Research ArticleExperimental Studies

Programmed Death-Ligand 1 and Programmed Death-Ligand 2 Expression Can Affect Prognosis in Extramammary Paget’s Disease

AYA KAWAGUCHI, JUN AKIBA, REIICHIRO KONDO, EIJI SADASHIMA, SACHIKO OGASAWARA, YOSHIKI NAITO, HIRONORI KUSANO, SAKIKO SANADA, IKKO MUTO, TAKEKUNI NAKAMA and HIROHISA YANO
Anticancer Research January 2021, 41 (1) 219-226; DOI: https://doi.org/10.21873/anticanres.14768

Abstract

Background: Extramammary Paget’s disease (EMPD) is a type of carcinoma that usually progresses slowly but may cause metastasis and subsequent death of patients. We investigated the relationship between the expression of programmed death-ligand 1 (PD-L1)/programmed death-ligand 2 (PD-L2) and stromal CD8+ tumor-infiltrating lymphocytes (TILs) in EMPD and clinicopathological findings, including prognosis. Materials and Methods: We examined 47 cases of EMPD and performed immunohistochemical staining of formalin-fixed paraffin-embedded full-face sections. Results: PD-L1 expression in tumor cells was observed in 13 cases (27.7%) while PD-L2 expression was observed in 21 cases (44.7%). The cumulative postoperative recurrence-free rate in the group with positivity for PD-L1 and/or PD-L2 with a low CD8+ TIL count was significantly lower than that of the corresponding group with a high CD8+ TIL count and of the PD-L1- and PD-L2-negative group (p=0.026). Conclusion: The expression of PD-L1/PD-L2 in tumor cells was shown to be a factor for poor prognosis.

Key Words:

Extramammary Paget’s disease (EMPD) is a rare cutaneous carcinoma that often manifests in the vulva, penis, scrotum, axillae, and perianal region in the elderly, and its etiology remains poorly understood (1-3). Histopathologically, the carcinoma tends to persist in the epidermis but infiltration into the dermis has also been observed. Local mass formation and regional lymph node metastases have also been noted, and mortality linked to the primary disease can also occur as a result of distant lymph node metastasis or hematogenous metastasis (4). The tumor-node-metastasis (TNM) classification for EMPD that is currently used in Japan is a system proposed by Ohara et al. (5) and is being implemented on a trial basis but there has been no international consensus regarding staging thus far. In addition, the current guidelines are based on histological features and do not yet define EMPD on a molecular basis that can guide curative therapies.

In recent years, immune checkpoint inhibitors (ICIs) such as nivolumab (a monoclonal antibody against human programmed death-1 (PD1) have been increasingly and frequently used as a new treatment for various malignant tumors such as malignant melanoma, non-small cell lung cancer and renal cell carcinoma (6, 7). ICIs are drugs that release suppression of the immune response to cancer, and by inhibiting binding to PD1 and its ligands, programmed death ligand-1 (PD-L1) and programmed death ligand-2 (PD-L2), these drugs effectively maintain the immune response to tumor. Response rates with a single ICI have been reported to be approximately 10-30% (8). The expression of PD-L1 and PD1 in tumor and immune cells infiltrating the stroma has been reported to be useful as a predictor of therapeutic efficacy (8-10).

The immunological microenvironment is currently being studied in many types of malignant tumor such as malignant melanoma, head and neck cancer, and hepatocellular carcinoma (11-14). However, few reports have examined the immunological tumor microenvironment in the context of EMPD (15). In this study, we investigated the relationship between the expression of PD-L1/PD-L2, immune checkpoint ligands, and tumor stromal CD8+ T-cells in EMPD, as well as the clinicopathological findings including prognosis.

Materials and Methods

In this study, we examined 47 cases diagnosed with EMPD. All EMPDs were surgically resected at our institutional hospital between 2009 and 2017. Clinical follow-up data were available for all 47 cases. Specimens were fixed in 10% neutral buffered formalin, following paraffin embedding. Consecutive sections measuring 4 μm in thickness were cut and stained with hematoxylin and eosin. A medical history of colorectal carcinoma was assessed to distinguish between primary and secondary diseases. Two pathologists (A.K. and J.A.) independently conducted immunohistochemical evaluation. Disagreement between pathologists was resolved by a joint review to obtain a single consensus.

Recurrence was defined as clinically confirmed post-operative lymph node metastasis. The date of recurrence was defined as the date of pathological diagnosis of lymph node metastasis. This study complies with the institutional guidelines on human experimentation by the Ethical Committee of our institution [approval #413].

Immunohistochemical (IHC) staining. We conducted IHC using paraffin-embedded sections. IHC was performed using antibodies as follows: anti-PD-L1 (1:200; clone E1L3N; Cell Signaling Technology, Denver, MA), anti-PD-L2 (1:200; clone 176611; R&D Systems, Minneapolis, MN), and anti-CD8 (1:200; clone 4B11; Leica Microsystems, Newcastle, UK). IHC was performed using a Leica Bond-III staining instrument (Leica Microsystems). Tonsil epithelium, alveolar macrophages, and lymph nodes were used as positive controls for PD-L1, PD-L2, and CD8, respectively. Vascular endothelium was used as a negative control. The expression of PD-L1 and PD-L2 in tumor cells was evaluated following previous reports, including our report (8, 12). Based on these reports, cut-off values for PD-L1 and PD-L2 were set as 1% and 50%, respectively. In brief, PD-L1 positivity was defined as PD-L1 expression in more than 1% of all tumor cells. PD-L2 positivity was defined as PD-L2 expression in more than 50% of all tumor cells. CD8+ tumor-infiltrating lymphocytes (TILs) were evaluated based on previous reports (16). To investigate lymphocyte infiltration of the stroma, CD8+ TILs were counted in five high-power fields of view (magnification: ×400) and the average number of cells per field of view was assessed. The median number of CD8+ TILs was 14.8 per high-power field of view (range=1.5-27.7). Cases with more CD8+ TILs than the median were collectively defined as having a high CD8+ TIL count, whereas cases with fewer CD8+ TILs than the median were defined having a low CD8+ TIL count.

Statistical analyses. Correlations between the number of CD8+ TILs in invasive and non-invasive regions in the same case were analyzed using Pearson’s correlation coefficients. The t-test and paired t-test were used to compare the average of continuous variables, and chi-square test or the Fisher’s exact probability test were used to compare the proportions of categorical variables in PD-L1 and PD-L2 expression, and CD8+ TILs. The survival of patients was estimated based on the Kaplan-Meier method and their differences were evaluated using the log-rank test for disease-free survival. Clinical and pathological variables were subjected to univariate analysis using a Cox proportional hazard model. All tests were two-sided and a p-value of less than 0.05 indicated a statistically significant difference. Statistical analyses were performed using JMP software version 13 (SAS Institute, Cary, NC, USA) and R software version 3.4.4 (R Foundation for Statistical Computing, Vienna, Austria).

Results

Patient characteristics. Patient characteristics are summarized in Table I. The mean age of patients at the time of first visit was 73.4±10.5 years, and the sex ratio was 22:25. The median period to diagnosis was 12 months (range=1-120 months). Lesions were located in the vulva/scrotum/penis in most cases (42/47, 89.4%). There were five cases (10.6%) with mass formation, and two cases (4.3%) with elevated serum carcinoembryonic antigen and cancer antigen-19-9 levels. Positive surgical margins were identified in 12 cases (25.5%), lymphatic invasion in 3 cases (6.4%), and preoperative lymph node metastasis in 2 cases (4.3%). Invasive carcinoma was present in only 14 cases (29.8%). Recurrence was found postoperatively in 7 cases (14.9%), and mortality from primary disease occurred in two cases (4.3%). The median follow-up period was 1,154 days (range=202-2,603 days).

View this table:
Table I.

Patient characteristics.

IHC findings. The staining patterns of PD-L1/PD-L2 and CD8+ TILs are shown in Figure 1. Cells expressing PD-L1 and PD-L2 in the cell membrane, cytoplasm, or both were defined as positive. While PD-L1 did not show any specific patterns of expression, a number of tumors demonstrated positive PD-L2 expression in deeper regions of the tumor.

Figure 1.
Figure 1.

Representative microphotographs of morphological findings and immunohistochemistry for programmed death-ligand 1 (PD-L1)/programmed death-ligand 2 (PD-L2) and CD8 in in situ and invasive extramammary Paget’s disease. A: Low magnification view showing invasion (blue) and in situ (red) regions. Morphological findings (B, F) and immunohistochemical findings for PD-L1 (C, G), PD-L2 (D, H) and CD8 (E, I) in invasive (upper panel) and in situ (lower panel) region.

PD-L1 was expressed in 13 cases (27.7%) in total and was observed in seven cases (14.5%) of carcinoma in situ. Of 14 invasive carcinoma cases, expression of PD-L1 was detected in both the non-invasive regions and invasive regions of six cases (42.9%). In the remaining eight cases, no expression was observed in either of these regions. The expression of PD-L1 was evenly distributed between the non-invasive and invasive areas in the cases with PD-L1-positive invasive carcinoma.

PD-L2 was expressed in 21 cases (44.7%). PD-L2 expression was observed in 12 cases (25.5%) of carcinoma in situ. Similar to PD-L1, PD-L2 was expressed in both the non-invasive and invasive regions of nine out of 14 invasive carcinoma cases (64.3%). In the remaining five cases, no expression was observed at all. PD-L2 expression was also evenly distributed between the non-invasive and invasive regions in PD-L2-positive invasive carcinoma cases. The number of CD8+ TILs was significantly corelated in invasive and non-invasive regions of invasive carcinoma when compared within the same case (Figure 2A, r=0.671, p=0.009). Moreover, the number of CD8+ TILs was significantly less in invasive than in non-invasive regions of invasive carcinoma (Figure 2B, p<0.001). The numbers of CD8+ TILs were comparable between non-invasive regions of invasive carcinoma and carcinoma in situ. No significant difference was observed in the number of CD8+ TILs between carcinoma in situ and non-invasive regions of invasive carcinoma cases.

Figure 2.
Figure 2.

Correlation of the number of CD8+ tumor-infiltrating lymphocytes (TILs) in invasive and non-invasive regions of invasive carcinoma. A: The number of CD8+ TILs in invasive and non-invasive regions was significantly positively correlated when compared within the same case (r=0.671, p=0.009). B: The number of CD8+ TILs was significantly less in invasive than in non-invasive regions of invasive carcinoma (p<0.001).

PD-L1/PD-L2 in tumor cells and clinicopathological correlations. There were no significant differences between the PD-L1-positive and PD-L1-negative groups with respect to clinicopathological factors patient age, sex, period to diagnosis, preoperative lymph node metastasis, surgical margin positive, lymphatic invasion, and presence of invasion to the dermis. In addition, there was no significant difference in PD-L1 expression and number of CD8+ TILs.

There were also no significant differences in clinicopathological factors between the PD-L2-positive and PD-L2-negative groups. In addition, there was no significant difference in PD-L2 and CD8+ TIL count (Table II).

View this table:
Table II.

Relationship between the expression programed death ligand-1 (PD-L1)/programmed death ligand-2 (PD-L2) and various factors.

Correlations between PD-L1/PD-L2/CD8 TIL count and patient prognosis. The PD-L1-positive group had a shorter recurrence-free survival than the PD-L1-negative group (Figure 3A, log-rank test: p<0.001). The PD-L2-positive group also exhibited a shorter recurrence-free survival period compared with the PD-L2-negative group (Figure 3B, log-rank test: p=0.041). Together, the group positive for PD-L1 and/or PD-L2 had a shorter recurrence-free survival than the PD-L1- and PD-L2-negative group (Figure 3C, log-rank test: p=0.041). The group positive for PD-L1 and/or PD-L2 with a low CD8+ TIL count exhibited shorter recurrence-free survival periods than the corresponding group with a high CD8+ TIL count, and the PD-L1- and PD-L2-negative group (Figure 3D, log-rank test: p=0.026). In the univariate analysis of recurrence-free survival, the presence of invasion to the dermis and lymphatic invasion were extracted as significant factors; although there was no statistically significant difference in recurrence, recurrence tended to be associated with PD-L1-positive, PD-L2 positive, and PD-L1- and/or PD-L2-positive status (Table III).

Figure 3.
Figure 3.

Kaplan–Meier analysis of recurrence-free survival of patients with extramammary Paget’s disease. A: Comparison of prognosis between cases with programmed death ligand 1 (PD-L1-)-positive and PD-L1-negative disease. The PD-L1-positive group had a shorter recurrence-free survival than the PD-L1-negative group (p<0.001). B: Comparison of prognosis between PD-L2-positive and PD-L2-negative cases. The PD-L2-positive group also exhibited a shorter recurrence-free survival period compared with the PD-L2-negative group (p=0.041). C: Comparison of prognosis between cases positive for PD-L1 and/or PD-L2 and cases negative for PD-L1 and PD-L2. The PD-L1/PD-L2-positive group had a shorter recurrence-free survival than the group negative for both PD-L1 and PD-L2 (p=0.041). D: Comparison of prognosis according to PD-L1 and PD-L2 status and the number of CD8+ tumor-infiltrating lymphocytes (TILs). Those positive for PD-L1 and/or PD-L2 with a low CD8+ TIL count exhibited shorter recurrence-free survival than those with a high CD8+ TIL count, and those negative for both PD-L1 and PD-L2 (p=0.026).

View this table:
Table III.

Univariate analysis of clinicopathological factors associated with recurrence-free survival.

Discussion

We evaluated the expression of PD-L1, PD-L2, and CD8+ TILs in patients with EMPD using IHC. Our data revealed that the expression of PD-L1 and PD-L2 in tumor cells increased with invasion, serving as a poor prognostic factor. CD8+ TILs were further shown to significantly decrease with infiltration. PD-L1 and PD-L2 status, as well as a low CD8+ TIL count were found to be associated with shorter recurrence-free survival.

The expression of PD-L1/PD-L2 in tumor cells differs depending on the type of carcinoma. PD-L1 and PD-L2 are also expressed in non-small cell lung cancer, malignant melanoma, and renal cell carcinoma, and it has been reported that PD-L2 is more widely expressed in gastric cancer and head and neck squamous cell carcinoma than PD-L1 (17). In this study, we observed expression of both PD-L1 and PD-L2. Umezu et al. reported that blocking both PD-L1 and PD-L2 may enhance the activity of antitumor immunity compared with blocking PD-L1 alone. The reason for this is that inhibition of PD-L1 induces PD-L2 expression on tumor-associated macrophages, and the function of PD-L2 is enhanced (18). It has been suggested that simultaneous inhibition of PD-L1 and PD-L2 is necessary to activate antitumor immunity, which would be particularly important in cases of EMPD expressing both PD-L1 and PD-L2.

There have been several reports regarding PD-L1 and PD-L2 expression in EMPD. Karpathiou et al. (19) reported that no PD-L1 expression was observed in any of the cases described in their study, while Duverger et al. (20) and Mauzo et al. (21) reported expression in 57.1% and 14.2% of EMPD cases, respectively. Although there are fewer reports of PD-L2 expression, Pourmaleki et al. (22) reported no expression in all of their cases. The difference in the positivity rate may be related to the cut-off value provided, differences in antibody clones, and the ratio of invasive carcinoma among the cases. Pourmaleki et al. also compared the expression levels of PD-L1/PD-L2 in invasive and non-invasive regions in the same case and reported a strong correlation between them (22). Our findings were largely consistent with these results. Stated differently, in the context of EMPD, it may be possible to extract cases at high risk of developing invasive carcinoma by examining PD-L1 expression in biopsy samples obtained from non-invasive portions. However, an additional study using a large cohort should be conducted to further accumulate case data. In various cancer types, the expression of PD-L1 in tumor cells and the number of CD8+ TILs were shown to be positively correlated (20, 23-27). CD8+ TILs that infiltrate the stroma are believed to be one factor associated with a favorable prognosis (28-31). In this study, cases with PD-L1 and/or PD-L2, and a low CD8+ TIL count had poor prognoses. Additionally, up-regulation of PD-L1/PD-L2 expression was observed along with invasion of tumor cells in this study. We believe that a dramatic change in the immune microenvironment occurred in parallel. As PD-L1/PD-L2 expression acts to suppress tumor immunity, tumor cells that express PD-L1/PD-L2 thereby evade the immune system, and we hypothesize that the tumor progresses due to suppression of the activation of CD8+ TILs.

By contrast, Iga et al. reported that in EMPD, CD8+ TILs in the tumor stroma were predominant in cases with poor prognosis (15). Duverger et al. reported that CD8+ TILs had no prognostic association with respect to cutaneous adnexal tumors, including EMPD (20). Thus, findings regarding CD8+ TILs in cases of EMPD are inconsistent. The report by Iga et al. offered a detailed phenotype analysis of CD8+ TILs. Infiltrate CD8+ TILs exhibit an exhausted phenotype, and although these cells are present in the tumor stroma, they are hypothesized to have no effective effect on antitumor immunity. Additionally, the proportion of cases with PD-L1-positive tumor cells in their study was similar to ours, despite the inclusion of more invasive carcinoma cases than our study. In our study, since the expression of PD-L1 was more evident in invasive carcinoma cases, it is possible that changes in the immune microenvironment due to PD-L1-positive carcinoma cells are involved in the degree of CD8+ TIL infiltration.

The use of ICIs may be limited to cases where surgery is not curative and the disease is progressive. In our study, while expression of PD-L1/PD-L2 was observed primarily in the tumor cells located in the invasive regions, almost no CD8+ TILs were detected in the tumor stroma. The presence of stromal immune cells as well as PD-L1/PD-L2 expression on tumor cells is essential in determining the proper application of ICIs (32). In our study, the immune environment in the invasive portions of EMPD cases corresponds to so-called ‘Desert or cold’ tumors, on which ICIs can be expected to have a negligible effect. The effective use of ICIs requires activation of the immune microenvironment to a ‘hot’ or inflamed state (33). EMPD has also been described as having an immunophenotype similar to that of breast cancer (34). In breast cancer, it has been reported that interleukin-17A and matrix metalloproteinase-9 antibodies alter the tumor microenvironment to a ‘hot’ state, and even in cases of EMPD, it may be necessary to employ these immune-activators together with ICIs for more effective therapeutic activity (35, 36).

In addition, tumors with PD-L1 expression have been reported in various types of carcinomas with highly malignant potential, which may be one of the reasons for poor prognosis in PD-L1/PD-L2-positive cases (37). Although there is currently no histological classification for EMPD, it may be possible that cases with high malignant potential may be identified using PD-L1/PD-L2 expression.

Our study has several limitations. Firstly, we used a retrospective cohort involving a relatively small number of patients from a single facility. Secondly, it was not possible to conduct a multivariate analysis due to the rarity of EMPD. Finally, with only two patients succumbing to their disease, it is difficult to correlate the current findings with precise outcomes. Therefore, future investigations and validations using prospective studies with a larger patient sample size are required.

In conclusion, the expression of PD-L1/PD-L2 was shown to be a prognostic factor in EMPD. Furthermore, the invasion of tumor cells appears to correlate with a dramatic change in the immune microenvironment, such as a reduction in the number of CD8+ TILs, which may result in the formation of a suppressive immune microenvironment and a corresponding poor prognosis. The expression of PD-L1/PD-L2 can also vary by case, and consideration of CD8+ TIL infiltration as well as PD-L1/PD-L2 expression when using an ICI may be valuable for the selection of cases in which treatment can be expected to be most effective.

Footnotes

  • Authors’ Contributions

    AK, JA, RK, SO, YN, HK, SS, TN and HY designed this study. AK drafted the article, and JA, TN and HY edited the article. AK and IM acquired and collected the data. ES performed the statistical analysis and drew the figures.

  • Conflicts of Interest

    The Authors have no conflicts of interest to disclose.

  • Funding

    This work was supported by Japan Society for the Promotion of Science KAKENHI Grant Number 20K16184.

  • Received November 19, 2020.
  • Revision received November 29, 2020.
  • Accepted November 30, 2020.

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Programmed Death-Ligand 1 and Programmed Death-Ligand 2 Expression Can Affect Prognosis in Extramammary Paget’s Disease
AYA KAWAGUCHI, JUN AKIBA, REIICHIRO KONDO, EIJI SADASHIMA, SACHIKO OGASAWARA, YOSHIKI NAITO, HIRONORI KUSANO, SAKIKO SANADA, IKKO MUTO, TAKEKUNI NAKAMA, HIROHISA YANO
Anticancer Research Jan 2021, 41 (1) 219-226; DOI: 10.21873/anticanres.14768
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