Prognostic indicators of malignancy in adrenal pheochromocytomas: clinical, histopathologic, and cell cycle/apoptosis gene expression analysis.
BACKGROUND
Pheochromocytomas are malignant in approximately 10% of patients. The histologic differentiation between benign and malignant tumors is difficult, the latter diagnosed by the presence of metastatic disease or recurrence.


AIM
To determine if postoperative histologic evaluation using the previously proposed Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) and cell cycle/apoptosis markers can predict patients at risk for recurrence.


METHODS
Using the Memorial Sloan-Kettering Cancer Center adrenal database, we identified 48 patients with 51 resected pheochromocytomas (1987-2006). A senior endocrine pathologist, blinded to clinical outcome, reviewed the histopathologic characteristics of all cases using the PASS system. This pheochromocytoma scoring system is based on the presence of 12 different histologic parameters, including tumor necrosis, mitotic rate, tumor cell spindling, and the presence of large cell nests. In addition, we constructed a tissue microarray of all 5 malignant tumors and 41 of the benign tumors. By immunostaining of the tissue microarray, we assessed the expression of 7 different cell cycle/apoptosis-related genes (p53, Ki-67, Bcl-2, mdm-2, cyclin D1, p21, and p27).


RESULTS
Forty-three patients had a benign clinical course while 5 patients harbored a clinically malignant pheochromocytoma. Tumor necrosis (focal or confluent) was a particularly powerful indicator of malignancy present in 4 of 5 patients (80%) with malignant tumors, but only in 3 of 42 cases (7%) with benign neoplasms (P = .0009). The presence of a high mitotic rate (>3/10 high power fields) and tumor cell spindling significantly correlated with malignancy (P = .026 and .041, respectively). High cellularity was more often present in the malignant lesions (P = .050). There was a highly significant difference in PASS scores between benign and malignant cases (P = .0003). All malignant pheochromocytomas had a PASS score >/=6, well above the previously proposed >/=4 cutoff value. Two of the 4 patients testing positive for Ki-67 (>2% nuclear staining) had a clinically malignant course while only 3 (7%) of the 41 cases with lower Ki-67 positivity rate behaved in a malignant fashion (P = .055). Ki-67-positive tumor had a significantly higher chance of harboring tumor necrosis than Ki-67-negative neoplasms (P < .01). There was no difference in staining between benign and malignant pheochromocytomas using p53, Bcl-2, mdm-2, cyclin D1, p21, and p27.


CONCLUSIONS
(1) A PASS score of <4 predicted benign pheochromocytomas. (2) All malignant pheochromocytomas had a PASS score >/=6, which was significantly higher compared with the benign lesions. Patients with a PASS score >/=4 should be followed closely for recurrence. (3) p53, Bcl-2, mdm-2, cyclin D1, p21, and p27 appear to have no role in predicting the behavior of pheochromocytomas. Ki-67 may help identify those neoplasms at risk for recurrence by prompting the pathologist to look aggressively for adverse histologic features.