Venous invasion detectable only by elastic stain shows weak prognostic value in colon cancer.

AIMS: Large venous invasion (VI) is prognostically significant in colon cancer. The increased use of elastic stains by pathologists results in higher VI detection rates compared to routine stains alone. This study assesses the prognostic value of VI detected by elastic versus routine stains. METHODS AND RESULTS: Colon cancers resected between 2014 and 2017 underwent pathology slide review for VI. Cases without VI on routine stain were stained by elastic trichrome and re-examined. Demographic, clinical, pathological and outcome data were gathered by retrospective review. Kaplan-Meier curves with log-rank tests were performed for survival categorised by VI status. Cox regression was performed for multivariate analysis. Of 277 cases, 97 (35%) showed VI by routine stain alone, with an additional 58 (21%) discovered by subsequent elastic stains. Thus, elastic trichrome increased VI detection by 60%. However, only VI detected by routine stain showed worse overall survival (P < 0.001). VI detected by elastic stain only was not prognostically different from cases without VI (P = 0.428). For stage 2 cancers, VI was not prognostically significant regardless of method of detection. For stage 3 cases, only VI detected by routine stain was prognostic for overall survival (P = 0.002) with a hazard ratio of 4.04 by multivariate regression (P = 0.028). CONCLUSIONS: VI detectable only by elastic stains do not show prognostic significance for survival in colon cancer. For pathologists with high baseline VI detections rates on routine stain, reflexive use of elastic stain may be of limited value.

Hot avulsion may be effective as salvage treatment for focal Barrett's esophagus remaining after endoscopic therapy for dysplasia or early cancer: a preliminary study.

BACKGROUND AND STUDY AIM: Both endoscopic mucosal resection (EMR) and radiofrequency ablation (RFA) are used to treat Barrett's esophagus (BE) complicated by dysplasia and intramucosal cancer. However, focal areas of BE can remain after otherwise successful application of these techniques. We report the results of hot avulsion using a hot biopsy forceps to resect these residual focal areas. PATIENTS AND METHODS: This was a retrospective study from a prospective database in a tertiary reference center from August 2013 to May 2015. All included patients had undergone hot avulsion for eradication of residual focal areas of BE that were ≤ 1 cm and not suspicious for dysplasia, following at least one previous endoscopic treatment for dysplasia or intramucosal cancer. RESULTS: 35 patients harboring 124 residual areas of 1 - 7 mm were treated with hot avulsion. After a mean follow-up of 17.4 months, all patients achieved complete eradication of residual focal BE. One of the patients required a second hot avulsion treatment. Hot avulsion provided samples in all cases but limited the assessment of dysplasia (cautery artifact) in 20.2 % of them. The only complication was bleeding in two patients, which was easily stopped by soft coagulation. CONCLUSIONS: Hot avulsion appears to be effective and safe in removing focal BE ≤ 1 cm at its greatest length remaining after endoscopic treatment for dysplasia or early cancer. Further studies are required before this technique can be considered the standard of care.

HtrA3 stromal expression is correlated with tumor budding in stage II colorectal cancer.

Tumor budding is a well-established adverse prognostic factor in colorectal carcinoma (CRC). It may represent a form of epithelial-to-mesenchymal transition (EMT), although the underlying mechanisms remain unclear. High-temperature requirement A3 (HtrA3) is an inhibitor of the bone morphogenetic protein pathway, the suppression of which has been linked to EMT. Since HtrA3 is highly expressed in the desmoplastic stroma at the CRC invasive front, we sought to evaluate the relationship between tumor budding and HtrA3 expression in 172 stage II CRC resection specimens. All tumors were evaluated for tumor budding, with the highest budding slide selected for pan-keratin (CK) and HtrA3 immunohistochemistry. Representative areas of tumor core and invasive front, including budding and non-budding areas, were marked on CK stained slides, and then evaluated on HtrA3 stained slides. HtrA3 expression in tumor cells (tHtrA3) and peritumoral stroma (sHtrA3) was assessed for staining percentage and intensity (the product yielding a final score). Tumors with high-grade tumor budding (HGTB) showed increased expression of sHtrA3 in budding areas compared to non-budding areas at the invasive front (P<0.001). In addition, sHtrA3 expression at the invasive front was significantly higher in HGTB tumors compared to minimally budding tumors (P<0.05). tHtrA3 expression at the invasive front was significantly associated with high histological grade (P<0.05). Higher sHtrA3 expression in the tumor core (but not invasive front) was significantly associated with decreased 5-year overall survival on univariate analysis (P<0.05), but not multivariate analysis. HtrA3 expression in the peritumoral stroma of patients with stage II CRC is associated with HGTB and may be a novel marker of poor outcome.

Folic Acid Supplementation Adversely Affects Chemosensitivity of Colon Cancer Cells to 5-fluorouracil.

Folic acid (FA) fortification and widespread supplemental use have significantly increased folate status in North America. Furthermore, >50% of colorectal cancer patients use FA supplement. The increased folate status may interfere with cancer chemotherapy. We investigated the effect of FA supplementation on chemosensitivity of human colon cancer cells to 5-fluorouracil (5-FU) using a xenograft model. Mice harboring human HCT116 colon cancer xenografts were randomized to receive the control, or 4× or 12.5× supplemental levels of FA. Within each diet group, mice were randomized to receive 5-FU+leucovorin or saline and xenograft growth and characteristics were determined. The expression of genes involved in folate metabolism and cancer treatment was determined. FA supplementation and 5-FU significantly interacted to influence xenograft growth (P < 0.007). At the control level, 5-FU significantly inhibited the growth of the xenografts (P < 0.0001). However, at the 4× supplemental level, 5-FU-treated xenografts grew faster than untreated xenografts (P = 0.048) while at the 12.5× supplemental level, 5-FU exhibited no effect. Cell proliferation, degree of necrosis, and expression of the selected genes did not significantly differ by the supplemental levels of FA. Our data suggest that FA supplementation may be detrimental to 5-FU chemotherapy of colon cancer and pose public health concern.

Response to Marabotto et al.

Biopsies have important value in assessing for nonerosive reflux disease.

Acute Pancreatitis as a First Presentation of Granulomatosis With Polyangiitis.

Granulomatosis with polyangiitis (GPA) is a rare necrotizing antineutrophil cytoplasmic antibody-associated vasculitis characterized by inflammation in small-sized arteries. Gastrointestinal involvement is exceedingly rare in GPA. Here, we present a case of recurrent acute pancreatitis as the initial presentation of GPA. The diagnosis was made based on radiological and pathological findings of acute pancreatitis in conjunction with positive anti-PR3 antibody which is strongly associated with GPA. Systemic vasculitides are rare but important to consider in cases of idiopathic acute pancreatitis. Early diagnosis and therapy allow for high rates of remission and improved survival rates.

The role of histology in the diagnosis of non-erosive reflux disease: A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Non-erosive reflux disease (NERD) accounts for over half of all gastroesophageal reflux cases and is characterized by reflux symptoms with pathologic acid exposure on pH monitoring but no evidence of erosions on upper endoscopy. Ambulatory pH monitoring is limited by availability and patient tolerance. The utility of performing esophageal mucosal biopsies in diagnosing NERD is unclear. We conducted a systematic review and meta-analysis to determine the sensitivity of esophageal mucosal biopsies in diagnosing NERD. METHODS: Data were obtained from Embase and Ovid MEDLINE from inception to April 2021. Studies were included if esophageal mucosal biopsies were taken and analyzed using conventional histopathologic analysis in symptomatic NERD patients. Relevant data was including histologic abnormalities and location of the biopsy. Sensitivity and specificity were calculated against healthy controls or those with functional heartburn. RESULTS: The search yielded 2871 studies, of which 10 studies met our inclusion criteria and contained raw data. Histological abnormalities included histologic sum scores, papillary elongation, basal cell hyperplasia, and dilated intraepithelial spaces. When assessing for the presence of any abnormality, biopsies taken <3 cm from the lower esophageal sphincter (LES) had a pooled sensitivity of 0.71 (95% CI 0.64-0.77) and specificity of 0.64 (95% 0.54-0.73); however, analysis of individual histologic features such as the presence of eosinophils improved the sensitivity. CONCLUSIONS: Although esophageal mucosal biopsies had poor sensitivity at diagnosing NERD, biopsies taken within 3 cm of the LES had higher sensitivity when pathologists reported upon eosinophils and dilated intraepithelial spaces.

Feasibility and Performance of Elastin Trichrome as a Primary Stain in Colorectal Cancer Resection Specimens: Results of an Interobserver Variability Study.

Venous invasion (VI) is a powerful prognostic factor in colorectal cancer (CRC) that is widely underreported. The ability of elastin stains to improve VI detection is now recognized in several international CRC pathology protocols. However, concerns related to the cost and time required to perform and evaluate these stains in addition to routine hematoxylin and eosin (H&E) stains remains a barrier to their wider use. We therefore sought to determine whether an elastin trichrome (ET) stain could be used as a "stand-alone" stain in CRC resections, by comparing the sensitivity, accuracy, and reproducibility of detection of CAP-mandated prognostic factors using ET and H&E stains. Representative H&E- and ET-stained slides from 50 CRC resections, including a representative mix of stages and prognostic factors, were used to generate 2 study sets. Each case was represented by H&E slides in 1 study set and by corresponding ET slides from the same blocks in the other study set. Ten observers (3 academic gastrointestinal [GI] pathologists, 4 community pathologists, 3 fellows) evaluated each study set for CAP-mandated prognostic factors. ET outperformed H&E in the assessment of VI with respect to detection rates (50% vs. 28.6%; P<0.0001), accuracy (82% vs. 59%, P<0.0001), and reproducibility (k=0.554 vs. 0.394). No significant differences between ET and H&E were observed for other features evaluated. In a poststudy survey, most observers considered the ease and speed of assessment at least equivalent for ET and H&E for most prognostic factors, and felt that ET would be feasible as a stand-alone stain in practice. If validated by others, our findings support the use of ET, rather than H&E, as the primary stain for the evaluation of CRC resections.

Prognostic and Predictive Value of Tumor Budding in Colorectal Cancer.

BACKGROUND: Tumor budding (TB) is an adverse prognostic factor in colorectal cancer (CRC). International consensus on a standardized assessment method has led to its wider reporting. However, uncertainty regarding its clinical value persists. This study aimed to (1) confirm the prognostic significance of TB, particularly in stage II CRC; (2) to determine optimum thresholds for TB risk grouping; and (3) to determine whether TB influences responsiveness to chemotherapy. METHODS: TB was assessed in CRC sections from 1575 QUASAR trial patients randomized between adjuvant chemotherapy and observation. Optimal risk group cutoffs were determined by maximum likelihood methods, with their influence on recurrence and mortality investigated in stratified log-rank analyses on exploratory (n = 504), hypothesis-testing (n = 478), and final (n = 593) data sets. RESULTS: The optimal threshold for high-grade TB (HGTB) was ≥ 10 buds per 1.23 mm2. High-grade TB tumors had significantly worse outcomes than those with lower TB: 10-year recurrence 36% versus 22% (risk ratio, 2.00 [95% CI, 1.62-2.45]; 2P < .0001) and 10-year mortality 50% vs. 37% (risk ratio, 1.53 [95% CI, 1.34-1.76]; 2P < .0001). The prognostic significance remained equally strong after allowance for other pathological risk factors, including stage, grade, lymphovascular invasion, and mismatch repair status. There was a nonsignificant trend toward increasing chemotherapy efficacy with increasing bud counts. CONCLUSIONS: TB is a strong independent predictor of recurrence. Chemotherapy efficacy is comparable in patients with higher and lower TB; hence, absolute reductions in recurrence and death with chemotherapy should be about twice as large in patients with ≥ 10 than < 10 TB counts.

Canadian Consensus for Biomarker Testing and Treatment of TRK Fusion Cancer in Adults.

The tyrosine receptor kinase (TRK) inhibitors larotrectinib and entrectinib were recently approved in Canada for the treatment of solid tumours harbouring neurotrophic tyrosine receptor kinase (NTRK) gene fusions. These NTRK gene fusions are oncogenic drivers found in most tumour types at a low frequency (<5%), and at a higher frequency (>80%) in a small number of rare tumours (e.g., secretory carcinoma of the salivary gland and of the breast). They are generally mutually exclusive of other common oncogenic drivers. Larotrectinib and entrectinib have demonstrated impressive overall response rates and tolerability in Phase I/II trials in patients with TRK fusion cancer with no other effective treatment options. Given the low frequency of TRK fusion cancer and the heterogeneous molecular testing landscape in Canada, identifying and optimally managing such patients represents a new challenge. We provide a Canadian consensus on when and how to test for NTRK gene fusions and when to consider treatment with a TRK inhibitor. We focus on five tumour types: thyroid carcinoma, colorectal carcinoma, non-small cell lung carcinoma, soft tissue sarcoma, and salivary gland carcinoma. Based on the probability of the tumour harbouring an NTRK gene fusion, we also suggest a tumour-agnostic consensus for NTRK gene fusion testing and treatment. We recommend considering a TRK inhibitor in all patients with TRK fusion cancer with no other effective treatment options.

Ixekizumab Associated New-Onset Inflammatory Bowel Disease.

Ixekizumab is a monoclonal antibody targeting interleukin-17 approved for the treatment of psoriasis. In a recent post hoc meta-analysis of Phase-I to Phase-III clinical trials of anti-interleukin-17 agents for the treatment of plaque psoriasis, there was a rare association (<1%) with induction or exacerbation of inflammatory bowel disease. We report a case of new-onset ileal Crohn's disease in a 48-year-old woman on ixekizumab for psoriasis.

Malformations of the fetal dural sinuses.

BACKGROUND: Dural sinus malformation (DSM) is a term used to describe congenital vascular malformations characterized by massive dilation of one or more dural sinuses: these dilatations are typically associated with arteriovenous shunts. Such malformations can present antenatally but their early natural history and anatomy is poorly defined. METHODS: We reviewed five years of autopsy experience and retrieved three primary vascular malformations of the fetal dural sinuses with ultrasound, magnetic resonance imaging (MRI) and post-mortem correlation. RESULTS: Fetal ultrasound and MRI obtained between 19 and 23 weeks gestational age demonstrated in all cases dilation of the dural sinuses. In two cases vascular thromboses were present in either the dilated dural sinus (one of three) or the associated arteriovenous fistula (one of three). All cases were autopsied at 22-23 weeks gestational age. In one there was imaging and autopsy evidence of remodeling of the dural sinuses associated with a pial arteriovenous fistula. In two cases, no arteriovenous malformation was identified on initial imaging, but only became evident at autopsy. One case showed morphological overlap with vein of Galen aneurysmal malformation, with a midline arteriovenous shunt and vein of Galen ectasia. The other demonstrated a perisylvian dural arteriovenous fistula. CONCLUSION: In utero thrombosis of feeding vascular malformations or of the dural sinus malformation may be prominent. The early in utero developmental trajectory of dural sinus malformation (DSM) is poorly defined and deserves further study.

Mantle cell lymphoma as a rare cause of intussusception: a report of 2 cases.

Intussusception is uncommon in adults and is only very rarely caused by malignant lymphoma. To our knowledge, there are only 2 previously reported cases of mantle cell lymphoma causing intussusception. We present 2 additional cases of intussusception at the ileocecal valve in patients being treated for mantle cell lymphoma, and a review of the pertinent literature is presented.

"Pagetoid" eccrine carcinoma of the vulva: report of an unusual case with review of the literature.

Sweat gland carcinoma of the vulva is rare and may be classified as being of eccrine, apocrine, or mixed origin. Most reported cases of vulvar sweat gland carcinomas associated with extramammary Paget disease describe a tumor of apocrine origin. We report a case of a vulvar sweat gland carcinoma of eccrine origin associated with Pagetoid extension. A review of the literature and the differential diagnosis are also presented. To our knowledge, this is the second case of vulvar sweat gland carcinoma of eccrine origin associated with extramammary Paget disease.

Cytokeratin-based assessment of tumour budding in colorectal cancer: analysis in stage II patients and prospective diagnostic experience.

Tumour budding in colorectal cancer is an important prognostic factor. A recent consensus conference elaborated recommendations and key issues for future studies, among those the use of pan-cytokeratin stains, especially in stage II patients. We report the first prospective diagnostic experience using pan-cytokeratin for tumour budding assessment. Moreover, we evaluate tumour budding using pan-cytokeratin stains and disease-free survival (DFS) in stage II patients. To this end, tumour budding on pan-cytokeratin-stained sections was evaluated by counting the number of tumour buds in 10 high-power fields (0.238 mm2), then categorizing counts as low/high-grade at a cut-off of 10 buds, in two cohorts. Cohort 1: prospective setting with 236 unselected primary resected colorectal cancers analysed by 17 pathologists during diagnostic routine. Cohort 2: retrospective cohort of 150 stage II patients with information on DFS. In prospective analysis of cohort 1, tumour budding counts correlated with advanced pT, lymph node metastasis, lymphovascular invasion, perineural invasion (all p < 0.0001), and distant metastasis (p = 0.0128). In cohort 2, tumour budding was an independent predictor of worse DFS using counts [p = 0.037, HR (95% CI): 1.007 (1.0-1.014)] and the low-grade/high-grade scoring approach [p = 0.02; HR (95% CI): 3.04 (1.2-7.77), 90.7 versus 73%, respectively]. In conclusion, tumour budding assessed on pan-cytokeratin slides is feasible in a large pathology institute and leads to expected associations with clinicopathological features. Additionally, it is an independent predictor of poor prognosis in stage II patients and should be considered for risk stratification in future clinical studies.

Gastric foveolar dysplasia: a survey of reporting habits and diagnostic criteria.

This study aimed to ascertain views, incidence of reporting and diagnostic criteria for gastric foveolar dysplasia. A questionnaire, a post-questionnaire discussion and microscopic assessment of selected cases was conducted by gastrointestinal pathologists to explore the above-stated aims. Fifty-four percent of respondents never or rarely diagnosed gastric foveolar-type dysplasia. The general consensus was that round nuclei, lack of nuclear stratification, presence of inflammation/damage and surface maturation favoured reactive change; while architectural abnormalities/complexity and nuclear enlargement mainly were used to separate low-grade from high-grade foveolar dysplasia. Immunohistochemistry was rarely used to make the diagnosis of dysplasia and was thought not to be of help in routine practice. Inter-observer agreement in grading of dysplasia versus reactive, and the type of dysplasia (foveolar versus adenomatous), was substantial/almost perfect amongst 35.7% and 21.4% of participants, respectively. This reflects low reproducibility in making these diagnoses. In conclusion, foveolar dysplasia was a rarely made diagnosis among 14 gastrointestinal pathologists, there are no uniform criteria for diagnosis and there is poor inter-observer agreement in separating low-grade foveolar dysplasia from reactive gastric mucosa and low-grade adenomatous dysplasia. Greater awareness and agreed criteria will prevent misdiagnosis of low-grade foveolar dysplasia as reactive, and vice versa.

Esophageal Intramural Pseudodiverticulosis and Concomitant Eosinophilic Esophagitis: A Case Series.

Background. Esophageal intramural pseudodiverticulosis (EIPD) is an idiopathic benign chronic disease characterized by flask-like outpouchings of the esophageal wall. It is unknown whether there is a genuine association between EIPD and eosinophilic esophagitis (EoE). Aims. To investigate a possible relationship between EIPD and EoE. Methods. Patients with radiographic or endoscopic evidence of pseudodiverticulosis were identified from the database at a single academic center. Cases were analyzed in three areas: clinical information, endoscopic findings, and course. Results. Sixteen cases of esophageal pseudodiverticulosis were identified. Five patients had histologic evidence of eosinophilic esophagitis. Patients with EoE had pseudodiverticula in the mid-to-distal esophagus while those with EIPD had pseudodiverticula predominantly in the proximal esophagus (p < 0.001). EoE with pseudodiverticulosis occurred in younger patients (p < 0.019). Food bolus obstructions were more common in patients with EoE and pseudodiverticulosis than in EIPD (p < 0.034). Conclusions. This is the first case series supporting a potential association between EoE and pseudodiverticulosis. We also identify characteristic features of pseudodiverticulosis that may raise clinical suspicion of underlying eosinophilic esophagitis.