diagnosis was broad because of the presence of a wide morphologic spectrum. For example, 1 tumor (case 5) exhibited cytologic features that closely simulated those of epithelioid melanoma. An adrenal cortical origin was supported by immunostaining results ITable 41 and ultrastructural findings that demonstrat- ed features of steroid-producing cells (ie, abundant smooth endoplasmic reticulum, numerous mitochondria with tubulovesicular cristae, and lipids). Two primary tumors (cases 6 and 8) were morphologically reminiscent of adrenal
cortical adenoma because the aspirates showed relatively bland cytologic features and were composed of small and rather uniform tumor cells with smooth nuclear outlines, evenly distributed chromatin, inconspicuous nucleoli, and
ITable 3 Cytologic Features of 20 Cases of ACC in 19 Patients*
| Feature | Results |
|---|---|
| Cellularity | |
| High | 14 (70) |
| Moderate | 5 (25) |
| Low | 1 (5) |
| Architecture | |
| Predominantly dyshesive | 8 (40) |
| Dyshesive and cohesive | 11 (55) |
| Predominantly cohesive | 1 (5) |
| Background | |
| Necrotic debris | 14 (70) |
| Neutrophils | 3 (15) |
| Lipid drops, focal | 3 (15) |
| Cytoplasm | |
| Finely granular | 20 (100) |
| Foamy or vacuolated | 6 (30) |
| Stripped off | 5 (25) |
| Nuclear pleomorphism | |
| Marked | 11 (55) |
| Moderate | 5 (25) |
| Mild | 4 (20) |
| Mitotic figures | |
| Frequent | 8 (40) |
| Occasional | 10 (50) |
| Not found | 2 (10) |
| Nucleoli | |
| Prominent | 12 (60) |
| Inconspicuous | 8 (40) |
* Data are given as number (percentage).
A
B
rare mitotic figures.5,6,20 Focally, tumor cells demonstrated abundant foamy/vacuolated cytoplasm that might be stripped off, resulting in numerous bare nuclei Image 31. 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 and focal necrosis were identified after careful scrutiny of the smears. Bland cytologic features also were found in 2 metastatic tumors (cases 15 and 16), in which the tumor cells were plasmacytoid with eccentrically placed uniform nuclei, fine chromatin, and inconspicuous nucleoli, raising a con- cern for metastatic low-grade neuroendocrine tumor from an extra-adrenal origin Image 41. 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 primary ACC (case 4) and diffusely in 1 metastatic ACC (case 13 in
A
B
| Antibody | Case No. | Detection Rate* | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 2 | 5 | 6 | 7 | 8 | 9 | 11 | 12A | 13 | 14 | 15 | 16 | 18 | ||
| 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
A
B
an axillary lymph node). The latter tumor showed abundant singly arranged or clusters of bizarre spindle cells with marked nuclear atypia and brisk mitotic figures IImage 51. These features raised a differential diagnosis that included sarcomatoid ACC, high-grade sarcoma, and spindle cell melanoma. The results of immunocytochemical staining supported 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 published histologic 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 each case. 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/or mitosis were found in each case. Metastatic ACCs generally showed 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 were obtained in 13 cases and showed features comparable to those of the direct smears. Tumor cells typically were arranged in diffuse/solid sheets or nests IImage 61, but a pat- tern of thin trabeculae separated by delicate sinusoidal spaces was observed in 2 tumors Image 71. The cells demonstrated eosinophilic cytoplasm with variable nuclear atypia, including pleomorphism, hyperchromasia, promi- nent nucleoli, and mitotic figures. Foci of necrosis were noted frequently.
Immunocytochemical Results
The results of the immunoperoxidase studies of the ACCs are summarized in Table 4. Positive staining for pancytoker- atin was found in 55% (6/11) of the tumors tested, A103 in 60% (3/5), calretinin in 50% (2/4), inhibin in 50% (4/8), vimentin in 67% (2/3), and synaptophysin in 29% (2/7). No tumor showed immunoreactivity to chromogranin, S-100, or HMB-45.
Discussion
Our study demonstrated that ACC can show a wide mor- phologic spectrum, which can cause diagnostic confusion. An adrenal cortical origin of an adrenal mass may be established readily by immunostaining, ultrastructural findings, and clini- cal information. Abnormal endocrine manifestations and/or laboratory tests are frequent findings because more than half of ACCs are functional owing to aberrant hormonal secre- tion.4,9 However, distinguishing ACC from adrenal cortical adenoma, 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 the presence of vascular or capsular invasion correlated with malignant behavior. Currently, the recommended histologic criteria for ACC are a modified system proposed by Weiss et al21 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-power fields, atypical mitotic figures, eosinophilic cytoplasm with fewer 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 is limited by small samples or insufficient sampling and the lack of an architectural pattern. In addition, macroscopic findings that 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 to distinguish 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 that ACC 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 prominent nucleoli. These features were similar to those described in the literature 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 nuclear membrane, fine and evenly distributed chromatin, and incon- spicuous nucleoli.5,6,20 The cells of a benign lesion tend to form cohesive clusters and often have stripped nuclei. Although focal anisonucleosis and mild nuclear atypia may be found, mitosis and necrosis are exceedingly rare in benign lesions.5,8,14 However, benign and malignant cortical tumors may show overlapping cytologic features,14 as illustrated by the 2 primary and the 2 metastatic ACCs in our study that showed rather bland cytologic features. Cell-block sections of ACCs also can show a predominantly thin trabecular pattern as most benign cortical lesions do.
Because no single specific feature allows a definitive diagnosis 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, and 40% met 3 criteria. Necrosis and/or mitosis were found in
each case. The frequency of each feature present in primary and metastatic ACCs generally was similar, except for necro- sis that was found less easliy in metastatic ACCs, probably because of the smaller tumor size. Even in cytologically bland cases, scattered mitoses and/or focal necrosis were detected. Although accurate quantification of these features is not appli- cable in FNA samples, identifying numerous and pronounced atypical features in multiple fields would enhance the diag- nostic certainty for ACC cytologically. Large tumor size is a supportive feature. Caution should be exercised in tumors showing bland cytologic features, especially if the tumors are relatively small.
Data presented at an international consensus conference3 demonstrated that more than 95% of ACCs were larger than 5 cm (mean, 10 cm). Similarly, in a review of 602 ACCs, Ng and Libertino9 found that tumor size ranged from 4 to 25 cm (mean ± SD, 9.8 ±4.1 cm). In our series, the 9 primary ACCs were all 10 cm or larger (mean, 11.9 cm). In contrast, benign lesions characteristically are smaller than 3.5 cm and rarely exceed 5 cm.5,6,26 Size overlapping between ACC and cortical adenoma has been reported, mostly within the range of 4.0 to 7.0 cm.3,10,27 It has been shown that adrenal cortical tumors larger than 5 cm likely behave aggressively, even if their mor- phologic features are not evidently malignant.7 Accordingly, a complete surgical excision of an adrenal mass larger than 5 cm has been recommended.3
Pheochromocytoma, a primary medullary tumor of the adrenal gland, can mimic an ACC in the growth pattern and cellular morphologic features and, thus, needs to be exclud- ed.28 A systematic approach using clinical, laboratory, radio- logic, cytologic, immunocytochemical, and ultrastructural findings can aid in the distinction.21
Because of anatomic proximity, ACC often directly extends into renal parenchyma.9 Morphologically, ACC and renal cell carcinoma resemble each other a great deal.7,14,17 We encountered a primary ACC that initially was diagnosed as renal cell carcinoma on histologic examination (case 14). The misinterpretation stemmed from the difficulty in determining where 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 be possible7,16 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-small cell carcinoma. Furthermore, ACC can simulate melanoma, not only on cytologic features, but also on immunoreactivity to antibody A103.29 Additional immunomarkers such as S-100 or HMB-45 should be used to differentiate between ACC and melanoma. Last, we found a metastatic ACC composed pre- dominantly of malignant spindle cells (case 13), raising the possibility 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 gland such as leiomyosarcoma,33 a direct extension of the retroperi- toneal sarcoma or sarcomatoid renal cell carcinoma, and metastatic spindle cell malignancy such as carcinoma, sarco- ma, and melanoma.
Patients with primary ACC usually present at advanced stages. The most common metastatic sites are liver, lung, retroperitoneal lymph nodes, and bone.9,28,34-36 Similarly, all the primary ACCs in our study were large (≥10cm), and more than half of the patients had synchronized distant metastasis (4 in liver and 1 in lung) at the time the adrenal masses were aspi- rated. Of the 11 metastatic ACCs aspirated, the liver was the most commonly involved organ. The median overall survival time of the 19 patients was 17 months, and the 5-year overall survival rate was 23%. These values are within the range of previously reported outcomes.4,9-11
Owing to its rich sinusoidal blood supply, the adrenal gland is the fourth most frequent metastatic site for tumor spread (after the lungs, liver, and bone).9,28 In fact, the inci- dence of metastatic tumor involving the adrenal gland is much higher 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 tumor may be indistinguishable cytologically from primary ACC. Likewise, when an ACC metastasizes to a visceral organ, the primary malignancy of that organ (especially hepatocellular carcinoma and renal cell carcinoma)7,14-16,40 needs to be con- sidered. For ACCs metastasizing to lymph node, soft tissue, or bone, the differential diagnosis should include metastatic car- cinoma, sarcoma, and melanoma of other sources. Although ultrastructural 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 with those of previous histologic or cytologic material (obtained from 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 rates varied 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 our study, we found that A103 was expressed in 60% of ACCs, cal- retinin in 50%, inhibin in 50%, and vimentin in 67%. We and others28,48 showed that ACCs variably expressed pancytoker- atin and synaptophysin but not chromogranin. Variable detec- tion rates in these immunomarkers could, in part, result from differences in fixative solution, antigen retrieval technique, and
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antibody used in different studies and insufficient sampling when the distribution of positively stained cells is focal and patchy. These findings highlight the need to include a panel of immunomarkers in the diagnostic workup.
FNA cytologic features of ACC are characteristic but not specific. Identifying at least 3 of the 5 cytologic features we have proposed, especially necrosis and mitosis, favors a diag- nosis of ACC. Correlation of cytologic, immunophenotypic, and ultrastructural findings with clinical information and knowledge of tumor size are crucial to achieve a proper FNA diagnosis.
From the Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston.
Address correspondence to Dr Gong: Dept of Pathology, Unit 53, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030.
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