The Value of Histological Algorithms to Predict the Malignancy Potential of Pheochromocytomas and Abdominal Paragangliomas-A Meta-Analysis and Systematic Review of the Literature

Abstract

Pheochromocytomas (PCCs) and abdominal paragangliomas (PGLs), collectively abbreviated PPGLs, are neuroendocrine tumors of the adrenal medulla and paraganglia, respectively. These tumors exhibit malignant potential but seldom display evidence of metastatic spread, the latter being the only widely accepted evidence of malignancy. To counter this, pre-defined histological algorithms have been suggested to stratify the risk of malignancy: Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) and the Grading system for Adrenal Pheochromocytoma and Paraganglioma (GAPP). The PASS algorithm was originally intended for PCCs whereas the GAPP model is proposed for stratification of both PCCs and PGLs. In parallel, advances in terms of coupling overtly malignant PPGLs to the underlying molecular genetics have been made, but there is yet no combined risk stratification model based on histology and the overall mutational profile of the tumor. In this review, we systematically meta-analyzed previously reported cohorts using the PASS and GAPP algorithms and acknowledge a "rule-out" way of approaching these stratification models rather than a classical "rule-in" strategy. Moreover, the current genetic panorama regarding possible molecular adjunct markers for PPGL malignancy is reviewed. A combined histological and genetic approach will be needed to fully elucidate the malignant potential of these tumors.

Keywords: GAPP; PASS; histology; meta-analysis; paraganglioma; pheochromocytoma.

Figure 1

Photomicrographs of metastatic (A,B) and non-metastatic (C,D) pheochromocytoma cases with elevated PASS scores previously diagnosed at our institution. Scale bars are 25 micrometers for A,B and D, and 100 micrometers for C. (A) Nuclear pleomorphism in a pheochromocytoma with a total PASS score of 8. This tumor was resected from a 61-year old female who developed metastatic disease 9 years after initial diagnosis. (B) Same case displaying hypercellularity and nuclear hyperchromasia, two additional parameters included in the PASS algorithm. (C) Large and irregular nests in a pheochromocytoma with a PASS score of 7, diagnosed in a 41-year old male. The patient is alive without metastatic disease after 20 years of follow-up. (D) Same case displaying focal tumor cell spindling with elongated nuclei, a phenomenon yielding two PASS points.

Figure 2

Schematic overview of the (A) PASS and (B) GAPP meta-analyses outcome in pheochromocytoma (PCC) and abdominal paraganglioma (PGL). Each tumor sample is represented by a square, in which green color indicates a benign tumor as according to the definition by each study. Orange squares denote cases defined as malignant. The left column of each classification system signifies number of cases with low algorithm scores, whereas the right column contains cases with scores ≥4 (PASS) and ≥3 (GAPP). As demonstrated here, both algorithms exhibit excellent sensitivity but reduced specificity towards malignant cases. These analyses indicate that low PASS and GAPP scores almost always are associated with a benign clinical course.