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Annals of Diagnostic Pathology 14 (2010) 204-208
Oncocytic adrenocortical carcinoma
Hiroya Ohtake, MD, PhDa,*, Hiroshi Kawamura, MD, PhDb, Masami Matsuzaki, MD, PhD°, Eiichi Yokoyama, MDb, Masayuki Kitajima, MDª, Shiro Onizuka, MD, PhDe, Mitsunori Yamakawa, MD, PhDa
ªDepartment of Pathology, Yamagata University School of Medicine, Yamagata 990-9585, Japan bDivision of Surgery, Sanyudo Hospital, Yonezawa 992-0045, Japan
“Division of Surgery, Hoshi General Hospital, Koriyama 963-8501, Japan
ªDivision of Urology, Saiseikai Kurihashi Hospital, Kurihashi 349-1105, Japan
“Division of Urology, Tokyo Women’s Medical University, Tokyo 162-8666, Japan
Abstract
Only 17 cases of oncocytic adrenocortical carcinoma have been reported in the English literature. Here, we report an incidental case of oncocytic adrenocortical carcinoma. The patient was a 69-year- old man with the chief complaint of abdominal pain. Abdominal computed tomography revealed a left adrenal tumor. No hormonal symptoms were observed. The excised tumor was whitish, encapsulated, and 75 × 60 × 45 mm in size. Large polygonal tumor cells were arranged in a generally diffuse architecture and exhibited abundant eosinophilic granular cytoplasm. Nuclear atypia with atypical mitotic figures and capsular and sinusoidal invasions were observed. The tumor cells were immunopositive for vimentin, neuron-specific enolase, and synaptophysin but not for a-inhibin, melan A, or p53. Diffuse and strong immunopositivity with an antimitochondrial antibody proved that this tumor was truly oncocytic. Upon review of previous cases of oncocytic adrenocortical tumors, we reconsidered the diagnostic findings of the potential for malignancy. @ 2010 Elsevier Inc. All rights reserved.
Keywords:
Adrenal gland; Oncocytic adrenocortical carcinoma; Bisceglia’s criteria; Immunohistochemistry
1. Introduction
Oncocytic adrenocortical neoplasms are a rare entity. To date, only 24 cases of adrenocortical oncocytoma, 8 cases of oncocytic neoplasm with uncertain malignant potential, and 17 cases of oncocytic adrenocortical carcinoma [1-8] have been reported in the English literature. There remains a paucity in our knowledge regarding this disease entity. Therefore, we present a case of oncocytic adrenocortical carcinoma and review previous reports to reconsider the diagnostic criteria about the potential for malignancy.
2. Case report
A 69-year-old man was hospitalized with abdominal pain. Significant prior medical history included total gastrectomy for gastric cancer 15 years ago. His abdominal symptom appeared to be the result of post- operative intestinal adhesion. During close examination for intestinal abnormality, a left adrenal tumor was found incidentally on computed tomography. He did not exhibit hypertension or any hormonal symptoms. Blood and urine analysis showed no abnormal data other than impaired glucose tolerance. Serum hormone levels were as follows: cortisol was 8.6 mg/dL (reference range, 5.0-17.9 mg/dL); adrenocorticotropic hormone, 18.9 pg/mL (7.1-53.8 pg/ mL); aldosterone, 4.9 ng/dL (3.5-24.0 ng/dL); epinephr- ine, 10 pg/mL (0-100 pg/mL); and norepinephrine, 150 pg/mL (100-450 pg/mL). The patient subsequently under- went left adrenalectomy.
* Corresponding author. Tel .: +81 23 628 5238; fax: +81 23 628 5240. E-mail address: hootake@med.id.yamagata-u.ac.jp (H. Ohtake).
3. Materials and methods
The resected left adrenocortical tumor was fixed in 10% formalin, and tissue samples were embedded in paraffin blocks. Four-micrometer-thick sections were
routinely prepared and stained with hematoxylin and eosin and elastica-Masson stains. Immunohistochemical staining was performed on paraffin-embedded sections using a labeled streptavidin-biotinylated peroxidase com- plex. The immunohistochemical panel included antibodies
*
*
S
Ad
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1
A
| A | B | ||
|---|---|---|---|
| C | D | E | F |
| G | H | 1 | J |
Fig. 1. Gross and histologic findings of the present case. (A) Macroscopic view of cut surface of the tumor. The tumor is composed of several nodules. (B) Eosinophilic tumor cells are arranged in a diffuse pattern (medium power). (C) A multinucleated tumor cell with a nuclear pseudoinclusion is present (high power). (D) An atypical mitotic figure is found (high power). (E) Sinusoidal invasion (S) of a tumor cell cluster (between arrows) is found (elastica-Masson, scanning). (F) The tumor (T) exhibits capsular invasion (*) and extends in the adjacent fibrous tissue (Ad) (elastica-Masson, scanning). (G) Immunohistologic findings of the present case. The tumor cell (T) shows diffuse cytoplasmic staining for antimitochondrial antibody (upper half); on the other hand, most of normal adrenal cells (N) show sparse cytoplasmic positivity (lower half). (H) The tumor cell is positive for antivimentin antibody. The tumor cells expressing neuron- specific enolase (I) are exclusively negative for synaptophysin (J), demonstrated in serial paraffin sections. (G-J) Counterstained with hematoxylin.
against mES-13 (antimitochondrial antibody; monoclonal, clone A-113-1, diluted 1:50; Biogenex, San Ramon, Calif), vimentin (monoclonal, clone V9, diluted 1:50; DAKO, Glostrup, Denmark), hydroxysteroid dehydrogen- ase type 1 (polyclonal, diluted 1:100; The Binding Site, Birmingham, UK) and type 2 (polyclonal, diluted 1:25, The Binding Site), neuron-specific enolase (polyclonal, prediluted; Nichirei, Tokyo, Japan), synaptophysin (poly- clonal, diluted 1:25, DAKO), epithelial membrane antigen (monoclonal, clone E29, diluted 1:50, DAKO), chromo- granin A (polyclonal, diluted 1:500, DAKO), a-inhibin (monoclonal, clone R1, diluted 1:50, DAKO), melan A (monoclonal, clone M2-7C10, prediluted; Nichirei), p53 (monoclonal, clone 1801, diluted 1:40; Novocastra, New- castle-upon-Tyne, UK), and Ki-67 (monoclonal, clone MIB-1, diluted 1:50; DAKO).
4. Results
4.1. Gross findings
The tumor mass was easily separated from the left kidney but was partially adherent to the pancreatic tail and peritoneum. The tumor was 75 × 60 × 45 mm in size (Fig. 1A). The cut surface was whitish and consisted of several nodules separated by fibrous tissue. The tumor was almost completely surrounded by a fibrous capsule. Necrotic and microhemorrhagic foci were also observed.
4.2. Light microscopy
The tumor was composed primarily of moderate- to large- sized polygonal cells filled with eosinophilic granular cytoplasm. The neoplastic cells were predominantly arranged in a diffuse pattern (Fig. 1B). In some areas, tumor cells were packed in large nests separated by sinusoids, although trabecular pattern was not observed. Regional discrete necrosis was also evident. Occasional nuclei were pleo- morphic and exhibited prominent nucleoli. Multinucleate giant cells and eosinophilic nuclear pseudoinclusions were often observed (Fig. 1C). On average, 3 mitoses were observed for 50 high power fields (HPFs) (original magnification ×400). Atypical mitosis was observed occa-
sionally (Fig. 1D). Capsular and sinusoidal invasion was also evident (Fig. 1E and F).
4.3. Immunohistologic findings
The eosinophilic granular cytoplasm of the neoplastic cells was diffusely and strongly immunostained with antimitochondrial antibody, indicating an increase in the number of mitochondria (Fig. 1G), antivimentin antibody (Fig. 1H), and anti-type 1 and type 2 hydroxysteroid dehydrogenase, respectively. These cells were focally positive for neuron-specific enolase (Fig. 1I) and synap- tophysin (Fig. 1J). No immunoreactivity was observed for epithelial membrane antigen, chromogranin A, a-inhibin, melan A, or p53. The average MIB-1 labeling index was 5.9%.
5. Discussion
We summarized the immunophenotypic characteristics of previous cases and compared them with the present case (Table 1). The pattern of immunostaining in the present case was roughly consistent with those previously reported for oncocytic adrenocortical carcinoma. Expression of a- inhibin in adrenocortical tumors is considered to be reflective of the hormonal status of the tumor [9]. Diverse immunoreactivity to a-inhibin in oncocytic adrenocortical tumors may also be indicative of their hormonal activity. In the present case, both neuron-specific enolase (NSE) and synaptophysin were expressed. However, the NSE-positive tumor cells were interestingly prone to a lack of expression of synaptophysin and vice versa (Fig. 1I and J), as described previously in normal adrenal cortex [10].
Though microscopic findings of eosinophilic cytoplasm and diffuse and strong immunopositivity against antimito- chondrial antibody (mES-13) seemed enough to lead us to diagnosis of oncocytic neoplasm, ultrastructural examina- tions were executed in former studies. Numerous mitochon- dria occupying cytoplasm of tumor cells are observed in oncocytic adrenocortical tumors. In oncocytic adrenocortical carcinoma, some authors reported paucity of tubular cristae and smooth endoplasmic reticulum commonly seen in
| Antibody | Adrenocortical oncocytoma | Oncocytic tumor with uncertain malignant potential | Oncocytic adrenocortical carcinoma | The present case |
|---|---|---|---|---|
| Vimentin | 7/15 (46.7%) | 4/6 (66.7%) | 14/15 (93.3%) | Positive |
| a .- Inhibin | 1/1 (100%) | 1/4 (25%) | 9/12 (75%) | Negative |
| Melan A | 3/3 (100%) | 4/4 (100%) | 2/5 (20%) | Negative |
| Synaptophysin | 8/9 (88.9%) | 2/7 (28.6%) | 6/12 (50%) | Positive |
| Neuron-specific enolase | 8/11 (72.7%) | 4/5 (80%) | 3/5 (60%) | Positive |
| Chromogranin A | 0/13 (0%) | 0/7 (0%) | 0/9 (0%) | Negative |
Values indicated positive/total cases previously reported.
| Histopathologic findings | Group with significant malignant findingsª (n = 10) | Group without significant malignant findings (n = 39) | The present case |
|---|---|---|---|
| Mitotic index (per 50 HPFs) | |||
| ≥10 | 3/7 (42.9%) | 1/28 (3.6%) | |
| ≥5,<10 | 1/7 (14.3%) | 1/28 (3.6%) | |
| <5 | 3/7 (42.9%) | 11/28 (39.3%) | 3 |
| Absent | 0/7 (0%) | 15/28 (53.6%) | |
| MIB-1 labeling index | |||
| ≥10% | 2/5 (40%) | 1/19 (5.3%) | |
| ≥5%, <10% | 1/5 (20%) | 6/19 (31.6%) | 5.9 |
| <5% | 2/5 (40%) | 12/19 (63.2%) | |
| Atypical mitosis | |||
| (+) | 2/4 (50%) | 1/21 (4.8%) | (+) |
| (-) | 2/4 (50%) | 20/21 (95.2%) | |
| Capsular invasion | |||
| (+) | 6/8 (75%) | 8/30 (26.7%) | (+) |
| (-) | 2/8 (25%) | 22/30 (73.3%) | |
| Sinusoidal invasion | |||
| (+) | 1/4 (25%) | 2/20 (10%) | (+) |
| (-) | 3/4 (75%) | 18/20 (90%) | |
| Confluent necrosis | |||
| (+) | 7/8 (87.5%) | 10/34 (29.4%) | (+) |
| (-) | 1/8 (12.5%) | 24/34 (70.6%) | |
| Size (cm) | |||
| ≥10 | 5/8 (62.5%) | 15/37 (40.5%) | |
| ≥5,<10 | 3/8 (37.5%) | 18/37 (48.6%) | 7.5 cm |
| <5 | 0/8 (0%) | 4/37 (10.8%) | |
| Weight (g) | |||
| ≥500 | 3/6 (50%) | 8/31 (25.8%) | |
| ≥100,<500 | 3/6 (50%) | 14/31 (45.2%) | 250 g |
| <100 | 0/6 (0%) | 9/31 (29%) | |
| Nuclear atypism | |||
| High | 7/9 (77.8%) | 30/37 (81.1%) | High |
| Low | 2/9 (22.2%) | 7/37 (18.9%) | |
| Dominant diffuse architecture | |||
| (+) | 7/8 (87.5%) | 30/35 (85.7%) | (+) |
| (-) | 1/8 (12.5%) | 5/35 (14.3%) | |
| P53 immunoreactivity | |||
| (+) | 1/2 (50%) | 0/8 (0%) | |
| (-) | 1/2 (50%) | 8/8 (100%) | (-) |
a Significant malignant findings include venous invasion, distant metastasis, and direct invasion into adjacent organs.
conventional adrenocortical adenoma [5], though it is not always the case [1].
The most problematic issue in treating oncocytic adrenocortical tumors is the determination of malignancy. The diagnostic system devised by Weiss [11] is commonly used in determining the malignancy of nononcocytic adrenocortical tumors. In general, oncocytic adrenocortical tumors include few clear cells, exhibit a diffuse architecture, and often show high nuclear atypia even when they lack malignant behavior [1,12]. Therefore, it is inappropriate to apply Weiss’s criteria to these cases. Bisceglia et al [1] proposed a new system that classifies them according to 3 categories. An oncocytic tumor is considered as malignant if it exhibits more than one of following features: a mitotic rate
more than 5 of 50 HPFs, any atypical mitoses, or venous invasion. Otherwise, it is considered to be a tumor with uncertain malignant potential when one or more of the following features are observed: large size (>10 cm and/or >200 g), necrosis, capsular invasion, or sinusoidal invasion. In the absence of all of these features, a tumor is considered to be benign. According to this system, the features observed in our case (atypical mitoses, sinusoidal and capsular invasion) led us to make the diagnosis of oncocytic adrenocortical carcinoma.
To date, 49 cases of oncocytic adrenocortical tumors have been reported in the English literature. These cases were classified according to the presence or absence of significant malignant findings, venous invasion, distant metastases, or direct invasion into adjacent organs. The differences between these groups were compared (Table 2). In most cases without significant malignant findings, the mitotic index was less than 5 per 50 HPFs, the MIB-1 labeling index was less than 10%, and atypical mitosis was not present. Capsular invasion and confluent necrosis were infrequent. High-grade nuclear atypism and predominant diffuse architecture were common, although they were generally interpreted as features suggesting malignancy in nononcocytic adrenocortical tumors. On the other hand, the group with significant malignant findings very frequently exhibited higher mitotic and MIB-1 labeling indices with atypical mitosis. Although there are a limited number of reported cases (n = 8), the group without significant malignant findings was exclusively negative for p53, suggesting that p53 could be an important factor in the diagnosis of malignant tumors.
In summary, the presence of venous invasion, distant metastasis, or direct invasion into adjacent organs is considered crucial in the diagnosis of malignant oncocytic tumors. The second best category of findings includes mitotic index higher than 5/50 HPFs, MIB-1 labeling index higher than 10%, presence of atypical mitosis, or possibly p53 expression.
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