HLA-E expression in cervical adenocarcinomas: association with improved long-term survival

Abstract

BackgroundCervical cancer is the third most common cancer in women worldwide. The most common histopathological subtype is cervical squamous cell carcinoma (SCC, 75-80%), followed by adenocarcinoma (AC) and adenosquamous carcinoma (ASC; together 15-20%). Rising incidence rates of AC have been observed relative and absolute to SCC and evidence is accumulating that cervical AC is a distinct clinical entity. Cervical SCC, ASC, and AC are caused by a persistent infection with high-risk human papillomavirus (HPV) and failed control of the immune system plays a pivotal role in the carcinogenesis of all three histopathological subtypes. Human leukocyte antigen E (HLA-E), a non-classical HLA class Ib molecule, plays an important role in immune surveillance and immune escape of virally infected cells. In this study we investigated HLA-E expression in three well-defined cohorts of cervical AC, ASC, and SCC patients, and determined whether HLA-E expression was associated with histopathological parameters and patient survival.Methods and resultsHLA-E expression was assessed by immunohistochemistry on formalin-fixed, paraffin-embedded tissue sections of 79 SCC, 38 ASC, and 75 AC patients. All patients included were International Federation of Gynaecology and Obstetrics stage I-II and underwent radical hysterectomy with lymphadenectomy as primary treatment. Significant differences between the histopathological subgroups were detected for age distribution, HPV positivity, HPV type distribution, tumour size, tumour infiltration depth, lymph-vascular space invasion, and adjuvant radiotherapy. High expression of HLA-E was found in 107/192 (56%) cervical carcinomas, with significantly more overexpression in cervical AC compared to SCC and ASC (37/79 SCC, 18/38 ASC, and 52/75 AC; P = 0.010). High HLA-E expression in cervical AC was associated with favourable long term disease-specific and recurrence-free survival (P = 0.005 and P = 0.001, respectively).ConclusionHigh expression of HLA-E occurred in the majority of all histopathological subtypes of cervical cancer; especially in cervical AC. High HLA-E expression in cervical AC was associated with improved patient survival. This study also highlights the importance of careful evaluation of cervical carcinomas to distinguish histopathological subtypes. In the future, insight into the biological behaviour and distinct molecular carcinogenetic processes of the AC, ASC, and SCC subtypes may contribute to the development of more tumour-specific treatment strategies.

Classical and non-classical HLA class I aberrations in primary cervical squamous- and adenocarcinomas and paired lymph node metastases

“…In contrast, we did not find significant associations between classical HLA expression and survival rates. Possibly, due to the obvious poor survival of this metastatic patient group, contrary to previous findings, we could not confirm survival advantage for AC patients with HLA-E expression in the primary tumor [24]. …”

“…Until now only HLA-E was studied in SCC and AC primary cervical cancer samples and high expression of HLA-E was found in 56 %, with significantly higher expression in cervical AC compared to SCC [24]. In contrast, in the present study, we found 30 % expression of HLA-E in the primary tumor for both groups.…”

“…The sum of both scores (percentage and intensity) were used to identify three categories for classical HLAs (0–2 as complete loss of expression, 3–6 as weak expression, and 7–8 as normal expression) and two categories for non-classical HLAs (0–4 as no expression and 5–8 as expression) as previously described by Ruiter et al [41]. For non-classical HLA score a cut off of 5 was used to define groups [24]. Total classical HLA scoring was based on the combined scores of HLA-A and -B/C [21].…”

“…In addition, some studies have compared HLA class I expression between primary cervical carcinoma and paired metastatic LNs [26–28]. In these studies, the patient groups were small and no comparison was made between the different histological subtypes, squamous cell carcinoma (SCC) and adenocarcinoma (AC), despite substantial differences between these two types regarding clinical outcome, oncogenic mutations, and immunological characteristics as shown by us and by others [24, 29–36]. …”

Identification of a Novel Fusion Gene (HLA-E and HLA-B) by RNA-seq Analysis in Esophageal Squamous Cell Carcinoma

“…Moreover, we also found that both HLA-E and HLA-B expression level were markedly increase in ESCC, nevertheless HLA-E was down regulated in breast cancer (de Kruijf et al, 2010) and glioblastomas (Kren et al, 2011) as a prognostic marker, also weekly expressed in multiple cell line (Marin et al, 2003), exception the higher expression predicted better survival in cervical adenocarcinomas (Spaans et al, 2012) while HLA-B was down-regulated in ovarian cancers (Le et al, 2002). Therefore, HLA-E and HLA-B may have specific function pattern in ESCC.…”