Clinical Data Do Not Reliably Predict Duodenal Histology at Follow-up in Celiac Disease: A 13 Center Correlative Study.

Validated nonbiopsy methods to assure duodenal mucosal healing in celiac disease are lacking, yet ongoing mucosal injury is associated with anemia, osteoporosis, and lymphoma. Most providers utilize clinical data as surrogates of mucosal status to avoid additional esophagogastroduodenoscopy. The reliability of such surrogates to predict mucosal recovery has been incompletely evaluated. The aim of this study was to rigorously assess patterns of histologic mucosal recovery at follow-up in celiac disease and to correlate findings with clinical data. Gastrointestinal pathologists from 13 centers evaluated initial and follow-up duodenal biopsies from 181 celiac disease patients. Marsh scores and intraepithelial lymphocytes (IELs)/100 enterocytes were assessed blindly. Histology at follow-up was correlated with symptoms, immunoglobulin A anti-tissue transglutaminase titers and gluten-free diet adherence. Fifty-six/181 (31%) patients had persistent villous blunting and 46/181 (25%) patients had just persistently elevated IELs at follow-up, with only 79/181 (44%) patients having complete histologic remission. IEL normalization (82/181; 45%) lagged villous recovery (125/181;69%). In a minority of patients, villous blunting was limited to proximal duodenal biopsies. No correlation was found between Marsh scores and symptoms, normalization of immunoglobulin A anti-tissue transglutaminase serology, or diet adherence. Children showed greater recovery of Marsh score ( P <0.001) and IELs ( P <0.01) than adults. Persistent mucosal injury is common in celiac disease, with discordant villous/IEL normalization. Pathologist awareness of expected findings in celiac disease follow-up biopsies, including their frequent lack of correlation with clinical data, is important for patient management, and has implications for eligibility criteria for therapeutics currently in development.

Clinicopathological significance of neutrophil-rich colorectal carcinoma.

AIMS: The importance of the interaction between tumour cells and neutrophils has recently begun to emerge. However, the significance of tumour-infiltrating neutrophil (TIN) in colorectal carcinomas (CRCs) remains unclear. The aim of this study was to investigate the prognostic significance of TIN in CRCs. METHODS: CRCs were evaluated for TIN and were classified as neutrophil-rich (NR), neutrophil-intermediate (NI) and neutrophil-poor (NP) based on the presence of >15, 5-15 and <5 TIN per 100 tumour cells, respectively. Various clinicopathological parameters were recorded in each case including age, gender, histological grade, tumour, node, metastasis (TNM) stage, tumour location and DNA mismatch repair (MMR) status. RESULTS: Among the 348 CRC cases reviewed, 38 cases were NR, 43 cases were NI and 267 cases were NP. High TIN was associated with higher histological grade (p=0.0222), right-sided tumour location (p=0.0025), advanced TNM stage (p=0.0346) and higher rate of MMR-deficient CRCs (p=0.0027). Patients with NR CRCs had significantly poorer 5-year recurrence-free survival comparing to patients with NI or NP CRCs on Kaplan-Meier analysis (p=0.0001) and high TIN remained an independent risk factor with multivariate analysis (p=0.0137; HR: 1.930, 95% CI: 1.144 to 3.255). NR CRCs are more commonly seen in MMR-deficient than in MMR-proficient CRCs (p=0.0006). Patients with MMR-deficient NR CRCs showed similar 5-year recurrence-free survival compared with MMR-proficient NR CRCs. CONCLUSIONS: Our findings reveal that high TIN confers poorer patient prognosis in both MMR-proficient and MMR-deficient CRCs.

Frontiers in Celiac Disease: Where Autoimmunity and Environment Meet.

Celiac disease is a chronic, immune-mediated enteropathy driven by dietary gluten found in genetically susceptible hosts. It has a worldwide distribution, is one of the most common autoimmune disorders globally, and is the only autoimmune condition for which the trigger is known. Despite advances in characterizing mechanisms of disease, gaps in understanding of celiac disease pathogenesis remain. A "frontier" concept is considering what moves an HLA-DQ2 or DQ8-positive individual from asymptomatic gluten tolerance to celiac disease manifestation. In this arena, environmental triggers, including age at the time of initial gluten exposure, the occurrence of usual childhood viral infections, and microbiome alterations have emerged as key events in triggering the symptomatic disease. Pathologists play a major role in frontier aspects of celiac disease. This includes the discovery that duodenal mucosal histology in follow-up biopsies does not correlate with ongoing patient symptoms, antitissue transglutaminase antibody titers and diet adherence in celiac disease patients. Further, in light of recent evidence that the detection of monoclonal T-cell populations in formalin-fixed biopsies is not specific for type II refractory celiac disease, pathologists should resist performing such analyses until common causes of "apparent" refractoriness are excluded. The promise of therapies in celiac disease has led to clinical trials targeting many steps in the inflammatory cascade, which depend upon a pathologist's confirmation of the initial diagnosis and evaluation of responses to therapies. As pathologists continue to be active participants in celiac disease research, partnering with other stakeholders, we will continue to impact this important autoimmune disease.

Intestinal metaplasia around the gastroesophageal junction is frequently associated with antral reactive gastropathy: implications for carcinoma at the gastroesophageal junction.

Increasing evidence suggests that bile reflux (BR) plays a major role in mucosal injury, leading to adenocarcinoma of the proximal stomach and distal esophagus. However, gastric BR is difficult to diagnose and investigate. Reactive gastropathy (RG), in the absence of nonsteroidal anti-inflammatory drugs (NSAIDs) and other known causes, likely represents bile-mediated injury to the gastric mucosa. The goal of this study is to explore the association between antral RG and gastroesophageal junction (GEJ) mucosal inflammation and intestinal metaplasia (IM). The pathology database was searched for patients who had gastric biopsies with a diagnosis of antral RG and concurrent gastric cardia/GEJ/distal esophagus biopsies from 2013 to 2015. Age- and sex-matched patients with normal gastric antral biopsies served as controls. Biopsies from the GEJ region were evaluated for histological changes, including inflammation, antral and pancreatic metaplasia, RG, the type of gastric glands, proton pump inhibitor (PPI) changes, and IM. Detailed clinical history and medication use (including PPIs and NSAIDs) were recorded. IM in the GEJ region was more frequent in patients with antral RG than in controls (33.0% vs. 5.2%, 95% confidence interval [18.3-37.3%]). In addition, inflammation, other mucosal changes around the GEJ (RG and foveolar hyperplasia), antral IM, and PPI-associated mucosal changes were also more frequently seen in patients with antral RG. Our results show that antral RG is associated with mucosal injury and IM around GEJ, suggesting a role of BR. Further studies are needed to study duodenogastric-esophageal BR and its role in development of proximal gastric and distal esophageal adenocarcinoma.

Elective Colectomy in a Patient with Active Ulcerative Colitis and Metastatic Melanoma Enabling Successful Treatment with Immune Checkpoint Inhibitors.

Checkpoint inhibitor immunotherapy has significantly advanced treatment of a growing number of advanced malignancies. A consequences of immune system activation that leads to tumor cell destruction by checkpoint inhibitor therapy is the development of immune-related adverse events, some of which can be life threatening. There are limited data on the use of checkpoint inhibitor therapy in patients with preexisting autoimmunity owing to concerns that underlying autoimmune disease may be exacerbated by checkpoint inhibitor treatment. Decisions to treat these patients are made after careful consideration of the risks and benefits of treatment. We describe a patient with active and severe ulcerative colitis with metastatic melanoma who underwent elective colectomy prior to initiation of anti-PD-1 and anti-CTLA-4. The patient had excellent tumor response without flare of his ulcerative colitis suggesting that in select patients with high-risk inflammatory bowel disease, elective colectomy may be an effective treatment option.

Adverse Histologic Features in Colorectal Nonpedunculated Malignant Polyps With Nodal Metastasis.

Tumor differentiation, lymphovascular invasion, margin status, polyp shape, and size are important parameters of malignant polyps (pT1) indicating possible node metastasis, which justifies a surgery. However, the size, margin, and lymphovascular invasion are often unknown or difficult to assess in a piecemeal polypectomy from a nonpedunculated malignant polyp. The aim of the study was to identify adverse histologic features in nonpedunculated malignant polyps associated with an increased risk of nodal metastasis, which may warrant a colectomy procedure. A total of 24 node-positive and 18 node-negative nonpedunculated malignant polyps and their corresponding subsequent resection specimens from 2005 to 2018 were reviewed. Cases with node metastasis were more often positive for high-grade tumor budding (70.8% vs. 16.7%; P=0.0005), poorly differentiated clusters (54.2% vs. 22.2%; P=0.0369), and both high-grade tumor budding and poorly differentiated clusters (45.8% vs. 11.1%; P=0.0160) compared with controls without nodal metastasis. High-grade tumor budding, poorly differentiated clusters, and combined high-grade tumor budding and poorly differentiated clusters increased the risk of nodal metastasis, with odds ratio of 12.1, 4.1, and 14.3, respectively. Furthermore, nodal metastasis could be seen in subsequent colectomy specimen even in completely excised malignant polyps with adverse histologic features. Our findings indicate that high-grade tumor budding and poorly differentiated clusters are important adverse histologic risk features in predicting lymph node metastatic potential. These histologic features should be reported and it may warrant a colectomy when they are present.

Neuroendocrine Tumors of the Gastrointestinal Tract and Pancreas.

Neuroendocrine neoplasms (NENs) of the gastrointestinal (GI) tract and pancreas are a rare and heterogeneous group of neoplasms characterized by common cellular features as well as unique site-specific traits. GI and pancreatic NENs are much rarer than the more common adenocarcinomas arising at these sites. However, the incidences of GI and pancreatic NENs have increased significantly, particularly in the stomach and common site, followed by rectum, appendix, colon, and stomach. Pancreatic NENs are also uncommon, with fewer than 1 per 100,000, accounting for 1% to 2% of all pancreatic neoplasms.

Graft-Versus-Host Disease After Pancreatic Transplantation.

Graft-versus-host disease (GVHD) is a common complication of hematopoietic stem cell transplantation but can rarely occur after solid organ transplants. Small bowel and liver transplants are typically implicated, but solid organ transplant-associated GVHD has also been associated with other organs. We present a 40-year-old diabetic woman who underwent renal followed by pancreatic transplantation over a span of 21 months and ultimately developed acute classic GVHD. The diagnosis proved to be challenging in the context of confounding infections and inconclusive bone marrow and skin biopsy findings. She had multiorgan failure at the time of endoscopic confirmation and died after having minimal response to aggressive immunosuppression.

Glucose Metabolic Reprogramming and Cell Proliferation Arrest in Colorectal Micropapillary Carcinoma.

BACKGROUND: Micropapillary carcinoma (MPC) has been reported as an aggressive variant of colorectal carcinoma (CRC) associated with frequent lymphovascular invasion and poor outcome. Altered glycogen metabolism by metabolic reprogramming plays a critical role for cancer cell growth and survival. We aimed to investigate glucose metabolic reprogramming in colorectal MPC. METHODS: Immmunostains for Ki-67 and glucose transporter 1 (GLUT1) were performed on 10 colorectal MPCs. Real-time PCR analysis of expressions of GLUT1 and glycogen metabolizing enzymes: glycogen synthase (GYS1) and glycogen phosphorylase (PYGL) was performed on cultured monolayer and three-dimensional (3D) spheroid HCT116 colon cancer cells. RESULTS: GLUT1 was strongly expressed in MPC as compared to adjacent conventional glandular component, and was also significantly increased expression in 3D spheroids. Upregulation of GYS1 and PYGL was markedly increased in 3D spheroids. The proliferation rate (Ki-67) of MPC was significantly lower compared to conventional glandular component. The 3D spheroids showed increased cell cycle arrest. Our results demonstrate altered glycogen metabolism in colorectal MPC. CONCLUSION: The reprogramming of glycogen metabolism in MPC provides a source of energy contributing to tumor cell survival in a low proliferation state. Targeting glucose-regulated metabolism may warrant consideration as possible MPC therapies.

Breast cancer histopathology is predictive of low-risk Oncotype Dx recurrence score.

BACKGROUND: Oncotype Dx is a genetic test that has been incorporated into the 2017 AJCC breast cancer staging system for ER positive, HER2-negative, lymph node-negative patients to predict the risk of recurrence. Recent data suggest that immunohistochemistry (ER, PR, HER2, and Ki-67) and histologic subtype may identify patients that will not benefit from Oncotype Dx testing. METHODS: A total of 371 patients underwent Oncotype Dx testing at our institution from 2012 to 2016. Oncotype recurrence score was categorized as low- (ORS = 0-10), intermediate- (11-25), or high risk (26-100). Invasive carcinomas were categorized based on histologic subtype as "favorable" (mucinous, tubular, cribriform, tubulolobular, and lobular) and "unfavorable" (ductal, mixed ductal and lobular, and micropapillary carcinoma). All cases were estrogen receptor positive and HER2-negative. Clinical and histologic predictors of low-risk ORS were assessed in univariate and multivariate logistic regression. RESULTS: A total of 371 patients were categorized by ORS as low risk (n = 85, 22.9%), intermediate risk (n = 244, 65.8%), and high risk (n = 42, 11.3%). The histologic subtypes with the highest percentage of high-risk ORS were invasive micropapillary (n = 4/17, 23.5%), pleomorphic lobular (n = 2/10, 20%), and ductal carcinoma (n = 28/235, 11.9%). Low-grade invasive carcinomas with favorable histology rarely had a high-risk ORS (n = 1/97, 1%). In a simple multivariable model, favorable histologic subtype (OR = 2.39, 95% CI: 1.10 to 5.15, P = 0.026), and histologic grade (OR = 1.76, 95% CI: 1.07 to 2.90, P = 0.025) were the only significant predictors of an ORS less than 11 in estrogen receptor positive, HER2-negative, and lymph node-negative patients. CONCLUSION: We question the utility of performing Oncotype Dx in subtypes of invasive carcinoma that are associated with excellent prognosis. We propose that immunohistochemistry for ER, PR, and HER2 is sufficient for patients with low-grade invasive carcinomas and can be used as a surrogate for Oncotype Dx.

Metabolic Signature on 18F-FDG PET/CT, HER2 Status, and Survival in Gastric Adenocarcinomas.

The human epidermal growth factor 2 (HER2)-overexpressing (HER2-positive [HER2+]) gastric (GC) and gastroesophageal junction adenocarcinomas (GEJC) are felt to represent a more aggressive form of disease, which may correlate to increased metabolic activity. Whether tumor SUVmax measured by 18F-FDG PET/CT could be a preoperative parameter used to predict HER2 status of GC/GEJC is unknown. METHODS: Pathology reports of HER2+ GC/GEJC biopsies and resections from 31 patients were reviewed and compared with HER2-negative (HER2-) cases distributed evenly over the same time period. We analyzed their SUVmax intensity and then compared the HER2 status and SUVmax parameters and their association with survival. RESULTS: After matching for age and sex, there was no difference in SUVmax between HER2+ and HER2- cases (9.7 and 8.4, respectively; P = 0.6). No difference was seen between HER2+ and HER2- cases in tumor histology (81% and 57% intestinal type, respectively; P = 0.11), size (2.6 and 3.8 cm, respectively; P = 0.12), differentiation (47% and 68% poorly differentiated, respectively; P = 0.06), or presence of lymph node metastasis (60% and 40%, respectively; P = 0.3). Although there was no difference in survival demonstrated by HER2+ and HER2- cases, there was a significant difference in survival between SUVmax above (12.2 mo) and below (30 mo) the median SUVmax (6.6, P = 0.01). CONCLUSION: Our study shows that SUVmax is not associated with HER2 status of GC/GEJC. Independent of HER2 overexpression, patients with a high SUVmax demonstrate a worse overall survival, suggesting that metabolic signature is a better predictor of biologic tumor aggressiveness than its histologic signature.

Autologous Stem Cell Mobilization in the Age of Plerixafor.

BACKGROUND: Autologous stem cell transplantation remains important in the treatment of myeloma and relapsed lymphoma. Plerixafor has been shown to significantly enhance stem cell mobilization but is very expensive. PATIENTS AND METHODS: We evaluated plerixafor use in the 3-year period after its approval in December 2008. RESULTS: A total of 277 patients with myeloma and lymphoma had stem cell mobilization; 97.5% were successfully mobilized, including 41.5% who received plerixafor. Plerixafor was generally used for rescue after suboptimal granulocyte-colony stimulating factor (G-CSF) mobilization ("just in time") or for remobilization after an unsuccessful attempt with chemotherapy plus G-CSF. In addition, 10% of patients received planned G-CSF plus plerixafor because of high risk factors for inadequate collection. Rescue plerixafor was more effective in patients with myeloma than lymphoma as after 1 dose of plerixafor; 85% versus 55% collected a minimum number of stem cells (2 × 10E6 CD34 cells/kg) for 1 transplant and 51% versus 15% collected > 5 × 10E6 CD34 cells/kg. After transplantation, there were no significant differences in engraftment as a consequence of plerixafor use. Among all patients, there were less platelet transfusions in patients provided ≥ 3.5 × 10E6 CD34(+) cells/kg. CONCLUSION: With the judicious use of plerixafor, nearly all patients can collect enough stem cells to proceed to transplantation. Further studies, including hematologic tolerance to posttransplantation therapy, are required to determine the cost-effectiveness of using plerixafor to convert adequate to more optimal mobilizers.

Fungal Mycotic Aneurysm of the Internal Carotid Artery Associated with Sphenoid Sinusitis in an Immunocompromised Patient: A Case Report and Review of the Literature.

In immunocompromised patients, invasive molds such as Aspergillus and Mucor can lead to locally aggressive angioinvasive infections that are often life-threatening. A particularly devastating complication is the development of a fungal mycotic aneurysm resulting from invasion of the arterial wall. Due to anatomic contiguity, the sphenoid sinus provides potential access for these fungi, which often colonize the respiratory sinuses, into the cavernous sinus and internal carotid artery (ICA), thus leading to the formation of ICA aneurysms. The ideal treatment of fungal ICA aneurysms includes a combination of surgical debridement and long-term effective antifungal therapy, but the role of endoscopic resection and the duration of antimicrobials are poorly defined. Here, we present the case of a 71-year-old immunocompromised patient who developed an ICA mycotic aneurysm, associated with a proven invasive fungal infection (presumptively Mucorales) of the sphenoid sinuses, as defined by EORTC/MSG criteria, and who survived after undergoing coil embolization with parent vessel sacrifice of the aneurysm in combination with liposomal amphotericin B. We also review the literature for published cases of invasive fungal sphenoid sinusitis associated with mycotic aneurysms of the ICA and provide a comparative analysis .