Mucinous Colorectal Carcinoma Research Articles

Mucinous Colorectal Carcinoma Arising in Nonulcerated Villous Adenoma (MAVA): A Distinct Pathologic Entity

Among 209 surgical specimens of resectable colorectal adenocarcinomas, nine mucinous carcinomas arising in nonulcerated villous adenoma (MA VA) were identified. They showed infUtration in the colorectal muscillaris própria or through it. However, their morphology was similar to the so-called pseudocarcinomatous submucous foci of villous adenomas. Only one of these tumors had lymph-node metastasis. We suggest that the mechanism of invasion of the colorectal wall in MAMA is diferent from that of the common adenocarcinoma, not implying an authentic carcinomatous transformation at cellular level.

Prognosis of mucinous colon cancer is determined by histological biomarkers rather than microsatellite instability.

The prognostic value of microsatellite instability (MSI), as well as other histological characteristics such as lymphovascular invasion (LI), perineural invasion (PNI) and extramural vascular invasion (EMVI), is unclear in colorectal mucinous carcinoma (MC). This study aims to determine the relevance of these factors in MC patients and analyses the role of MSI in stage III MC patients treated with adjuvant chemotherapy. A cohort of 650 patients diagnosed with stages I-IV colonic MC from 2000 to 2010 was selected from PALGA, the nationwide Dutch pathology databank. Histopathology was revised and mismatch repair (MMR) status determined. Univariate and multivariate survival analyses were performed. Deficient MMR (dMMR) was found in 33% of MCs and correlated with female gender and right-sidedness, but also with lower tumour stage (stages I/II: 73.2 versus 47%; P < 0.0001) and the absence of EMVI (9.7 versus 23.7%; P < 0.0001) and PNI (5.6 versus 12.7%; P=0.005). On univariate analysis OS was better for dMMR MC than for proficient MMR (pMMR) MC (median OS of 9.7versus 5.0 years; P=0.009), but MMR status was no longer a relevant prognostic factor on multivariate analysis [hazard ratio (HR)=0.91, 95% confidence interval (CI)=0.70-1.18]. Stage III MC patients benefited from adjuvant chemotherapy, and dMMR status was associated with better OS in this group (HR=0.35, 95% CI=0.13-0.94). EMVI, LI and PNI, but not MMR, status are independent prognostic factors for survival in MC patients. Stage III MC patients benefit from adjuvant chemotherapy and dMMR status is associated with improved survival when adjuvant chemotherapy is given.

Patient-derived organoids identify an apico-basolateral polarity switch associated with survival in colorectal cancer.

The metastatic progression of cancer remains a major issue in patient treatment. However, the molecular and cellular mechanisms underlying this process remain unclear. Here, we use primary explants and organoids from patients harboring mucinous colorectal carcinoma (MUC CRC), a poor-prognosis histological form of digestive cancer, to study the architecture, invasive behavior and chemoresistance of tumor cell intermediates. We report that these tumors maintain a robust apico-basolateral polarity as they spread in the peritumoral stroma or organotypic collagen-I gels. We identified two distinct topologies - MUC CRCs either display a conventional 'apical-in' polarity or, more frequently, harbor an inverted 'apical-out' topology. Transcriptomic analyses combined with interference experiments on organoids showed that TGFβ and focal adhesion signaling pathways are the main drivers of polarity orientation. Finally, we show that the apical-out topology is associated with increased resistance to chemotherapeutic treatments in organoids and decreased patient survival in the clinic. Thus, studies on patient-derived organoids have the potential to bridge histological, cellular and molecular analyses to decrypt onco-morphogenic programs and stratify cancer patients. This article has an associated First Person interview with the first author of the paper.

Nanosecond pulsed electric fields impair viability and mucin expression in mucinous colorectal carcinoma cell

Nanosecond pulsed electric fields (nsPEFs) are a non-thermal technology that can induce a myriad of biological responses and changes in cellular physiology. nsPEFs have gained significant attention as a novel cancer therapy. However, studies investigating the application of nsPEF in mucinous carcinomas are scarce. In this study, we explored several biological responses in two mucinous colorectal adenocarcinoma cell lines, LS 174T and HT-29, to nsPEF treatment. We determined the overall cell survival and viability rates following nsPEF treatment using CCK-8 and colony formation assays. We measured the intracellular effects of nsPEF treatment by analyzing cell cycle distribution, cell apoptosis and mitochondrial potential. We also analyzed mucin production at both mRNA and protein levels. Our results showed that nsPEF treatment significantly reduced mucinous cell viability in a dose-dependent manner. nsPEF treatment increased cell cycles arrest at G0/G1 while the proportion of G2/M cells gradually decreased. Cell apoptosis increased following nsPEF treatment with a clear loss in mitochondrial membrane potential. Furthermore, the protein expression of functional mucin family members decreased after nsPEF treatment. In conclusion, nsPEF treatment reduced MCRC cell viability, cell proliferation, and mucin protein production while promoted apoptosis. Our work is a pilot study that projects some insights into the potential clinical applications of nsPEFs in treating mucinous colorectal carcinoma.

Distinct Genomic Landscape of Colorectal Mucinous Carcinoma Determined via Comprehensive Genomic Profiling: Steps to a New Treatment Strategy.

Colorectal mucinous carcinoma (MC) is associated with inferior prognosis and response to treatment compared to adenocarcinoma (AC). The molecular landscapes of MC and adenocarcinoma with mucous composition (AMC) are not well-defined. We aimed to describe the genomic landscape of MC and AMC in a large colorectal cancer cohort. Tumor samples from patients with MC, AMC, or AC were analyzed using next-generation sequencing. MC had a molecular signature distinct from that of AC; genomic features were similar between AMC and MC but not between AMC and AC. HER2 amplification and TP53 and APC mutation rates were lower, whereas SMAD4, PIK3CA, ACVR2A, KMT2D, LRP1, TGFBR2, GRIN2A, BRAF V600E, PTEN, and BRCA2 mutation rates were higher in MC than in AC. The mutation frequencies in MAPK, PI3K, and TGF- pathways were higher, whereas those of cell cycle proteins and Wnt were lower in MC and AMC than in AC. The proportion of hypermutated tumors was significantly higher in MC and AMC than in AC. As MC has a distinct molecular signature from AC, immunotherapy can be potentially applied in treating MC. Similar molecular profiles of AMC and MC suggest that treatment strategies for MC, but not AC, can be used for AMC treatment.

Abstract PO-021: Humans cannot accurately detect mucinous colorectal carcinoma from CT images, can AI help?

Abstract Background: Mucinous colorectal carcinoma (CRC) is found in 10-20% of patients and is associated with worse prognosis and treatment resistance. The early identification of mucinous tumor component at baseline and monitoring resistant clones at follow-up is challenging in clinical practice, which hinders appropriate and timely treatment selection. At CT, being routinely acquired in clinical practice, mucinous tumors can be characterized by semantic features, such as hypoattenuation and more heterogeneous enhancement than the non-mucinous tumors (Wnorowski et al 2019). However, the diagnostic accuracy of such CT findings reaches at most 62% (Young et al 2007). This can be substantially improved by utilizing robust feature quantification using state-of-art machine learning and neural network techniques. Materials and Methods: 7 mucinous and 7 non-mucinous CRC CTs were included in the model development (80% training and 20% validation) and 2 mucinous and 2 non-mucinous independent patients were used to test the model performance. Multiple lesions (primary and metastatic) were semi-automatically segmented in 3D Slicer (N=32 development and N=12 test). Three different classification models were generated using CT images: (1) a logistic regression model based on a newly developed hypodense tissue connectivity (HTC) metric, (2) a logistic regression model using a set of automatically selected radiomics (RAD) features (shape, 1st order and 2nd order) and (3) a convolutional neural network model (CNN) based on the ResNet architecture and automatically selected features. HTC was computed as a ratio between the volume of the connected hypodense tissue (0&amp;lt;HU&amp;lt;30) and total tumor volume. CT images were converted to 2D axial sections to increase the input size for CNN (resulting in 952 images). Class weights were used to mitigate the effect of in-balance between the number of mucinous and non-mucinous images. Performance of the model was quantified with Accuracy (Acc), Sensitivity (Sen), Specificity (Spec) and AUC. Results: The classification performance of all three models was first assessed using 10-fold cross validation, where the RAD and CNN models performed better than HTC model. (Mean±std) RAD: Acc 0.9±0.15, Sen 0.92±0.15, Spec 0.9±0.2, AUC 0.95±0.13; CNN: Acc 0.93±0.05, Sen 0.93±0.03, Spec 0.93±0.19, AUC 0.95±0.01; HTC: Acc 0.72±0.23, Sen 0.7±0.4, Spec 0.75±0.33, AUC 0.84±0.32. However, the situation changed in test set, where HTC and CNN models provide the best results. RAD: Acc 0.67, Sen 1.0, Spec 0, AUC 0.5; CNN: Acc 0.97, Sen 0.98, Spec 0.96, AUC 0.97; HTC: Acc 0.92, Sen 1.0, Spec 0.75, AUC 1.0. Conclusions: All studied models improved the accuracy of mucinous lesion identification compared to the literature reported value. Further method development and validation on larger multi-center cohorts would allow gaining confidence in models applicability in the clinical setting. Citation Format: Kinga Bernatowicz, Raquel Perez Lopez, Hector Garcia Palmer, Elena Elez Fernandez, Jose Fernandez Navarro, Marta Ligero Hernandez, Alonso Garcia Ruiz, Manuel Escobar Amores. Humans cannot accurately detect mucinous colorectal carcinoma from CT images, can AI help? [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr PO-021.

Mucinous Histology, BRCA1/2 Mutations, and Elevated Tumor Mutational Burden in Colorectal Cancer.

Mucinous colorectal carcinomas (MC) constitute 10% of colorectal malignancies. Recently, an increased risk of colorectal cancer has been demonstrated in germline BRCA1/2 mutation carriers. Furthermore, BRCA1/2 germline mutation carriers have exhibited a higher-than-expected frequency of MC tumors. Here, we investigate the relationship between BRCA mutations and mucinous histology in colorectal carcinoma patients, using both an existing cohort of sequenced colorectal tumors and a prospective case-control study comparing MC and conventional adenocarcinoma (AC) patients tested for BRCA mutations. We discovered that MC tumors exhibit a statistically significantly higher incidence of BRCA mutations in addition to a higher average mutation count when compared to AC tumors in the existing cohort. The strongest predictor of the mutation count was mucinous histology, independently of other variables including microsatellite instability. Contrary to our hypothesis, the first association did not recur in the prospective case-control study, likely due to our pathological definition of MC tumors and small sample size. Finally, we observed a higher tumor mutational burden (TMB) in MC tumors compared with AC tumors. We suggest that the association between MC histology, BRCA mutations, and increased TMB may open the door to the utilization of simple tests (such as histopathologic characterization) to detect patients who may benefit from immunotherapy in colorectal cancer.

Distinct genomic landscape in colorectal mucinous carcinoma via comprehensive genomic profiling.

222 Background: Mucinous carcinoma (MC), accounting for 10-15% of colorectal cancer (CRC), has long been associated with an inferior response to treatment. MC as an unfavorable prognostic factor in early stage CRC remains questionable. In this study, we used a large CRC cohort to define the genomic landscape of MC and identify prognostic and clinically actionable information. Methods: The 1226 CRC patient cohort included 997 adenocarcinomas (AC), 129 MC, and 110 adenocarcinomas with mucous composition (AMC). All of the pathological sections were verified by an experienced pathologist. FFPE tumor samples and matched peripheral blood were sequenced using a 450-cancer-related gene panel. Results: MC was significantly associated with right colon (p&lt;0.001) and regional lymph node metastasis (p=0.004) compared to AC. We found a higher mutation rate of BRAF V600E (10.9% vs. 3.3%), PIK3CA (28.7% vs. 19.2%), SMAD4 (34.1% vs. 19.1%), BRCA1/2 (16.3% vs. 6.8%) and homology recombination pathway (40.3% vs. 22.7%), and a lower rate of TP53 (53.5% vs. 79.5%), APC (46.5% vs. 75.1%,), and HER2 amplification (0% vs. 2.1%,) in MC than in AC. MC had a significantly higher proportion of microsatellite instability-high (MSI-H) tumors (22.5% vs. 6.8%, p&lt;0.001). Furthermore, in tumors with MSI stable, POLE mutation was more frequent in MC than in AC (7.0% vs. 2.6%, p=0.094) and resulted in dramatic elevated tumor mutational burden (TMB, range 79.5-591.5 muts/Mb), indicating up to 30% of MC patients may benefit from immunotherapy. MSI-H was associated with better prognosis (5-y DFS, MSI-H 86.7% vs. MSS 56.7%) in stage II/III CRC patients with MC. Importantly, AMC mimicked the genomic features of MC rather than AC. Conclusions: For the first time, comprehensive genomic analysis revealed that MC had distinct molecular features, indicating promising clinically application for both immunotherapy and targeted therapy. Early stage MC had a diverse prognosis due to MSI status and should be interpreted differently. The similarity of molecular profile between AMC and MC suggested the possible usage of MC, but not AC, clinical strategy for AMC.

Prognostic significance of mucinous colorectal carcinoma

Prognostic significance of mucinous colorectal carcinoma

Tumor clinicopathological characteristics and their prognostic value in mucinous colorectal carcinoma.

Aim: This study analyzed clinicopathological features of colorectal mucinous carcinoma and their prognostic values. Patients & method: This study enrolled 265 patients with mucinous colorectal cancer. Clinicopathological information and prognosis were reviewed retrospectively. Kaplan-Meier method, log- rank test and COX proportional hazard regression models were used. Results: In postoperative mucinous carcinoma patients (median age 56, 119 [44.9%] female), advanced tumor stage (odds ratio [OR]: 2.378; 95% CI: 1.512-3.741;p=0.0002), poor differentiation (OR: 1.896; CI: 1.217-2.955;p =0.0047) and right-sided tumors (OR: 2.421; CI: 1.145-5.102;p=0.0206) were associated with shorter overall survival. Appendiceal/ileocecal cecal tumors were not different for prognosis. Conclusion: Mucinous colorectal carcinoma exhibits distinct tumor characteristics. Poor differentiation, advanced stage at presentation and the right side serve as negative prognostic factors.

642P - Frequent BRAF, GNAS and SMAD4 mutations identified in colorectal mucinous carcinomas

BackgroundColorectal mucinous carcinoma (MAC) is a distinct subtype of colorectal carcinoma (CRC) accounting for approximately 10-20% of all CRCs. Mucinous carcinomas characterized by the presence of abundant extracellular mucin which occupies at least 50% of the tumour volume. Patients are often diagnosed at an advanced stage in young patients showing a poor prognosis with the 3-year overall survival rate of 57%. Although clinicopathologic findings of colorectal MACs are relatively well known, their molecular alterations have not elucidated. We investigate molecular alterations of colorectal MACs revealed by next-generation sequencing (NGS). MethodsWe retrospectively reviewed cases of CRCs with mucinous component and 111 MACs subject to molecular profiling using NGS on the Ion Proton (Thermo Fisher Scientific). We examined substitutions and small indels in 409 cancer-related genes using Ion ampliseq Cancer Hotspot and Ion ampliseq Comprehensive Cancer panels. ResultsOf the 111 patients included in the analysis, 60 (54.1%) were male: the median age was 58 years. BRAF was mutated in 17% of colorectal MACs (19 of 111) and 9.0% of CRCs (18 of 200), V600E mutations were predominantly identified in MACs, representing 95% (18 of 19) of BRAF mutated cases (p=0.0438). GNAS mutations were frequently detected in 14.4% of colorectal MACs (19 of 111) and 1.5% of CRC (3 of 200), R201C and R201H were more commonly mutated, representing 95% (18 of 19) of GNAS mutated cases (p<0.001). SMAD4 mutations were frequently noted in colorectal MACs compared with those of CRCs (24 of 111 vs. 22 of 200, p=0.0187). ConclusionsThis study demonstrates distinct genomic differences in colorectal MACs compare with CRCs. The genomic profiling of colorectal MACs revealed by NGS can identify potentially targetable molecular alterations in the majority of colorectal MACs (95.5%). Overall, colorectal MACs harbor relatively high frequencies of BRAF, GNAS, and SMAD4 mutations compared with those of CRCs. This distinct activating or inactivating mutations of these genes suggest promising consideration of targeted therapy by inhibiting related pathways in patients with advanced colorectal MACs. Legal entity responsible for the studySun Mi Lee. FundingJeju National University Hospital. DisclosureThe author has declared no conflicts of interest.

Tumor Budding in Colorectal Carcinoma Showing a Paradoxical Mitotic Index (Via PHH3) With Possible Association to the Tumor Stromal Microenvironment.

Colorectal carcinomas (CC) are one of the most commonly diagnosed malignancies. Tumor budding (the histologic process of dissociation that occurs at the invasive margin of colorectal cancer), has significant prognostic implications, in that higher tumor budding is associated with adverse histopathologic and clinical outcomes. Because of this prognostic significance, more research is needed to further understand the pathologic and immunohistochemical (IHC) associations pertaining to this important prognostic variable. In this study, we will further evaluate selective clinopathologic and IHC variables with possible association to tumor budding. A total of 234 cases of CC diagnosed in our health system were retrospectively reviewed and routine hematoxylin and eosin-stained slides of these cases were collected. A representative slide for tumor budding was selected per case and selective IHC staining was performed. Clinicopathologic data were collected for each case and analyzed in relation to tumor budding scores. In exploratory analyses, tumor budding scores per individual investigator and consensus tumor budding scores were compared with selected IHC stains (MLH1, PMS2, and PHH3) as well as numerous clinicopathologic variables. We found a paradoxical association between tumor budding and mitosis score using PHH3 immunostaining in univariate and multivariable analysis. Furthermore, patients with intact nuclear expression for MLH1 and/or PMS2 are more likely to have higher tumor budding compared with patients with lost expression. For multivariable analysis, the following covariates were significantly associated with higher tumor budding: the presence of lymphovascular invasion, higher pathologic tumor stage, and finally infiltrating border was more likely to be associated with higher tumor budding compared with cases with a pushing border. Regarding nonmucinous versus mucinous CC, nonmucinous adenocarcinoma (MCA) was more likely to be associated with higher tumor budding compared with MCA. Numerous clinicopathologic variables were found to be associated with tumor budding including lymphovascular invasion, tumor stage, infiltrating tumor border, non-MCA was more likely to be associated with higher tumor budding compared with MCA, possibly related to MUC-2 and MSI. Furthermore, regarding the paradoxical association between tumor budding and mitosis score using a PHH3 immunostaining (high tumor budding having lower mitosis), this is possibly related to the tumoral stomal microenvironment and cancer associated fibroblasts. An idea for a future study would be to look at the maturity of cancer-associated fibroblasts (immature vs. mature) and the tumoral stroma microenvironment, with regards to markers of tumor aggressiveness such as mitosis. In addition, we found that patients with intact nuclear expression for MLH1 and/or PMS2 were more likely to have higher tumor budding compared with patients with lost expression, possibly related to mismatch repair CC's not being as reliant on tumor budding. Future research will hopefully concede further insight into the variables that affect tumor budding, especially regarding the tumoral microenvironment and variations between different patient populations, inclusive of patients lacking activity of the mismatch repair. Ultimately, this will allow for better prognostic information, and more precise treatment modalities.

Genomic alterations in signet ring and mucinous patterned colorectal carcinoma

BackgroundThe genetic alterations (GAs) in two specific histological subtypes of colorectal cancer (CRC), signet ring cell colorectal carcinoma (SRC) and mucinous colorectal carcinoma (MC), are not well known. In the present study, we employed next-generation sequencing to perform genetic profiling of SRC and MC, and compared the spectrum of GAs with the alterations found in conventional type colorectal cancer (CON). Materials and methodsWe selected 46 CRCs comprising 17 SRCs and mucinous carcinoma with signet ring cell component (SRCCs), 17 MCs, and 12 CONs with microsatellite stability or microsatellite instability-low. Deep sequencing was performed using a targeted cancer panel composed of 171 cancer-related genes. SMAD4 protein expression was evaluated by immunohistochemical staining. ResultsWe detected 108 mutations in 18 different genes. Overall, 2.34 GAs were detected per tumor (range, 0–14). The overall frequency of GA and alteration in targetable genes was less prevalent in SRC/SRCC compared to the frequency of alteration in MC/CON (p = 0.040 and p < 0.001, respectively). The GA profile of SRC/SRCC included TP53 (8/17, 47.1%), SMAD4 (5/17, 29.4%), KRAS (4/17.23.5%), APC (4/17.23.5%), PIK3CA, ATM, BRAF, and PIK3R1 (1/17, 5.9%, each). KRAS mutation was significantly less prevalent in SRC/SRCC compared to the number of KRAS mutations in MC (12/17, 70.6%) and CON (9/12, 75.0%) (p = 0.015 and 0.01, respectively). Compared to the 152 non-hypermutated CONs from TCGA database, SMAD4 alteration was predominant in SRC/SRCC (p = 0.045) with aberrant loss of SMAD4 expression (13/17, 76.5%) compared to the SMAD4 alterations in CON (5/15, 33.3%) (p = 0.031). Accordingly, KRAS (12/17, 70.6%), APC (6/17, 35.3%), SMAD4, TP53 (4/17, 23.5%, each), PIK3CA (3/17, 17.6%), AKT1, ATM, BRAF, EGFR, and EZH2 (1/17, 5.9%, each) were altered in MC. APC and TP53 mutations were less frequent in MC compared to those in TCGA-CON (p < 0.001 and 0.003, respectively) whereas KRAS mutation was prevalent (p = 0.041). ConclusionAlterations of known cancer associated genes and targetable genes in SRC/SRCC are infrequent. The profile of GAs in SRC/SRCC and MC differs from the GA profile of CON. Specifically, SMAD4 mutation and loss of SMAD4 expression is frequently found in SRC/SRCC. The genetic profiles revealed in the present study may aid in developing precision medicine for CRC treatment based on histological subtype.

Comprehensive genomic profiling of mucinous ovarian carcinoma with comparisons to mucinous colorectal carcinoma

Comprehensive genomic profiling of mucinous ovarian carcinoma with comparisons to mucinous colorectal carcinoma

A Comprehensive Evaluation of Special AT-rich Sequence-binding Protein 2 (SATB2) Immunohistochemical Staining in Mucinous Tumors From Gastrointestinal and Nongastrointestinal Sites

Special AT-rich sequence-binding protein 2 (SATB2) is an accurate marker for conventional colorectal carcinoma (CRC), although its sensitivity and specificity in mucinous tumors from the colon and other sites remains unknown. The objective of this study is to evaluate the accuracy of SATB2 expression detected by immunohistochemical assay, as a marker of primary CRC in mucinous adenocarcinomas. SATB2 immunohistochemical stains were performed on whole sections from 63 conventional CRCs (controls), 47 mucinous CRCs (mCRC), and 182 noncolorectal mucinous tumors. SATB2 intensity was scored as 1 to 3 based on the estrogen receptor/progesterone receptor grading system, and the percent positive cells was scored in broad categories as follows: 0 (negative)≤5%, 1=5% to 49%, 2≥50%. An optimal sensitivity/specificity pairing (83% and 95%, respectively) was achieved in the mCRCs when the additive intensity and percent score was ≥3 (ie, intensity score+percent score=total score). Defining this total score (histologic score/"H score") as a "positive" result, the sensitivity of SATB2 for conventional CRC was 98% (62/63) versus 83% (39/47) for mCRCs (P=0.02); whereas 5% (9/182) of all noncolorectal mucinous tumors were considered positive. SATB2 especially demonstrated reduced specificity when applied to mucinous gastroesophageal and breast carcinomas, which showed significant expression in 27% and 9% of cases, respectively. In summary, SATB2 is a less sensitive marker of colorectal origin in mCRC compared with conventional CRC and shows significantly reduced specificity in mucinous gastroesophageal and breast primaries.

Role of ERCC1 expression in colorectal adenoma-carcinoma sequence and relation to other mismatch repair proteins expression, clinicopathological features and prognosis in mucinous and non-mucinous colorectal carcinoma.

There are several DNA repair pathways that protect cellular DNA from injury, such as nucleotide excision repair (NER) and mismatch repair (MMR). The protein product of the excision repair cross-complementation group 1 (ERCC1) gene plays a pivotal role in NER. The exact relationship between MMR proteins and ERCC1 is not well known in colorectal carcinoma (CRC). To investigate expression of ERCC1 and MMR proteins in colorectal mucinous carcinoma (MA) and non-mucinous carcinoma (NMA) using tissue microarray technique. We studied tumor tissue specimens from 150 patients with colorectal mucinous (MA) and non-mucinous adenocarcinoma (NMA). Tissue microarrays were constructed using modified mechanical pencil tips technique and immunohistochemistry for ERCC1, MLH1, MSH2, MSH6, and PMS2. NMA showed a significantly more frequent aberrant cytoplasmic expression than MA while MA showed a more frequent intact nuclear expression than NMA. There were no significant differences between the NMA and MA groups in the expression of MMR proteins. In NMA cases, ERCC1 expression was significantly related to MMR status while was not significantly related in MA cases. ERCC1 expression was not significantly related to overall and disease-free survival in both NMA and MA groups. this study is the first to investigate the relation between MMR status and ERCC1 expression in colorectal MA and NMA. ERCC1 expression was significantly related to MMR status only in NMA cases. Hence, the current study emphasizes that further research about the relation between various DNA repair pathways is needed.

Clinical and Histopathologic Features of Colorectal Adenocarcinoma in Crohn's Disease.

The aim of this study was to assess the histopathologic characteristics of colorectal carcinomas (CRC) in patients with Crohn's disease (CD). A higher frequency of microsatellite instability (MSI) is seen in mucinous compared with nonmucinous CRC which suggests that its pathogenesis involves distinct molecular pathways. Several publications reported a higher percentage of mucinous adenocarcinoma in CD patients with CRC. So far, there has been no investigation of MSI in CD patients with mucinous CRC. The medical records of patients who underwent surgery for CRC were reviewed and those with a history of CD identified. The data of histologic classification and MSI status of the tumor were investigated. Fourteen patients with CD-associated CRC were identified (5 female, 9 male) resulting in 20 CRC in total. Histologic investigation revealed 7 adenocarcinomas without a mucinous or signet ring cell component. All other CRCs harbored a mucinous (n=11) and/or signet ring cell (n=6) component. All tumors assessed for MSI were found to be microsatellite stable. Our data indicate that CRCs with signet ring cell and mucinous components were much more common in patients with CD than in patients with sporadic CRC. This observation suggests that CRC in CD represent an own entity with distinct histopathologic and molecular features. This may implicate potential consequences for diagnosis and therapy of CRC in CD in the future as well as new factors to identify patients with an increased risk for developing CRC in CD.

Massively parallel sequencing analysis of mucinous ovarian carcinomas: genomic profiling and differential diagnoses

ObjectiveMucinous ovarian cancer (MOC) is a rare type of epithelial ovarian cancer resistant to standard chemotherapy regimens. We sought to characterize the repertoire of somatic mutations in MOCs and to define the contribution of massively parallel sequencing to the classification of tumors diagnosed as primary MOCs. MethodsFollowing gynecologic pathology and chart review, DNA samples obtained from primary MOCs and matched normal tissues/blood were subjected to whole-exome (n = 9) or massively parallel sequencing targeting 341 cancer genes (n = 15). Immunohistochemical analysis of estrogen receptor, progesterone receptor, PTEN, ARID1A/BAF250a, and the DNA mismatch (MMR) proteins MSH6 and PMS2 was performed for all cases. Mutational frequencies of MOCs were compared to those of high-grade serous ovarian cancers (HGSOCs) and mucinous tumors from other sites. ResultsMOCs were heterogeneous at the genetic level, frequently harboring TP53 (75%) mutations, KRAS (71%) mutations and/or CDKN2A/B homozygous deletions/mutations (33%). Although established criteria for diagnosis were employed, four cases harbored mutational and immunohistochemical profiles similar to those of endometrioid carcinomas, and one case for colorectal or endometrioid carcinoma. Significant differences in the frequencies of KRAS, TP53, CDKN2A, FBXW7, PIK3CA and/or APC mutations between the confirmed primary MOCs (n = 19) and HGSOCs, mucinous gastric and/or mucinous colorectal carcinomas were found, whereas no differences in the 341 genes studied between MOCs and mucinous pancreatic carcinomas were identified. ConclusionsOur findings suggest that the assessment of mutations affecting TP53, KRAS, PIK3CA, ARID1A and POLE, and DNA MMR protein expression may be used to further aid the diagnosis and treatment decision-making of primary MOC.

The utility of KRAS mutation analysis in differentiating a lung primary mucinous carcinoma from a metastatic colorectal mucinous carcinoma

A 58-year old male has a past medical history of a rectal low-grade mucinous adenocarcinoma with a KRAS codon 12/13 mutation (GGT&gt;GAT), for which he received neoadjuvant chemotherapy and radiation. Five months after diagnosis, the patient underwent a low anterior resection showing persistent tumor with the pathological staging being (ypT3, ypN0, ypMx). Six months after surgery, follow-up PET scan showed two right upper lung nodules measuring 1.0 and 1.8 cm. Subsequent video-assisted thoracic surgery with a lung wedge resection revealed two tumors: a mucinous adenocarcinoma and an acinar-predominant adenocarcinoma. The mucinous adenocarcinoma showed similar cytologic features as the rectal tumor; however, it showed more of a lepidic pattern. The immunohictochemical profile of the lung mucinous adenocarcinoma was positive CK7 (cytoplasmic), negative CK20, TTF1, napsin-A, and CDX2. KRAS codon 12/13 analysis also showed a mutation in the lung, however it was different compared to the previous rectal tumor and showed a GGT&gt;AGT mutation. The acinar adenocarcinoma had a wild-type KRAS. In this case, we favored a primary lung mucinous carcinoma over a metastasis from the rectum based on the lepidic morphology, CK20 negativity and differing KRAS codon 12 mutations. A year after the resection of the lung adenocarcinomas, the patient presented with dyspnea and abnormal liver functions. Abdominal US and MRI revealed multiple liver lesions (up to 1.9 cm). Core liver biopsies showed a poorly-differentiated mucinous adenocarcinoma with positive CK7 (cytoplasmic) and negative CK20, TTF-1, napsin-A, CDX2 and HSA. KRAS codon 12/13 analysis also showed a mutation GGT&gt;AGT, similar to that of the lung mucinous adenocarcinoma. The immunohistochemical profile and the KRAS mutation sequence of the hepatic tumor suggests a metastasis from the lung primary and corroborates the earlier premise that the lung tumor is distinct from the rectal one. In conclusion, in the unusual circumstance of a lung mucinous adenocarcinoma in a patient with established gastrointestinal mucinous primary, KRAS mutation analysis sequencing could help distinguish whether the lung mucinous is a primary tumor or metastasis from colorectal origin.

Mucinous colorectal carcinoma: A single center experience.

e15116 Background: The aim of this study was to evaluate the clinical features and treatment outcomes of mucinous colorectal adenocarcinoma (MCA) followed in a single institution. Methods: Seventy-nine patients diagnosed with MCA admitted to our center between January 2003 and August 2016 included in this study. Demographic and clinico-pathologic characterictics of patients were analysed using patient medical records retrospectively. Results: Median age of the patients was 57 (24-83) with a male to female ratio of 1/3. Common symptoms were abdominal pain, rectal bleeding, abdominal distention, tenesmus and constipation in 44 (55.7%), 17 (21.5%), 7 (8.9%), 6 (7.6%), 5 (6.3%) of patients respectively. At the time of the diagnosis ECOG performance score was 0 or 1 in 74 (93.7%) of the patients. One (1.3%), 26 (32.9%), 37 (46.8%) and 15 (19%) of the patients had stage 1,2,3 and 4 disease respectively. Neoadjuvant chemo-radiotherapy with 5 FU and leucovorin (FUFA) was the treatment of choice in 11 (13.9%) of rectal MUC patients. The type of surgery was curative, palliative and emergent in 60 (76%), 9 (12.4%) and 9 (12.4%) respectively. Localisation of the primary tumor was right colon, left colon and rectum in 31 (39.2%), 30 (38%) and 18 (24.8) patients respectively. In the adjuvant setting, 59 (74.7%) of patients were received adjuvant chemotherapy. Only 6 patients had MSI, 26 patients had k-RAS, n-RAS and b-RAF mutation results. Metastatic sites were mostly visceral organ, intra-abdominal and local recurrence in 13 (16.5%), 12 (15.2%) and 6 (7.6%) of patients respectively. The median disease free survival, progression free survival and overall survival (OS), were 15.5 months, 17.5 months and 44.1 months, respectively. Conclusions: Survival rates were higher than literature in this study. This may be partly explained by better ECOG performance score of our patient group. We also found that better ECOG score, left sided tumor, younger age, were associated with better OS.