Differences in histological features and PD-L1 expression between sporadic microsatellite instability and Lynch-syndrome-associated disease in Japanese patients with colorectal cancer

Yamada, Ryuzo; Yamaguchi, Tatsuro; Iijima, Takeru; Wakaume, Rika; Takao, Misato; Koizumi, Koichi; Hishima, Tsunekazu; Horiguchi, Shinichiro

doi:10.1007/s10147-018-1238-y

Cited by 13 publications

(17 citation statements)

References 38 publications

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“…In our previous study, MSI CRCs with MLH1 methylation showed a higher frequency of PD-L1 expression (28.3%) than MSI CRCs without MLH1 methylation (6.1%) [67]. Yamada et al [71] reported similar results, which showed increased PD-L1 expression in sporadic MSI-H CRCs (25.0%) compared to Lynch syndrome-associated CRCs (3.6%). The underlying mechanism of PD-L1 overexpression in sporadic MSI CRCs should be further investigated.…”

Section: Pd-l1 Expressionmentioning

confidence: 59%

Immune landscape and biomarkers for immuno-oncology in colorectal cancers

Bae

Yoo

Kim

et al. 2020

J Pathol Transl Med

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Colorectal cancer (CRC) is the second most commonly diagnosed cancer and the third leading cause of cancer-related death in Korea [1]. Because of rapid spread of colonoscopy screening, there was a general decrease in CRC until 2010. However, recent studies have reported that the decline in CRC incidence has reversed during the last few years, especially in middle-aged persons, and the occurrence of early-onset CRC has rapidly increased [2]. Most patients with CRC are diagnosed at an operable stage; however, approximately 20% of patients with stage III or high-risk stage II CRC relapse within 5 years after curative resection [3]. Moreover, the 5-year relative survival rate for metastatic CRC is 14% [2]. To improve clinical outcomes for patients with CRC, a more effective treatment modality is required to fulfill those unmet needs. Cancer is fundamentally a genetic disease since the accumulation of mutations, fusions, and copy number alterations drives tumorigenesis. However, recent research on the tumor immune microenvironment (TIME) has revealed the importance of interactions between tumor cells and surrounding immune cells in tumorigenesis [4]. Immune checkpoint inhibitor (ICI) treatment , such as anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibodies and anti-programmed death-1 (PD-1) antibodies, has shown marked clinical benefits in many types of cancer [5,6]. CRC also holds promise for cancer immunotherapy use, and the U.S. Food and Drug Administration (U.S. FDA) approved immunotherapeutic agents for microsatellite instability-high (MSI-H) CRC in 2017 (Fig. 1) [7,8]. In this review, we describe the landscape of the immune microenvironment in CRC and summarize the clinical usefulness of several suggested biomarkers in CRC immunotherapy. IMMUNE LANDSCAPE OF COLORECTAL CANCERS Historical use of microscopic evaluation of immune environment in CRCs To our knowledge, Spratt and Spjut [9] published the first study on integrative histologic evaluation of CRCs in 1967. In that study, the authors evaluated histologic grade, mucinous elements, depth of invasion, characteristics of tumor border, lym

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Section: Pd-l1 Expressionmentioning

confidence: 59%

Immune landscape and biomarkers for immuno-oncology in colorectal cancers

Bae

Yoo

Kim

et al. 2020

J Pathol Transl Med

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“…Patients with a left-sided or rectal MSI/dMMR tumor are likely to have LS. Indeed, while more than 75% of sporadic MSI cancers occur in the proximal colon, LS-associated CRC have no preferential location, since up to 45% are diagnosed in the left colon and rectum [30]. In their study, Mas-Moya et al [32] showed that nearly all patients with left-sided or rectal adenocarcinoma (23/24, 96%) demonstrated a germline MMR gene mutation confirming LS.…”

Section: Colorectal Cancersmentioning

confidence: 97%

“…), whereas LS-associated CRC tend to occur in younger patients (45-60 y.o.) [27][28][29][30][31], with a slight male predominance [2,29]. Patients with a left-sided or rectal MSI/dMMR tumor are likely to have LS.…”

Section: Colorectal Cancersmentioning

confidence: 99%

“…Several studies attempted to identify the morphologic features specific to LS-related tumors, but this led to conflicting results. Some studies demonstrated a tendency towards more frequent poor differentiation [27,30], medullary morphology [29,30], mucinous component [27,33], TILs [29], or PDL1 expression [30] in sporadic MSI CRC vs. LS-associated tumors. In contrast, other studies, including prospective studies [29] and studies with well-defined LS patients (i.e., with a germline mutation), demonstrated no significant difference between sporadic-and LS-related CRC [34,38,39].…”

Section: Colorectal Cancersmentioning

confidence: 99%

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Diagnosis of Lynch Syndrome and Strategies to Distinguish Lynch-Related Tumors from Sporadic MSI/dMMR Tumors

Leclerc

Vermaut²,

Buisine

2021

Cancers

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Microsatellite instability (MSI) is a hallmark of Lynch syndrome (LS)-related tumors but is not specific to it, as approximately 80% of MSI/mismatch repair-deficient (dMMR) tumors are sporadic. Methods leading to the diagnosis of LS have considerably evolved in recent years and so have tumoral tests for LS screening and for the discrimination of LS-related to MSI-sporadic tumors. In this review, we address the hallmarks of LS, including the clinical, histopathological, and molecular features. We present recent advances in diagnostic and screening strategies to identify LS patients. We also discuss the pitfalls associated with the current strategies, which should be taken into account to improve the diagnosis of LS and avoid inappropriate clinical management.

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“…Our results also showed that most MSI cases were deficient in MLH1/PMS2. In patients with colorectal cancer, tumors with a poor differentiation, Crohn-like lymphoid reaction, and PD-L1 expression occurred more frequently in sporadic MSI cases than in Lynch syndrome-associated cases [35]. In the present study, we did not examine MLH1 promoter methylation status, MMR germline status, POLE mutation, or mutation burden status.…”

Section: Discussionmentioning

confidence: 94%

Dedifferentiated Endometrial Carcinoma Could be A Target for Immune Checkpoint Inhibitors (Anti PD-1/PD-L1 Antibodies)

Ono

Nakayama

Nakamura

et al. 2019

IJMS

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Dedifferentiated endometrial carcinoma (DDEC) is defined as an undifferentiated carcinoma admixed with differentiated endometrioid carcinoma (Grade 1 or 2). It has poor prognosis compared with Grade 3 endometrioid adenocarcinoma and is often associated with the loss of mismatch repair (MMR) proteins, which is seen in microsatellite instability (MSI)-type endometrial cancer. Recent studies have shown that the effectiveness of immune checkpoint inhibitor therapy is related to MMR deficiency; therefore, we analyzed the immunophenotype (MMR deficient and expression of PD-L1) of 17 DDEC cases. In the undifferentiated component, nine cases (53%) were deficient in MMR proteins and nine cases (53%) expressed PD-L1. PD-L1 expression was significantly associated with MMR deficiency (p = 0.026). In addition, the presence of tumor-infiltrating lymphocytes (CD8+) was significantly associated with MMR deficiency (p = 0.026). In contrast, none of the cases showed PD-L1 expression in the well-differentiated component. Our results show that DDEC could be a target for immune checkpoint inhibitors (anti PD-L1/PD-1 antibodies), especially in the undifferentiated component. As a treatment strategy for DDEC, conventional paclitaxel plus carboplatin and cisplatin plus doxorubicin therapies are effective for those with the well-differentiated component. However, by using immune checkpoint inhibitors in combination with other conventional treatments, it may be possible to control the undifferentiated component and improve prognosis.

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Differences in histological features and PD-L1 expression between sporadic microsatellite instability and Lynch-syndrome-associated disease in Japanese patients with colorectal cancer

Abstract: Therefore, compared with Lynch-syndrome-associated cancers, sporadic MSI cancers are more frequently solid, poorly differentiated medullary cancers that express PD-L1.

Cited by 13 publications

References 38 publications

Immune landscape and biomarkers for immuno-oncology in colorectal cancers

Immune landscape and biomarkers for immuno-oncology in colorectal cancers

Diagnosis of Lynch Syndrome and Strategies to Distinguish Lynch-Related Tumors from Sporadic MSI/dMMR Tumors

Dedifferentiated Endometrial Carcinoma Could be A Target for Immune Checkpoint Inhibitors (Anti PD-1/PD-L1 Antibodies)

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