A Critical Evaluation of sst3 and sst5 Immunohistochemistry in Human Pituitary Adenomas

Abstract

Background: Somatostatin receptor (sst) overexpression in neuroendocrine tumors allows sst-targeted tumor imaging and therapy with long-acting, cold, or radioactive somatostatin analogs. sst2 has been most important, owing to its wide overexpression and high affinity for somatostatin analogs, but other sst subtypes become of increasing clinical interest due to drug development. Immunohistochemistry is the preferred method to detect sst in resected tumor tissues. While it is established for sst2 using the antibody UMB-1, there is less experience for other sst subtypes. Methods: sst3 and sst5 immunohistochemistry using the antibodies UMB-5 and UMB-4 was evaluated in 60 pituitary adenomas and compared with in vitro sst autoradiography (ARG), the in vitro gold standard method to assess sst. Results: UMB-4 immunohistochemistry for sst5 yielded membranous staining of tumor cells. It correlated fairly well with ARG, results matching in 80% of tumors. UMB-5 immunohistochemistry for sst3 showed not only a membranous, but also cytoplasmic background staining. Agreement with ARG was limited. All tumors showed UMB-5 staining, while only 57% were positive by ARG. In comparison, UMB-1 staining levels showed a highly significant correlation with autoradiographic sst2 density levels (R² = 0.797). Not only tumor cells, but also intratumoral blood vessels were immunohistochemically positive for sst2, 3, and 5. Conclusion: UMB-1 immunohistochemistry for sst2 is excellent. sst3 immunohistochemistry using UMB-5 is not yet optimal, with suspected limited specificity, and should be applied with caution. UMB-4 immunohistochemistry for sst5 appears to be equivalent to sst5-ARG and suitable for diagnostic applications.

Excellent response to pasireotide therapy in an aggressive and dopamine-resistant prolactinoma

“…Whether a subgroup of patients will benefit from targeting these receptors with a multireceptor ligand with an improved affinity for SST 3 receptor remains to be elucidated. However, immunohistochemistry with the rabbit monoclonal antihuman SST 3 receptor antibody UMB-5 were not performed due to limited specificity for the SST 3 receptor (28).…”

Somatostatin receptor expression in parathyroid neoplasms

“…The scoring system used by Körner et al . (42) (examining SST 2 , in particular) yielded a strong correlation with the binding of the somatostatin receptor measured using in vitro receptor autoradiography. This was, however, primarily focused on membrane expression, which was marginally prevalent in our tumor samples.…”

“…Analyses using either a higher cut-off point (counting weakly positive spots scored 1 as negative) or a minimum of 10% stained cells for positivity yielded insignificant results and the number of positive tumors decreased considerably. A cut-off point of 10% to be considered positive has been suggested for staining of SST 2 (25); however, there is no consensus on the matter, as also a small number of receptor-positive tumor cells might be biologically and/or clinically relevant (42). A cut-off point as low as 1% has been used regarding other markers, such as PDL-1 (44).…”

ANNIVERSARY REVIEW: Octreotide, 40 years later

“…A positive SST scan predicts whether the patient is a candidate for SST2-targeted radiotherapy (vide infra). Recently with the introduction of PET imaging molecular imaging with 68 Ga-labeled somatostatin analogs has been developed; this new compound allows an even greater spatial resolution than 111 In-DTPA-octreotide (59).…”

“…Pasireotide is a multireceptor-targeted somatostatin analog with an in comparison to octreotide slightly lower affinity to SST2, but a nearly 40 times higher affinity to SST5 (66). Corticotropinomas predominantly express SST5 (67,68) and ACTH secretion by cultured tumor cells obtained at transsphenoidal operation is suppressed by pasireotide in nanomolar concentrations in 60% of cases (69). In a multicenter study pasireotide (600 μg (82 patients) or 900 μg (80 patients) twice daily) normalized urinary free cortisol concentrations in 15 and 25% of patients with Cushing's disease, respectively (70).…”