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ORIGINAL ARTICLE Table of Contents  
Ahead of print publication
Is programmed death-ligand 1 of prognostic significance in triple-negative female mammary carcinoma?


1 Department of Pathology, Faculty of Medicine, Tanta Cancer Center, Tanta University, Tanta, Egypt
2 Department of Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt
3 Department of Pathology, Tanta Cancer Center, Tanta University, Tanta, Egypt

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Date of Submission12-Sep-2021
Date of Decision30-Aug-2022
Date of Acceptance13-Oct-2021
Date of Web Publication14-Nov-2022
 

  Abstract 


Introduction: The most widespread female malignancy is breast cancer (BC), considerable percentage of patients with triple-negative BC (TNBC) experience rapid progression, recurrence, and metastasis. BC has not historically been treated as an immunogenic cancer. Nonetheless, several researchers have started to concentrate on immunotherapy. Aim: The aim of the study is to investigate the immunohistochemical (IHC) expression of programmed death-ligand 1 (PD-L1) by stromal tumor-infiltrating lymphocytes (TILs) and tumor cells (TC) in female (TNBC) and to correlate with pathological features of such tumors, particularly those determine biologic behavior, such as the grade and stage the overall survival. Methodology: This is a retrospective study which includes 49 paraffin-embedded tumor tissue sections which were collected from breast surgery specimens either radical or conservative of female patients with TNBC. The samples were analyzed immunohistochemically for PD-L1 expression. Results: There were statistically significant relations among TC PD-L1 expression and TILs PD-L1 expression as well as relations among TILs PD-L1 expression with histologic grade, stromal TILs, and Ki-67 were statistically significant. Correlations between TC PD-L1 expression and N stage, histologic grade, and anatomic stage were statistically significant. Improved survival was detected within TILs PD-L1-positive cases; however, the correlation between the overall survival and PD-L1 expression in both TCs and stromal TIL was not statistically significant. Conclusion: PD-L1 expressed in tumors with poor prognostic features such as the high grade, advanced T stage, and high Ki-67 index, TILs PD-L1-positive cases experienced improved survival supporting its prognostic significance. However, the correlation with overall survival was not statistically significant.

Keywords: Immunohistochemical, overall survival, programmed death-ligand 1, prognosis, triple-negative breast cancer


How to cite this URL:
Sanad AM, Ibrahim WS, Ezzo IM, Sabry RM. Is programmed death-ligand 1 of prognostic significance in triple-negative female mammary carcinoma?. J Microsc Ultrastruct [Epub ahead of print] [cited 2022 Nov 30]. Available from: https://www.jmau.org/preprintarticle.asp?id=361126





  Introduction Top


The most widespread female malignancy is breast cancer (BC) and has a major role in deaths among female's malignancies.[1]

In Egypt, “The National Population-Based Cancer Registry Program” reported that BC accounts for 38% of all female cancers.[2]

Triple-negative BC (TNBC) represents 15%–20% of all BC, this subtype does not express human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), and progesterone receptor (PR), representing 15%–20% of all BC.[3]

TNBC is common in young premenopausal African-American women, and they are recognized as highly undifferentiated tumors, aggressive cancer with a poor prognosis when compared to other subtypes of BC. These tumors are with a high proliferation index, and it does not respond to endocrine or anti-HER2 therapy. It is characterized by shorter disease-free intervals and overall survival in the metastatic situation and more frequent relapse of central nervous system or visceral metastases than other subtypes.[4]

The linkage between tumor-infiltrating lymphocytes (TILs) with treatment response and disease-free survival in TNBC patients demonstrates the prognostic relevance of antitumor immunity in TNBC patients. The presence of TILs is serving as a predictor of immunotherapy response, making TNBC immunotherapy research particularly essential.[5]

Programmed death-ligand 1 (PD-L1) is a glycoprotein on the cell surface. PD-L1 binds PD-1 and CD80 like counter receptors that can provide negative signals that regulate and inhibit that response of cytotoxic T lymphocytes.[6],[7]

Due to its inhibitory effect on antitumor immunity, PD-L1 detection is considered a negative prognostic marker in BC. Some researches detected quite the contrary, that better outcomes regarding this correlation.[8]

Several studies have researched the existence and function of the host immune system, as well as its association with tumor progression in a range of solid tumors, including BC, and have found that spontaneous intratumoral lymphocytic infiltration is linked to patient prognosis.[6]

Thus, the purpose of this study was to evaluate immunohistochemical (IHC) expression of PD-L1 marker in tumor cells (TCs) and stromal TILs in female TNBC.

Correlation of PD-L 1 IHC expression with pathological characteristics of such tumors, particularly the grade and stage denote the biologic behavior of the tumor.


  Materials and Methods Top


A retrospective research includes 49 paraffin-embedded (BC) tissue sections which were obtained as modified radical mastectomy and conservative breast surgery specimens of female patients with ER, PR and HER2, negative tumor expression. Cases with missing data, unpresentable sampling, or lacking IHC reports and cases received neoadjuvant therapy were excluded from the study. Patients were monitored from 6 up to 60 months, with a median of 43 months, the cases were gathered from the pathology department of cancer center in the time period between January 2016 and December 2019. The study is ethically approved by Research Ethics Committee, Faculty of Medicine Cairo University MS-287-2019.

The tumors have been histopathological revised according to the WHO 2019 updates.[9] Tumors were graded according to the “Nottingham Grading System.”[10] For further statistical evaluation, Grades 1 and 2 cases were considered as low grade, while Grade 3 cases were considered as high grade.[11],[12]

As for the TILs, they were assessed according to the guidelines of the “2014 International TILs Working Group.” The mononuclear cells in the stroma of the invasive tumor borders were considered as a percentage of the stromal area. The following findings were exempted from the scoring, TILs beyond the tumor line, around ductal carcinoma in situ and normal breast tissue, as well as in areas of necrosis and hyalinosis. A clinically significant threshold(s) for TILs assessment was not recommended by the working group;[13] therefore, low TILs (<30%) while high TILs (approximately 30%).[6],[14]

The presence of TCs beyond the tumor boundary in vascular space (lymphatic and/or blood vessel) was described as lymphovascular invasion (LVI).[15]

Regarding the latest version of “the AJCC Staging Manual,” tumor staging was carried out using the TNM staging system.[16]

Immunohistochemical staining for programmed death-ligand 1

F07686 PD-L1 (SP142) is an IHC assay that uses the rabbit monoclonal anti-PD-L1 clone SP142, as recommended by the manufacturer, for IHC evaluation of the PD-L1 protein in TCs and tumor-infiltrating immune cells in breast carcinoma tissues. On a BenchMark XT instrument, the unique antibody was detected using OptiView DAB IHC Detection Kit and OptiView Amplification Kit.

Evaluation of expression of programmed death-ligand 1

Tumor tissue sections were examined and scored under Olympus microscope model BX 53 at low-power then high-power magnification by the trained research team.

Assessment PD-L1 status is based on either the proportion of TCs (%) that express the marker of any intensity (excluding normal breast tissue, hyalinosis, and necrosis) and PD-L1 expressing tumor-infiltrating immune cells (% IC) of any intensity.

In tumor cells and TILs, PD-L1 was considered as positive if more than 1% displayed any intensity of entire or incomplete cell membrane and cytoplasmic staining. Cytoplasmic and membranous staining for PD-L1 were accepted as positive. Tonsillar tissue was utilized as a positive control (lymphocytes and macrophages in the germinal zone, reticulated crypt epithelium) and negative control (inter-follicular lesion and overlying squamous epithelium).[17]

The previously mentioned clinical, histopathological, and IHC data transferred to Microsoft Excel (office 2013) was used for data entry,and the Statistical Package for Social Science (SPSS) version 21 (SPSS, Armonk, New York: International Business Machines Corporation) to be statistically analyzed. Survival analyses were demonstrated using Kaplan–Meier curves. An Olympus microscope type BX 53 was used to take microscopic pictures.


  Results Top


Regarding the histopathological types, 32 cases were( invasive breast carcinoma not otherwise specified [IBC-NST]) (65.31%) and 8 cases were carcinoma with medullary pattern (16.33%). Two cases were mixed IBC-NST and invasive lobular carcinoma (4.8%), two cases were carcinoma with osteoclast-like stromal giant cells (4.8%), two cases were metaplastic squamous cell carcinoma (4.8%) as illustrated in [Figure 1], one case was pleomorphic lobular carcinoma (2.4%), one case was of invasive papillary adenocarcinoma (2.4%), and one case was carcinoma with secretory pattern (2.4%). For further statistical analysis, the last 3 histologic subtypes (pleomorphic lobular carcinoma, invasive papillary adenocarcinoma, and carcinoma with secretory pattern) were grouped together named as other types.
Figure 1: (a) Case of invasive breast cancer -NST low grade (H andE x100 original magnification), (b) Case of carcinoma with medullary pattern (Hand E x100 original magnification), (c) Case of metaplastic carcinoma with areas of necrosis (Hand E x100 original magnification),(d) Case of invasive pleomorphic lobular carcinoma (H and E x200original magnification), (e)Case of high stromal TILs of breast carcinoma with medullary pattern(≥ 30% of the stromal area) with areas of necrosis (Hand E x200 original Magnification), (f) Case of IBC with low stromalTILS (< 30% of the Stromal area) (Hand Ex 100 Original magnification)

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Within the studied cases, the mean age was 54.2 years at the time of pathological diagnosis.

Among the collected cases, 25 cases (51.02%) were on the right breast and 24 cases (48.98%) were on the left breast. The cases with high-grade tumors were representing 84.5% of cases. 63.27% of cases were T2 stage. Lymph node (LN) metastasis was detected in 34 cases accounting for 69.3% of cases with prevalence of N1 (26.5%). Most of the studied cases were negative for distant metastasis (M0) accounting for 75.5% of cases. Early-stage incidences (I and II) were nearly equal to late-stage cases (III and IV). 75.5% of cases were negative for LVI, while 24.5% showed positive LVI. 69.3% of cases showed high stromal TILs while (30.7%) of the cases displayed low stromal TILs, as illustrated in [Figure 1]. Most of cases were considered to have high Ki-67 index representing (87.76%) of cases.

As regards the stromal TILs PD-L1 IHC expression, 16 cases (32.65%) showed positive expression while 33 cases (67.32%) showed negative expression, as shown in [Table 1] and [Figure 2].
Table 1: Tumor-infiltrating lymphocytes programmed death-ligand 1 expression

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Figure 2: (a) Case of carcinoma with medullary pattern showing positive both TC and TILs PD-L1 Expression and the arrow pointed to TC (x100 original magnification, (b and c) Higher magnification of the previous case (x200 and x400 Original Magnification), (d) Case of IBC showing negative TC PD-L1 expression ( x 100 original magnification),(e) Case of IBCshowing high stromal TILs and positive TC PD-L1 expression (x100 original magnification), (f) Case of IBC carcinoma showing positive TILs PD-L1 expression (x200 original magnification)

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While TC PD-L1 IHC expression, 4 cases were positive expression (8.6%) and 45 cases were negative expression (91.8%), as shown in [Table 2] and [Figure 2].
Table 2: Tumor cells programmed death-ligand 1 expression

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Improved survival within TILs PD-L1-positive cases, however, there was no statistically significant relation between overall survival and PD-L1 expression in both TC and stromal TIL [Table 3].
Table 3: Kaplan–Meier curves, a. Analysis of survival in relation to the expression of programmed death-ligand 1 in tumor-infiltrating lymphocytes, b. Analysis of survival in relation to tumor cells expression of programmed death-ligand 1

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There was a statistically significant relationship between TC PD-L1 expression and TILS PD-L1 expression, as well as, relations between TILS PD-L1 expression and histologic grade, stromal TILS, and Ki-67 were statistically significant. Relations between TC PD-L1 expression and N stage, histologic grade, and anatomic stage were statistically significant, as shown in [Table 4], [Table 5], [Table 6].
Table 4: Relation between tumor cells programmed death-ligand 1 expression and tumor-infiltrating lymphocytes programmed death-ligand 1 expression

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Table 5: Clinicopathological characteristic of tumor-infiltrating lymphocytes programmed death-ligand 1 expression

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Table 6: Clinicopathological characteristic of tumor cells programmed death-ligand 1 expression

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  Discussion Top


As regards the histopathological types in this study, most of cases were IBC-NST (32 cases; 65.31%), followed by carcinoma with medullary pattern (8 cases; 16.33%). This was consistent with the studies done by Amirifard et al., 2016; Wang and Liu, 2020, that recorded the prevalence of IBC-NST followed by carcinoma with medullary pattern. Lee et al., 2012, on the other hand, reported a high number of IBC-NST followed by metaplastic carcinoma and Kreike et al., 2007 reported that IBC-NST cases were the highest followed by adenoid cystic carcinoma.[17],[18],[19],[20]

In this study, low-grade cases represented 7 cases (15%), while the high-grade cases were 42 cases (84. 5%). The study of Amirifard et al., 2016, reported (51.3%) high-grade cases while equal numbers of low and high-grade cases were reported in the study done by Wang and Liu, 2020.[18],[17]

Concerning the T stage, the majority of cases were T2 stage (31 cases; 63.3%), followed by T3 stage (14 cases; 28.6%), then T1 stage (4 cases; 8.2%). This was further supported by the findings of Kreike et al., 2007, who reported predominant T2 cases (62.8%). On the contrary, Lee et al., 2010 and Zhang et al., 2014, studies reported predominance of T1 stage cases.[20],[21],[22]

Within the node-positive cases in the present study, N1 stage was the most common followed by N3 stage and then N2 stage cases. Adamo's et al., 2017 research findings are in accordance with the findings of the current research. However, Kreike et al., 2007 and Zhang et al., 2014 reported higher rates of node-negative cases.[4],[20],[22]

Regarding the M stage of the studied cases, 37 cases (75.5%) were negative for metastatic disease (M0) and 12 cases (24.5%) were positive for metastasis (M1). These results were consistent with study done by Suresh et al., 2013, in which cases diagnosed in (M1) stage were 15%. Cases were grouped according to anatomical stages, into the early-stage cases (25 cases; 51%) that were a bit higher than late-stage cases (24 cases; 49%). The study of Suresh et al., 2013 reported that early-stage cases were higher than late-stage cases (75%).[23]

As for the Ki-67 proliferation index, 6 cases (12.24%) showed low indices and 43 cases (87.76%) showed high indices. Adamo's et al., 2017, research findings are in accordance with reported prevalence of high Ki-67 indices by 59%, while differ from Hao et al., 2016 who found that cases with low Ki-67 index were 57.6%. This variation in results may be due to differences between cut-off points used in Ki-67 assessment.[4],[24]

By studying the cases for evidence of LVI, LVI-negative cases (37 cases; 75.5%) were more than LVI-positive cases (12 cases; 24.5). This was consistent with studies done by Amirifard et al., 2016 and Kreike et al., 2007 in which 57% and 87% of cases showed no LVI, respectively.[18],[20]

Regarding the extent of TILs, 15 cases showed low TILs (30.6%) and 34 cases showed high TILs (69.3%). This was consistent with the result of Vinayak et al., 2014 that reported predominance of high TILs cases (76%), TNBC is the BC subtype most related with the presence of TILs, according to the evidence. However, Polónia et al., 2017 reported that different results as 81% of cases showed low TILS may due to that study includes different molecular subtypes of BC other than TNBC.[6],[25]

Concerning the TILs PD-L1 expression, 16 cases (32.7%) showed positive expression. 25% of cases done by Wang and Liu, 2020 study detected positive expression.[17]

In this study, 4 cases (8.6%) expressed TC PD-L1 positively, while 45 cases (91.8%) did not express the marker. The studies done by Wang and Liu, 2020 and Polónia et al., 2017 reported near results to the current study, where PD-L1 expressed in TCs 8.5% and 16%, respectively. The difference of results may be due to many factors such as the variability of the used antibodies produced by different agencies, the use of full-face sections versus tissue microarray, the different positivity cut-off values used, and the interpretation of cytoplasmic or membranous staining.[6],[17]

In the present study, TILs PD-L1 expressed cases were 32.7% in comparison to 8.6% represented TC PD-L1 expressed cases, in concordance with Koboldt et al., 2012 and Wang and Liu, 2020 researches. The contrary was found in a study by Guo et al., 2016, who detected the reverse. The difference may be due to different variants of histopathological cases included and the variability of the used antibodies produced by different agencies.[7],[17],[26]

Regarding the relation between the various histopathological types and TILs PD-L1 expression, 28.12% of the cases of IBC-NST showed positive expression. 100% of the cases of carcinoma with osteoclast-like stromal giant cells showed positive expression. 50% of the cases of carcinoma with medullary features showed positive expression. 33.3% of the other types displayed positive expression. There is no expression in metaplastic squamous cell carcinoma cases.

Furthermore, cases of carcinoma with medullary pattern had the highest rate of TC PD-L1 expression. Then cases IBC-NST.

These findings on PD-L1 expression in TC and TILs in various histopathological categories were similar to those of Dill et al., 2017 who detected that more PD-L1 expressed in both compartments (TC, TILs) in cases with medullary pattern. There was no expression in lobular cancers in the studied cases. This observation was consistent with Guo et al., 2016 who observed PD-L1 expression in IBC-NST cases rather than ILC cases.[7],[27]

In this study, high-grade cases had a significantly higher rate of PD-L1 expression in both TC and TILs than low-grade cases that were consistent with Guo et al., 2016; Dill et al., 2017; Wang and Liu, 2020 studies.[7],[17],[27]

Concerning relationships between T stage and TC, TILs PD-L1 expressions, the large-sized tumor cases (T3) stage showed higher incidence of PD-L1 expression than other (T) stages cases. This was supported by Baptista et al., 2016, who detected higher TC and TILS PD-L1 expression in cases with advanced (T) stage. Park et al., 2016, on the other hand, detected higher PD-L1 expression in cases with small-sized tumors. This could be explained by the fact that both of these studies were concerned with early-stage BC (a greater number of cases were T1 and T2 stages than T3 cases).[28],[29]

In this study, cases with N0 showed higher rate of PD-L1 expressed within TC and TILs than cases with N1, 2, and 3. This was supported by the findings of Dill et al., 2017; Polónia et al., 2017; and Baptista et al., 2016 researches. However, this disagreed with Park et al., 2016, that recorded higher incidence of PD-L1 expression in node-positive cases.[27],[28],[29]

In the present study, cases with M0 stage showed higher incidence of expression of TC and TILs PD-L1 than cases with M1 stage. This was consistent with the Dill et al., 2017 study while the study done by Baptista et al., 2016 reported the reverse.[27],[28]

On grouping the studied cases according to the anatomic stages, most of cases in early stage showed TC and TILs PD-L1 expression. This was in line with the findings of Kitano et al., 2017, who stated that TC and TILs PD-L1 expressed more in cases of early stage.[30]

In this study, LVI-negative cases had a higher rate of TC and TILs PD-L1 expression than LVI-positive cases. This was in line with Guo et al., 2016's findings. TC and TILs PD-L1 expression in LVI-negative cases were 15% while in LVI-positive cases were 4.5%.[7]

Regarding the Ki-67 proliferation index, cases with high indices and showed positive TC and TILs PD-L1 expression were more than cases with low indices. These results were consistent with study done by Polónia et al., 2017. The statically significant relationship between Ki-67 index and TILs PD-L1 (P = 0.023) in this study could be owing to that highly proliferative TCs have more mutation rates that are responsible for greater immunogenicity and rapid development of neoantigens. In contrast, Park et al., 2016 study showed that low Ki-67 cases displayed more PD-L1 expressed cells. Lack of definite cut-off point and scoring system for ki-67 and its weakly reproducible results can explain those inconsistent findings.[6],[29]

In the present study, cases with high stromal TILs (≥30% of the stroma) showed higher rate of TC and TILs PD-L1 expression than cases with low stromal TILs. This was in line with the findings of Kitano et al., 2017 and Polónia et al., 2017 research.[6],[30]

The expression of PD-L1 in TC and TILs was found to be highly statistically significant in this study (P = 0.003). This was in line with the findings of Dill et al. 2017.[27]

Finally, the correlation between the overall survival and PD-L1 expressed in both TCs and stromal TIL was not statistically significant, in agreement with results of Sobral-Leite et al., 2018.[31]

Although the current study detected that PD-L1 expression is evident in tumors showed poor prognostic features such as the high grade, large tumor size, and high Ki-67 index, the literature showed wide debatable opinions about the prognostic value of PD-L1 expression in TNBC and in BC generally.

Some literatures considered that PD-L1 expression in BC is an independent poor prognostic factor as expected from its immunosuppressive function as Wang and Liu, 2020. The study of Polónia et al., 2017 showed association of PD-L1 expression in BC with favorable prognosis. This favorable prognosis may be due to the presence of high stromal TILs in PD-L1-positive tumor tissue, which associated with better patient outcome after chemotherapy.[6],[17]

After all, more research into the relationship between tumoral and immune stromal PD-L1 expression levels and clinical response to PD-L1 suppression will be vital and highly encouraged, particularly among high-grade TNBCs (highlighting them as promising responder for anti-PD-1/PD-L1 therapy). If a response is identified in the presence of any tumor staining and/or peri-tumoral immune staining, approximately one-third of all TNBC patients should respond to these immunotherapies.

Limitation

The sample size and absence of molecular testing are both limitations of this study.


  Conclusion Top


PD-L1 expression is more in tumors showed poor prognostic features such as the high-grade advanced (T) stage and high Ki-67 index.

TILs PD-L1-positive cases experienced improved survival, however, the correlation between the overall survival and PD-L1 expressed in both TCs and stromal TIL was not statistically significant.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Correspondence Address:
Rania Mohamed Sabry,
Department of Pathology, Faculty of Medicine, Cairo University, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jmau.jmau_77_21



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    -  Sanad AM
    -  Ibrahim WS
    -  Ezzo IM
    -  Sabry RM


Abstract
Introduction
Materials and Me...
Results
Discussion
Conclusion
References
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