Metastatic Pheochromocytoma and Paraganglioma: Somatostatin Receptor 2 Expression, Genetics, and Therapeutic Responses

Abstract

Context: Pheochromocytomas and paragangliomas (PPGLs) with pathogenic mutations in the succinate dehydrogenase subunit B (SDHB) are associated with a high metastatic risk. Somatostatin receptor 2 (SSTR2)-dependent imaging is the most sensitive imaging modality for SDHB-related PPGLs, suggesting that SSTR2 expression is a significant cell surface therapeutic biomarker of such tumors.

Objective: Exploration of the relationship between SSTR2 immunoreactivity and SDHB immunoreactivity, mutational status, and clinical behavior of PPGLs. Evaluation of SSTR-based therapies in metastatic PPGLs.

Methods: Retrospective analysis of a multicenter cohort of PPGLs at 6 specialized Endocrine Tumor Centers in Germany, The Netherlands, and Switzerland. Patients with PPGLs participating in the ENSAT registry were included. Clinical data were extracted from medical records, and immunohistochemistry (IHC) for SDHB and SSTR2 was performed in patients with available tumor tissue. Immunoreactivity of SSTR2 was investigated using Volante scores. The main outcome measure was the association of SSTR2 IHC positivity with genetic and clinical-pathological features of PPGLs.

Results: Of 202 patients with PPGLs, 50% were SSTR2 positive. SSTR2 positivity was significantly associated with SDHB- and SDHx-related PPGLs, with the strongest SSTR2 staining intensity in SDHB-related PPGLs (P = .01). Moreover, SSTR2 expression was significantly associated with metastatic disease independent of SDHB/SDHx mutation status (P < .001). In metastatic PPGLs, the disease control rate with first-line SSTR-based radionuclide therapy was 67% (n = 22, n = 11 SDHx), and with first-line "cold" somatostatin analogs 100% (n = 6, n = 3 SDHx).

Conclusion: SSTR2 expression was independently associated with SDHB/SDHx mutations and metastatic disease. We confirm a high disease control rate of somatostatin receptor-based therapies in metastatic PPGLs.

Keywords: SDHB mutation; SDHx mutation; PRRT; metastatic pheochromocytoma/paraganglioma; somatostatin receptor 2; somatostatin receptor–based therapies.

Figure 1.

(A) Mutational landscape of n = 71 SSTR2 IHC-positive PPGLs according to clusters. Tumors without mutations detected in germline or somatic sequencing are depicted under “No mutation”. (B) Mutational landscape of n = 53 SSTR2 IHC-negative PPGLs according to clusters. Tumors without mutations detected in germline or somatic sequencing are depicted under “No mutation.”

Figure 2.

(A) Mean SSTR2 staining intensity in SDHx-related PPGLs compared with PPGLs without SDHx mutations. SSTR2 IHC staining intensity was scored semiquantitatively according to the Volante score (0 = absence of staining, 3 = strong staining). Statistical significance is denoted with stars (*P < .05). Error bars show standard error of the mean (SEM). (B) Mean SSTR2 staining intensity according to cluster. SSTR2 IHC staining intensity was scored semiquantitatively according to the Volante score (0 = absence of staining, 3 = strong staining). According to their mutation profile, PPGLs are divided into 3 main molecular clusters: (1) pseudohypoxia cluster (1A and 1B), (2) kinase-signaling cluster 2, and (3) Wnt signaling cluster 3. Cluster 1 is further divided into cluster 1A (mutations in the Krebs cycle associated genes) and 1B (mutations in the hypoxia-signaling pathway). Statistical significance is denoted with stars (***P < .001). Error bars show standard error of the mean (SEM).

Figure 3.

Kaplan–Meier curves for patients receiving SSTR-based therapies. Abbreviations: PRRT, somatostatin peptide receptor–based radionuclide therapy; SSA, somatostatin analogs.