HER2 evaluation for clinical decision making in human solid tumours: pearls and pitfalls.

The significant clinical benefits of human epidermal growth factor receptor 2 (HER2)-targeted therapeutic agents have revolutionized the clinical treatment landscape in a variety of human solid tumours. Accordingly, accurate evaluation of HER2 status in these different tumour types is critical for clinical decision making to select appropriate patients who may benefit from life-saving HER2-targeted therapies. HER2 biomarker scoring criteria is different in different organ systems, and close adherence to the corresponding HER2 biomarker testing guidelines and their updates, if available, is essential for accurate evaluation. In addition, knowing the unusual patterns of HER2 expression is also important to avoid inaccurate evaluation. In this review, we discuss the key considerations when evaluating HER2 status in solid tumours for clinical decision making, including tissue handling and preparation for HER2 biomarker testing, as well as pathologist's readout of HER2 testing results in breast carcinomas, gastroesophageal adenocarcinomas, colorectal adenocarcinomas, gynaecologic carcinomas, and non-small cell lung carcinomas.

High risk features in colorectal adenomatous polyps: A multi-institutional study.

High risk features in colorectal adenomatous polyps include size >1 cm and advanced histology: high-grade dysplasia and villous architecture. We investigated whether the diagnostic rates of advanced histology in colorectal adenomatous polyps were similar among institutions across the United States, and if not, could differences be explained by patient age, polyp size, and/or CRC rate. Nine academic institutions contributed data from three pathologists who had signed out at least 100 colorectal adenomatous polyps each from 2018 to 2019 taken from patients undergoing screening colonoscopy. For each case, we recorded patient age and sex, polyp size and location, concurrent CRC, and presence or absence of HGD and villous features. A total of 2700 polyps from 1886 patients (mean age: 61 years) were collected. One hundred twenty-four (5 %) of the 2700 polyps had advanced histology, including 35 (1 %) with HGD and 101 (4 %) with villous features. The diagnostic rate of advanced histology varied by institution from 1.7 % to 9.3 % (median: 4.3 %, standard deviation [SD]: 2.5 %). The rate of HGD ranged from 0 % to 3.3 % (median: 1 %, SD: 1.2 %), while the rate of villous architecture varied from 1 % to 8 % (median: 3.7 %, SD: 2.5 %). In a multivariate analysis, the factor most strongly associated with advanced histology was polyp size >1 cm with an odds ratio (OR) of 31.82 (95 % confidence interval [CI]: 20.52-50.25, p < 0.05). Inter-institutional differences in the rate of polyps >1 cm likely explain some of the diagnostic variance, but pathologic subjectivity may be another contributing factor.

Optimising rapid on-site evaluation-assisted endobronchial ultrasound-guided transbronchial needle aspiration of mediastinal lymph nodes: The real-time cytopathology intervention process.

INTRODUCTION: Lymph node sampling by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is the state of art procedure for staging the mediastinum and hilar regions in lung cancer patients. Our experience of implementing the real-time cytopathology intervention (RTCI) process for intraoperative EBUS-TBNAs is presented. This study is aimed to describe in detail the RTCI process for EBUS-TBNAs, and assess its utility and diagnostic yield before and after its implementation in parallel to conventional rapid on-site evaluation (c-ROSE). METHODS: A retrospective review of all EBUS-TBNAs between July 2016 and July 2017 at the University of Rochester Medical Center was performed. Final diagnoses, patient clinical data, and number of non-diagnostic samples (NDS) were reviewed. The numbers of NDS obtained from EBUS-TBNAs with no cytology assistance (NCA), with RTCI and with c-ROSE were analysed. RESULTS: Non-diagnostic lymph node samples were found in 20 out of 116 (17%), three out of 114 (2.6%) and 33 out of 286 (11.5%) cases with NCA, RTCI and c-ROSE, respectively. Application of statistical analysis revealed significant difference in the NDS between the groups of cases in the operating room with NCA and RTCI (P = .005). The different settings and variables between the cases performed using RTCI in the operating room and those assisted with c-ROSE in the bronchoscopy suite preclude legitimate comparison. CONCLUSION: Our results indicate that the use of RTCI could yield a significantly low proportion of NDS when assisting EBUS-TBNA of mediastinal and hilar lymph node for lung cancer patients enhancing the diagnostic efficiency of the procedure.

Lone aortic insufficiency and conduction disease: a marker of reactive arthritis.

A 48-year-old male with history of chronic arthritis and uveitis presented with 1 year of progressively reduced exercise capacity and nonexertional chest pain. Physical examination was consistent with severe aortic insufficiency. An electrocardiogram demonstrated sinus rhythm with first degree atrioventricular block. Transthoracic and transesophageal echocardiography demonstrated severe lone central aortic insufficiency of a trileaflet valve due to leaflet thickening, retraction of leaflet margins and mild aortic root dilation in the setting of left ventricular dilatation. In addition, computed tomographic angiography revealed a small focal aneurysm of the distal transverse arch. He was found to be positive for the immunogenetic marker HLA-B27. The patient subsequently underwent uncomplicated mechanical aortic valve replacement. The diagnosis of HLA-B27 associated cardiac disease should be entertained in any individual with lone aortic insufficiency, especially if accompanied by conduction disease.

Clinicopathologic Characterization of Sarcina ventriculi in the Upper Gastrointestinal Tract.

The bacterium Sarcina ventriculi (SV) is rarely identified in the upper gastrointestinal (GI) tract and has been associated with diverse clinical presentations. We aimed to characterize the clinicopathologic features of SV in the GI tract. Seventeen specimens (3 gastrectomy and 14 biopsy specimens) with histologic diagnosis of SV were identified and analyzed. The patients (9 female, 8 male) had a median age of 65 (range 32-86) years. Five (30%) patients presented acutely with GI bleeding or altered mental status. Other relevant symptoms included abdominal pain (n = 6, 35%), diarrhea (n = 4, 24%), dysphagia/dyspepsia (n = 3, 18%), and nausea/vomiting (n = 3, 18%). SV organisms were mainly identified in the stomach (n = 14, 82%), rarely at the gastroesophageal junction (n = 2, 12%), esophagus (n = 2, 12%), or duodenum (n = 1, 6%). Endoscopically, retained food debris was found in 5 of 13 (38%) examined patients. Histologically, the majority of specimens (12 out of 17, 71%) showed mild alterations including reactive gastropathy, inactive gastritis, or reflux (Grade 1). The other 5 specimens (29%) demonstrated erosion, ulcer, necrosis, or perforation (Grade 2). The most commonly associated comorbidities were diabetes mellitus (n = 10, 59%), gastroparesis/outlet obstruction (n = 10, 59%), and gastroesophageal reflux disease (n = 6, 35%). Upon follow-up, 3 (18%) patients with acute phlegmonous gastritis died shortly after gastrectomy. Our case series, the largest reported so far, describes a spectrum of histologic severity associated with SV infection. Diabetes and gastroparesis/outlet obstruction manifested as retained food debris endoscopically are common findings with SV, and may provide a growth medium for this organism and provoke pathogenicity contributing to fatality in acute conditions.

Clinical Implications of Microscopic Colitis Isolated to Polyps.

Microscopic colitis is generally identified on random colon biopsies performed for chronic diarrhea, but rarely incidental polyps have histologic features of microscopic colitis. We compared patients with polypoid microscopic colitis to control patients with conventional polyps to determine the implications of polypoid microscopic colitis.Medical records were searched for patients without prior or concurrent microscopic colitis who were found to have polypoid microscopic colitis. For each patient with polypoid microscopic colitis, one patient with conventional polyps was selected as a control. We reviewed the histologic features of each polypoid microscopic colitis specimen, and evaluated endoscopic and clinical findings for polypoid microscopic colitis patients and controls.Twenty-six patients with polypoid microscopic colitis were identified with histologic features of collagenous colitis in 8 patients (31%) and lymphocytic colitis in 18 patients (69%). Polypoid microscopic colitis was unifocal in 14 patients (54%) and multifocal in 12 patients (46%). Patients with polypoid microscopic colitis were older than control patients (median age = 60 years vs 66 years, P = .04). On follow-up 7 patients with polypoid microscopic colitis (33%) developed chronic diarrhea compared to 3 (12%) controls (P = .16). Of patients with follow-up biopsies, 1 patient with polypoid microscopic colitis (13%) and no control patients developed microscopic colitis (P = 1).Polypoid microscopic colitis may be identified in asymptomatic patients and most patients do not develop chronic diarrhea, but some patients with polypoid microscopic colitis develop diarrhea (33% vs 12% in controls) or conventional microscopic colitis on follow-up. Thus pathologists should distinguish polypoid microscopic colitis from conventional microscopic colitis but may inform clinicians of the uncertain association with chronic diarrhea to guide decisions regarding follow-up.

Intestinal "Piggybacking Lipoma", A Unique Lipoma Composed of Lipoma and Overlying Epithelial Lesions: A Case-control Study and Review of Literature.

BACKGROUND/AIM: Lipomas are rare but the most common benign mesenchymal lesions of the gastrointestinal (GI) tract, composed of mature adipose cells. The "piggybacking lipoma" is formed by lipomas with overlying polypoid epithelial lesions, such as sessile serrated lesion, tubular adenoma, or hyperplastic polyp, and the literature on these lesions is limited. In this study, we systematically investigated the clinical, endoscopic, and pathologic characteristics of these unique lipomas. PATIENTS AND METHODS: This is a single-institution retrospective study of gastrointestinal tract lipomas diagnosed from 2016-2021. Those with concurrent polypoid epithelial or mesenchymal lesions during the same endoscopic episode were included and reviewed in this study, and the lipomas were classified as "piggybacking lipoma" or "non-piggybacking lipoma" depending on whether the concurrent lesion was overlying the lipoma or was at a different location in the intestine. Demographic, clinical, and endoscopic data were obtained from electronic medical records. RESULTS: A total of 100 lipomas with concurrent epithelial or mesenchymal lesions were included in this study. Among them, 21 cases were classified as "piggybacking lipoma" and 79 were classified as "non-piggybacking lipoma". Patients with piggybacking lipomas showed a female predilection, and were more likely to be symptomatic and less likely to exhibit classic endoscopic features of lipoma. Histologically, the piggybacking polyps showed overlying sessile serrated lesions (SSL) (76.2%) and tubular adenoma (TA) (19%), whereas the non-piggybacking group had differing characteristic lesions with TA (57.5%) and SSL (6.0%). CONCLUSION: Piggybacking lipomas are rare lipomas with overlying polypoid epithelial lesions, most commonly SSL. They present different clinical, endoscopic, and pathologic features compared to non-piggybacking lipomas.

Expression of PSMA in Tumor-Associated Vasculature Predicts Poorer Survival in Patients With Hepatocellular Carcinoma and Is Likely Associated With PD-L1.

BACKGROUND: PSMA (prostate-specific membrane antigen) is a type II transmembrane glycoprotein recently found to be expressed in hepatocellular carcinoma (HCC). We aimed to characterize the expression pattern of PSMA in HCC and its association with clinicopathologic parameters and other biomarkers. METHODS: Immunohistochemical studies for PSMA were performed on a previously established tissue microarray of 103 surgically resected HCC. RESULTS: Conceivable PSMA expression in ≥5% tumor-associated vasculature (TAV) was considered positive, and was identified in 56 (54.4%) tumors. Eight (7.8%) tumors also showed membranous/cytoplasmic and/or canalicular staining in tumor cells. By chi-square tests, only PSMA-positive TAV was associated with moderate-to-poorly differentiated HCC and the modified higher tumor stage (P < .05). PSMA-positive TAV was not associated with age, sex, or expression of glypican-3, keratin 7, CD3, CD8, HHLA-2, but marginally correlated with programmed death-ligand 1 (PD-L1) expression (P = .052). Kaplan-Meier survival analysis revealed PSMA-positive TAV as an independent risk factor for poorer disease-specific survival (P = .008). Co-expression of PD-L1 did not ameliorate the adverse prognostication of PSMA-positive TAV. Membranous/cytoplasmic/canalicular expression of PSMA alone was not prognostically significant. CONCLUSIONS: Our study confirmed that PSMA-positive TAV is a prospective diagnostic and prognostic biomarker for HCC. Co-expression of PSMA with PD-L1 may suggest potential crosstalk between the 2 proteins, likely regulating the tumor microenvironment.

SWI/SNF chromatin remodeling complex in pancreatic ductal adenocarcinoma: Clinicopathologic and immunohistochemical study.

The SWItch/Sucrose Non-Fermentable (SWI/SNF) complex is a multimeric protein involved in transcription regulation and DNA damage repair. SWI/SNF complex abnormalities are observed in approximately 14-34 % of pancreatic ductal adenocarcinomas (PDACs). Herein, we evaluated the immunohistochemical expression of a subset of the SWI/SNF complex proteins (ARID1A, SMARCA4/BRG1, SMARCA2/BRM, and SMARCB1/INI1) within our PDAC tissue microarray to determine whether SWI/SNF loss is associated with any clinicopathologic features or patient survival in PDAC. In our cohort, 13 of 353 (3.7 %) PDACs showed deficient SWI/SNF complex expression, which included 11 (3.1 %) with ARID1A loss, 1 (0.3 %) with SMARCA4/BRG1 loss, and 1 (0.3 %) with SMARCA2/BRM loss. All cases were SMARCB1/INI1 proficient. The SWI/SNF-deficient PDACs were more frequently identified in older patients with a mean age of 71.6 years (SD = 7.78) compared to the SWI/SNF-proficient PDACs which occurred at a mean age of 65.2 years (SD = 10.95) (P = 0.013). The SWI/SNF-deficient PDACs were associated with higher histologic grade, compared to the SWI/SNF-proficient PDACs (P = 0.029). No other significant clinicopathologic differences were noted between SWI/SNF-deficient and SWI/SNF-proficient PDACs. On follow-up, no significant differences were seen for overall survival and progression-free survival between SWI/SNF-deficient and SWI/SNF-proficient PDACs (both with P > 0.05). In summary, SWI/SNF-deficient PDACs most frequently demonstrate ARID1A loss. SWI/SNF-deficient PDACs are associated with older age and higher histologic grade. No other significant associations among other clinicopathologic parameters were seen in SWI/SNF-deficient PDACs including survival.

Diffuse Pagetoid Squamous Cell Carcinoma in Situ of the Esophagus: A Rare Case Report and Review of Literature.

Squamous cell carcinoma in situ (SCCIS) with diffuse pagetoid features has been well-described in skin and external genitalia. Diffuse pagetoid SCCIS of the esophagus is extremely rare with only two cases published in the English literature. In this article, we report a rare case of diffuse pagetoid SCCIS of the esophagus in an 89-year-old female with no significant past medical history who presented with dysphagia. Endoscopic examination of the esophagus was remarkable for multiple clean base ulcers spanning 4 cm in the proximal esophagus. Biopsy showed enlarged and hyperchromatic dysplastic cells in the basal half of the epithelium with scattered large individual pagetoid cells as well as several apoptotic dyskeratotic cells in the superficial half of the epithelium. Immunohistochemically, the dysplastic cells were positive for CK7 and p40 with overexpression of p53, and were negative for cytokeratin 20, SOX10, GATA3, CDX2, TTF1. Kreyberg stain was negative for mucin. The histologic features and immunohistochemical profile supported the diagnosis of esophageal diffuse pagetoid SCCIS.

Intraoperative Cytology for Video-Assisted Thoracic Surgery: A Quality Improvement Analysis.

BACKGROUND: Frozen section is a standard of care procedure during thoracic surgery when an immediate diagnosis is needed. An alternative procedure is intraoperative cytology. Video-assisted thoracic surgery is currently widely used for thoracic surgical procedures. The aim of this study was to assess intraoperative cytology together with frozen section for accuracy, turnaround time, and total response time during video-assisted thoracic surgery. METHODS: We included patients having video-assisted thoracic surgery between August 2018 and February 2019 at our institution. A cytopathologist and a surgical pathologist independently performed intraoperative cytology and frozen sections, respectively. Final histologic diagnosis was the reference standard. Intraoperative cytology, frozen section turnaround, and total response times were analyzed. RESULTS: A total of 52 specimens from 27 patients were included. The intraoperative cytology correlated with final histology in 98% of cases. Frozen section correlated with final histology in 100% of cases. Intraoperative cytology turnaround and total response times were equal (mean, 4.35 minutes; range, 2-15 minutes). Mean frozen section turnaround and response times were 26.2 minutes (range, 9-61 minutes) and 36.7 minutes (range, 16-90 minutes), respectively. We found a statistically significant difference between intraoperative cytology and frozen section turnaround time and total response times (P < .001). CONCLUSIONS: This study highlights that intraoperative cytology could be as accurate as frozen section and considerably faster during video-assisted thoracic surgery (P < .001). Total response time could potentially be used as a quality metric for video-assisted thoracic surgery.

Microscopic Esophageal Sloughing Is Not Specific to "Sloughing Esophagitis".

OBJECTIVES: "Sloughing esophagitis" (SE) is characterized by a 2-toned squamous epithelium with superficial necrotic keratinocytes overlying viable epithelium. We compared histologic and clinical findings to determine how cases clinically diagnosed as SE differed from cases with histologic sloughing but a different clinical diagnosis. In addition, we compared cases with inflammatory and noninflammatory histology. METHODS: We searched departmental archives for esophageal biopsies with histologic sloughing features. We compared clinical and histologic findings for cases with and without clinical confirmation of SE and with and without histologic inflammation. RESULTS: We identified 52 patients, of whom 10 (19%) had clinically diagnosed SE, 18 (35%) had another diagnosis, and 24 (46%) had an unclear diagnosis. Endoscopic sloughing tended to be reported more often in cases with SE (P = .07). Histologic features did not discriminate between SE and other etiologies. Esophagitis resolved in 18 of 31 patients with follow-up, with no difference between sloughing and nonsloughing cases (P = .26). There were no clinical differences based on inflammatory and noninflammatory histology. CONCLUSIONS: SE has a classic microscopic appearance, but its findings are not specific, although endoscopic sloughing helps correlate histologic and clinical findings. In cases with histologic sloughing, pathologists should raise a broad differential diagnosis.

ROC analysis of p16 expression in cell blocks of metastatic head and neck squamous cell carcinoma.

BACKGROUND: Oropharyngeal squamous cell carcinoma is associated with human papillomavirus (HPV) and often presents with early metastasis to cervical neck lymph nodes that are amenable to fine-needle aspiration (FNA). The most common method of HPV status determination is p16 immunohistochemistry (IHC). The literature suggests that a lower threshold is needed for p16 positivity on cell block. We examined and quantified p16 IHC staining on cell block and used receiver operating characteristics (ROC) curve analysis to determine an optimal cutoff value with high sensitivity and specificity. METHODS: Thirty-six FNAs of metastatic squamous cell carcinoma from cervical lymph nodes with p16 IHC were evaluated. The p16 stain was quantified in 5% increments and high-risk HPV mRNA in situ hybridization was performed as a gold standard test. Statistical analysis was performed. RESULTS: Interobserver variability was evaluated and was shown to be low with an intraclass correlation coefficient of 0.857. ROC analysis was performed and showed that a cell block p16 IHC cutoff of 15% yielded the highest sensitivity (80%) and specificity (81.8%). CONCLUSION: Our data show that a threshold of 15% p16 staining in cell block maximizes sensitivity and specificity.

Metastases can occur in cirrhotic livers with patent portal veins.

OBJECTIVES: Metastases are common in non-cirrhotic livers but are considered unlikely in the setting of cirrhosis. However, the degree of fibrosis in cirrhosis may vary; thus metastases may still access the liver vasculature and present as a mass in cirrhotic livers. This possibility may affect pathologists' diagnostic algorithms when faced with a liver mass biopsy. METHODS: We hypothesized that metastases can occur in cirrhotic livers if fibrous remodeling is not severe or abnormal veno-arterial shunting exists to override an obstructed portal system. We searched departmental archives for cirrhotic livers with masses, categorizing fibrosis by Laennec staging: 4A = mild cirrhosis, 4B = moderate, 4 C = severe. RESULTS: Of 1453 cirrhotic livers with masses, 1429 were primary tumors and 24 were metastases (1.7 %). Of livers with metastases, most had 4A or 4B cirrhosis by Laennec staging (n = 17; 71 %). Eleven patients were evaluated by ultrasound Doppler; 2 of 5 with Laennec 4 C had reversal of portal vein flow, but all 4A & 4B patients had patent portal veins without reversed flow. Echocardiograms (13 patients) showed no ventricular or atrial septal defects or arteriovenous shunts. CONCLUSIONS: Metastases are uncommon in cirrhotic livers, accounting for 1.7 % of masses. Most involved livers had mild or moderate cirrhosis (Laennec 4A/4B) and patent portal veins; however, as some Laennec 4 C cases also contained metastases, obstructed portal access may not be enough to deter metastatic access.

Expression and prognostic value of NSD1 and SETD2 in pancreatic ductal adenocarcinoma and its precursor lesions.

Epigenetic regulation is emerging as a critical mechanism for pancreatic ductal adenocarcinoma (PDA) development. Histone methylation is an important regulatory mechanism, altering chromatin structure and promoter accessibility and causing aberrant gene expression. NSD1 and SETD2 genes encoding two histone H3K36 methyltransferases, are mutated or altered in 8-10% of PDA cases. However, whether there is altered protein expression of NSD1 or SETD2 in PDA and its precursors, and whether they have diagnostic or prognostic utility is unknown. Tissue microarrays composed of a total of 190 and 192 duplicated cases of PDA (n=74 and 75), metastatic PDA (n=17 and 18), pancreatic intraepithelial neoplasia (PanIN; n=19 and 24), intraductal papillary mucinous neoplasm (IPMN; n=36), mucinous cystic neoplasm (MCN; n=12) and benign pancreatic tissues (n=27 and 32) were analysed for expression of NSD1 and SETD2 by immunohistochemistry. We assessed intensity and percentage of positive cells. NSD1 expression was significantly increased in metastatic PDA compared to benign ducts, primary PDA, and all other lesions combined (p=0.03, 0.02, and 0.03 respectively). Additionally, significantly decreased SETD2 protein expression was found in metastatic PDA and PanIN lesions compared to benign ducts (p=0.04 and 0.007, respectively). High NSD1 expression was associated with clinical stage III/IV disease (p=0.026), tumour grade 2 (p=0.022), use of neoadjuvant therapy (p=0.037), and overall higher clinical stage (p=0.022). There is no significant difference in overall and progression-free survival between NSD1/SETD2 high and low PDA. Expression of NSD1 and SETD2 is specifically altered in metastatic PDA and some of the PDA precursor lesions, supporting their important role in PDA development and metastasis. In addition, increased NSD1 expression is significantly associated with higher clinical stage and neoadjuvant therapy, suggesting that NSD1 may be a useful prognostic marker.

Role of JAM-A tyrosine phosphorylation in epithelial barrier dysfunction during intestinal inflammation.

Junctional adhesion molecule-A (JAM-A), an epithelial tight junction protein, plays an important role in regulating intestinal permeability through association with a scaffold signaling complex containing ZO-2, Afadin, and the small GTPase Rap2. Under inflammatory conditions, we report that the cytoplasmic tail of JAM-A is tyrosine phosphorylated (p-Y280) in association with loss of barrier function. While barely detectable Y280 phosphorylation was observed in confluent monolayers of human intestinal epithelial cells under basal conditions, exposure to cytokines TNFα, IFNγ, IL-22, or IL-17A, resulted in compromised barrier function in parallel with increased p-Y280. Phosphorylation was Src kinase dependent, and we identified Yes-1 and PTPN13 as a major kinase and phosphatase for p-JAM-A Y280, respectively. Moreover, cytokines IL-22 or IL-17A induced increased activity of Yes-1. Furthermore, the Src kinase inhibitor PP2 rescued cytokine-induced epithelial barrier defects and inhibited phosphorylation of JAM-A Y280 in vitro. Phosphorylation of JAM-A Y280 and increased permeability correlated with reduced JAM-A association with active Rap2. Finally, we observed increased phosphorylation of Y280 in colonic epithelium of individuals with ulcerative colitis and in mice with experimentally induced colitis. These findings support a novel mechanism by which tyrosine phosphorylation of JAM-A Y280 regulates epithelial barrier function during inflammation.

Approach to the Liver Biopsy in the Patient With Chronic Low-Level Aminotransferase Elevations.

Pathologists sometimes encounter a liver biopsy from an asymptomatic patient with unexplained low-level parenchymal liver enzyme elevations. These biopsies often have minor histologic changes but are otherwise almost entirely normal. This can lead to the quandary of whether or not the features are clinically meaningful and how one must formulate a diagnosis from the possibly nonspecific findings of a near-normal biopsy. The following discussion focuses on the histologic changes that can be seen in these biopsies and the practical issues involved in making a diagnosis that provides useful information to the clinician. The literature and textbooks addressing the histologic and clinical features of these cases are reviewed with an emphasis on the clinical implications of finding nonspecific histologic alterations in these patients.

Clinical features, histology, and histogenesis of combined hepatocellular-cholangiocarcinoma.

Combined hepatocellular-cholangiocarcinoma (CHC) is a rare tumor with poor prognosis, with incidence ranging from 1.0%-4.7% of all primary hepatic tumors. This entity will be soon renamed as hepato-cholangiocarcinoma. The known risk factors for hepatocellular carcinoma (HCC) have been implicated for CHC including viral hepatitis and cirrhosis. It is difficult to diagnose this tumor pre-operatively. The predominant histologic component within the tumor largely determines the predominant radiographic features making it a difficult distinction. Heterogeneous and overlapping imaging features of HCC and cholangiocarcinoma should raise the suspicion for CHC and multiple core biopsies (from different areas of tumor) are recommended before administering treatment. Serum tumor markers CA19-9 and alpha-fetoprotein can aid in the diagnosis, but it remains a challenging diagnosis prior to resection. There is sufficient data to support bipotent hepatic progenitor cells as the cell of origin for CHC. The current World Health Organization classification categorizes two main types of CHC based on histo-morphological features: Classical type and CHC with stem cell features. Liver transplant is one of the available treatment modalities with other management options including transarterial chemoembolization, radiofrequency ablation, and percutaneous ethanol injection. We present a review paper on CHC highlighting the risk factors, origin, histological classification and therapeutic modalities.

Frequency and pathological characteristics of drug-induced liver injury in a tertiary medical center.

Drug-induced liver injury (DILI) accounts for approximately 10% of acute hepatitis cases. DILI can arise as idiosyncratic or intrinsic injury from hundreds of drugs, herbals, and nutritional supplements and is essential to recognize as one of the differential diagnoses of hepatitis in a liver biopsy. The purpose of this study is to investigate the frequency and pathological characteristics of DILI related to the variety of hepatotoxic agents. We searched our pathology database for all patients with hepatitis diagnosed on liver biopsy from January 2012 to May 2016, and selected patients with a diagnosis of DILI. Electronic medical records were reviewed for patient medication list, history of herbal medicine or supplement use, and pre-biopsy liver function test (LFT) results. Clinical and pathologic correlation was used to determine the causative or related agents for DILI. We then assessed histopathologic features of liver injury and categorized biopsy findings as primarily bile duct injury, lobular/portal hepatitis, or mixed changes. Six hundred four total liver biopsies for hepatitis or liver injury were identified, of which 70 cases (11.6%) carried the diagnosis of DILI confirmed by clinical correlation. The most common etiologies associated with DILI were supplements and herbal products (31.4%), antimicrobials (14.3%), chemotherapeutics (11.4%), antilipidemics (7.1%) and immunomodulatory agents (7.1%). LFT results positively correlated with histological findings. Nutritional/herbal supplements have emerged as one of the major hepatotoxicity agents. DILI can manifest as predominantly hepatitis, bile duct injury or combination. Histological pattern recognition in the liver biopsy may help identify specific hepatotoxic agents causing DILI.

Modification of the pT2 substage classification in prostate adenocarcinoma.

The current substage classification of pT2 prostate cancer (AJCC, 7th edition, 2010) into pT2a (unilateral tumors <1/2 of lobe), pT2b (unilateral tumors ≥1/2 of lobe), and pT2c (bilateral tumors) is of questionable relevance. Many studies show no difference in prognosis between substages, and incidence of pT2b prostate cancer is low. Other classification systems have been proposed based on tumor volume, as measured by dominant nodule size or tumor percentage. We characterized pT2b tumors and assessed the utility of current pT2 substaging in predicting biochemical recurrence-free survival after radical prostatectomy and compared them with different substaging methods based on tumor volume. Patients with pT2 tumors were selected among patients who underwent radical prostatectomy from 1998 to 2008. Dominant nodule size was dichotomized as <1.6 cm versus ≥1.6 cm. Tumor percentage was dichotomized as ≤25% versus >25%. Kaplan-Meier analysis and multivariate Cox proportional hazard regression models were used to evaluate pathological parameters predictive of biochemical recurrence-free survival. Of 785 patients who met criteria, 145 (18.5%) were pT2a, 15 (1.9%) were pT2b, and 625 (79.6%) were pT2c. The pT2 substages were not significant predictors of biochemical recurrence-free survival on univariate or multivariate analysis. In a multivariate model, tumor percentage >25% (P=.002) was associated with decreased biochemical recurrence-free survival. In patients with stage pT2 prostate cancer, the current substaging method lacks predictive value for biochemical recurrence-free survival after accounting for other pathologic and clinical predictors. However, tumor percentage (≤25% versus >25%) is a promising approach to substaging of pT2 prostate cancer based on its prognostic significance.