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Programmed death ligand-1 (PD-L1) immunostaining, which aids clinicians in decision-making on immunotherapy for non-small cell lung cancer (NSCLC) patients, is sometimes performed on cytological specimens. In this study, differences in cytology fixation and cell block (CB) processing between pathology laboratories were assessed, and the influence of these differences on interlaboratory variation in PD-L1 positivity was investigated. Questionnaires on cytology processing were sent to all Dutch laboratories. Information gathered from the responses was added to data on all Dutch NSCLC patients with a mention of PD-L1 testing in their cytopathology report from July 2017 to December 2018, retrieved from PALGA (the nationwide network and registry of histo- and cytopathology in the Netherlands). Case mix-adjusted PD-L1 positivity rates were determined for laboratories with known fixation and CB method. The influence of differences in cytology processing on interlaboratory variation in PD-L1 positivity was assessed by comparing positivity rates adjusted for differences in the variables fixative and CB method with positivity rates not adjusted for differences in these variables. Twenty-eight laboratories responded to the survey and reported 19 different combinations of fixation and CB method. Interlaboratory variation in PD-L1 positivity was assessed in 19 laboratories. Correcting for differences in the fixative and CB method resulted in a reduction (from eight (42.1%) to five (26.3%)) in the number of laboratories that differed significantly from the mean in PD-L1 positivity. Substantial variation in cytology fixation and CB processing methods was observed between Dutch pathology laboratories, which partially explains the existing considerable interlaboratory variation in PD-L1 positivity.

Background: Post-colonoscopy colorectal cancers (PCCRCs) pose challenges in clinical practice. PCCRCs occur due to a combination of procedural and biological causes. In a nested case–control study, we compared clinical and molecular features of PCCRCs and detected CRCs (DCRCs). Methods: Whole-genome chromosomal copy number changes and mutation status of genes commonly affected in CRC were examined by low-coverage WGS and targeted sequencing, respectively. MSI and CIMP status was also determined. Results: In total, 122 PCCRCs and 98 DCRCs with high-quality DNA were examined. PCCRCs were more often located proximally (P < 0.001), non-polypoid appearing (P = 0.004), early stage (P = 0.009) and poorly differentiated (P = 0.006). PCCRCs showed significantly less 18q loss (FDR < 0.2), compared to DCRCs. No significant differences in mutations were observed. PCCRCs were more commonly CIMP high (P = 0.014) and MSI (P = 0.029). After correction for tumour location, only less 18q loss remained significant (P = 0.005). Conclusion: Molecular features associated with the sessile serrated lesions (SSLs) and non-polypoid colorectal neoplasms (CRNs) are more commonly seen in PCCRCs than in DCRCs. These together with the clinical features observed support the hypothesis that SSLs and non-polypoid CRNs are contributors to the development of PCCRCs. The future focus should be directed at improving the detection and endoscopic removal of these non-polypoid CRN and SSLs. Clinical trial registration: NTR3093 in the Dutch trial register (www.trialregister.nl).

Objectives: Immunohistochemical expression of programmed death-ligand 1 (PD-L1) is used as a predictive biomarker for prescription of immunotherapy to non-small cell lung cancer (NSCLC) patients. Accurate assessment of PD-L1 expression is therefore crucial. In this study, the extent of interlaboratory variation in PD-L1 positivity in the Netherlands was assessed, using real-world clinical pathology data. Materials and Methods: Data on all NSCLC patients in the Netherlands with a mention of PD-L1 testing in their pathology report from July 2017 to December 2018 were extracted from PALGA, the nationwide network and registry of histo- and cytopathology in the Netherlands. PD-L1 positivity rates were determined for each laboratory that performed PD-L1 testing, with separate analyses for histological and cytological material. Two cutoffs (1% and 50%) were used to determine PD-L1 positivity. Differences between laboratories were assessed using funnel plots with 95% confidence limits around the overall mean. Results: 6,354 patients from 30 laboratories were included in the analysis of histology data. At the 1% cutoff, maximum interlaboratory variation was 39.1% (32.7%-71.8%) and ten laboratories (33.3%) differed significantly from the mean. Using the 50% cutoff, four laboratories (13.3%) differed significantly from the mean and maximum variation was 23.1% (17.2%-40.3%). In the analysis of cytology data, 1,868 patients from 23 laboratories were included. Eight laboratories (34.8%) differed significantly from the mean in the analyses of both cutoffs. Maximum variation was 41.2% (32.2%-73.4%) and 29.2% (14.7%-43.9%) using the 1% and 50% cutoffs, respectively. Conclusion: Considerable interlaboratory variation in PD-L1 positivity was observed. Variation was largest using the 1% cutoff. At the 50% cutoff, analysis of cytology data demonstrated a higher degree of variation than the analysis of histology data.

Umbilical metastases form a clinical challenge, especially when they represent the first sign of malignant disease and the primary tumor is unknown. Our study aims to generate insight into the origin and timing of umbilical metastasis, as well as patient survival, using population‐based data. A nationwide review of pathology records of patients diagnosed with an umbilical metastasis between 1979 and 2015 was performed. Data was collected from the Nationwide Network and Registry of Histopathology and Cytopathology (PALGA) and the Netherlands Cancer Registry. Kaplan‐Meier analyses and log‐rank testing were used to estimate overall survival and a Cox proportional hazard model was used to determine multivariable hazard ratios. A total of 806 patients with an umbilical metastasis were included. There were 210 male (26.1%) and 596 female (73.9%) patients. Distribution of umbilical metastases was different between male and female patients due to the high incidence of umbilical metastases originating from the ovaries in females. They most frequently originated from the ovaries in female patients (38.8%) and from the colon in male patients (43.8%). In 18% of cases no primary tumor could be identified. Prognosis after diagnosis of an umbilical metastasis was dismal with a median survival of 7.9 months (95% confidence interval 6.7‐9.1). The origin of the primary tumor was an independent prognostic factor for overall survival. In conclusion, umbilical metastases relatively rare, mainly originating from intraabdominal primary tumors. Survival is dependent on the origin of the primary tumor and poor overall survival rates warrant early recognition., What's new? Umbilical metastases are a rare consequence of malignant disease that pose unique clinical challenges. Very little is known about these metastases, especially regarding incidence and survival. This population‐based analysis of more than 800 patients in the Netherlands shows that the distribution in umbilical metastases differs between males and females. In females, metastases most commonly originated from the ovaries, while in males, the colon was most common. Umbilical metastases, however, were linked to a variety of primary tumors and were frequently diagnosed synchronously with the primary tumor. While prognosis was poor overall, survival was influenced by primary tumor origin.

Background: In a previous worldwide survey, the authors showed a drastic reduction in the number of cytological specimens processed during the coronavirus disease 2019 “lockdown” period along with an increase in malignancy rates. To assess the continued impact of the pandemic on cytological practices around the world, they undertook a second follow-up worldwide survey collecting data from the post-lockdown period (2020). Methods: Participants were asked to provide data regarding their cytopathology activity during the first 12 weeks of their respective national post-lockdown period (2020), which ranged from April 4 to October 31. Differences between the post-lockdown period and the corresponding 2019 period were evaluated, and the authors specifically focused on rates of malignant diagnoses. Results: A total of 29 respondents from 17 countries worldwide joined the survey. Overall, a lower number of cytological specimens (n = 236,352) were processed in comparison with the same period in 2019 (n = 321,466) for a relative reduction of 26.5%. The overall malignancy rate showed a statistically significant increase (12,442 [5.26%] vs 12,882 [4.01%]; P

BackgroundPost-colonoscopy colorectal cancers (PCCRCs) pose a challenge in clinical practice. PCCRCs occur due to a combination of procedural and biological causes. Specific features of lesions may contribute for this. In a nested case-control study, we compared clinical and molecular features of PCCRCs and detected CRCs (DCRCs).MethodsPCCRCs were defined according to the WEO 2018 classification, as cancers occurring after a complete index colonoscopy, which excluded CRC. CRCs in patients without colonoscopy or with colonoscopy >10 years before were defined as DCRCs. Whole genome chromosomal copy number changes and mutation status of genes commonly affected in CRC (including APC, KRAS, BRAF, FBXW7, PIK3CA, NRAS, SMAD4 and TP53) were examined by low-coverage WGS and targeted sequencing, respectively. MSI and CIMP status were also determined.ResultsIn total, 122 PCCRCs and 98 DCRCs with high quality DNA were examined. PCCRCs were more often located proximally in the colon (pConclusionAlthough PCCRCs show molecular characteristics that are common to the canonical CIN, MSI and hypermethylation pathways, molecular features associated with the sessile serrated lesions (SSLs) and non-polypoid colorectal neoplasms (CRNs) are more commonly seen in PCCRCs than in DCRCs. This and the clinical features observed in PCCRCs support the hypothesis that sessile serrated lesions and non-polypoid CRNs are contributors to the development of these cancers. In order to further reduce the occurrence of PCCRCs, the focus should be directed at improving the detection, determination and endoscopic removal of these non-polypoid CRN and SSLs.Clinical Trial RegistrationNTR3093 in the Dutch trial register (www.trialregister.nl)

Background Excisional procedures of cervical intraepithelial neoplasia (CIN) may increase the risk of preterm birth. It is unknown whether this increased risk is due to the excision procedure itself, to the underlying CIN, or to secondary risk factors that are associated with both preterm birth and CIN. The aim of this study is to assess the risk of spontaneous preterm birth in women with treated and untreated CIN and examine possible associations by making a distinction between the excised volume of cervical tissue and having cervical disease. Methods and findings This Dutch population-based observational cohort study identified women aged 29 to 41 years with CIN between 2005 and 2015 from the Dutch pathology registry (PALGA) and frequency matched them with a control group without any cervical abnormality based on age at and year of pathology outcome (i.e., CIN or normal cytology) and urbanization (, In a population-based study, Diede Loopik and colleagues investigate associations between cervical intraepithelial neoplasia and risk of preterm birth among Dutch women., Author summary Why was this study done? Women who are treated for a precancerous cervical lesion may have an increased risk of preterm birth. It is unknown whether this increased risk is due to the treatment itself, to the cervical disease, or to secondary risk factors that are associated with both preterm birth and cervical disease. What did the researchers do and find? We identified women with untreated and treated cervical disease and matched them with a control group through the Dutch pathology registry and compared their pregnancy outcomes through the Dutch perinatal database. The control group (29,907 pregnancies) showed a 4.8% proportion of preterm birth, which increased to 6.9% in the untreated cervical disease group (5,940 pregnancies), 9.5% in the treated cervical disease group (9,412 pregnancies), and 15.6% in the group with multiple treatments (505 pregnancies). After adjustment for 19 potential confounders for preterm birth, women with untreated cervical disease had a 1.4 times and women with treated cervical disease had a more than 2 times increased odds of preterm birth compared to the control group. Independent from cervical disease, a volume excised from the cervix of 0.5 cc or more was associated with an approximately 2 times greater odds of preterm birth. What do these findings mean? We observed a strong association between women with a 0.5 cc or more excised cervical tissue volume (through biopsy and/or treatment) and the odds of preterm birth, regardless of severity of cervical disease or secondary risk factors associated with both preterm birth and cervical disease. Our findings suggest that caution should be taken when performing multiple biopsies or treatment for CIN in women of reproductive age and that women with such a history may benefit from close surveillance during pregnancy.

Background: Standardized structured reporting (SSR) improves quality of diagnostic cancer reporting and interdisciplinary communication in multidisciplinary team (MDT) meetings, resulting in more adequate treatment decisions and better health outcomes. However, use of SSR varies widely among pathologists, but might be encouraged by MDT members (MDTMs). Our objectives were to identify barriers and facilitators (influencing factors) for SSR implementation in oncologic pathology from the perspective of MDTMs and their determinants. Methods: In a multimethod design, we identified influencing factors for SSR implementation related to MDT meetings, using 5 domains: (1) innovation factors, (2) individual professional factors, (3) social setting factors, (4) organizational factors, and (5) political and legal factors. Four focus groups with MDTMs in urologic, gynecologic, and gastroenterologic oncology were conducted. We used an eSurvey among MDTMs to quantify the qualitative findings and to analyze determinants affecting these influencing factors. Results: Twenty-three MDTMs practicing in 9 oncology-related disciplines participated in the focus groups and yielded 28 barriers and 28 facilitators in all domains. The eSurvey yielded 211 responses. Main barriers related to lack of readability of SSR: difficulties with capturing nuances (66%) and formulation of the conclusion (43%); lack of transparency in the development (50%) and feedback processes of SSR templates (38%); and lack of information exchange about SSR between pathologists and other MDTMs (45%). Main facilitators were encouragement of pathologists’ SSR use by MDTMs (90%) and expanding the recommendation of SSR use in national guidelines (80%). Oncology-related medical discipline and MDT type were the most relevant determinants for SSR implementation barriers. Conclusions: Although SSR makes diagnostic reports more complete, this study shows important barriers in implementing SSR in oncologic pathology. The next step is to use these factors for developing and testing implementation tools to improve SSR implementation.

BACKGROUND: Patients with longstanding inflammatory bowel disease (IBD; ie, ulcerative colitis and Crohn's disease) have an increased risk of colorectal cancer (CRC). Due to ongoing inflammation, IBD-associated dysplastic lesions can develop. These lesions have an increased risk to progress to cancer compared with sporadic adenomas, which are also found in these patients. Differentiating between these 2 types of dysplasia remains challenging, both clinically and histologically, while treatment strategies may differ. Therefore, the aim of this study was to investigate molecular alterations associated with colorectal dysplasia to cancer progression in IBD and evaluate to what extent these alterations differ from sporadic adenomas. METHODS: DNA copy number aberrations and mutation analyses of 48 genes were performed by next-generation sequencing in 43 IBD-associated dysplastic lesions, 30 of which were dysplastic and 13 of which were cancers. Results were compared with existing DNA copy number and mutation data from 118 sporadic adenomas and 24 sporadic cancers. RESULTS: Inflammatory bowel disease-associated dysplastic lesions harbor patterns of DNA copy number aberrations comparable to carcinomas, which are rare in sporadic adenomas. TP53 mutation was the most frequent mutation observed in IBD-associated dysplastic lesions and in cancers. FBXW7 was mutated significantly more often in IBD-associated dysplastic lesions than in sporadic adenomas. CONCLUSIONS: Inflammatory bowel disease-associated dysplastic lesions show more DNA copy number aberrations than sporadic adenomas. TP53 and FBXW7 mutations appear to be involved in the development of IBD-associated dysplastic lesions and cancer. These findings indicate that IBD-associated dysplastic lesions are more genomically unstable, possibly reflecting a faster progression toward cancer.

Vulvar squamous cell carcinoma (VSCC) and precancerous vulvar intraepithelial neoplasia (VIN) can develop through human papillomavirus (HPV)‐dependent and ‐independent pathways, indicating a heterogeneous disease. Only a minority of VIN progress, but current clinicopathological classifications are insufficient to predict the cancer risk. Here we analyzed copy number alterations (CNA) to assess the molecular heterogeneity of vulvar lesions in relation to HPV and cancer risk. HPV‐status and CNA by means of whole‐genome next‐generation shallow‐sequencing were assessed in VSCC and VIN. The latter included VIN of women with associated VSCC (VINVSCC) and women who did not develop VSCC during follow‐up (VINnoVSCC). HPV‐testing resulted in 41 HPV‐positive (16 VINVSCC, 14 VINnoVSCC, and 11 VSCC) and 24 HPV‐negative (11 VINVSCC and 13 VSCC) lesions. HPV‐positive and ‐negative VSCC showed a partially overlapping pattern of recurrent CNA, including frequent gains of 3q and 8q. In contrast, amplification of 11q13/cyclinD1 was exclusively found in HPV‐negative lesions. HPV‐negative VINVSCC had less CNA than HPV‐negative VSCC (P = .009), but shared chromosome 8 alterations. HPV‐positive VINnoVSCC had less CNA than VINVSCC (P = .022). Interestingly, 1pq gain was detected in 81% of HPV‐positive VINVSCC and only in 21% of VINnoVSCC (P = .001). In conclusion, HPV‐dependent and ‐independent vulvar carcinogenesis is characterized by distinct CNA patterns at the VIN stage, while more comparable patterns are present at the cancer stage. Cancer risk in VIN seems to be reflected by the extent of CNA, in particular chromosome 1 gain in HPV‐positive cases.

Vulvar squamous cell carcinoma (VSCC) and precancerous high-grade vulvar intraepithelial neoplasia (VIN) can develop through human papillomavirus (HPV)-dependent and -independent pathways, indicating a heterogeneous disease. Only a minority of VIN progress, but current clinical and histological classifications are insufficient to predict the cancer risk. Here we analyzed copy number alterations (CNA) to assess the molecular heterogeneity of vulvar lesions in relation to HPV and cancer risk. HPV-status and CNA by means of whole-genome next-generation shallow-sequencing were assessed in 24 VSCC and 41 VIN lesions. The latter included VIN of women with associated VSCC (VINVSCC) and women who did not develop VSCC during >10 year follow-up (VINnoVSCC). HPV-testing resulted in 41 HPV-positive lesions (16 VINVSCC, 14 VINnoVSCC and 11 VSCC) and 24 HPV-negative lesions (11 VINVSCC and 13 VSCC). HPV-positive and -negative VSCC showed a partially overlapping pattern of recurrent CNA, including frequent gains of 3q and 8q. In contrast, amplification of 11q13/cyclinD1 was exclusively found in HPV-negative lesions. HPV-negative VINVSCC had less CNA than VSCC (P = 0.009), mainly 8q gains and 8p losses. In HPV-positive lesions, CNA frequencies were lower in VINnoVSCC than in VINVSCC (P = 0.022) and VSCC. Interestingly, a 1pq gain was detected in 81% of VINVSCC and only 29% of VINnoVSCC. In conclusion, HPV-dependent and -independent vulvar carcinogenesis is characterized by distinct CNA patterns at the VIN stage, while more comparable patterns are present at the cancer stage. Progression risk in VIN is reflected by the extent of CNA, in particularly chromosome 1 gain. Citation Format: Maaike CG Bleeker, Dorian RA Swarts, Quirinus JM Voorham, Saskia M. Wilting, Marc van Beurden, Renske DM Steenbergen. Molecular heterogeneity in HPV-dependent and -independent vulvar carcinogenesis: Chromosome 1 gain reflects the cancer risk in vulvar intraepithelial neoplasia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5050.

Background and Aim: The transition of pre-malignant colorectal adenomas (CRAs) into malignant colorectal carcinomas (CRCs) is accompanied by accumulation of somatic genetic alterations. The contribution of small nucleotide variants (SNVs, such as gene point mutations) and numerical DNA copy number aberrations (CNAs, such as gains and losses of large chromosomal segments) in tumor genomes has been studied extensively. In contrast, studies that systematically detect recurrent structural variants (SVs, such as chromosomal breaks) across large series of clinically well-defined samples are scarce. We recently developed “GeneBreak”, a computational method to identify genes that are recurrently affected by the genomic location of CNA-associated chromosomal breaks, and demonstrated high prevalence and clinical relevance of recurrent breakpoint genes in advanced CRCs (PLoS One 2015;10(9):e0138141). Using a similar approach, the present study aimed to determine what recurrent breakpoint genes contribute to colorectal adenoma-to-carcinoma progression. Methods: Differences in somatic CNA-associated gene breakpoint frequencies in 466 CRC and 118 CRA samples were examined using high-resolution array-comparative genomic hybridization (aCGH) profiles. Pearson's Chi-square statistic was applied to determine differences in gene breakpoint frequencies between CRC and CRA samples. Results: In total 21 recurrent breakpoint genes were more frequently affected in CRCs compared to CRAs (p Conclusion: We identified 21 recurrent breakpoint genes that are frequently affected by SVs in CRCs but not in CRAs. Additional studies are needed to further elaborate the biological and clinical role of these 21 candidate driver genes for colorectal tumor progression. Citation Format: Evert van den Broek, Maurits J.J. Dijkstra, Quirinus J.M. Voorham, Beatriz Carvalho, Mark A. van de Wiel, Sanne Abeln, Gerrit A. Meijer, Remond J.A. Fijneman. Detection of structural variants and recurrent breakpoint genes in colorectal adenoma-to-carcinoma progression. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr A07.

Response to drug therapy in individual colorectal cancer (CRC) patients is associated with tumour biology. Here we describe the genomic landscape of tumour samples of a homogeneous well-annotated series of patients with metastatic CRC (mCRC) of two phase III clinical trials, CAIRO and CAIRO2. DNA copy number aberrations of 349 patients are determined. Within three treatment arms, 194 chromosomal subregions are associated with progression-free survival (PFS; uncorrected single-test P-values, Response to drug therapy in colorectal cancer (CRC) patients has been associated with tumour heterogeneity. Here the authors analyse DNA copy number aberrations in primary tumours from CRC patients and identify genetic variants that influence drug response.

OBJECTIVES: Nonpolypoid colorectal neoplasms (NP-CRNs) are proposed as a major contributor to the occurrence of interval cancers, but their underlying biology remains controversial. We conducted a systematic review and meta-analysis to clarify the major biological events in NP-CRNs. METHODS: We systematically searched for studies examining molecular characteristics of NP-CRNs. We performed random effect meta-analyses. We measured the heterogeneity among studies using I 2 and possible publication bias using funnel plots. RESULTS: Fifty-three studies on KRAS, APC, or BRAF mutations, microsatellite instability (MSI), CpG island methylator phenotype (CIMP), or DNA promoter hypermethylation were included. We observed less KRAS mutations (summary odds ratio (OR) 0.30, confidence interval (CI) = 0.19-0.46, I-2 = 77.4 %, CI = 70.1-82.9) and APC mutations (summary OR 0.42, CI = 0.24-0.72, I-2 = 22.6 %, CI = 0.0-66.7) in NP-CRNs vs. protruded CRNs, whereas BRAF mutations were more frequent (summary OR 2.20, CI = 1.01-4.81, I-2 = 0 %, CI = 0-70.8), albeit all with large heterogeneity. Less KRAS mutations were especially found in NP-CRNs subtypes: depressed CRNs (summary OR 0.12, CI = 0.05-0.29, I-2 = 0 %, CI = 0-67.6), non-granular lateral spreading tumors (LSTs-NG) (summary OR 0.61, CI = 0.37-1.0, I 2 = 0 %, CI = 0-74.6), and early nonpolypoid carcinomas (summary OR 0.11, CI = 0.06-0.19, I-2 = 0 %, CI = 0-58.3). MSI frequency was similar in NP-CRNs and protruded CRNs (summary OR 0.99, CI = 0.21-4.71, I-2 = 70.3 %, CI = 38.4-85.7). Data for promoter hypermethylation and CIMP were inconsistent, precluding meaningful conclusions. CONCLUSIONS: This meta-analysis provides indications that NP-CRNs are molecularly different from protruded CRNs. In particular, some subtypes of NP-CRNs, the depressed and LST-NG, are featured by less KRAS mutations than polypoid CRNs. Prospective, multicenter studies are needed to clarify the molecular pathways underlying nonpolypoid colorectal carcinogenesis and potential implications for surveillance intervals.

Background Nonpolypoid adenomas are a subgroup of colorectal adenomas that have been associated with a more aggressive clinical behaviour compared to their polypoid counterparts. A substantial proportion of nonpolypoid and polypoid adenomas lack APC mutations, APC methylation or chromosomal loss of the APC locus on chromosome 5q, suggesting the involvement of other Wnt-pathway genes. The present study investigated promoter methylation of several Wnt-pathway antagonists in both nonpolypoid and polypoid adenomas. Methods Quantitative methylation-specific PCR (qMSP) was used to evaluate methylation of four Wnt-antagonists, SFRP2, WIF-1, DKK3 and SOX17 in 18 normal colorectal mucosa samples, 9 colorectal cancer cell lines, 18 carcinomas, 44 nonpolypoid and 44 polypoid adenomas. Results were integrated with previously obtained data on APC mutation, methylation and chromosome 5q status from the same samples. Results Increased methylation of all genes was found in the majority of cell lines, adenomas and carcinomas compared to normal controls. WIF-1 and DKK3 showed a significantly lower level of methylation in nonpolypoid compared to polypoid adenomas (p APC mutation and both WIF-1 and DKK3 methylation was observed (p Conclusions Methylation of Wnt-pathway antagonists represents an additional mechanism of constitutive Wnt-pathway activation in colorectal adenomas. Current results further substantiate the existence of partially alternative Wnt-pathway disruption mechanisms in nonpolypoid compared to polypoid adenomas, in line with previous observations.

Purpose: Flat adenomas are a subgroup of colorectal adenomas that have been associated with a more aggressive clinical behavior compared with their polypoid counterparts. Here, we aimed to compare one of the molecular changes most explicitly associated with adenoma to carcinoma progression, that is, chromosomal instability, between flat and polypoid colorectal adenomas. Experimental Design: Consecutive series of 83 flat and 35 polypoid adenomas were analyzed for DNA copy number changes using a high-resolution array comparative genomic hybridization platform, microsatellite instability (MSI) status, and for mutations in the adenomatous polyposis coli (APC) gene. Immunohistochemical stainings for CD3, CD8, and FoxP3 expression were carried out. Results: Patterns of DNA copy number changes differed between the two phenotypes, with significantly more frequent loss of 5q14.3 and 5q15-q31.1 in flat adenomas, whereas losses of 1p36.32-p35.3, 10q25.3, 17p12, and chromosome 18 were more frequent in polypoid adenomas (false discovery rate < 0.2). MSI was observed in one flat adenoma. As the 5q15-q31.1 region harbors the APC locus, APC mutation status was investigated, showing significantly less mutations in flat adenomas (P = 0.04). An initial exploration of a possible association of 5q loss with inflammation indicated that tumor-infiltrating lymphocytes were more abundant in the stroma of flat adenomas compared with that of polypoid adenomas. Conclusion: Flat and polypoid adenomas have partially distinct chromosomal profiles, consistent with differences in the biology underlying these phenotypes. Alterations more specific to flat adenomas, in particular 5q loss, may be associated with inflammation. Clin Cancer Res; 18(17); 4560–9. ©2012 AACR.

Background: Flat adenomas are a subgroup of colorectal adenomas that have been associated with a distinct biology and a more aggressive clinical behavior compared to their polypoid counterparts. In the present study, we aimed to compare the mutation spectrum of 14 cancer genes, between these two phenotypes. Methods: A consecutive series of 106 flat and 93 polypoid adenomas was analyzed retrospectively for frequently occurring mutations in "hot spot" regions of KRAS, BRAF, PIK3CA and NRAS, as well as selected mutations in CTNNB1 (β-catenin), EGFR, FBXW7 (CDC4), PTEN, STK11, MAP2K4, SMAD4, PIK3R1 and PDGFRA using a high-throughput genotyping technique. Additionally, APC was analyzed using direct sequencing. Results: APC mutations were more frequent in polypoid adenomas compared to flat adenomas (48.5% versus 30.3%, respectively, p = 0.02). Mutations in KRAS, BRAF, NRAS, FBXW7 and CTNNB1 showed similar frequencies in both phenotypes. Between the different subtypes of flat adenomas (0-IIa, LST-F and LST-G) no differences were observed for any of the investigated genes. Conclusion: The lower APC mutation rate in flat adenomas compared to polypoid adenomas suggests that disruption of the Wnt-pathway may occur via different mechanisms in these two phenotypes. Furthermore, in contrast to previous observations our results in this large well-defined sample set indicate that there is no significant association between the different morphological phenotypes and mutations in key genes of the RAS-RAF-MAPK pathway. © 2012 Voorham et al.

with 10,492 patient-years of follow-up. One hundred ninety patients (26.6%) had at least one adenoma at baseline, of which 38 (20%) had 3 or more adenomas, 22 (12%) had an adenoma 1 cm or larger, 25 (13%) had an adenoma with villous histology, and 2 (1%) had an adenoma with high-grade dysplasia. Patients with adenomas at baseline underwent 714 surveillance colonoscopies over 2,685 person-years of follow-up, equivalent to one procedure every 3.8 years. Patients without adenomas at baseline underwent 1401 colonoscopies over 7,745 person-years of follow-up, equivalent to one procedure every 5.5 years (p