[Risk predication for metastasis and grading system in complex adrenal pheochromocytoma and paraganglioma]

Objective: To score pheochromocytoma and paraganglioma (PPGL) by using the composite pheochromocytoma and paraganglioma grading system (COPPS), to analyze the correlations of COPPS, the pheochromocytoma of the adrenal gland scaled score (PASS), and the grading system for adrenal pheochromocytoma and paraganglioma (GAPP) with tumor metastasis or recurrence and to explore the relationship between gene mutations and metastasis or recurrence in some PPGL. Methods: Clinicopathological data of the 186 paragangliomas diagnosed from January 2012 to December 2022 at Beijing Friendship Hospital, Beijing, China, the Peking University Third Hospital, Beijing, China, and the First Affiliated Hospital of Shihezi University, Shihezi, China were collected and analyzed. Predictive values of the three systems for tumor metastasis or recurrence were evaluated. Immunohistochemistry was performed using the EnVision staining method. Whole-exome sequencing was used to detect gene mutations in 15 tumors. Results: Among the 186 PPGL patients, there were 93 females and 93 males, age 49 (47, 50) years old. Metastasis or recurrence occurred in 60 cases. 34 of the tumors were located in the retroperitoneum. The maximum tumor diameter was >7 cm in 42 cases. A COPPS score ≥3 was observed in 97 cases (52.2%, 97/186), among whom 53 cases (54.6%, 53/97) experienced metastasis or recurrence. The metastasis/recurrence rate in the COPPS score≥3 group was significantly higher than that in the <3 group (χ²=46.469,P<0.001). Tumor location in the retroperitoneum, presence of large nests of cells, pathological mitosis, spindle cells, capsular invasion, and fat infiltration were all associated with a COPPS score ≥3 (χ²=18.370, 51.730, 8.914,18.750, 62.481, 19.354, all P<0.05). The sensitivity of COPPS for predicting metastasis/recurrence was 88.3% (53/60), while the specificity was 65.1% (82/126). Negative expression of SDHB was observed in 50 cases, and negative expression of S-100 protein was observed in 96 cases. DNA extraction failed to produce qualified DNA in 3 cases; among the remaining 12 tumors that were subject to DNA extraction, 739 mutations (in 658 genes) were detected, including 300 germline mutations (in 265 genes) and 439 somatic mutations (in 408 genes). Related pathogenic germline mutation genes occurred on: SDHA, MDH2, MEN1, EGLN1, RET and SDHB. All 12 patients had more than four pathogenic germline mutations. Somatic pathogenic mutation genes included ATRX, KIF1B, EPAS1, HRAS, NF1, and MAML3. Conclusions: A higher COPPS score (≥3 versus <3) is associated with a higher metastasis/recurrence rate. Its sensitivity for predicting tumor metastasis/recurrence is higher than that of GAPP, while its specificity is higher than that of PASS. The combined use of negative SDHB and S-100 protein expression with COPPS could be used to stratify the risk of metastasis/recurrence in PPGL.