Phosphorylated S6 as an immunohistochemical biomarker of vulvar intraepithelial neoplasia

Abstract

As life expectancy lengthens, cases of non-viral-associated vulvar squamous cell carcinoma and its precursor lesion, so-called differentiated vulvar intraepithelial neoplasia (VIN), continue to increase in frequency. Differentiated VIN often is difficult to recognize and failure to detect it before invasion results in morbidity and mortality. Thus, identification of a reliable biomarker for this type of lesion would be of great clinical benefit. Our recent studies have identified activation (ser235/236 phosphorylation) of ribosomal protein S6 (p-S6) in basal epithelial cells as an event that precedes and accompanies laminin c 2 overexpression in most preinvasive oral dysplasias. To test this as a potential biomarker of vulvar dysplasia, we immunostained seven differentiated VINs and nine papillomavirusrelated 'classic' VINs, most of which were associated with carcinoma, for p-S6. All carcinomas, all differentiated VINs, and most classic VINs contained regions of p-S6 staining in the basal layer, whereas basal and parabasal cells of normal vulvar epithelium and hyperplastic and inflamed lesions lacking cellular atypia were p-S6 negative. Laminin c 2 was expressed in a subset of VINs, always occurring within basal p-S6 positive regions, as we had found previously for oral dysplasias. Lichen sclerosus is considered a potential precursor of vulvar carcinoma. Two lichen sclerosus lesions of patients with a concurrent carcinoma and one of six lichen sclerosus lesions without atypia or known concurrent carcinoma were basal p-S6 positive. In summary, there is a distinct difference in p-S6 basal cell layer staining between benign and neoplastic vulvar squamous epithelium, with consistent staining of differentiated VIN and of some lichen sclerosus lesions. These results support further studies to assess the potential of p-S6 as a biomarker to identify vulvar lesions at risk of progressing to invasive cancer.

Ribosomal Protein S6 Phosphorylation

“…The usage of the phosphorylation state of Ser235/236 in rpS6 as a biomarker for activation of the PI3K/mTORC1/S6K pathway in tissue samples from tumor biopsies (Li et al, 2014;Pinto et al, 2013;Robb et al, 2006Robb et al, , 2007 or transplants (Lepin et al, 2006;Li et al, 2015) has been repeatedly proposed in recent years. However, these sites can also be phosphorylated by RSK (Roux et al, 2007), and therefore, their phosphorylation cannot be used as an indication for therapeutic strategy involving blockage of PI3K/ mTORC1/S6K signaling.…”

Ribosomal Protein S6: A Potential Therapeutic Target against Cancer?

“…High-level phosphorylation and/or overexpression of RPS6 has been reported in various types of cancers, including acute myeloid leukemia (AML) [ 433 ], breast cancer [ 434 ], cervical cancer [ 435 ], esophageal squamous cell carcinoma (ESCC) [ 436 ], GC [ 437 ], glioblastoma multiforme (GBM) [ 438 ], HNSCC [ 439 ], melanoma [ 440 ], non-Hodgkin’s lymphoma [ 338 ], NSCLC [ 38 ], oral squamous cell carcinoma (OSCC) [ 441 , 442 ], ovarian epithelial cancer (OEC) [ 40 , 443 ], pancreatic cancers [ 13 , 17 , 444 ], renal cell carcinoma (RCC) [ 445 ], sarcoma [ 446 ], and vulva squamous cell carcinoma (VSCC) [ 447 ]. More interestingly, mTOR-independent phosphorylation of RPS6 was frequently identified in primary central nervous system lymphoma (PCNSL) and DLBCL [ 338 , 355 ].…”

Squamous precursor lesions of the vulva: current classification and diagnostic challenges

“…Others likened dVIN to well-differentiated squamous lesions seen in the oral cavity. 84 Pinto et al . studied 11 cases of dVIN with six associated VSCC and sequenced exons 2–11 of TP53 .…”