Clinical and endoscopist factors associated with post-colonoscopy colorectal cancer in a population-based sample.

AIM: Factors associated with verified post-colonoscopy colorectal cancers (PCCRC) have not been well defined and survival for these patients is not well described. We aimed to assess the association of patient, tumour and endoscopist characteristics with PCCRC. METHODS: Using population-based data, we identified individuals diagnosed with CRC from 1 January 2000 to 31 December 2005 who underwent a colonoscopy within 3 years prior to diagnosis. Detected cancers were those diagnosed ≤6 months following colonoscopy; PCCRC were diagnosed >6 months to ≤3 years following colonoscopy. Post-colonoscopy and detected cancers were verified through chart review using a hospital-based simple random sampling frame. We used multivariable conditional logistic regression to determine the association of patient, tumour and endoscopist factors with PCCRC and compared overall survival using Cox proportional hazard models. RESULTS: Using the random sampling frame, we identified 498 patients with PCCRC and 498 with detected CRC; we obtained records and confirmed 367 patients with PCCRC and 412 with detected cancers. In multivariable analysis, patient age (OR 1.01; 95% CI 1.00-1.03) and tumour location (distal vs. proximal OR 0.36; 95% CI 0.25-0.53) were associated with PCCRC; endoscopist quality measures were not significantly associated with PCCRC. We did not find significant differences in overall survival between PCCRC and detected cancers (hazard ratio 1.12; 95% CI 0.92-1.32). CONCLUSION: Although endoscopic quality measures are important for CRC prevention, endoscopist factors were not associated with PCCRC. This study highlights the need for further research into the role of tumour biology in PCCRC development.

Synchronous anal canal carcinoma in a heterosexual couple.

BACKGROUND: Sexually transmitted Human Papilloma Virus (HPV) infection is a known risk factor for cancer of the anal canal in both men and women. CASE PRESENTATION: We describe a report of synchronous carcinoma of the anal canal in a heterosexual couple. High risk type 16 HPV DNA was detected in both tumors. CONCLUSION: Longstanding sexual partners may share risk of HPV-associated anal canal cancer.

Late gadolinium enhancement of colorectal liver metastases post-chemotherapy is associated with tumour fibrosis and overall survival post-hepatectomy.

PURPOSE: To determine whether late gadolinium MRI enhancement of colorectal liver metastases (CRCLM) post-chemotherapy is associated with tumour fibrosis and survival post-hepatectomy. MATERIALS AND METHODS: The institutional review board approved this retrospective cohort study and waived the requirement for informed consent. A cohort of 121 surgical patients who received preoperative MRI after chemotherapy between 2006-2012 was included in this study. Target tumour enhancement (TTE), defined as the mean contrast-to-noise ratio of up to two target lesions on late-phase gadobutrol-enhanced MRI, was determined by two independent raters. The average TTE was correlated with tumour fibrosis on post-hepatectomy specimens using Spearman correlation and with survival post-hepatectomy using Kaplan-Meier and Cox regression. Inter-rater reliability was determined using relative intra-class correlation coefficients. RESULTS: In the surgical cohort (mean age: 63.0 years; male: 58%), TTE was associated with tumour fibrosis (r = 0.43, p < 0.001). Strong TTE was associated with improved survival compared to weak TTE (3-year survival: 88.4% vs. 58.8%, p = 0.003) with a hazard ratio of 0.32 (95% CI: 0.14-0.75, p = 0.008), after taking into account known prognostic variables. Inter-rater reliability was very good with a relative intraclass correlation of 0.84 (95% CI: 0.77-0.89). CONCLUSION: Late gadolinium MRI enhancement of CRCLM post-chemotherapy is associated with tumour fibrosis and survival. KEY POINTS: • MRI enhancement of colorectal liver metastases is associated with survival post-hepatectomy • MRI enhancement of chemotherapy-treated colorectal liver metastases correlates with tumour fibrosis • Measuring late MRI enhancement using target tumour enhancement is reliable.

Sessile serrated polyps at screening colonoscopy: have they been under diagnosed?

OBJECTIVES: The sessile serrated adenoma/polyp (SSA/P) is increasingly recognized as an important precursor to colorectal cancer (CRC) and may contribute to proximal postcolonoscopy CRCs. Hyperplastic polyps (HPs) generally follow a more benign course than do SSA/Ps, but they have a similar histologic appearance. Our aims were to identify patient and polyp factors associated with reclassification of HPs as SSA/Ps during a central pathology review and to characterize and compare their subsequent clinical management with other polyps. METHODS: From 2003 to 2008, we prospectively enrolled asymptomatic persons aged 50-74 years in a study of screening colonoscopy. Because criteria for SSA/P diagnosis evolved over our study period, we initiated a second review of all HPs >5 mm in size in 2011, with reclassification of polyps if indicated. Rates of subsequent colonoscopies, polypectomies, and CRCs were identified. RESULTS: We enrolled 2,527 persons who underwent colonoscopy in whom 111 had HPs >5 mm. Thirty-two of the 111 participants (28.8%) with HPs >5 mm had their polyps reclassified as SSA/Ps. There were no significant differences in patient characteristics between those with reclassified SSA/Ps and those who had HPs >5 mm. SSA/Ps were more likely to be proximal (P<0.001) and larger (P<0.007) than the HPs. In all, 48.3% of those with high-risk adenomas received appropriate follow-up compared with 26.1% of those with high-risk SSA/Ps. CONCLUSIONS: Almost 1/3 of recently diagnosed HPs >5 mm were reclassified as SSA/Ps. Patients previously diagnosed with larger HPs in the proximal colon may benefit from a pathologic review to ensure appropriate diagnosis and follow-up.

Advanced proximal neoplasia of the colon in average-risk adults.

BACKGROUND: Estimating risk for advanced proximal neoplasia (APN) based on distal colon findings can help identify asymptomatic persons who should undergo examination of the proximal colon after flexible sigmoidoscopy (FS) screening. OBJECTIVE: We aimed to determine the risk of APN by most advanced distal finding among an average-risk screening population. DESIGN: Prospective, cross-sectional study. SETTING: Teaching hospital and colorectal cancer screening center. PATIENTS: A total of 4651 asymptomatic persons at average risk for colorectal cancer aged 50 to 74 years (54.4% women [n = 2529] with a mean [± standard deviation] age of 58.4 ± 6.2 years). INTERVENTIONS: All participants underwent a complete colonoscopy, including endoscopic removal of all polyps. MAIN OUTCOME MEASUREMENTS: We explored associations between several risk factors and APN. Logistic regression was used to identify independent predictors of APN. RESULTS: A total of 142 persons (3.1%) had APN, of whom 85 (1.8%) had isolated APN (with no distal findings). APN was associated with older age, a BMI >27 kg/m(2), smoking, distal advanced adenoma and/or cancer, and distal non-advanced tubular adenoma. Those with a distal advanced neoplasm were more than twice as likely to have APN compared with those without distal lesions. LIMITATIONS: Distal findings used to estimate risk of APN were derived from colonoscopy rather than FS itself. CONCLUSION: In persons at average risk for colorectal cancer, the prevalence of isolated APN was low (1.8%). Use of distal findings to predict APN may not be the most effective strategy. However, incorporating factors such as age (>65 years), sex, BMI (>27 kg/m(2)), and smoking status, in addition to distal findings, should be considered for tailoring colonoscopy recommendations. Further evaluation of risk stratification approaches in other asymptomatic screening populations is warranted.

Hot Seat Diagnosis.

CONTEXT.­: Competency-based medical education relies on frequent formative in-service assessments to ascertain trainee progression. Currently at our institution, trainees receive a summative end-of-rotation In-Training Evaluation Report based on feedback collected from staff pathologists. There is no method of simulating report sign-out. OBJECTIVE.­: To develop a formative in-service assessment tool that is able to simulate report sign-out and provide case-by-case feedback to trainees. Further, to compare time- versus competency-based assessment models. DESIGN.­: Twenty-one pathology trainees were assessed for 20 months. Hot Seat Diagnosis by trainees and trainee assessment by pathologists were recorded in the laboratory information system. In the first iteration, trainees were assessed by using a time-based assessment scale on their ability to diagnose, report, use ancillary tests, comment on clinical implications, and provide intraoperative consultation and/or gross cases. The second iteration used a competency-based assessment scale. Trainees and pathologists completed surveys on the effectiveness of the In-Training Evaluation Report versus the Hot Seat Diagnosis tool. RESULTS.­: Scores from both iterations correlated significantly with other assessment tools including the Resident In-Service Examination (r = 0.93, P = .04 and r = 0.87, P = .03). The competency-based model was better able to demonstrate improvement over time and stratify junior versus senior trainees than the time-based model. Trainees and pathologists rated Hot Seat Diagnosis as significantly more objective, detailed, and timely than the In-Training Evaluation Report, and effective at simulating report sign-out. CONCLUSIONS.­: Hot Seat Diagnosis is an effective tool for the formative in-service assessment of pathology trainees and simulation of report sign-out, with the competency-based model outperforming the time-based model.

How well is Helicobacter pylori treated in usual practice?

BACKGROUND: Helicobacter pylori is a WHO class I carcinogen also associated with nonmalignant gastrointestinal diseases. Effective treatment exists, and all persons infected with H pylori should receive treatment. However, data regarding the rates of treatment prescription in clinical practice are lacking. OBJECTIVE: To determine the rates of H pylori treatment in usual practice. METHODS: Patients with histological evidence of H pylori infection between January 1, 2007, and December 31, 2007, at Sunnybrook Health Sciences Centre (Toronto, Ontario) were identified. Charts were reviewed to determine the rates of H pylori treatment and confirmation of eradication, when indicated. Questionnaires were subsequently sent to endoscopists of patients identified as not having received treatment to determine the reasons for lack of treatment. RESULTS: A total of 102 patients were H pylori positive and were appropriate candidates for treatment, of whom 58 (57%) were male and 78 (76%) were outpatients, with 92 (90%) receiving eradication therapy. When indicated, 15 of 22 (68%) patients received confirmation of eradication, 13 of 18 (72%) patients underwent repeat endoscopy and 86% received complete therapy. Outpatients were more likely to receive eradication therapy (OR 10.3 [95% CI 2.6 to 40.4]; P=0.001) and complete therapy (OR 13.2 [95% CI 3.8 to 45.7]; P=0.0001) compared with inpatients. Having a follow-up appointment resulted in higher treatment rates (OR 12.0 [95% CI 3.0 to 47.5]; P=0.001). CONCLUSION: During the time period studied, adequate rates of H pylori treatment were achieved in outpatients and patients who had formal follow-up at Sunnybrook Health Sciences Centre. However, some aspects of care remain suboptimal including treatment of inpatients and care following treatment. Additional studies are required to identify strategies to improve the care of patients infected with H pylori.

Delayed MRI Enhancement of Colorectal Cancer Liver Metastases Is Associated With Metastatic Mutational Profile.

BACKGROUND/AIM: Individual tumor genomics plays a key role in determining patient prognosis, response to chemotherapy and in guiding therapy. In prior studies, it was shown that the degree of late enhancement of colorectal liver metastases (CRCLM) target tumor enhancement (TTE) as seen on magnetic resonance imaging (MRI) was associated with overall survival. In order to better understand the relationship between MRI enhancement and survival, the aim of this study was to characterize genomic profiles of tumors clustered by MRI TTE, and investigate the association between TTE and genetic mutations. MATERIALS AND METHODS: Matched tumor and normal tissue samples from patients with weak TTE and strong TTE were analyzed by Next-generation sequencing (NGS) technology using a custom colorectal cancer panel. RESULTS: We discovered a total of 42 non-synonymous somatic mutations from 10 patients with weak TTE and 26 with 10 patients with strong TTE. Adenomatosis Polyposis Coli (APC) was the most commonly altered gene, 18 of those APC mutations were found in the weak TTE and 9 in the strong TTE group. CONCLUSION: An association exists between TTE and mutational status of CRCLM, which may offer some explanation as to why TTE is associated with overall survival in patients with CRCLM.

Screening and Treatment Outcomes in Adults and Children With Type 1 Diabetes and Asymptomatic Celiac Disease: The CD-DIET Study.

OBJECTIVE: To describe celiac disease (CD) screening rates and glycemic outcomes of a gluten-free diet (GFD) in patients with type 1 diabetes who are asymptomatic for CD. RESEARCH DESIGN AND METHODS: Asymptomatic patients (8-45 years) were screened for CD. Biopsy-confirmed CD participants were randomized to GFD or gluten-containing diet (GCD) to assess changes in HbA1c and continuous glucose monitoring over 12 months. RESULTS: Adults had higher CD-seropositivity rates than children (6.8% [95% CI 4.9-8.2%, N = 1,298] vs. 4.7% [95% CI 3.4-5.9%, N = 1,089], P = 0.035) with lower rates of prior CD screening (6.9% vs. 44.2%, P < 0.0001). Fifty-one participants were randomized to a GFD (N = 27) or GCD (N = 24). No HbA1c differences were seen between the groups (+0.14%, 1.5 mmol/mol; 95% CI -0.79 to 1.08; P = 0.76), although greater postprandial glucose increases (4-h +1.5 mmol/L; 95% CI 0.4-2.7; P = 0.014) emerged with a GFD. CONCLUSIONS: CD is frequently observed in asymptomatic patients with type 1 diabetes, and clinical vigilance is warranted with initiation of a GFD.

Population-Level Symptom Assessment Following Pancreaticoduodenectomy for Adenocarcinoma.

Importance: Postoperative morbidity associated with pancreaticoduodenectomy (PD) for pancreatic adenocarcinoma (PA) remains as high as 70%. However, to our knowledge, few studies have examined quality of life in this patient population. Objective: To identify symptom burden and trajectories and factors associated with high symptom burden following PD for PA. Design, Setting, and Participants: This population-based cohort study of patients undergoing PD for PA diagnosed between 2009 and 2015 linked population-level administrative health care data to routinely prospectively collected Edmonton Symptom Assessment System (ESAS) scores from 2009 to 2015, with a data analysis undertaken in 2018. Exposures: Baseline characteristics, including age, sex, income quintile, rurality, immigration status, and comorbidity burden, as well as treatment characteristics, including year of surgery and receipt of chemotherapy. Main Outcome and Measures: The outcome of interest was moderate to severe symptoms (defined as ESAS ≥4) for anxiety, depression, drowsiness, lack of appetite, nausea, pain, shortness of breath, tiredness, and impaired well-being. The monthly prevalence of moderate to severe symptoms was presented graphically for each symptom. Multivariable regression models identified factors associated with the reporting of moderate to severe symptoms. Results: We analyzed 6058 individual symptom assessments among 615 patients with PA who underwent resection (285 women [46.3%]) with ESAS data. Tiredness (443 [72%]), impaired well-being (418 [68%]), and lack of appetite (400 [65%]) were most commonly reported as moderate to severe. The proportion of patients with moderate to severe symptoms was highest immediately after surgery (range, 14%-66% per symptom) and decreased over time, stabilizing around 3 months (range, 8%-42% per symptom). Female sex, higher comorbidity, and lower income were associated with a higher risk of reporting moderate to severe symptoms. Receipt of adjuvant chemotherapy was not associated with the risk of moderate to severe symptoms. Conclusions and Relevance: There is a high prevalence of symptoms following PD for PA, with improvement over the first 3 months following surgery. In what to our knowledge is the largest cohort reporting on symptom burden for this population, we have identified factors associated with symptom severity. These findings will aid in managing patients' perioperative expectations and designing strategies to improve targeted symptom management.

CK19 and CD99 immunoexpression profile in goblet cell (mucin-producing neuroendocrine tumors) and classical carcinoids of the vermiform appendix.

The immunoexpression of CK19 recently has been identified as a marker of poor prognosis in pancreatic endocrine tumors and hepatocellular carcinoma. Conversely, the loss of expression of CD99 has been suggested to play a role in the tumorigenesis and dedifferentiation and is associated with poor outcome in some malignancies. The purpose of this study was to explore CK19 and CD99 immunostaining in mucin-producing neuroendocrine (goblet cell) and classical carcinoids of the appendix. Eighteen goblet cell carcinoids (GCCs) and 20 classic carcinoids were stained with CK19, CD99, and Ki-67, and these results were correlated with known pathological features of aggression: extent of invasion, mitoses, necrosis, and histological pattern. All 18 GCCs were CK19 strongly positive, whereas 16/20 classic carcinoids were also CK19 positive. Fourteen of 18 GCCs and 14/20 classic carcinoids were CD99 positive. CK19/CD99 immunoexpression did not correlate with extent of tumor invasion and mesoappendiceal extension, mitotic activity, Ki-67 labeling index, presence of extracellular mucinous pools dissecting muscle, and angiolymphatic and perineural/neural invasion. There is no difference in the immunostaining for CK19 and CD99 between GCCs and classic carcinoids, and both types of neuroendocrine tumor show the same extent of expression of both markers.

The importance of functional testing in the genetic assessment of Muir-Torre syndrome, a clinical subphenotype of HNPCC.

A majority of families with hereditary nonpolyposis colorectal cancer (HNPCC) are attributable to germline mutations in three DNA mismatch repair (MMR) genes, MLH1, MSH2 and MSH6. However, the clinical phenotype appears to reflect a complex interplay between the predisposing mutation and putative constitutional and somatic modifiers. Certain MMR gene mutations predispose to combined occurrence of cutaneous sebaceous gland neoplasms and visceral malignancies, which is known as Muir-Torre syndrome (MTS) and regarded as a phenotypic variant of HNPCC. The sebaceous tumors associated with MTS appear in many patients before visceral malignancies providing important predictability of HNPCC-related integral cancers in mutation carriers. Since most sebaceous skin tumors are, however, sporadic, the contribution of non-truncating mutations found in skin cancer patients is difficult to interpret and genetic assessment of MTS requires a functional test. Here, we studied the repair efficiency of the two MSH2 missense mutations, L187P and C697F, found in HNPCC families including a few mutation carriers with sebaceous skin tumors. Both mutations were completely deficient in an MMR assay, which together with tumor findings suggested their predisposing role in both internal and skin malignancies in the families.

Basaloid squamous carcinoma of the anal canal with an adenoid cystic pattern: histologic and immunohistochemical reappraisal of an unusual variant.

Two cases of a distinctive variety of basaloid squamous carcinoma (BSC) of the anal canal are described. Both occurred in female patients who presented with bleeding per rectum. Histologic evaluation of the tumors showed lobules and aggregates of medium-sized basaloid cells with distinctive peripheral palisading and focal areas of central, comedo-necrosis. Accompanying dysplasia of the overlying squamous mucosa was absent. However, the microscopic pattern was dominated by the presence of eosinophilic, hyaline, paucicellular basement membrane-like material around and within tumor nests. This appearance together with microcystic spaces simulated that of an adenoid cystic carcinoma. Immunohistochemistry of the tumors revealed the following profile: CK7, CK5/CK6, 34betaE12 positive, CK14 focally positive but CK20 negative. The following were all negative: EMA, CEA, smooth muscle and muscle-specific actin, calponin, and S-100. The tumor cells exhibited diffuse nuclear positivity with p63. The eosinophilic basement membrane hyaline material was positive for collagen type IV and also for laminin. BSC of the anal canal with an adenoid cystic pattern is an infrequently encountered and reported variant, although it is seen more often in the aerodigestive tract. There may be an increased propensity for BSC with an adenoid cystic pattern to metastasize to the liver, but the number of cases encountered are too small to be definitive. The histologic differential diagnosis is true salivary gland-type adenoid cystic carcinoma and basal cell adenocarcinoma. Immunohistochemistry and awareness of this unusual pattern of BSC will facilitate the correct diagnosis being reached.

Cutaneous T-cell lymphoma with bilateral full-thickness eyelid ulceration.

A case report of a 72-year-old man with widely disseminated cutaneous T-cell lymphoma (CTCL) who developed bilateral full-thickness eyelid ulceration. This is a rare ocular manifestation of CTCL.

Multiplex Ligation-dependent Probe Amplification Can Clarify HER2 Status in Gastric Cancers with "Polysomy 17".

Therapy with trastuzumab confers a survival benefit in HER2 positive advanced gastric and gastroesophageal adenocarcinoma. HER2 status is evaluated by immunohistochemistry (IHC) and in situ hybridization (ISH). An ISH ratio of HER2 to centromere 17 (CEP17) ≥2.0 is considered amplified. This assumes that CEP17 reflects chromosomal copy number. Cases where CEP17 exceeds 3 are classified as polysomic, but it's unknown if they represent true polysomy or centromeric amplification. This has implications on the validity of current ISH criteria. Multiplex ligation-dependent probe amplification (MLPA) allows simultaneous quantification of multiple loci and can distinguish between true polysomy and centromeric amplification. We selected 13 gastric cancers with CEP17 counts ≥3.0 (polyCEP17), and 8 non-polyCEP17 gastric cancer controls. Silver ISH for HER2 and CEP17 were performed and scored by manufacturer guidelines. We also performed an MLPA HER2 assay that evaluates 22 genes on chromosome 17. MLPA identified HER2 amplification in 7 polyCEP17 cases compared to 2 identified by ISH. Overall, 9 of 13 polyCEP17 cases had amplification of the peri-centromeric gene WSB1, compared to 1 of 8 non-polyCEP17 controls (p=0.02). This could account for ISH CEP17 counts ≥3.0. MLPA did not show any cases of complete chromosome 17 duplication and peri-centromeric amplification can explain most cases of ISH polyCEP17. Current ISH criteria may under-diagnose HER2 amplification in polyCEP17 cases due to flawed assumptions about polysomy. MLPA can detect HER2 amplification missed by IHC and ISH, and thus may be an effective ancillary technique in evaluating HER2 status.

Barriers to optimal assessment of lymph nodes in colorectal cancer specimens.

Lymph node (LN) retrieval and assessment is critically important for accurate staging and treatment planning in colorectal cancer (CRC). Practicing pathologists in Ontario were identified and surveyed by phone to identify barriers to optimal retrieval and assessment. Of the pathologists surveyed, 57.9% were aware of guidelines for LN retrieval in CRC, but only 25.0% identified that a minimum of 12 LNs are necessary for accurate designation of node negativity. An important role exists for an education strategy aimed at bridging the knowledge gap among practicing pathologists and surgeons regarding optimal LN assessment in CRC specimens.

Matched biopsy and resection specimens of gastric and gastroesophageal adenocarcinoma show high concordance in HER2 status.

In advanced gastric and gastroesophageal junction (GEJ) adenocarcinomas that overexpress human epidermal growth factor receptor 2 (HER2), treatment with trastuzumab confers a survival benefit. To select patients for treatment, HER2 status is evaluated by immunohistochemistry (IHC) and in situ hybridization. Gastric and GEJ adenocarcinomas demonstrate heterogeneity in HER2 expression. Nonetheless, testing is often performed on biopsies alone, which raises the issue of nonrepresentative sampling. We investigated the correlation of HER2 status between matched biopsy and resection specimens and the role of tumor heterogeneity in contributing to discrepancy. A total of 128 patients with gastric or GEJ adenocarcinoma had tissue available from a biopsy and subsequent resection. HER2 IHC was performed and evaluated by the criteria used in the Trastuzumab for Gastric Cancer clinical trial. In situ hybridization was performed if IHC was equivocal (2+) in either the biopsy or resection and in discrepant cases. Tumor heterogeneity was defined as 3+ or 2+ staining in 10% to 60% of tumor cells. Overall, HER2 was overexpressed in 18 tumors (14%), with a biopsy-resection concordance of 96.1%. Five cases were discrepant; 2 were positive on biopsy only, and 3 were positive on resection only. Tumor heterogeneity was seen in 80% of discrepant biopsies and resections, compared with 24% of concordant cases (P = .016). Our study demonstrates strong concordance between biopsy and resection specimens for HER2 overexpression in gastric cancer. Discordance was correlated with tumor heterogeneity. Overall, both biopsy and resection specimens are appropriate for HER2 testing, but generous sampling for biopsy specimens is necessary to ensure accurate assessment.