Pheochromocytomas (PHEOs) are relatively rare
catecholamine-producing
tumors derived from adrenal medulla. Tumor microenvironment (TME) including neoangiogenesis has been explored in many human
neoplasms but not necessarily in PHEOs. Therefore, in this study, we examined tumor infiltrating lymphocytes (CD4 and CD8), tumor associated macrophages (CD68 and CD163), sustentacular cells (S100p), and angiogenic markers (CD31 and areas of intratumoral
hemorrhage) in 39 cases of PHEOs in the quantitative fashion. We then compared the results with
pheochromocytoma of the adrenal gland scaled score (PASS), grading system for
pheochromocytoma and
paraganglioma (GAPP) and the status of intra-tumoral
catecholamine-synthesizing
enzymes (TH, DDC, and PNMT) as well as their clinicopathological factors. Intratumoral CD8 (p = 0.0256), CD31 (p = 0.0400), and PNMT (p = 0.0498) status was significantly higher in PHEOs with PASS <4 than PASS ≧4. In addition, intratumoral CD8+ lymphocytes were also significantly more abundant in well-than moderately differentiated PHEO according to GAPP score (p = 0.0108) and inversely correlated with
tumor size (p = 0.0257). Intratumoral CD68+ cells were significantly higher in PHEOs with regular or normal histological patterns than those not (p = 0.0370) and inversely correlated with
tumor size (p = 0.0457). The status of CD163 was significantly positively correlated with that of CD8 positive cells (p = 0.0032). The proportion of intratumoral
hemorrhage areas was significantly higher in PHEOs with PASS ≧4 (p = 0.0172). DDC immunoreactivity in
tumor cells was significantly positively correlated with PASS score (p = 0.0356) and TH status was significantly higher in PHEOs harboring normal histological patterns (p = 0.0236) and cellular monotony (p = 0.0219) than those not. Results of our present study did demonstrate that abundant CD8+ and CD68+ cells could represent a histologically low-scored
tumor. In particular, PHEOs with increased intratumoral
hemorrhage should be considered rather malignant. In addition, abnormal
catecholamine-producing status of
tumor cells such as deficient PNMT and TH and increased DDC could also represent more aggressive PHEOs.