Andrew M Bellizzi

This review is based on a presentation given at the Hans Popper Hepatopathology Society companion meeting at the 2019 United States and Canadian Academy of Pathology Annual Meeting. It presents updates on the diagnosis and classification of neuroendocrine neoplasms, with an emphasis on the role of immunohistochemistry. Neuroendocrine neoplasms often present in liver biopsies as metastases of occult origin. Specific topics covered include 1. general features of neuroendocrine neoplasms, 2… Show more

This review is based on a presentation given at the Hans Popper Hepatopathology Society companion meeting at the 2019 United States and Canadian Academy of Pathology Annual Meeting. It presents updates on the diagnosis and classification of neuroendocrine neoplasms, with an emphasis on the role of immunohistochemistry. Neuroendocrine neoplasms often present in liver biopsies as metastases of occult origin. Specific topics covered include 1. general features of neuroendocrine neoplasms, 2. general neuroendocrine marker immunohistochemistry, with discussion of the emerging marker INSM1, 3. non-small cell carcinoma with (occult) neuroendocrine differentiation, 4. the WHO Classification of neuroendocrine neoplasms, with discussion of the 2019 classification of gastroenteropancreatic neoplasms, 5. use of Ki-67 immunohistochemistry, 6. immunohistochemistry to assign site of origin in neuroendocrine metastasis of occult origin, 7. immunohistochemistry to distinguish well-differentiated neuroendocrine tumor G3 from poorly differentiated neuroendocrine carcinoma, 8. lesions frequently misdiagnosed as well-differentiated neuroendocrine tumor, and 9. required and recommended data elements for biopsies and resections with associated immunohistochemical stains. Next-generation immunohistochemistry, including lineage-restricted transcription factors (e.g., CDX2, islet 1, OTP, SATB2) and protein-correlates of molecular genetic events (e.g., p53, Rb), is indispensable for the accurate diagnosis and classification of these neoplasms. Show less

AIMS: Special AT-rich sequence-binding protein 2 (SATB2) is a transcriptional regulator with critical roles in brain, craniofacial and skeletal development. It has emerged as a key marker of lower gastrointestinal (GI) tract columnar epithelial and osteoblastic differentiation. This study sought to evaluate the role of SATB2 in assigning site of origin in neuroendocrine epithelial neoplasms.
METHODS AND RESULTS: Tissue microarrays were constructed from the following: 317 NETs (37 thyroid, 46… Show more

AIMS: Special AT-rich sequence-binding protein 2 (SATB2) is a transcriptional regulator with critical roles in brain, craniofacial and skeletal development. It has emerged as a key marker of lower gastrointestinal (GI) tract columnar epithelial and osteoblastic differentiation. This study sought to evaluate the role of SATB2 in assigning site of origin in neuroendocrine epithelial neoplasms.
METHODS AND RESULTS: Tissue microarrays were constructed from the following: 317 NETs (37 thyroid, 46 lung, 16 stomach, 12 duodenum, 70 pancreas, 106 jejunoileum, 24 appendix, and six rectosigmoid), 44 phaeochromocytomas/paragangliomas, and 79 NECs (29 Merkel cell, 30 lung, and 20 extrapulmonary visceral); nine appendiceal and 19 rectal NETs were examined in whole sections. SATB2 immunohistochemistry was scored for extent (%) and intensity (0-3+), with an H-score being calculated. SATB2 was expressed by 96% of rectosigmoid NETs, 79% of appendiceal NETs, and only 7% of other well-differentiated neoplasms (P < 0.0001). Expression in lower GI tract NETs (median H-score of 255) was stronger than in other positive tumours (median H-score of 7) (P < 0.0001). Any SATB2 expression was 86% sensitive/93% specific for lower GI tract origin. SATB2 was expressed by 79% of Merkel cell carcinomas (median H-score of 300), 33% of lung NECs (median H-score of 23), and 60% of extrapulmonary visceral NECs (median H-score of 110), with stronger expression in Merkel cell carcinoma (P < 0.001). At an H-score cutoff of ≥150, SATB2 was 69% sensitive/90% specific for Merkel cell carcinoma.
CONCLUSIONS: SATB2 is frequently and strongly expressed by lower GI tract NETs; we have adopted it as our rectal NET marker. Relatively frequent and strong expression in Merkel cell carcinoma may have value in assigning NEC site of origin. Show less

This review reflects a collaboration between the American Registry of Pathology (the publisher of the Armed Forces Institute of Pathology Fascicles) and Annals of Diagnostic Pathology. It is part of a series of expert recommendations on topics encountered in daily practice. The authors, three pathologists with expertise in gastrointestinal tract pathology and immunohistochemistry, met on 30 July 2019 tasked with developing expert recommendations for evaluating poorly differentiated and… Show more

This review reflects a collaboration between the American Registry of Pathology (the publisher of the Armed Forces Institute of Pathology Fascicles) and Annals of Diagnostic Pathology. It is part of a series of expert recommendations on topics encountered in daily practice. The authors, three pathologists with expertise in gastrointestinal tract pathology and immunohistochemistry, met on 30 July 2019 tasked with developing expert recommendations for evaluating poorly differentiated and undifferentiated malignant neoplasms encountered on mucosal biopsies of the gastrointestinal tract. We focused on esophageal, gastric, small intestinal, colorectal, and anal (i.e., tubal gut) samples. When faced with diagnostic uncertainty on the initial H&E, it is best to begin by trying to assign the broad tumor class with screening markers such as pankeratin, S100 protein or SOX10, and CD20 or CD45. Once a broad tumor class is established, more specific differentiation markers can be pursued (e.g., lineage-restricted transcription factors for adenocarcinoma; p40 for squamous cell carcinoma; chromogranin A and synaptophysin or INSM1 for neuroendocrine neoplasms). Every small biopsy containing tumor should be considered a potential molecular pathology sample; cutting extra unstained slides with this testing in mind is strongly encouraged. Show less

Here, we discuss recent updates and a continuing controversy in the diagnosis and management of Barrett's esophagus, specifically the recommendation that the irregular Z-line not be biopsied, the diminished status of ultrashort-segment Barrett's esophagus, the evidence basis for excluding and including the requirement of goblet cells for the diagnosis of Barrett's esophagus, and the conclusion that histologically confirmed low-grade dysplasia is best managed with endoscopic ablation rather than… Show more

Here, we discuss recent updates and a continuing controversy in the diagnosis and management of Barrett's esophagus, specifically the recommendation that the irregular Z-line not be biopsied, the diminished status of ultrashort-segment Barrett's esophagus, the evidence basis for excluding and including the requirement of goblet cells for the diagnosis of Barrett's esophagus, and the conclusion that histologically confirmed low-grade dysplasia is best managed with endoscopic ablation rather than surveillance. We reference the American Gastroenterological Association and College of Gastroenterology and the British Society of Gastroenterology guidelines throughout, with the thesis that the field is converging on the concept of applying scarce medical resources to the diagnosis, surveillance, and therapy of patients most likely to derive benefit. Show less

DNA mismatch repair (MMR) protein immunohistochemistry (IHC) is useful to screen for Lynch syndrome (LS), as well as to identify the larger population of patients with sporadic MMR deficiency (dMMR). In this review, in addition to briefly discussing the molecular genetic basis and phenotype of LS and sporadic dMMR tumours, the universal LS screening program employed at the University of Iowa Hospitals and Clinics, the frequency of dMMR in adenomas from LS patients, and potential pitfalls in the… Show more

DNA mismatch repair (MMR) protein immunohistochemistry (IHC) is useful to screen for Lynch syndrome (LS), as well as to identify the larger population of patients with sporadic MMR deficiency (dMMR). In this review, in addition to briefly discussing the molecular genetic basis and phenotype of LS and sporadic dMMR tumours, the universal LS screening program employed at the University of Iowa Hospitals and Clinics, the frequency of dMMR in adenomas from LS patients, and potential pitfalls in the interpretation of MMR IHC, several recent discoveries that should impact testing will be covered, namely: 1. EPCAM deletion as a cause of MSH2 deficiency, 2. availability of BRAFV600E mutation-specific IHC, and especially 3. Lynch-like syndrome (i.e., patients with dMMR tumours in whom a sporadic tumour due to MLH1 promoter methylation has been excluded and an MMR germline mutation is not detected). Show less

This review discusses the role of molecular analysis in the diagnosis and treatment of gastrointestinal (GI) neoplasms. It is divided into 3 sections. The first section describes clinical applications of 11 immunohistochemical stains (p53, HER2, KIT, SDHB, SMAD4, beta-catenin, L-FABP, MLH1, PMS2, MSH2, and MSH6), the results of which directly reflect underlying genetic or epigenetic events. These applications are mainly diagnostic but in a few instances are predictive. Germline mutation testing… Show more

This review discusses the role of molecular analysis in the diagnosis and treatment of gastrointestinal (GI) neoplasms. It is divided into 3 sections. The first section describes clinical applications of 11 immunohistochemical stains (p53, HER2, KIT, SDHB, SMAD4, beta-catenin, L-FABP, MLH1, PMS2, MSH2, and MSH6), the results of which directly reflect underlying genetic or epigenetic events. These applications are mainly diagnostic but in a few instances are predictive. Germline mutation testing is a diagnostic cornerstone in the hereditary cancer predisposition syndromes (HCPSs). Section two will describe the genotype and phenotype of 8 HCPSs presenting in the GI tract. Where available, guidelines based on evidence and/or expert opinion as to whom to test are presented. With our ever-expanding knowledge of the molecular genetic basis of cancer and an increasingly "biologic-oriented" therapeutic armamentarium, pathologists play a vital role in directing molecular-based predictive testing. The final section will discuss the 4 most mature examples in the GI tract: (1) HER2 testing to select patients with advanced gastroesophageal adenocarcinoma for anti-HER2 therapy, (2) KIT and PDGFRA mutation analysis to direct tyrosine kinase inhibitor therapy in gastrointestinal stromal tumor, (3) DNA mismatch repair function testing to determine the applicability of adjuvant chemotherapy in patients with stage II colorectal cancer (CRC), and (4) KRAS mutation analysis and related testing to determine the appropriateness of anti-EGFR monoclonal antibody therapy in patients with metastatic CRC. Show less

The neuroendocrine epithelial neoplasms (NENs) include well-differentiated neuroendocrine tumors (WDNETs) and poorly differentiated neuroendocrine carcinomas (PDNECs). Whereas PDNECs are highly lethal, with localized Merkel cell carcinoma somewhat of an exception, WDNETs exhibit a range of "indolent" biologic potentials-from benign to widely metastatic and eventually fatal. Within each of these 2 groups there is substantial morphologic overlap. In the metastatic setting, the site of origin of a… Show more

The neuroendocrine epithelial neoplasms (NENs) include well-differentiated neuroendocrine tumors (WDNETs) and poorly differentiated neuroendocrine carcinomas (PDNECs). Whereas PDNECs are highly lethal, with localized Merkel cell carcinoma somewhat of an exception, WDNETs exhibit a range of "indolent" biologic potentials-from benign to widely metastatic and eventually fatal. Within each of these 2 groups there is substantial morphologic overlap. In the metastatic setting, the site of origin of a WDNET has significant prognostic and therapeutic implications. In the skin, Merkel cell carcinoma must be distinguished from spread of a visceral PDNEC. This review intends to prove the thesis that determining the site of origin of a NEN is clinically vital and that diagnostic immunohistochemistry is well suited to the task. It will begin by reviewing current World Health Organization terminology for the NENs, as well as an embryologic and histologic pattern-based classification. It will present population-based data on the relative frequency and biology of WDNETs arising at various anatomic sites, including the frequency of metastases of unknown primary, and comment on limitations of contemporary imaging techniques, as a means of defining the scope of the problem. It will go on to discuss the therapeutic significance of site of origin. The heart of this review is a synthesis of data compiled from >100 manuscripts on the expression of individual markers in WDNETs and PDNECs, as regards site of origin. These include proteins that are considered "key markers" and others that are either useful "secondary markers," potentially very useful markers that need to be further vetted, or ones that are widely applied despite a lack of efficacy. It will conclude with my approach to the metastatic NEN of unknown origin. Show less

Immunohistochemistry (IHC) has broad applications in neoplastic gastrointestinal surgical pathology. Although classically used as a diagnostic tool, IHC increasingly provides prognostic and predictive information. This review highlights 11 key uses of IHC (Box 1). Emphasis is placed on specific clinical applications and qualitative aspects of interpretation. Common pitfalls are specifically highlighted. The potential application of emerging markers is discussed in relation to several of the 11… Show more

Immunohistochemistry (IHC) has broad applications in neoplastic gastrointestinal surgical pathology. Although classically used as a diagnostic tool, IHC increasingly provides prognostic and predictive information. This review highlights 11 key uses of IHC (Box 1). Emphasis is placed on specific clinical applications and qualitative aspects of interpretation. Common pitfalls are specifically highlighted. The potential application of emerging markers is discussed in relation to several of the 11 topics. In many instances, an immunostain serves as a surrogate for specific molecular genetic events. Survey of relevant articles forms the evidence basis for this review. Show less

Lynch syndrome (LS) is an autosomal dominant cancer predisposition syndrome attributable to deleterious germline mutations in mismatch repair (MMR) genes. The syndrome is typified by early-onset, frequently right-sided colorectal cancers (CRCs) with characteristic histologic features and tendency for multiplicity and an increased risk for extracolonic tumors at particular sites; it accounts for 1% to 5% of CRC. Deficient mismatch repair (dMMR) function manifests as immunohistochemically… Show more

Lynch syndrome (LS) is an autosomal dominant cancer predisposition syndrome attributable to deleterious germline mutations in mismatch repair (MMR) genes. The syndrome is typified by early-onset, frequently right-sided colorectal cancers (CRCs) with characteristic histologic features and tendency for multiplicity and an increased risk for extracolonic tumors at particular sites; it accounts for 1% to 5% of CRC. Deficient mismatch repair (dMMR) function manifests as immunohistochemically detectable absence of one or more MMR proteins and microsatellite instability (MSI). Approximately 15% of sporadic, noninherited CRC are characterized by high-level MSI, nearly always owing to transcriptional silencing of MLH1; these sporadic and LS cases exhibit considerable phenotypic overlap. Identification of CRC with dMMR is desirable to identify LS and because MSI status is prognostic and potentially predictive. This review will discuss the history of LS, the principles of MMR and MSI, the clinicopathologic features of LS-associated and sporadic high-level MSI CRC, the fundamentals of clinical testing for dMMR CRC, and the results of the Columbus-area Lynch syndrome study. We conclude with our approach to population-based LS screening based on institutional experience with nearly 2000 cases. Show less

CONTEXT: Pancreatic cytopathology plays an important role in the diagnosis and management of patients with solid and cystic lesions of the pancreas.
OBJECTIVE: To serve as a practical guide to pancreatic cytopathology for the practicing pathologist. Data Sources.-A comprehensive assessment of the medical literature was performed.
CONCLUSIONS: We review pancreatic cytopathology, with specific discussions of its role in patient management, specimen types and specimen processing, specific… Show more

CONTEXT: Pancreatic cytopathology plays an important role in the diagnosis and management of patients with solid and cystic lesions of the pancreas.
OBJECTIVE: To serve as a practical guide to pancreatic cytopathology for the practicing pathologist. Data Sources.-A comprehensive assessment of the medical literature was performed.
CONCLUSIONS: We review pancreatic cytopathology, with specific discussions of its role in patient management, specimen types and specimen processing, specific diagnostic criteria, and the use of ancillary testing and advanced techniques. Show less