Predicting Metastatic Potential in Pheochromocytoma and Paraganglioma: A Comparison of PASS and GAPP Scoring Systems

Abstract

Purpose The Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) and the Grading System for Adrenal Pheochromocytoma and Paraganglioma (GAPP) are scoring systems to predict metastatic potential in pheochromocytoma and paragangliomas (PCC/PGL). The goal of this study is to assess PASS and GAPP as metastatic predictors and to correlate with survival outcomes. Methods The cohort included PCC/PGL with ≥5 years of follow-up or known metastases. Surgical pathology slides were re-reviewed. PASS and GAPP scores were assigned. Univariable and multivariable logistic regression, Kaplan-Meier survival analysis, and Cox proportional hazards were performed to assess recurrence free survival (RFS) and disease specific survival (DSS). Results From 143 subjects, 106 tumors were PCC, and 37 were PGL. Metastases developed in 24%. The median PASS score was 6.5 (IQR:4.0-8.0) and median GAPP score was 3.0 (IQR:2.0-4.0). Interrater reliability was low-moderate for PASS (ICC:0.6082) and good for GAPP (ICC:0.7921). Older age (OR:0.969, p=0.0170) was associated with longer RFS. SDHB germline pathogenic variant (OR:8.205, p=0.0049), extra-adrenal tumor (OR:6.357, p&0.0001), Ki-67 index 1-3% (OR:4.810, p=0.0477), and higher GAPP score (OR:1.537, p=0.0047) were associated with shorter RFS. PASS score was not associated with RFS (p=0.1779). On Cox regression, a GAPP score in the moderately-differentiated range was significantly associated with disease recurrence (HR:3.367, p=0.0184) compared to well-differentiated score. Conclusion Higher GAPP scores were associated with aggressive PCC/PGL. PASS score was not associated with metastases and demonstrated significant inter-observer variability. Scoring systems for predicting metastatic PCC/PGL may be improved by incorporation of histopathology, clinical data, and germline and somatic tumor markers.

Colorectal paragangliomas with immunohistochemical deficiency of succinate dehydrogenase subunit B

“…The AJCC commented on the difficulty of reproducing histological grading due to interobserver inconsistency [13,19]. However, GAPP was improved to be more consistent through the use of objective parameters for diagnosis, and the utility was validated by pathologists [20,21]. In addition to our cases, Yu and Wang [2] reported their rectal PGL with lymph node metastasis that was 40 mm in size, and the histological grading by PASS was 6.…”

Diagnosis for Pheochromocytoma and Paraganglioma: A Joint Position Statement of the Korean Pheochromocytoma and Paraganglioma Task Force

“…Like the PASS system, the GAPP model also has a high sensitivity (90%) and low specificity [ 58 ]. Wachtel et al [ 85 ] recently published a retrospective cohort study, including 143 subjects with PPGLs about the comparison PASS and GAPP scoring system. They found that a higher GAPP score was associated with metastatic PPGLs, whereas the PASS score was not.…”

Challenges in Paragangliomas and Pheochromocytomas: from Histology to Molecular Immunohistochemistry

“…The scheme has been confirmed in several independent series [66][67][68][69][70], but not in other [71,72]. Moreover, in terms of intra-observer variability, the PASS algorithm has been proven subpar-with different pathologists reaching different scores for a considerable proportion of cases [72,73].…”

“…Thus, the diverse group of α-KG dependent dioxygenase enzymes (including PHD enzymes targeting the HIF oncoprotein for degradation as well as TET proteins respon-sible for de-methylating the genome) is functional. Upon aberrant TCA cycle regulation (via mutations in genes encoding enzymes catalyzing key steps of the TCA cycle), accumulation of extra-mitochondrial succinate, fumarate and α-KG metabolites will inhibit dioxygenase function, leading to impaired PHD and TET enzyme activity-thereby promoting HIF pathway activation and genomic hypermethylation algorithm has only been reproduced in few independent studies and is still a fairly young study in need of additional verification [72,74,78]. In the meta-analysis discussed above, the GAPP system exhibited a well-trusted "rule-out" function based on the excellent negative predictive value, similarly to what was shown for PASS (Fig.…”