Gonadotroph Tumors Show Subtype Differences That Might Have Implications for Therapy

Abstract

Gonadotroph tumors, although frequent, are poorly studied and understood, being usually included in the larger nonfunctioning pituitary neuroendocrine tumors (PitNETs) group. Moreover, in comparison to the other types of PitNETs, no established medical treatment is currently available for gonadotroph tumors. Here, we performed a retrospective study and analyzed the clinicopathological characteristics of 98 gonadotroph tumors operated in a single large pituitary center. Although being larger in men (p = 0.01), the aggressiveness of gonadotroph tumors did not appear to be sex-related. LH tumors were rare (4/98) and exclusively encountered in men. Somatostatin receptor type 5 (SST5) was absent in all analyzed tumors. The immunoreactive score (IRS) of somatostatin receptor type 2 (SST2) and of estrogen receptor alpha (ERα) was associated with the histological subtype (p = 0.01 and p = 0.02). IRS ERα correlated moderately with IRS SST2 in all (rho = 0.44, adjusted p-value = 0.0001) and in male (rho = 0.51, adjusted p-value = 0.0002) patients, and with follicle-stimulating hormone (FSH) percentage in all (rho = 0.40, adjusted p-value = 0.0005) and in female (rho = 0.58, adjusted p-value = 0.004) patients. In conclusion, gonadotroph tumors exhibit histological characteristics pinpointing the existence of several subtypes. Their heterogeneity warrants further investigations and may have to be taken into account when studying these tumors and investigating treatment options.

Keywords: estrogen receptor alpha (ERα); gonadotroph adenomas; gonadotroph tumors; sex differences; somatostatin receptor 2 (SST2); somatostatin receptor 5 (SST5); tumor heterogeneity; tumor subtype.

Figure 1

Immunohistochemical analysis of estrogen receptor alpha (ERα) and of somatostatin receptor 2 (SST2) expression in gonadotroph tumors using the immunoreactive score (IRS). IRS is calculated as the percentage of positive nuclei (0 to 4) × the intensity of the staining (0 to 3) (original magnification, ×200). (A). IRS ERα = 12 in a FSH-LH tumor (strong nuclear immunoexpression in 95% of neoplastic cells). (B). IRS ERα = 2 in a FSH-LH tumor (moderately intense immunopositivity in 5% of neoplastic cells). (C). IRS SST2 is negative in this FSH-LH tumor (absence of immunopositivity in the neoplastic cells; faint vascular expression as a positive internal control). (D). IRS SST2 = 12 in a FSH tumor (strong membranous immunoexpression in 100% of neoplastic cells). Abbreviations: follicle-stimulating hormone (FSH), luteinizing hormone (LH).

Figure 2

Tumor subtype-related comparison of IRS SST2 distribution in all (A), male (B) and female (C) cases. Graphs: median with interquartile range; each individual point represents a tumor: circles represent FSH tumors, down-pointing triangles FSH-LH tumors, and up-pointing triangles LH tumors. (A). Statistical test: Kruskal–Wallis, p = 0.01, n = 21, 72, 4, with Dunn’s test for columns comparison. (B). Statistical test: Kruskal–Wallis, p = 0.15, n = 8, 52, 4. (C). Statistical test: Mann–Whitney, p = 0.01, n = 13, 20. Abbreviations: immunoreactive score (IRS), somatostatin receptor 2 (SST2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), not significant (ns), p < 0.05 (*).

Figure 3

Tumor subtype-related comparison of IRS ERα distribution in all (A), male (B) and female (C) cases. Graphs: median with interquartile range; each individual point represents a tumor: circles represent FSH tumors, down-pointing triangles FSH-LH tumors, and up-pointing triangles LH tumors. (A). Statistical test: Kruskal–Wallis, p = 0.02, n = 21, 73, 4, with Dunn’s test for columns comparison. (B). Statistical test: Kruskal–Wallis, p = 0.057, n = 8, 52, 4. (C). Statistical test: Mann–Whitney, p = 0.19, n = 13, 21. Abbreviations: immunoreactive score (IRS), estrogen receptor alpha (ERα), follicle-stimulating hormone (FSH), luteinizing hormone (LH), not significant (ns), p < 0.05 (*).