Under expression of the Sonic Hedgehog receptor, Patched1 (PTCH1), is associated with an increased risk of local recurrence in squamous cell carcinoma of the vulva arising on a background of Lichen Sclerosus

Abstract

ObjectiveDysregulation of the Hedgehog (Hh) pathway has been described in a variety of cancers, including cervical cancer, a disease which shares a common aetiology with vulval squamous cell carcinoma (VSCC). Here, we investigate a large number of primary VSCC cases for evidence of Hedgehog pathway activation and examine the implications of pathway activity on clinical outcomes in a cohort of patients with primary VSCC.MethodsArchival histology blocks containing VSCC and histologically normal adjacent epithelium were retrieved from a cohort of 91 patients who underwent treatment for primary VSCC. Immunohistochemistry staining was undertaken to assess for the expression of key Hh pathway components (SHH, PTCH1, GLI1). A competing risks statistical model was used to evaluate the implications of the levels of key Hh pathway components on clinical outcomes.ResultsWe show that 92% of primary VSCC cases over-expressed one or more components of the Hh signalling pathway when compared to the adjacent normal epithelium. While expression of SHH and GLI1 did not correlate with any clinicopathological criteria, over- or under-expression of PTCH1 was associated with a reduced or increased risk of developing a local disease recurrence, respectively. In VSCC arising on a background of Lichen Sclerosus, the risk of local recurrence was potentiated in cases where PTCH1 was under-expressed.ConclusionsOur findings reveal, for the first time, that the Hh pathway is activated in VSCC and that PTCH1 expression can be used as a biomarker to stratify patients and inform clinicians of the risk of their local recurrence, particularly in cases of VSCC associated with LS.

Sonic Hedgehog is a novel prognostic biomarker in patients with oral squamous cell carcinoma

“…In relation to previous reports [7,32], which revealed significant positive correlation between SHH overexpression and lymphatic metastasis of patients with OSCC, our study showed slight trend toward higher SHH expression in OSCC with lymph node metastasis. Similarly, to Yap et al [13], who pointed the clinical benefit from SHH overexpression in patients with squamous cell carcinoma of the vulva (VSCC), we might suggest that high SHH expression in OSCC tissue can be used as a biomarker to stratify patients of the risk of lymph node metastasis. SHH protein was an independent prognostic biomarker for poor prognosis in patients with OSCC.…”

“…In the present study, we estimated SHH, p53, HPV expression and association between these proteins in OSCC tissue in order to establish their impact on tumor progression as well to define its prognostic significance in patients with OSCC. The majority of published data claims that uncontrolled upregulation of the Sonic hedgehog signaling pathway results in carcinogenesis and tumor growth [9,13,26]. Upregulation of SHH was described in some solid tumors (e.g., breast, esophageal, lung cancer) suggesting that SHH may be responsible for highly invasive biological behavior of tumor, but it is still little known about its role in OSCC [29,30,31].…”

“…Recent studies reported that SHH overexpression is closely related with tumorigenesis, metastasis, angiogenesis and cancer relapse [5,8,9,13]. However, the role of SHH in OSCC remains still unclear.…”

Sonic Hedgehog signaling pathway in gynecological and genitourinary cancer (Review)

“…Although it was proven in that study that the overexpression of Kif7 in the choriocarcinoma cell lines, JAR and JEG-3, suppressed cell migration, the role of SHH in the development of gestational trophoblastic neoplasms remains unclear ( 160 ). Furthermore, only one study focused on SHH expression in vulvar squamous cell carcinoma (VSCC); Yap et al ( 161 ) performed semi-quantitative IHC of tissue specimens from 91 VSCC cases for SHH, PTCH1 and GLI1 proteins. Although an increased immunoreactivity of one or more of the assessed proteins was reported, only the decreased expression of PTCH1 was associated with an increased risk of developing a local disease recurrence ( 161 ).…”

“…Furthermore, only one study focused on SHH expression in vulvar squamous cell carcinoma (VSCC); Yap et al ( 161 ) performed semi-quantitative IHC of tissue specimens from 91 VSCC cases for SHH, PTCH1 and GLI1 proteins. Although an increased immunoreactivity of one or more of the assessed proteins was reported, only the decreased expression of PTCH1 was associated with an increased risk of developing a local disease recurrence ( 161 ).…”