Infiltration by immunocompetent cells in early stage invasive carcinoma of the uterine cervix: a prognostic study

doi:10.1080/00313029600169274

Pathology

Volume 28, Issue 4, 1996, Pages 321-327

https://doi.org/10.1080/00313029600169274 Get rights and content

Summary

In various tumor types dentritic cell, infiltration and the presence of tumor-infiltrating lymphocytes have been associated with an improved clinical outcome. In the uterine cervix these immunocompetent cells have been associated with improved prognosis in high stage disease. The current study examines the significance of stromal and tumor T-lymphocyte infiltration together with S-100 positive dendritic cell infiltration in a series of 73 women with low stage (FIGO Ib) invasive squamous and adenosquamous cervical carcinoma. Thirty four percent of cases contained S-100 positive dendritic cells. These were under-represented in cases showing pelvic recurrence or distant disease (1 of 11 compared to 24 of 62 free of recurrence, P = 0.05) and over-represented in cases showing lymphatic/capillary space involvement (12 of 23 compared to 13 of 46 without vascular space invasion, P = 0.05). The women were followed up for an average of 5.2 years and the five-year survival for women whose tumors contained S-100 positive dendritic cells was 92% compared to 73% for negative cases (P= 0.04). There was a significant association between a low density of tumor infiltrating T-cells and risk of pelvic lymph node spread and subsequent local or distant disease control failure (P = 0.008). A five year survival advantage was seen with five or more CD 3 positive tumor infiltrating T-lymphocytes per high power field (90%) compared to a lower count (68%) (P = 0.04). A similar advantage could not be demonstrated for a high stromat infiltrate of T-cells. As yet neither the specific mechanisms that induce these cells to infiltrate some cervical carcinomas nor the nature of the immunological injury that the cells co-ordinate in tumor tissue are well understood.

References (32)

J. Viac et al.
Langerhans’ cells and epithelial cell modifications in cervical intraepithelial neoplasia: correlation with human pappilloma virus infection
Immuno-biology
(1990)
A. Spinillo et al.
Langerhans’ cell counts and cervical intraepithelial neoplasia in women with human immunodeficiency virus infection
Gynecol Oncol
(1993)
T. Hachisuga et al.
Immunohistochemical demonstration of histiocytes in normal ectocervical epithelium and epithelial lesions of the uterine cervix
Gynecol Oncol
(1989)
A. Giannini et al.
Prognostic significance of accessory ceils and lymphocytes in nasopharyngeal carcinoma
Pathol Res Pract
(1991)
Y. Becker
Anticancer role of dendritic cells in human and experimental cancers — a review
Anticaneer Res
(1992)
P. Bethwaite et al.
Effect of tumor-associated tissue eosinophilia on the survival of women with stage Ib carcinoma of the uterine cervix
J Clin Pathol
(1993)
T. Nakano et al.
Roles of Langerhans’ and Tlymphocytes infiltrating cancer tissues in patients treated by radiation therapy for cervical cancer
Cancer
(1992)
J. Van Nagell et al.
The significance of vascular invasion and lymphocytic infiltration in invasive cervical cancer
Cancer
(1978)
T. Nakano et al.
Prognostic significance of Langerhans” celt infiltration in radiation therapy for squamous cell carcinoma of the uterine cervix
Arch Pathol Lab Med
(1989)
K. Oka et al.
Adenocarcinoma of the cervix treated with radiation alone: prognostic significance of S-100 protein and vimentin immunostaining
Obstet Gynecol
(1992)

S. Knight et al.

Development and function of dendritic cells in health and disease

J Invest Dermatol

(1992)

A. Morelli et al.

Density and distribution of Langerhans’ cells in the human uterine cervix

Arch Gynecol Obstet

(1992)

S. Tay et al.

Subpopulafions of Langerhans’ cells in cervical neoplasia

Br J Obstet Gynecol

(1987)

R. Hughes et al.

Expression of major histocompatibility class II antigens by Langerhans’ cells in cervical interepithelial neoplasia

J Clin Pathol

(1988)

R. Hawthorn et al.

Langerhans’ cells and subtypes of human papillomavirus in cervical interepithetial neoplasia

B Med J

(1988)

S. Tay et al.

Langerhans’ ceil population in early invasive squamous cell carcinoma of the uterine cervix

Aust NZ J Obstet Gynecol

(1989)

Cited by (75)

Disfunction of communication among immune cells in minimal-deviation adenocarcinoma of the cervix as an immunotherapeutic opportunity
2023, International Immunopharmacology
Minimal deviation adenocarcinoma (MDA) of the uterine cervix, also referred to as malignant adenoma, is a rare subtype of cervical adenocarcinoma that exhibits histological characteristics resembling those of benign tumors, resulting in a low diagnostic rate and a lack of effective treatment options. The transcriptomic features of MDA at the single-cell resolution and within the tumor microenvironment (TME) remain unclear. In this study, we conducted single-cell transcriptomic analyses of MDA samples (Ca) and adjacent normal tissues (PCa). The present study reveals the prevalence of dendritic cells (DCs) and T cells in the carcinoma (Ca) of mammary ductal adenocarcinoma (MDA), with DCs undergoing significant metabolic reprogramming and immune stress. Additionally, our findings demonstrate the crucial involvement of DCs and T cells in the pathogenesis and metastatic progression of MDA, as evidenced by single-cell transcriptomic profiling of MDA and HPV samples. This resource provides a more profound understanding of the indolent nature of MDA and may prove useful in the development of MDA immunotherapy.
Tumor-infiltrating lymphocytes predict survival outcomes in patients with cervical cancer treated with concurrent chemoradiotherapy
2020, Gynecologic Oncology
To (i) identify correlations between selected immunogenic factors and clinicopathological characteristics, (ii) determine whether intratumoral abundance of various specific tumor-infiltrating lymphocytes (TILs) is a prognostic indicator in women with Stage II and III cervical cancer who undergo treatment with cisplatin-based concurrent chemoradiotherapy (CCRT), and (iii) investigate subtypes of FOXP3⁺ T cells in 15 fresh samples of cervical cancer.
In this retrospective study, intratumoral lesions in colposcopic biopsies from 55 women with advanced cervical cancer who subsequently underwent CCRT at our institution were subjected to automatic immunological staining using the following six mouse monoclonal antibodies: anti-CD3, anti-CD4, anti-CD8, anti-CD20, anti-CD206, and anti-FOXP3. Associations between the findings on automatic scoring of the number of each type of TIL in each specimen and various clinicopathological characteristics were analyzed, as were associations between the abundance of various specific types of TIL and survival. Subtypes of FOXP3⁺ TILs in 15 additional fresh tumor samples were also investigated using flow cytometry.
Infiltration with CD8⁺ TILs was associated with pelvic lymph node metastasis. Abundant infiltration by CD3⁺, CD4⁺, CD8⁺, CD206⁺, and FOXP3⁺ TILs were statistically significant indicators of better progression-free and overall survival. Regarding subtypes of FOXP3⁺ TILs, non-Tregs (Fr-III) were found in all samples tested for this.
The abundance of various specific intratumoral TILs may be prognostic indicators in patients with advanced cervical cancer undergoing CCRT.
Immune stromal features in cervical squamous cell carcinoma are prognostic factors for distant metastasis: A retrospective study
2020, Pathology Research and Practice
Citation Excerpt :
Most studies to date have focused on the assessment of TILs within the primary tumor while largely ignoring peritumoral patterns of immune infiltrates. Consistent with earlier studies [28–34], our current data, therefore, highlight the prognostic utility of TILs infiltrating the primary tumor or peritumor. Macrophages are critical immune effector cells and one of the major components of tumor-infiltrating leukocytes.
Malignant tumors are complex structures that must interact with the surrounding environment for growth and invasiveness. This study aimed to comprehensively catalogue the features of immune cell stromal infiltrates within tumor tissue and peri-tumoral tissue and to determine whether these features have prognostic value in cervical squamous cell carcinoma (CxSCC).
Immune stromal features in primary tumors in 122 patients enriched for CxSCC were histologically and immunohistochemically characterized.
Distant metastasis was positively correlated with tumor-node-metastasis (TNM) stage (P < 0.001), lymph-vascular invasion (LVI) (P < 0.001), lymph node metastasis (LNM) (P < 0.001), and tumor budding (P = 0.012). Distant metastasis was also associated with the eosinophil infiltration (P = 0.006); Stromal, intratumoral, invasive-margin, squamous intraepithelial lesion (SIL), and perivascular tumor-infiltrating lymphocytes (TILs); CD68+, CD163+, and CD204+ macrophage infiltration. Multivariate proportional hazard regression analyses revealed that LVI; TNM stage; lymph node metastasis; tumor budding; eosinophil infiltration; CD163+ macrophage infiltration; and stromal and intratumoral TILs were independent predictors of poor DMFS in patients with CxSCC.
Primary tumor immune stromal features can be useful in predicting distant metastasis in CxSCC.
The Role of Biomarkers for the Prediction of Response to Checkpoint Immunotherapy and the Rationale for the Use of Checkpoint Immunotherapy in Cervical Cancer
2019, Clinical Oncology
Checkpoint immunotherapy has revolutionised the way that melanoma is treated and has also shown significant effectiveness in lung, bladder, renal, and head and neck cancers. At the present time, trials of checkpoint immunotherapy in cervical cancer are at early phases, but there is very good rationale for pursuing this as a treatment option, especially as cervical cancer is a virally driven cancer and therefore should be recognised by the immune system as being foreign. This review explores the biomarkers for the selection of patients for immunotherapy in other cancers, such as programmed death ligand 1 (PD-L1) expression, tumour infiltrating lymphocytes and total mutational burden, and relates these biomarkers to cervical cancer. A PubMed search was carried out for publications published in English with the terms ‘immunotherapy’ OR ‘cervical cancer’ OR ‘checkpoint blockade’ OR ‘tumour infiltrating lymphocytes’ OR ‘total mutational burden’. Articles that met these criteria and were available on PubMed before 8 October 2018 were included. The results showed that PD-L1 is positive in up to 90% of cervical cancers and that the total mutational burden is moderately high, with 5–6 mutations per megabase. In addition, the tumour microenvironment in cervical cancer has an impact on prognosis, with higher ratios of CD8+ tumour infiltrating lymphocytes to CD4+ T regulatory cells being associated with improved survival. Clinical studies to date have shown the response rate of cervical cancer to checkpoint immunotherapy to be in the region to 10–25%. Cervical cancer exhibits many of the features that have been shown to be correlated with response to checkpoint immunotherapy in other tumour sites. However, response rates to date are in the region of 10–25%. Therefore, combinations of immunotherapeutic agents or checkpoint inhibitors with radiotherapy may be required to maximise the therapeutic benefit of harnessing the host immune system to fight cancer.
Gyneco-oncological genomics and emerging biomarkers for cancer treatment with immune-checkpoint inhibitors
2018, Seminars in Cancer Biology
Citation Excerpt :
The detection of significant numbers of tumor-infiltrating lymphocytes [TIL] in cervical carcinoma tissues underlines the importance of cell mediated immune response in this malignancy [24]. Bethwaite et al. found an association among low density of TIL, risk of pelvic lymph node involvement, and subsequent local or distant failure (p = 0.008) in women with early-stage cervical cancer [24]. Overall survival was significantly better for patients with >5 CD3 + TIL per high power field [HPF] compared with those with lower CD3 + TIL count.
In gynecological cancers tumor infiltrating lymphocytes and upregulation of immune-related gene signatures have been associated with a better prognosis. Knowledge of tumor immunogenicity and associated gene signatures suggests that the tumor immune landscape is a key determinant to define patient prognosis and potentially to predict response to immune-checkpoint inhibitors. The aim of this review is to give an overview of immune gene signatures across gynecology histological cancer types, defining their prognostic and potential predictive role. In the current review we will present data on these gene signatures, on immunohistochemical features and their potential importance to select patients potentially eligible to trials with immune-checkpoint inhibitors.
Immunotherapy
2017, Oral, Head and Neck Oncology and Reconstructive Surgery

View all citing articles on Scopus

View full text

Infiltration by immunocompetent cells in early stage invasive carcinoma of the uterine cervix: a prognostic study

Summary

Immuno-biology

Gynecol Oncol

Gynecol Oncol

Pathol Res Pract

Anticancer role of dendritic cells in human and experimental cancers — a review

Anticaneer Res

Effect of tumor-associated tissue eosinophilia on the survival of women with stage Ib carcinoma of the uterine cervix

J Clin Pathol

Roles of Langerhans’ and Tlymphocytes infiltrating cancer tissues in patients treated by radiation therapy for cervical cancer

Cancer

The significance of vascular invasion and lymphocytic infiltration in invasive cervical cancer

Cancer

Prognostic significance of Langerhans” celt infiltration in radiation therapy for squamous cell carcinoma of the uterine cervix

Arch Pathol Lab Med

Adenocarcinoma of the cervix treated with radiation alone: prognostic significance of S-100 protein and vimentin immunostaining

Obstet Gynecol

Development and function of dendritic cells in health and disease

J Invest Dermatol

Density and distribution of Langerhans’ cells in the human uterine cervix

Arch Gynecol Obstet

Subpopulafions of Langerhans’ cells in cervical neoplasia

Br J Obstet Gynecol

Expression of major histocompatibility class II antigens by Langerhans’ cells in cervical interepithelial neoplasia

J Clin Pathol

Langerhans’ cells and subtypes of human papillomavirus in cervical interepithetial neoplasia

B Med J

Langerhans’ ceil population in early invasive squamous cell carcinoma of the uterine cervix

Aust NZ J Obstet Gynecol