Elsevier

Gynecologic Oncology

Volume 151, Issue 2, November 2018, Pages 196-201
Gynecologic Oncology

Independent validation of the prognostic significance of invasion patterns in endocervical adenocarcinoma: Pattern A predicts excellent survival

https://doi.org/10.1016/j.ygyno.2018.09.013Get rights and content

Highlights

  • Pattern of invasion classification was validated on an independent cohort of n = 82 usual type cervical adenocarcinomas (AC).

  • The non-destructive invasion pattern A was associated with excellent recurrence-free-, and disease-specific survival.

  • Tumours with invasion pattern B and C exhibited multiple mutations in genes of the PI3K/Akt-pathway.

  • Pattern of invasion classification is a good adjunct to conventional measurements in predicting lymph node metastasis.

  • We plea for a clinical trial to prove safety of a less radical surgical approach in AC patients with invasion pattern A.

Abstract

Objective

Recently, the pattern of invasion in usual-type human papillomavirus-associated endocervical adenocarcinoma (AC) was put forward as a novel variable to select patients with favourable prognosis. Based on destructiveness of stromal invasion, three patterns were proposed: A – no destructive stromal invasion, B – focal destructive stromal invasion, and C – diffuse destructive stromal invasion. We aimed to independently validate the clinical significance of this classification-system in 82 AC patients, and explored associations between invasion pattern and somatic mutations.

Methods

All patients surgically treated for FIGO stage IB-IIA usual type AC (1990–2011, n = 82) were retrospectively reviewed and classified into pattern A, B or C. Additional immunohistochemical analyses were performed for p53, MSH6, and PMS2. Moreover, previously obtained data on somatic hotspot mutations in 13 relevant genes was integrated.

Results

Of 82 AC, 22% showed pattern A, 37% pattern B, and 41% pattern C. Significant differences were observed between invasion patterns and tumour size, depth of invasion (DOI), lymph-vascular invasion (LVI), and lymph-node metastasis. Significantly fewer mutations were present in tumours with pattern A morphology (p = 0.036). All pattern A patients survived (p = 0.002) without recurrent disease (p = 0.005). In multivariate regression analysis including tumour size, DOI, LVI, and lymph node metastasis, invasion pattern was a strong independent predictor for recurrence-free and disease-specific survival (HR 3.75, 95%CI 1.16–12.11, and HR 5.08, 95%CI 1.23–20.98, respectively).

Conclusions

We have independently validated the clinical significance of invasion patterns for usual type endocervical AC. Pattern A predicts excellent survival, and a clinical trial should prove safety of a more conservative treatment for these patients.

Introduction

Cervical cancer is the fourth most lethal cancer in women worldwide [1]. Adenocarcinoma (AC) is the second most common histological subtype, comprising approximately 15–25% of all cervical cancer cases [2,3]. Contrary to squamous cell carcinoma (SCC), incidence rates of AC are rising, especially in young women and in western countries [4,5].

Cervical cancer is clinically staged according to the FIGO (International Federation of Gynaecology and Obstetrics) classification [2,3]. Tumour size (horizontal spread) and depth of invasion (DOI) are important microscopic/morphological parameters in assigning FIGO stage. The choice of treatment of cervical cancer patients primarily depends on the FIGO stage and the presence of lymph-vascular invasion (LVI) [3]. Stage IA tumours, without LVI, are treated more conservatively by cone biopsy or simple hysterectomy alone, whilst larger tumours or tumours invading the cervix more deeply (stage IB), are treated by radical hysterectomy or trachelectomy with pelvic lymph node sampling in the form of a lymphadenectomy or sentinel lymph node biopsy [3]. The latter concerns major surgery associated with high morbidity and infertility. However, in cervical AC, tumour size and especially the DOI are poorly reproducible measurements, because AC often presents in large exophytic masses, in which it is difficult to distinguish the in situ component (AIS) from the invasive tumour [2,6].

Therefore, a potentially more reproducible pattern-based classification-system for usual type endocervical AC was proposed [[7], [8], [9], [10], [11]]. This system classifies AC into three categories, based on the destructiveness of stromal invasion. Pattern A tumours consist of well-demarcated glands, and are without destructive stromal invasion and without LVI. Pattern B tumours present focally destructive stromal invasion, arising from pattern A glands spanning no >5 mm contiguously. And pattern C tumours show diffuse destructive stromal invasion with an associated desmoplastic response. LVI may be present in Pattern B and C [11]. Pattern C tumours were associated with higher FIGO stages, lymph-node metastasis, disease recurrence and tumour associated death, whilst pattern A tumours lacked lymph-node metastasis and showed no disease recurrence, independent of tumour size or DOI [7,9,12]. A more conservative approach for AC patients with pattern A morphology was suggested [9,13].

Usual type endocervical AC is caused by a persistent infection with carcinogenic Human Papillomavirus (HPV) [14]. However, the progression from initial HPV infection to invasive cervical cancer is a complex and multifactorial process in which various immunological, molecular and genetic alterations play a role [[15], [16], [17]]. The Cancer Genome Atlas (TCGA) evaluation of cervical cancer concluded that over 70% of cervical cancers exhibited genomic alterations in either one or both the PI3K/Akt- and TGFβ-pathways [15]. However, the few AC included in TCGA analysis were not classified by pattern of invasion. We have reported on the mutation status in different histological subtypes, and found PIK3CA mutations occurring more frequently in SCC than AC (25% vs. 11%, p = 0.025), whereas KRAS mutations occurred more frequently in AC than SCC (24% vs. 3%, p < 0.001) [17]. However, also in the latter study, patterns of invasion were not assigned. Recent work by Hodgson et al. revealed a higher prevalence of oncogene and tumour suppressor gene abnormalities in the PI3K/Akt-pathway in pattern B and C tumours compared to pattern A tumours [18]. Although this study consisted of a relatively small (n = 20) and heterogeneous (FIGO stage IB-IVB) cohort of AC, with only a short follow-up period (mean follow-up 38 months), it provided the first molecular support for the proposed pattern-based classification [18].

In the present study, based on a large cohort of n = 82 usual type endocervical AC with mature follow-up data, we aimed to independently validate the clinical significance of the pattern-based classification-system and we investigated whether the patterns of invasion are associated with p53 expression, mismatch repair (MMR) deficiency or somatic hot-spot mutations in genes of the PI3K/Akt-pathway.

Section snippets

Case selection

All patients with usual type endocervical AC FIGO stage IB1 – IIA1, who underwent a radical hysterectomy or trachelectomy with pelvic lymphadenectomy as primary treatment at the Leiden University Medical Centre between January 1990 and December 2011, were included in this study. All cases were used according to the Code of Conduct for Proper Secondary Use of Human Tissue, established by the Federation of Dutch Medical Scientific Societies [19]. Clinical and histological parameters were

Patient samples

In total 82 patients with usual type endocervical AC were included in this study; 52 with molecular data from a prior data set, published by our group [17]. Eighteen (22%) tumours were classified as pattern A, 30 (37%) as pattern B, and 34 (41%) as pattern C. Baseline characteristics are summarized in Table 1 for the total cohort, and for pattern A, B, and C separately. When comparing the clinicopathological parameters between the various invasion patterns, there was a significant association

Discussion

In this retrospective, single-centre, cohort study we independently validated the pattern-based classification-system as proposed by Diaz de Vivar et al. [7] on a large cohort of usual type endocervical AC (n = 82). Patients with pattern A tumours showed excellent long term recurrence-free and disease-specific survival. In combination with the absence of both lymph node metastasis and parametrial invasion in these tumours, our data support the suggestion by Park and Roma for a less radical

Conflict of interest statement

The authors have nothing to disclose.

Financial support

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author contributions

Study concept by CdK, GF, TB, and EJ; study design by VS, BB, TB, and EJ; data acquisition by VS, DS, BB, GF, and TB; quality control of data and algorithms by VS, CdK, EJ; data analysis and interpretation by VS, BB, GF, and TB, statistical analysis by VS and EJ; manuscript preparation by VS; manuscript editing by CdK, TB, EJ; manuscript review by VS, DS, BB, CdK, GF, TB, and EJ.

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    1

    Present address: University of Milan, Faculty of Medicine and Surgery, Milan, Italy.

    2

    Authors contributed equally.

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