Creation of a Quality Payment Program Measure for Mismatch Repair or Microsatellite Instability Biomarker Testing Status in Colorectal, Endometrial, Gastroesophageal, or Small Bowel Carcinoma.

CONTEXT.­: Quality measures that are supported by evidence-based clinical practice guidelines are preferred for assessing the quality of pathologists' practices. Careful testing of a measure ensures that scores obtained by that measure reflect the quality of a pathologist's practice. OBJECTIVE.­: To specify a new quality measure and to demonstrate through testing that it is suitable for measuring pathologists' appropriate incorporation of information regarding microsatellite instability (MSI) and/or mismatch repair (MMR) status in pathology reports for colorectal, endometrial, gastroesophageal, and small bowel carcinoma. DESIGN.­: The College of American Pathologists collaborated with the American Gastroenterological Association to specify and test the new measure. Face validity testing was used to investigate the validity of the measure. Feasibility testing was conducted to understand if data elements required by the measure specification were readily accessible. Signal-to-noise analysis was used to characterize the measure's reliability. RESULTS.­: Guideline recommendations for MSI and/or MMR testing supported specifications for the measure. Face validity testing indicated that the measure could distinguish the quality of care provided. Data elements required by the measure specification were found to be accessible, which supported the measure's feasibility. Reliability testing showed that differences in measure score were attributable to real differences in performance rather than random variation in scoring. CONCLUSIONS.­: The Mismatch Repair or Microsatellite Instability Biomarker Testing Status in Colorectal Carcinoma, Endometrial, Gastroesophageal, or Small Bowel Carcinoma measure was appropriately specified, and testing demonstrated that it is well suited for characterizing the quality of pathologists' communication of MMR and/or MSI status.

IgG4 plasma cell neoplasm in liver transplant biopsy masquerading as rejection.

IgG4 plasma cell neoplasm and myeloma are rare disease entities, not associated with systemic fibroinflammatory IgG4 related disease. We herein present a case of IgG4 plasma cell neoplasm in a liver transplant biopsy. A 55 year old female was treated with living donor transplant and had a complicated post-operative course. Three months post-transplant, she presented with small for size syndrome, biliary stricture, and inferior vena cava stenosis. Concomitant liver biopsy revealed mild acute cellular rejection with central perivenulitis pattern, and mild centrilobular fibrosis. She was treated with steroids which resulted in improvement of liver enzymes. Seven months post-transplant, she presented with subtherapeutic prograf levels and cholestatic pattern of elevated liver tests. ERCP revealed a stone which was removed. Hematological evaluation revealed an abnormal serum protein electrophoresis (SPEP). Monoclonal IgG kappa was elevated along with mildly elevated free Kappa/Lambda ratio. She was followed up and readmitted two months later for worsening liver function tests. The liver biopsy showed monotypic Kappa-and IgG4-restricted plasma cell infiltrates in portal, periportal, sinusoidal and centrilobular regions, compatible with plasma cell neoplasm. In the clinical context of positivity for a serum M-spike, the monoclonal hepatic infiltrates were deemed consistent with a Kappa-and IgG4-restricted plasma cell neoplasm. Patient was treated with pulsed steroids, and liver function tests subsequently downtrended. She was followed up by Hemoncology, and the treatment plan included carfilzomib-based induction therapy and dexamethasone to prevent end-organ damage from evolving myeloma. In the meanwhile, she developed acute appendicitis, underwent appendectomy, and passed away in the post-operative period.

Dual-color immunocytochemistry (Ki-67 with LCA) for precise grading of pancreatic neuroendocrine tumors with applicability to small biopsies and cell blocks.

Ki-67 (MIB-1) immunostaining to quantify the proliferative index of neuroendocrine tumors (NETs) has been recommended (especially for small biopsies). However, this has a number of challenges with nonrepresentative Ki-67 index due to interference by Ki-67 immunoreactive proliferating lymphocytes infiltrating the tumor and also some proliferating stromal cells including endothelial cells in the background. Our pilot project showed that dual-color immunostaining with inclusion of leukocyte common antigen (LCA) (Ki-67: nuclear brown; LCA: cytoplasmic red) can facilitate the weeding out of lymphocyte interference. We analyzed the results with 23 surgical cases of pancreatic NETs. This was followed by poststudy examination of 11 cases of endoscopic ultrasound-guided fine-needle aspiration of the pancreatic NETs (PanNETs) to evaluate the findings of the study. Dual-color immunostaining for Ki-67 with LCA increased the precision of quantifying Ki-67 index, due to ability to exclude LCA immunoreactive lymphocytes. Other nontumor Ki-67 immunoreactive cells such as endothelial and stromal cells could be distinguished morphologically. Digital methods were also attempted, but this approach could not distinguish infiltrating lymphocytes and other cells in sections resulting in erroneous results. This study demonstrated that grading of PanNET can be performed with increased precision with dual-color Ki-67 immunostaining protocol standardized in this study. As evaluated on a few cytopathology cases, this protocol is especially useful for the evaluation of small biopsies and cell block sections of fine-needle aspiration biopsy material where 50 high-power fields cannot be evaluated but have >500 tumor cell nuclei.

Molecular Diagnostics in Colorectal Carcinoma: Advances and Applications for 2018.

The molecular pathogenesis and classification of colorectal carcinoma are based on the traditional adenomaecarcinoma sequence, serrated polyp pathway, and microsatellite instability (MSI). The genetic basis for hereditary nonpolyposis colorectal cancer is the detection of mutations in the MLH1, MSH2, MSH6, PMS2, and EPCAM genes. Genetic testing for Lynch syndrome includes MSI testing, methylator phenotype testing, BRAF mutation testing, and molecular testing for germline mutations in MMR genes. Molecular makers with predictive and prognostic implications include quantitative multigene reverse transcriptase polymerase chain reaction assay and KRAS and BRAF mutation analysis. Mismatch repair-deficient tumors have higher rates of programmed death-ligand 1 expression. Cell-free DNA analysis in fluids are proving beneficial for diagnosis and prognosis in these disease states towards effective patient management.

Molecular Diagnostics in the Neoplasms of Small Intestine and Appendix: 2018 Update.

Neoplasms of the small intestine are rare in comparison with colorectal tumors. The most common tumor types arising in the small intestine are adenocarcinomas, well-differentiated neuroendocrine tumors, gastrointestinal stromal tumors, and lymphoma. Primary appendiceal neoplasms are rare and found in less than 2% of appendectomy specimens with an incidence of approximately 1.2 cases per 100,000 people per year in the United States. This article explores molecular diagnostics in the neoplasms of small intestine and appendix.

Molecular Diagnostics in Esophageal and Gastric Neoplasms: 2018 Update.

Esophageal cancer (EC) is rapidly increasing in incidence in the United States. Genetic changes associated with the development of EC involve the p16, p53, and APC genes. Human epidermal growth factor 2 (HER-2) overexpression is seen in gastroesophageal junction carcinoma and a subset gastric carcinoma (GC). Interestingly, up to 50% cases of GC are related to Helicobacter pylori infection and up to 16% are related to EBV infection. Microsatellite instability is observed in up to 39% of GC and cell free nucleic acid analysis provides additional opportunities for diagnosis and prognosis of disease.

Molecular Diagnostics in the Neoplasms of the Pancreas, Liver, Gallbladder, and Extrahepatic Biliary Tract: 2018 Update.

Pancreatic neoplasms, including ductal adenocarcinoma, solid pseudopapillary neoplasm, pancreatic endocrine neoplasms, acinar cell carcinoma, and pancreatoblastoma, are associated with different genetic abnormalities. Hepatic adenomas with beta-catenin exon 3 mutation are associated with a high risk of malignancy. Hepatic adenoma with arginosuccinate synthetase 1 expression or sonic hedgehog mutations are associated with a risk of bleeding. Hepatocellular carcinoma and choangiocarcinoma display heterogeneity at both morphologic and molecular levels Cholangiocellular carcinoma is most commonly associated with IDH 1/2 mutations.

Mucinous intrahepatic cholangiocarcinoma: a distinct variant.

Mucinous variant of intrahepatic cholangiocarcinoma (iCC) is rare, and its clinicopathological features and prognosis are far less clear. Six patients who had iCCs with more than 50% of mucinous component and 79 conventional iCCs were included in the study. The mean size of mucinous and conventional iCCs was 6.2 and 6.0 cm, respectively. Most patients (83%) with mucinous iCC presented at T3 stage or above compared with 28% of the conventional group (P < .01). Three patients with mucinous iCC (50%) died within 1 year. The average survival time of patients with mucinous iCCs was significantly reduced compared with that of the conventional group (9 months versus 2 years; P < .001). Immunohistochemistry was performed on 6 mucinous and 12 conventional iCCs with matched age, sex, and stage, which revealed positive immunoreactivity in MUC1 (83% versus 58%), MUC2 (33% versus 17%), MUC5AC (100% versus 42%), MUC6 (50% versus 0), CK7 (83% versus 83%), CK20 (0 versus 17%), CDX2 (17% versus 0), p53 (67% versus 67%), Smad4 (67% versus 58%), and EGFR (83% versus 42%) in mucinous and conventional iCCs, respectively. Molecular studies showed one mucinous iCC with KRAS G12C mutation and no BRAF or IDH1/2 mutations. Mucinous iCC is a unique variant that constitutes 7% of iCCs. It is more immunoreactive for MUC1, MUC2, MUC5AC, and MUC6. Unlike adenocarcinomas of colorectal primary, mucinous iCCs are often CK7+/CK20-/CDX2- and microsatellite stable. Patients with mucinous iCC likely present at advanced stage upon diagnosis with shorter survival time compared with the conventional counterparts.

Histopathological evidence of neoplastic progression of von Meyenburg complex to intrahepatic cholangiocarcinoma.

Von Meyenburg complex (VMC) is generally thought to be benign, although its preneoplastic potential for intrahepatic cholangiocarcinoma (iCC) has been a subject of contention. We retrospectively reviewed 86 hepatectomy specimens with a diagnosis of iCC. Morphologically, an association between iCC and VMC was appreciated in 35% of cases that illustrated a gradual neoplastic progression from benign VMC to dysplasia and then to iCC. Among them, 24 cases had VMC lined by epithelial cells with low-grade biliary dysplasia and 13 with high-grade biliary dysplasia. VMC-associated iCCs were smaller in size and well to moderately differentiated, with features of anastomosing glandular architecture, ductal carcinoma in situ-like growth pattern, peritumoral lymphocytic infiltrate, central fibrous scar, and complete pushing border. They often presented as T1 tumors. In contrast, non-VMC-associated iCCs were moderately to poorly differentiated with solid, cribriform or papillary growth patterns. They likely exhibited necrosis, perineural invasion, positive surgical margin, lymphovascular invasion, and high T stage. Additionally, Ki67 and p53 immunostains support the continuing neoplastic evolution from benign VMC to dysplasia and then to iCC. VMC could become neoplastic, serving as an in situ carcinoma lesion to transform to iCC. The underlying molecular alteration and clinical implication of this neoplastic transformation deserves further investigation.

Etiologic factors related to unsatisfactory ThinPrep(®) cervical cytology: Evaluation and potential solutions to improve.

BACKGROUND: In cervical cytology, the unsatisfactory rates for ThinPrep (TP) are slightly higher compared to SurePath. We examined various causes and explored potential for resolution of this discrepancy. MATERIALS AND METHODS: Totally, 19,422 cases were reviewed and 1000 unsatisfactory specimens were selected and analyzed. 531 specimens were available for wash protocol. Out of 114 unsatisfactory specimens associated with atrophic cellular changes (ACC), 48 were resubmitted by provider and reevaluated. RESULTS: Lubricant and lubricant-like debris/contamination (LUBE) was the most common cause of unsatisfactory specimens (68%; 681/1000) followed by blood (7.5%); ACC only (without other interfering factors) (2.4%); inflammation (3.0%); and combinations thereof (1.9%). 11.5% showed scant cellularity without an identifiable cause. 3.3% were virtually acellular. Wash protocol improved cellularity in 48% (256/531) of cases. However, only 29% (73/256) of those were satisfactory (with more than 5000 cells). Quantitative reduction in LUBE after wash protocol varied with different morphological subtypes. Interpretation patterns on satisfactory specimens after wash protocol were comparable to the results on selected cohort of specimens during the same study period. Out of 114 ACC, wash protocol was performed on 68 ACC specimens leading to satisfactory TP in 24% (16/68). Totally, 48 cases reported as unsatisfactory with ACC, were resubmitted by the providers between 2 weeks and 2 years. 44 (92%) showed increased cellularity, out of which 52% (23/44) did not show ACC. CONCLUSION: LUBE was the most common cause of unsatisfactory TP in addition to interference by blood and association with atrophic changes. Knowing the morphological spectrum of LUBE would help to identify it as the cause of unsatisfactory TP. Communicating the cause of unsatisfactory TP such as LUBE, ACC, and blood would hint the provider to take appropriate precaution during submission of the repeat specimen, leading to improved patient care.

Primary adrenal leiomyosarcoma: a case report and review of the literature.

Primary adrenal leiomyosarcoma has been reported previously in 25 patients. The patient presented herein is the only case where the definitive diagnosis was made with core needle biopsy evaluation. A 45-year-old male presented with pain in the back and right groin. Radiological evaluation demonstrated a heterogeneous 11 cm right adrenal mass, multiple liver masses, and an enlarged aortocaval lymph node. No retroperitoneal mass was identified. Core needle biopsies revealed a malignant mesenchymal neoplasm composed of atypical spindle shaped cells arranged in intersecting fascicles, with high mitotic activity and focal tumor necrosis. Immunohistochemical stains revealed immunoreactivity for smooth muscle actin and desmin. S-100 and c-kit stains were negative. The diagnosis of adrenal leiomyosarcoma with liver metastasis was rendered. It was an aggressive tumor with clinical presentation at Figure 1. Core needle biopsy, a an advanced stage. Definitive diagnosis of this tumor by core needle biopsy can obviate the need for surgical biopsy in patients with advanced disease.

Isolated gastric amyloidoma in the setting of marginal zone MALT lymphoma: case report and review of the literature.

A 52-year-old female presented with hematochezia. A computed topography (CT) scan revealed diffuse proximal gastric thickening with enlarged perigastric lymph nodes. The esophagogastroduodenoscopy (EGD) revealed a diffusely thickened gastric wall with hemorrhagic, friable mucosa, and multiple areas of ulceration. The biopsies showed diffuse amyloid deposition along with transmural proliferation of small- to medium-sized lymphocytes and plasma cells. The gastric mucosa showed lymphoepithelial lesions and chronic inactive gastritis. Immunohistochemical staining of the neoplastic lymphocytes revealed expression of CD20, bcl-2, bcl-10, Ki-67 proliferative index of 5%, and lambda light chain restriction. There was no expression of CD5, CD43, CD10, CD3, cyclin D1, and bcl-6. Immunophenotyping by flow cytometry revealed an abnormal B lymphocyte population with expression of CD45, CD19, CD20, and FMC7. The histomorphological, immunohistochemical and flow cytometric features were consistent with primary gastric amyloidosis associated with extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT lymphoma).

Molecular diagnostics in colorectal carcinoma.

Molecular pathogenesis and classification of colorectal carcinoma are based on the adenoma-carcinoma sequence in the Vogelstein model, serrated polyp pathway, and microsatellite instability. The genetic basis for hereditary nonpolyposis colorectal cancer is based on detection of genetic mutations. Genetic testing for Lynch syndrome includes microsatellite instability, methylator phenotyping, BRAF mutation, and molecular testing. Molecular makers include quantitative multigene reverse transcriptase-polymerase chain reaction assay and KRAS and BRAF mutation analysis. Potential biomarkers include one-step nucleic acid amplification and epigenetic inactivation of endothelin 2 and endothelin 3 in colon cancer. Molecular screening approaches in colorectal cancer using stool DNA are under investigation.

Molecular diagnostics in the neoplasms of small intestine and appendix.

Adenocarcinoma of the small intestine is relatively rare in comparison to colorectal carcinoma. Adenocarcinoma of the small intestine arises through the adenoma-carcinoma sequence in the colon. However, adenocarcinomas arising in the background of inflammatory bowel disease develop through the dysplasia-carcinoma sequence. Most of the cases occur in the duodenum; however, adenocarcinoma occurring in association with Crohn disease is more common in the ileum.

Molecular diagnostics in esophageal and gastric neoplasms.

Esophageal carcinoma is the most rapidly increasing tumor in incidence in the United States. It has an established association with a precursor lesion (Barrett esophagus). Gastric carcinoma (GC) is the second leading cause of cancer death in the world. The prognosis for patients with advanced stage GC and esophageal carcinoma is poor. Human epidermal growth factor 2 (HER-2) overexpression is seen in gastroesophageal junction carcinoma and a subset of GC. HER-2 overexpressing tumors are eligible for HER-2 targeted therapies, which lead to a better survival in these patients.

Molecular diagnostics in the neoplasms of the pancreas, liver, gall bladder, and extrahepatic biliary tract.

Pancreatic neoplasms, including ductal adenocarcinoma, intraductal papillary mucinous neoplasm, solid pseudopapillary neoplasm, pancreatic endocrine neoplasms, acinar cell carcinoma, and ampullary carcinoma, are associated with different genetic abnormalities. Liver neoplasms, including hepatic adenomas, hepatocellular carcinomas, and cholangiocarcinomas, are associated with identifiable risk factors and genetic changes. Gall bladder adenomas and adenocarcinomas arise from distinct molecular pathways. The molecular abnormalities seen in these tumors are not used routinely in the molecular diagnostic laboratory.

Russell body gastritis in an HIV positive patient: case report and review of literature.

Russell body gastritis is characterized by accumulation of plasma cells, filled with Russell bodies, in the gastric mucosa. Twelve cases have been reported in the English language medical literature. Its association with Helicobacter pylori gastritis or immunosuppression is known. The present case is the third to be reported in association with HIV infection. An 82-year-old male presented with dyspepsia, loose stools, loss of appetite and weight. Computed tomography scan showed esophageal and gastric wall thickening. Gastrointestinal endoscopy revealed gastritis. Microscopic examination of the biopsy revealed gastric mucosa with diffuse plasma cell infiltration in the lamina propria, associated with large eosinophilic Russell bodies. Immunoperoxidase stains revealed positivity for CD 138 and lambda and kappa chains. Special stain for Helicobacter pylori and immunostain for CD68 were negative. The differential diagnoses include plasmacytoma and mucosa associated lymphoid tissue (MALT) lymphoma with plasmacytic differentiation, which are entities with different prognostic and therapeutic implications.

The Immunohistochemical Expression of the Oestrogen Receptor (ER), HER-2/NEU and Cytokeratin 8/18 and 5/6 in Invasive Breast Carcinoma.

INTRODUCTION: Carcinoma is the most common malignancy of the breast and breast cancer is the most common non-skin malignancy in women. Ideally, prevention or very early detection of breast cancer reduce both morbidity and mortality of the disease. Effective use of tumour markers might permit the application of screening and treatment more efficiently. MATERIALS AND METHODS: Immunohistochemical study was done in 39 cases of invasive breast carcinoma for further sub-classification for predicting prognosis and therapeutic approach. The cases were evaluated for expression of cytokeratin Ck 8/18, ER & Her-2/neu and 28 cases were subjected to cytokeratin Ck 5/6 including especially the cases negative for all the three markers. RESULTS: ER was positive in seven cases with Her-2/neu being positive in eight cases and cytokeratin 8/18 positive in 33 cases. Cytokeratin 5/6 was positive in seven cases with four cases showing Ck 5/6 and Ck8/18 positivity, three cases showing positivity for Ck 5/6 only and three cases were negative for all the four markers. CONCLUSION: Thus classifying them to be luminal A, luminal B, combined, basal and null type respectively. Luminal A tmours show the best prognosis while luminal B tumours , combined , basal and null type are associated with less favouable outcome. Thus it is important to categorise them according to the cell of origin for prognosis and treatment.