Advances In Anatomic Pathology最新文献

The addition of "avoiding immune destruction" to the hallmarks of cancer demonstrated the importance of cancer immunology and in particular the role of immune surveillance and escape from malignancies. However, the underlying mechanisms contributing to immune impairment and immune responses are diverse. Loss or reduced expression of the HLA class I molecules are major characteristics of human cancers resulting in an impaired recognition of tumor cells by CD8 + cytotoxic T lymphocytes. This is of clinical relevance and associated with worse patients outcome and limited efficacy of T-cell-based immunotherapies. Here, we summarize the role of HLA class I antigens in cancers by focusing on the underlying molecular mechanisms responsible for HLA class I defects, which are caused by either structural alterations or deregulation at the transcriptional, posttranscriptional, and posttranslational levels. In addition, the influence of HLA class I abnormalities to adaptive and acquired immunotherapy resistances will be described. The in-depth knowledge of the different strategies of malignancies leading to HLA class I defects can be applied to design more effective cancer immunotherapies.

Immunotherapy has shown promising results in the treatment of recurrent and metastatic head and neck cancers. Antiprogrammed cell death (PD)-1 therapies have been recently approved in this setting and they are currently tested also in the treatment of locally advanced diseases and in the neoadjuvant setting. However, the clinical benefits of these treatments have been quite variable, hence the need to select those patients who may obtain the maximal efficacy through the identification of predictive biomarkers. Currently, PD-L1 immunohistochemical expression by tumor and immune cells is the most widely used predictive biomarker for immunotherapy in head and neck squamous cell carcinoma. Nevertheless, patients with PD-L1 - tumors may still respond to treatments, thereby emphasizing the need for the identification of other predictive biomarkers. In this review, we summarize the current data on histologic and molecular parameters that can be used to select patients with head and neck cancers for immunotherapy, with a focus on squamous cell carcinoma and salivary gland carcinomas.

Inactivation of different subunits of the SWItch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex has emerged as one of the most frequent genetic pathways driving a variety of neoplasms of diverse histogenesis, originating in different organs. With few exceptions, most SWI/SNF-deficient malignancies pursue a highly aggressive clinical course resulting in widespread disease dissemination either at or soon after diagnosis, ultimately causing patients' death soon after diagnosis, despite the apparently curative treatment intention. To date, no satisfactorily effective systemic chemotherapy has been established for treating these diseases. This disappointing finding underlines the urgent need for an effective systemic therapy that would enable sufficient intermediate to long-term disease control. Recently, SWI/SNF-deficiency has increasingly emerged as pivotal in cancer immunogenicity and hence a promising biomarker predicting response to immune-checkpoint inhibition therapy utilizing several recently established drugs. This review summarizes the most recent literature on this topic with emphasis on the entities that most likely represent suitable candidates for immune therapy.

Until very recently, surgery, chemotherapy, and radiation therapy have been the mainstay of treatment in non-small cell carcinomas (NSCLCs). However, recent advances in molecular immunology have unveiled some of the complexity of the mechanisms regulating cellular immune responses and led to the successful targeting of immune checkpoints in attempts to enhance antitumor T-cell responses. Immune checkpoint molecules such as cytotoxic T-lymphocyte associated protein-4, programmed cell death protein-1, and programmed death ligand (PD-L) 1 have been shown to play central roles in evading cancer immunity. Thus, these molecules have been targeted by inhibitors for the management of cancers forming the basis of immunotherapy. Advanced NSCLC has been the paradigm for the benefits of immunotherapy in any cancer. Treatment decisions are made based on the expression of PD-L1 on the tumor cells and the presence or absence of driver mutations. Patients with high PD-L1 expression (≥50%) and no driver mutations are treated with single-agent immunotherapy whereas, for all other patients with a lower level of PD-L1 expression, a combination of chemotherapy and immunotherapy is preferred. Thus, PD-L1 blockers are the only immunotherapeutic agents approved in advanced NSCLC without any oncogenic driver mutations. PD-L1 immunohistochemistry, however, may not be the best biomarker in view of its dynamic nature in time and space, and the benefits may be seen regardless of PD -L1 expression. Each immunotherapy molecule is prescribed based on the levels of PD-L1 expression as assessed by a Food and Drug Administration-approved companion diagnostic assay. Other biomarkers that have been studied include tumor mutational burden, the T-effector signature, tumor-infiltrating lymphocytes, radiomic assays, inflammation index, presence or absence of immune-related adverse events and specific driver mutations, and gut as well as local microbiome. At the current time, none of these biomarkers are routinely used in the clinical decision-making process for immunotherapy in NSCLC. However, in individual cases, they can be useful adjuncts to conventional therapy. This review describes our current understanding of the role of biomarkers as predictors of response to immune checkpoint molecules. To begin with a brief on cancer immunology in general and in NSCLC, in particular, is discussed. In the end, recent advancements in laboratory techniques for refining biomarker assays are described.

Over the last years, immune checkpoint inhibitors (ICIs) have demonstrated remarkable anti-tumor activity and beneficial effects in patients with early and advanced melanoma. However, ICIs provide clinical benefit only in a minority of patients due to primary and/or acquired resistance mechanisms. Immunotherapy resistance is a complex phenomenon relying on genetic and epigenetic factors, which ultimately influence the interplay between cancer cells and the tumor microenvironment. Information is accumulating on the cellular and molecular mechanisms underlying the production of resistance and the resulting diminished therapeutic efficacy. In addition, current knowledge on predictors of response and toxicity to immunotherapy and on biomarkers that reliably identify resistant patients is in progress. In this review, we will focus on the tumor microenvironment changes induced by ICIs in melanoma, summarizing the available evidence of clinical trials in the neoadjuvant and metastatic setting. We will also overview the role of potential biomarkers in predicting disease response to ICIs, providing insight into current and future research in this field.

Immune checkpoint inhibitors (ICIs) have changed therapy strategies in breast cancer (BC) patients suffering from triple-negative breast cancer (TNBC). For example, in Europe the anti-programmed cell death 1 ligand 1 (PD-L1) ICI Azetolizumab is approved for adult patients with locally advanced or metastasized TNBC (mTNBC), depending on the immunohistochemical (IHC) PD-L1 expression of immune cells in the tumor area [immune cell (IC) score ≥1%); the anti-programmed cell death 1 (PD-1) ICI pembrolizumab is approved for mTNBC if PD-L1 Combined Positive Score (CPS), that is PD-L1 expression on tumor and/or immune cells, is ≥10. For early TNBC, in contrast, neoadjuvant use of pembrolizumab is approved in the United States and Europe independent from PD-L1 IHC expression. The determination of PD-L1 expression in tumor tissue to predict response to ICI therapy requires sensitive immunostaining with appropriate primary antibodies and staining protocols and a standardized and meticulous assessment of PD-L1 IHC stained breast cancer tissue slides. For the selection of the test material and continuous quality control of the dyeing, high standards must be applied. The evaluation is carried out according to various evaluation algorithms (scores). Here, the role of PD-L1 in BC and the currently most relevant PD-L1 assays and scores for TNBC will be explained. Furthermore, other tissue-based biomarkers potentially predictive for ICI therapy response in BC, for example, tumor mutational burden (TMB), will be presented in this review.

Immune checkpoint inhibitors have been increasingly used to treat various malignant neoplasms. Despite their superior efficacy in treating certain ones, their global immune-activation effect leads to systemic side effects, referred to as immune-related adverse events. Immune-related adverse events affect a variety of organs, including the skin, gastrointestinal, hepatobiliary, and endocrine organs. Gastrointestinal tract immune-related adverse events present with a wide range of symptoms with variable severity, which may lead to treatment interruption and administration of immunosuppression therapy in many cases. Histopathologic changes are diverse, overlapping with many other conditions. Therefore, recognizing these changes is crucial in diagnosing immune-related adverse events. This review discusses the pathologic manifestations of gastrointestinal immune-related adverse events and discusses the primary differential diagnoses.

Immune-checkpoint-inhibitor (ICI) therapy has been one of the major advances in the treatment of a variety of advanced or metastatic tumors in recent years. Therefore, ICI-therapy is already approved in first-line therapy for multiple tumors, either as monotherapy or as combination therapy. However, there are relevant differences in approval among different tumor entities, especially with respect to PD-L1 testing. Different response to ICI-therapy has been observed in the pivotal trials, so PD-L1 diagnostic testing is used for patient selection. In addition to PD-L1 testing of tumor tissue, liquid biopsy provides a noninvasive way to monitor disease in cancer patients and identify those who would benefit most from ICI-therapy. This overview focuses on the use of ICI-therapy and how it relates to common and potential future biomarkers for patient-directed treatment planning.

Despite the innovations made to enhance smarter screening and conservative management for low-grade prostate cancer, overdiagnosis, and overtreatment remains a major health care problem. Driven by the primary goal of reducing harm to the patients, relabeling of nonlethal grade group 1 (GG 1) prostate cancer has been proposed but faced varying degrees of support and objection from clinicians and pathologists. GG 1 tumor exhibits histologic (invasive) and molecular features of cancer but paradoxically, if pure, is unable to metastasize, rarely extends out of the prostate, and if resected, has a cancer-specific survival approaching 100%. Most of the arguments against relabeling GG 1 relate to concerns of missing a higher-grade component through the unsampled area at biopsy. However, the designation of tumor benignity or malignancy should not be based on the shortcomings of a diagnostic procedure and sampling errors. This review explores possible solutions, mainly the feasibility of renaming GG 1 in radical prostatectomy (RP) with ramifications in biopsy diagnosis, acceptable for both pathologists and clinicians. One workable approach is to rename GG 1 in RP with a cautious neutral or nonbenign non-cancer term (eg, acinar neoplasm) using "defined criteria" that will stop the indiscriminate reporting of every GG 1 in biopsy as carcinoma including eventual insignificant microtumors in RPs. Use of a corresponding noncommittal term at biopsy while commenting on the possibility of an undersampled nonindolent cancer, might reduce the pathologist's concerns about upgrading. Dropping the word "carcinoma" in biopsy preempts the negative consequences of labeling the patient with cancer, including unnecessary definitive therapy (the root cause of overtreatment). Renaming should retain the status quo of contemporary grading and risk stratifications for management algorithms while trying to minimize overtreatment. However, the optimal approach to find answers to this issue is through multidisciplinary discussions of key stakeholders with a specific focus on patient-centered concerns and their ramifications in our practices. GG 1 renaming has been brought up in the past and came up again despite the continued counterarguments, and if not addressed more comprehensively will likely continue to reemerge as overdiagnosis, overtreatment, and patient's sufferings persist.