Changqing Ma

Programmed Death-Ligand 1 Expression Is Common in Gastric Cancer Associated With Epstein-Barr Virus or Microsatellite Instability.

Blockade of the programmed death 1 (PD-1) pathway has emerged as a novel therapy for cancer. Therefore, development of biomarkers for response prediction, such as PD-ligand 1 (PD-L1) expression by immunohistochemistry, may help to stratify patients. Solid tumors with CD8 T-cell rich tumor microenvironment have been implicated to be associated with increased PD-L1 expression. We hypothesized that gastric cancers associated with Epstein-Barr virus infection (EBV+) or microsatellite instability (MSI), both of which are known to harbor such tumor microenvironment, are associated with increased PD-L1 expression. Forty-four resected gastric cancers including 7 EBV+, 16 MSI, and 21 microsatellite stable cancers without EBV (EBV−/MSS) were studied for PD-L1 expression and T-cell subpopulations by immunohistochemistry. Positive PD-L1 expression (PD-L1+), defined as membranous staining in either tumor cells or tumor immune infiltrates, was seen in 32 (72%) gastric cancers. EBV+ or MSI cancers showed significantly higher rates of PD-L1+ compared with EBV−/MSS cancers (7/7, 100%; 14/16, 87%; 11/21, 52%; P=0.013). PD-L1+/EBV+ and PD-L1+/MSI cancers had significantly more CD8 T cells at tumor invasive front than PD-L1+/EBV−/MSS cancers (P<0.001). PD-L1+ was not associated with the depth of invasion or nodal metastasis (P=0.534, 0.288). Multivariate analysis showed PD-L1+ was not an independent predictor of disease-free survival while MSI was (P=0.548, 0.043). In summary, EBV+ or MSI gastric cancers are more likely to express PD-L1 and have increased CD8 T cells at tumor invasive front than EBV−/MSS cancers. Our results suggest EBV infection and MSI should be investigated for predicting response to PD-1 blockade.

Radiologic and intraoperative detection of need for mesenteric vein resection in patients with adenocarcinoma of the head of the pancreas

OBJECTIVE The need for mesenteric venous resection (MVR) is determined by a combination of preoperative radiologic and intraoperative surgical assessments. A single-centre review was performed to determine how efficient these processes are in evaluating the need for MVR. METHODS A retrospective study was performed of 343 patients who received resection for adenocarcinoma of the head of the pancreas, 100 of whom underwent MVR. Three radiologic signs (abutment, fat plane obliteration, focal narrowing) were evaluated for their ability to predict the need for MVR. Pathologic assessment was performed to determine if MVR had been necessary to achieve negative-margin (R0) resection. Microscopic tumour in the vein wall, or within 1 mm of the vein wall, was considered to indicate that MVR had been necessary to achieve an R0 resection. RESULTS Radiologic evaluation (showing any of the three signs) had sensitivity of only 60%. Overall, 40% of the patients who required MVR showed none of the signs. Specificity was 77%. A total of 80% of patients who underwent MVR had either microscopic invasion or abutment. R0 resection at the vein margin was achieved in 98% of patients in both the MVR and non-MVR groups. CONCLUSIONS Preoperative radiologic evaluation is not highly reliable in predicting the need for MVR. Therefore, surgical teams performing resections of cancers of the head of the pancreas must be skilled in MVR as the need for this procedure may arise unexpectedly. Surgical assessment of the need for MVR has an accuracy of about 80% and is nearly 100% accurate in determining when MVR is not required.

Upper tract juvenile polyps in juvenile polyposis patients: dysplasia and malignancy are associated with foveolar, intestinal, and pyloric differentiation.

Patients with juvenile polyposis syndrome (JPS), a hereditary autosomal dominant hamartomatous polyposis syndrome, are at increased risk for colorectal adenocarcinoma. The upper gastrointestinal tract is less often involved by JPS than the colorectum, and, consequently, upper tract juvenile polyps (JPs) are not well studied. We reviewed upper endoscopies and corresponding biopsies in JPS patients documented in our Polyposis Registry. A total of 199 upper gastrointestinal biopsies from 69 endoscopies were available in 22 of 41 (54%) JPS patients. Thirteen of the 22 patients (59%) had ≥1 gastric JP; 5 also had 6 small bowel JPs. Gastric JP was identified as early as age 7 in a patient with an SMAD4 gene mutation. Two patients (9%) had high-grade dysplasia in gastric JP. Invasive adenocarcinoma was diagnosed in the gastrectomy specimen of 1 patient. Five patients had a huge gastric polyp burden; 3 underwent total gastrectomy. Three patients died of complications associated with extensive upper JP. Histologically, 8 of the 56 (14%) gastric JPs identified had dysplasia. All of the 8 polyps demonstrated intestinalized and pyloric gland differentiation intermixed with foveolar epithelium. Dysplasia was seen arising in all 3 types of epithelium. The flat gastric mucosa in 11 patients was unremarkable without inflammation or intestinal metaplasia. The 6 small bowel JPs had no dysplasia. Our findings suggest that JPS patients are at increased risk for gastric adenocarcinoma. Detection of malignancy in syndromic gastric JP indicates that the current screening procedures are insufficient in removal of precursor lesions to prevent progression to carcinoma.

Histopathologic evaluation of liver biopsy for cirrhosis.

In current medical practice, the clinical diagnosis of cirrhosis is rendered when a patient has suggestive imaging findings or features of portal hypertension (pHTN). Liver biopsy may be considered to assess potential underlying cause(s). Cirrhosis, however, is not the only etiology of pHTN; in fact, schistosomiasis remains a significant factor worldwide. pHTN results from obstruction of hepatic blood flow; it is classified clinically based on either the anatomic location of obstruction or hepatic venous pressure gradient measurements. The clinical categories carry clinicopathologic significances. Histopathologically, pHTN is manifest with either cirrhotic or noncirrhotic features. Noncirrhotic pHTN results from a heterogeneous group of disease processes, all of which result in vascular remodeling with variable parenchymal nodularity and fibrosis. This review summarizes liver biopsy findings of cirrhosis and possible etiologies and provides a stepwise approach for the histologic differential diagnosis of a liver biopsy done for “cirrhosis.”

Acute graft-versus-host disease is more prevalent and severe in the lower than the upper gastrointestinal tract

It is unclear whether acute gastrointestinal (GI) graft-versus-host disease (GVHD) affects all segments of the GI tract equally. Up to 45% patients reported showed discrepancy in involvement between upper GI (UGI) and lower GI (LGI) tract. We compared the prevalence and the severity of acute GVHD in UGI and LGI tract on histologic examination. A cohort of 110 cases of simultaneous UGI and LGI biopsies from 105 allogeneic hematopoietic stem cell transplantation recipients with clinically confirmed GI GVHD were reviewed retrospectively. The χ(2) test and 1-way analysis of variance test were used for statistical analysis. Most (75%) of the cases had GVHD involvement in both UGI and LGI tracts, whereas UGI-only GVHD was found in 6% and LGI-only GVHD in 19%. GVHD prevalence was the lowest in stomach (61%) and significantly increased toward duodenum/jejunum (81%; P = .0019). The LGI tract showed similar GVHD prevalence (P = .3648); the highest was in the sigmoid colon (97%). The histologic grade was lowest in the stomach (mean ± SD, 1.6 ± 0.8) and was similar across all UGI segments (P = .0883). The histologic grade in LGI significantly increased (P = .0265) from the terminal ileum (2.0 ± 1.3) to the rectum (2.9 ± 1.0). Overall, both the prevalence and the histologic grade of GVHD in LGI were significantly higher than those of UGI (P < .0001 for both). Our results show that acute GVHD had a higher prevalence and was more severe in the LGI than in UGI tract. A small subset of patients had only UGI involvement.

A comparative clinicopathologic study of collagenous gastritis in children and adults: The same disorder with associated immune-mediated diseases

Collagenous gastritis is a rare condition characterized by surface epithelial damage, subepithelial collagen deposition, and a lamina propria inflammatory infiltrate. Previous studies have proposed 2 clinicopathologic subtypes: (1) children (18 y of age or younger) presenting with severe anemia, nodular gastric mucosa, and isolated gastric disease; and (2) adults with chronic watery diarrhea that is associated with diffuse collagenous involvement of the gastrointestinal tract. However, notable exceptions exist. In fact, broad variability in clinical presentation, etiology, treatment and disease course has been reported. To better define the clinicopathologic features of collagenous gastritis, we have collected 10 pediatric and 21 adult cases and describe their clinical, endoscopic, pathologic, and follow-up findings. Both children and adults presented with similar clinical symptoms such as anemia (50%, 35%, respectively), epigastric/abdominal pain (50%, 45%), and diarrhea (40%, 55%). Concomitant immune disorders were identified in 2 (20%) children and 3 (14%) adults. Further, 7 of 17 (41%) adults were taking medications associated with other immune-related gastrointestinal diseases including olmesartan and antidepressants. Histologically, there were no differences between children and adults with collagenous gastritis in the location of gastric involvement, mean collagenous layer thickness, and prominence of eosinophils (P>0.05). Extragastric collagenous involvement was also seen with comparable frequencies in each cohort (44%, 59%). Follow-up information was available for 22 of 31 (71%) patients and ranged from 2 to 122 months (mean, 33.6 mo). Despite medical management in most cases, persistence of symptoms or collagenous gastritis on subsequent biopsies was seen in 100% of children and 82% of adults. Of note, treatment for 1 adult patient involved cessation of olmesartan resulting in resolution of both symptoms and subepithelial collagen deposition on subsequent biopsies. Contrary to prior reports, no clinicopathologic differences were identified among pediatric and adult patients with collagenous gastritis. Whereas collagenous gastritis remains an enigmatic condition, our findings suggest that immune abnormalities and medications, such as olmesartan, may be possible triggers. However, current treatment options have had limited success and, thus, highlight the need for improved therapeutic regimens.

Predictive value of immunohistochemistry in pre-malignant lesions of the gastrointestinal tract

Immunohistochemistry can be an important adjunct to histopathology for the diagnosis of pre-malignant lesions of the gastrointestinal tract and in patient risk stratification. The purpose of this review is to provide information and guidance on the usefulness of immunohistochemical markers that facilitate the diagnosis of dysplasia and help to predict risk for the development of carcinoma in pre-malignant lesions of the gastrointestinal tract. Particular emphasis is given to the role of immunohistochemistry in the assessment of epithelial dysplasia in the setting of Barretts esophagus and inflammatory bowel disease; supplementary immunohistochemistry for subtyping adenomas of the stomach and ampulla and serrated polyps of the colon and rectum; and ancillary markers of squamous neoplasia of the anal canal.

Parenchymal alterations in cirrhotic livers in patients with hepatopulmonary syndrome or portopulmonary hypertension

Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PPH) are distinct pulmonary vascular complications of cirrhosis. Little is known about possible associated hepatic histopathological features. Explanted livers from patients clinically diagnosed with HPS (n = 8) or PPH (n = 7) and cirrhotic explants from controls (n = 30) without HPS or PPH were evaluated with trichrome histochemistry, anti–glutamine synthetase (anti‐GS), and anti‐CD34 immunohistochemistry (IHC). Trichrome stains were characterized by cirrhotic nodules (CNs) of various sizes, including incomplete septal cirrhosis (ISC). ISC was overrepresented in the HPS (4/8 or 50%) and PPH livers (3/7 or 43%); in addition, neither group had micronodular cirrhosis. The control explants showed the entire spectrum of nodules: micronodular, macronodular, mixed CNs, and ISC (P = 0.04). The variability of cirrhosis severity was shown with the Laennec grading system (0‐6). The cirrhosis of the majority of the HPS (6/8) and PPH livers (6/7) was scored as mild, whereas the control explants were more evenly distributed across the mild (14/30) and moderate/severe grades (16/30). GS positivity was retained in a perivenular location as the dominant pattern in each explant group. CD34 staining detected capillarized sinusoids of CNs as well as vascular channels within septa, but no significant differences were found between the groups. None of the observed light microscopy or histochemistry and IHC patterns showed a correlation with the underlying liver disease. Although our results demonstrate variable architectural and vascular remodeling within and between explant livers regardless of the presence or types of pulmonary complications, there were differences in explants with HPS or PPH versus controls that correlated with less severe cirrhosis. Liver Transpl 19:741–750, 2013.

DNA mismatch repair deficiency but not ARID1A loss is associated with prognosis in small intestinal adenocarcinoma

Small intestinal adenocarcinoma is an uncommon neoplasm with poor prognosis. It is clinically approached similarly to colorectal carcinoma (CRC). The prognostic value of DNA mismatch repair protein deficiency (dMMR) in CRC is well established, but its role in small intestinal adenocarcinoma remains inconclusive. Recently, loss of expression of ARID1A, a tumor suppressor gene product, by immunohistochemistry (IHC) was linked to dMMR and poor outcome in small intestinal adenocarcinoma, suggesting that it may be an emerging prognostic biomarker. We hypothesized that dMMR and/or ARID1A loss may be associated with clinical outcome in small intestinal adenocarcinoma. We examined dMMR and ARID1A loss by IHC in 120 surgically resected, nonampullary small intestinal adenocarcinomas collected from 2 tertiary centers. ARID1A loss was detected in 6 (7%) of 92 ARID1A-stained adenocarcinomas, whereas 21 (18%) of 120 adenocarcinomas demonstrated dMMR. ARID1A loss was not associated with survival or dMMR. dMMR adenocarcinomas had no distant metastasis, whereas 22 (22%) of 99 MMR-proficient adenocarcinomas had (P = .01). dMMR was an independent, positive predictor of disease-free survival (P = .035, hazard ratio: 0.2). Compared with dMMR CRC, dMMR small intestinal adenocarcinomas more frequently demonstrated loss of MSH2 and MSH6 and less often showed loss of MLH1 and PMS2 (both P < .001). In summary, ARID1A loss by IHC is uncommon in small intestinal adenocarcinomas. dMMR small intestinal adenocarcinomas are nonmetastatic tumors, frequently demonstrate loss of MSH2 and MSH6, and have superior disease-free survival. Our results suggest that all small intestinal adenocarcinomas should be tested for MMR protein deficiency.

Terminal hepatic venule injury in liver biopsies of allogeneic haematopoietic stem cell recipients-a study of 63 cases.

Subtle lesions of terminal hepatic venules (THVs) may be overlooked in liver biopsies from haematopoietic stem cell transplant (HSCT) receipients when graft‐versus‐host disease is the clinical concern. The aim of this study was to evaluate the frequency of THV injury resembling sinusoidal obstruction syndrome (SOS).