Immunohistochemistry as predictive and prognostic markers for gastrointestinal malignancies

Biomarkers play a key role in the comprehensive pathologic evaluation of gastrointestinal malignancies. These biomarkers can be predictive, indicating whether a tumor is likely to respond to a particular therapy, or prognostic, providing information about the likely course and outcome of a disease. This review article will discuss available immunohistochemical stains for assessing these markers, including staining rationale, scoring criteria, associated systemic therapies, and pictorial examples. PD-L1, HER2, and mismatch repair status can be evaluated via immunohistochemistry for esophageal, gastric, and colorectal carcinomas. Biomarkers currently play a more limited role in evaluation of pancreatic and small bowel malignancies. Immunohistochemistry can also be used to evaluate biomarker status in gastrointestinal stromal tumors, gastrointestinal malignancies with NTRK gene fusions, and undifferentiated carcinomas with switch-sucrose non-fermentable complex abnormalities.     

A review of prognostic and predictive biomarkers in breast cancer

Clinical and Experimental Medicine - Breast cancer (BC) is a common cancer all over the world that affects women. BC is one of the leading causes of cancer mortality in women, which today has...     

Morphological characteristics and prognostic criteria for gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal neoplasms of the gastrointestinal tract. Analysis of GIST morphology is necessary for selection of primary patients with the high risk of tumor progression for adjuvant treatment with gleevek following complete gross resection of KIT (CD 117)-positive GIST. In this study we've analyzed morphological parameters and survival of 120 GIST patients before target therapy. According to risk stratification of primary GIST by tumor location, size and mitotic index (mitoses per 50 visual fields) 44% of gastric GISTs, 87,5% of small bowel GISTs and 100% of rectum GISTs have been classified as high risk group. There was no significant difference between survival of patients with different type of GIST, Ki-67 proliferative index and presence of necrosis.     

Review of diagnostic,prognostic, and predictive biomarkers in melanoma

Melanoma is an aggressive cutaneous malignancy with rapidly rising incidence. Diagnosis of controversial melanocytic lesions, correct prognostication of patients, selection of appropriate adjuvant and systemic therapies, and prediction of response to a given therapy remain very real challenges. Despite these challenges, multiple high throughput, nucleic-acid based biomarkers have been developed that can be assayed from histologic tissue specimens. FISH, CGH, Decision-Dx, and other multi-marker assays have been combined to improve overall predictability. This review discusses some of the most promising nucleic acid based assays that can be obtained from tissue specimens to assist with diagnosis, prognostication, and prediction of treatment response.     

Diagnostic and prognostic markers for gastrointestinal stromal tumors in Norway.

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor in the gastrointestinal tract. The diagnosis of GIST is based on histology together with a panel of immunohistochemical markers; the most important is KIT (CD117). A total of 434 cases of GISTs were confirmed by histology and immunohistochemistry, and incorporated into tissue microarrays. Validation of histological features as well as the prognostic value of two immunohistochemical biomarkers (p16 and L1) was assessed. High mitotic rate, large tumor size, nuclear atypia, and small bowel primary site were all validated as negative prognostic factors in GISTs. Expression of p16 was significantly correlated with unfavorable prognosis, whereas L1 expression was not.     

Cell‐free microRNAs as diagnostic,prognostic, and predictive biomarkers for lung cancer

Lung cancer is the most common cancer worldwide, accounting for over 1.37 million deaths annually. The clinical outcome and management of lung cancer patients could be substantially improved by the implementation of non‐invasive biomarker assays for the early detection, prognosis as well as prediction and monitoring of treatment response. MicroRNAs (miRNAs) have been implicated in the regulation of virtually all signaling circuits within a cell and their dysregulation has been shown to play an essential role in the development and progression of cancer. Recently, miRNAs were found to be released into the circulation and to exist there in a remarkably stable form. Furthermore, various cancers were shown to leave specific miRNA fingerprints in the blood of patients suggesting that cell‐free miRNAs could serve as non‐invasive biomarkers for the detection or monitoring of cancer and putative therapeutic targets. Since that, a considerable effort has been devoted to decode the information carried by circulating miRNAs. In the current review, we give an insight into the mechanisms of miRNA release into the bloodstream, their putative functional significance and systematically review the studies focused on the identification of cell‐free miRNAs with the diagnostic, prognostic, and predictive significance in lung cancer and discuss their potential clinical utility. © 2012 Wiley Periodicals, Inc.     

Still waiting for predictive biomarkers in Barrett's oesophagus

Barrett's oesophagus is important as a precursor of oesophageal adenocarcinoma via a metaplasia-dysplasia-carcinoma sequence. It is often detected on upper gastrointestinal endoscopy. In the absence of glandular dysplasia the risk of progression to cancer is low but ascertainment of dysplasia is not always straightforward. Sparse mucosal sampling may miss dysplasia, or reactive changes may be overinterpreted due to inter and intraobserver variation. Low-grade and even high-grade dysplasia do not necessarily progress, provided prevalent cancer has been rigorously excluded. This indeterminacy motivates an ongoing search for clinically useful predictive biomarkers. Although many genetic and epigenetic abnormalities have been associated with neoplastic progression in Barrett's mucosa no molecular tests have as yet been accepted into routine pathology practice. Challenges of assay definition remain and many marker studies lack statistical power or have other methodological flaws. Even where strong evidence of clinically relevant predictive value does exist (in the case of ploidy analysis by flow or image cytometry) adoption has been minimal, likely reflecting technological and possible reimbursement obstacles. Well designed multicentre studies are likely to be required to translate improved knowledge of Barrett's carcinogenesis into clinically significant progress on predictive testing, and will require a degree of cooperation not so far widely seen in the field.     

Diagnostic and prognostic molecular biomarkers for prostate cancer

Prostate cancer is the most common malignant tumour in men and is a major research focus of pathologists, urologists and uro-oncologists alike. The pathologist is confronted with an increasing number of biospsies, necessitating ancillary tests in morphologically challenging cases. Next to basal cell markers, additional positive markers that aid in the differential diagnosis are presented here. The clinical decision of urologists, whom and how to treat these men, is dependent predominantly on pathological parameters, but still the grid spanned by these is too wide to allow a sufficient prognostication of the individual case. Here, a brief and critical overview is given of recent developments of prognostic biomarkers in prostate cancer.     

Diagnostic and prognostic biomarkers in pancreatic carcinoma

Pancreatic ductal carcinoma, one of the leading causes of cancer mortality, is typically diagnosed at an advanced stage, which significantly contributes to its high mortality rates. Studies have demonstrated that resection of small pancreatic tumors and tumors at lower stages correlates with improved survival. Detection of pancreatic carcinoma at an early, surgically resectable stage is the key to decreasing mortality and improving survival. Identification of sensitive diagnostic biomarkers as screening tools is crucial in detecting preinvasive pancreatic neoplasms. Numerous new DNA-, RNA- and protein-based biomarkers have been extensively investigated. This review aims to provide an update on these molecular markers, including biomarkers from blood, tissue as well as pancreatic juice and cystic fluid. These biomarkers hold potential utility in early diagnosis and prognostification of pancreatic ductal carcinoma, though many of which need to be validated in large-scale prospective studies before they can be used in clinical settings.     

Retrospective study of the clinicopathological characteristics and prognostic factors of gastrointestinal stromal tumors in Chinese patients

The purpose of this study was to investigate the clinicopathological characteristics and prognostic factors of patients with gastrointestinal stromal tumors (GISTs) in mainland China. We retrospectively analyzed the clinicopathological characteristics and survival data of 149 patients with GISTs admitted to Shengjing Hospital of China Medical University from July 2011 to October 2017. The following details were collected from all patients: sex, age, symptoms, preoperative examination, pathology, surgical procedures, and follow-up data. Recurrence-free survival (RFS) and overall survival (OS) were used to assess survival outcomes. The Kaplan–Meier method was performed to draw survival curves and calculate the survival rate. The log-rank test was performed for univariate analysis, and the significant factors were included in multivariate analysis using a Cox proportional hazards model to determine prognostic factors. The 5-year RFS rate was 78.5 % and 5-year OS rate was 83.2 %. The univariate analysis showed that the following prognostic factors could significantly predict 5-year RFS and OS: tumor size, initial status, modified NIH classification, mitotic index, CD117 expression, Ki67 index, and surgical procedure (P < 0.05). The multivariate analysis showed that mitotic index, CD117, and Ki67 index were independent prognostic factors associated with 5-year RFS and 5-year OS. This study provides a reference for the clinicopathological characteristics and prognostic factors of patients with GISTs in mainland China, and the results suggest that focusing on immunohistochemical markers in clinical practice may be more reliable for the prediction of clinical outcomes.     

Diagnostic and prognostic biomarkers in salivary gland tumours

Salivary glands are a heterogeneous group of neoplasms and are diagnostically challenging with overlapping microscopic features between tumours as well as intra-tumour morphological diversity. Correct diagnosis is essential to ensure appropriate management and follow-up. Morphological and cytological analysis of haematoxylin and eosin stained tissue sections is supplemented by a large number of immunohistochemical and special stains as well as molecular rearrangements. A broad literature search was performed to provide an overview of all biomarkers used for diagnosis and prognosis prediction of salivary gland tumours. The wide range of biomarkers reported in the literature can be overwhelming but used in the correct context can aid diagnosis and predict the behaviour of these challenging tumours. They can also help identify recently described new entities.     

Gene expression profiling for the investigation of soft tissue sarcoma pathogenesis and the identification of diagnostic, prognostic, and predictive biomarkers

Soft tissue sarcomas are malignant neoplasms derived from mesenchymal tissues. Their pathogenesis is poorly understood and there are few effective treatment options for advanced disease. In the past decade, gene expression profiling has been applied to sarcomas to facilitate understanding of sarcoma pathogenesis and to identify diagnostic, prognostic, and predictive markers. In this paper, we review this body of work and discuss how gene expression profiling has led to advancements in the understanding of sarcoma pathobiology, the identification of clinically useful biomarkers, and the refinement of sarcoma classification schemes. Lastly, we conclude with a discussion of strategies to further optimize the translation of gene expression data into a greater understanding of sarcoma pathogenesis and improved clinical outcomes for sarcoma patients.     

Criteria for malignancy in gastrointestinal endocrine tumors

In contrast with the large amount of data generated from endocrine tumors of the pancreas, sparse and mostly unconfirmed data are available on the criteria for the assessment of malignancy risk and patient outcome in endocrine tumors of the gastrointestinal tract. In these conditions the 2000 WHO classification with its standardized scheme of pathologic report constitutes a framework facilitating the assessment of tumor malignancy and has been regarded as useful for clinical purposes, providing the basis for proper management of the patients and for the design of treatment protocols. The classification is based on a combination of pathological and clinical features with parameters specific for each organ in which the endocrine tumors originate. Three main categories, one further subdivided into two subgroups, are considered: (1) well-differentiated endocrine tumors, further subdivided into tumors with benign and with uncertain behavior; (2) well-differentiated endocrine carcinomas, low grade; and (3) poorly differentiated endocrine carcinomas, high grade. In this review the differential tumor characteristics between the different categories are summarized. Moreover, the relevance of additional features with respect to tumor prognostication, chiefly the Ki-67 proliferation index and malignancy-associated genetic changes, is discussed with emphasis on the discrepancies emerging between tumors of foregut and of midgut origin.     

Predicting uveitis in juvenile idiopathic arthritis: from biomarkers to clinical practice

Introduction: Uveitis is a sight-threatening eye inflammation and common manifestation of juvenile idiopathic arthritis (JIA). New biomarkers that can predict uveitis are needed to alleviate personalized clinical screening. In this review, we outline clinical and molecular risk factors for uveitis and discuss their putative biology and value for clinical practice.

Areas covered: The recent discovery of the YST-amino acid motif in the Human Leukocyte Antigen DRB1 gene exposed a strong genetic predisposition for uveitis in females and can be used to identify low-risk cases and redefine screening policies. The established predictor ‘young age at arthritis onset’ appeared to only hold true for females, emphasizing the importance of sex-stratification in biomarker applications. Aqueous humor profiling studies have shown unique mediator changes. Finally, erythrocyte sedimentation rate and S100A12 levels can be used to stratify patients at high risk for uveitis.

Expert commentary: Various markers have been identified and may significantly improve risk assessment for uveitis in JIA. However, there remains an unmet need to better predict uveitis in advance. Here, we propose a set of markers with high potential for prospective studies, which subsequently can be integrated to develop optimal prediction tools that complement improved screening guidelines for early disease detection and personalized care strategies.     

The gastric hypercellular microleiomyoma as a precursor lesion for clinical gastrointestinal stromal tumors

Differentiation features and proliferation activity of 67 gastric microleiomyomas (microLMs) and 53 clinical gastrointestinal stromal tumors (GISTs) of the stomach were compared. The 67 microLMs were divided into two categories on the basis of cellularity: 53 hypocellular and 14 hypercellular types, and the 39 GISTs were divided into 13 low-grade and 40 high-grade lesions. Immunohistochemically, 49 hypocellular microLMs (92%) were positive for alpha-smooth muscle actin and desmin, whereas only 16 (30%) were stained for vimentin. Conversely, all 14 hypercellular microLMs were positive for vimentin, and only one (7%) was positive for alpha-smooth muscle actin and desmin. Five low-grade (38%) and 14 high-grade GISTs (35%) were positive for alpha-smooth muscle actin, and 12 low-grade (92%) and all 40 high-grade GISTs were stained for vimentin. CD34 was positive in 10 hypocellular microLMs (19%), all 14 hypercellular microLMs, 10 low-grade GISTs (77%), and 38 high-grade GISTs (95%). Hypercellular microLM thus showed similarities to clinical GIST and also exhibited significantly higher proliferation activity than hypocellular microLM on analysis of the Ki-67 labeling index and argyrophilic nucleolar organizer regions staining. The findings indicate that the hypercellular microLM may be a direct precursor for clinical GIST, both showing a primitive mesenchymal cell nature.