Left-sided Colorectal Carcinoma Research Articles

TROP2 in colorectal carcinoma: associations with histopathology, molecular phenotype, and patient prognosis.

Antibody-drug conjugates (ADCs) directed to trophoblast cell surface antigen 2 (TROP2) have gained approval as a therapeutic option for advanced triple-negative breast cancer, and TROP2 expression has been linked to unfavourable outcomes in various malignancies. In colorectal carcinoma (CRC), there is still a lack of comprehensive studies on its expression frequency and its prognostic implications in relation to the main clinicopathological parameters. We examined the expression of TROP2 in a large cohort of 1,052 CRC cases and correlated our findings with histopathological and molecular parameters, tumour stage, and patient outcomes. TROP2 was heterogeneously expressed in 214/1,052 CRCs (20.3%), with only a fraction of strongly positive tumours. TROP2 expression significantly correlated with an invasive histological phenotype (e.g. increased tumour budding/aggressive histopathological subtypes), advanced tumour stage, microsatellite stable tumours, and p53 alterations. While TROP2 expression was prognostic in univariable analyses of the overall cohort (e.g. for disease-free survival, p < 0.001), it exhibited distinct variations among important clinicopathological subgroups (e.g. right- versus left-sided CRC, microsatellite stable versus unstable CRC, Union for International Cancer Control [UICC] stages) and lost its significance in multivariable analyses that included stage and CRC histopathology. In summary, TROP2 is quite frequently expressed in CRC and associated with an aggressive histopathological phenotype and microsatellite stable tumours. Future clinical trials investigating anti-TROP2 ADCs should acknowledge the observed intratumoural heterogeneity, given that only a subset of TROP2-expressing CRC show strong positivity. The prognostic implications of TROP2 are complex and show substantial variations across crucial clinicopathological subgroups, thus indicating that TROP2 is a suboptimal parameter to predict patient prognosis.

Molecular characteristics of left-sided, advanced stage colorectal cancer: A Mexican perspective

Background: Predictive molecular markers based on the consensus molecular classification of colorectal carcinoma are tested following expert recommendations. Specifically, they are tested when target molecular therapy is being considered for treatment. Their presence depends on biology but their frequency seems to be increased in advanced stages. Objective: We developed a study of cases of left-sided CRC in advanced clinical stages from a cohort of Mexican patients to evaluate the presence of predictive molecular markers. Method: Predictive molecular markers were analyzed, including BRAF, KRAS, NRAS and mismatch repair genes, in cases of advanced, left-sided colorectal carcinoma.

Comparison of conventional unstained lymph nodal harvesting vs methylene blue–stained lymph nodal harvesting in colorectal specimen in staging left-sided colorectal carcinoma: a randomized controlled trial

The management and prognosis of colorectal carcinomas (CRCs) are related to the stage of the disease, which, in turn, relies on the lymph node harvest from the surgical specimen. The guidelines recommend that at least 12 lymph nodes are required, which is not achieved in most resections. In this study, we propose a method to improve the lymph node yield in such cases. This study aimed to determine whether ex vivo injection of methylene blue into the inferior mesenteric artery or its branches improves lymph node retrieval in left-sided CRCs. This study was conducted as a single-center, double-blinded, superiority randomized controlled trial. Patients who underwent elective surgery for left-sided CRCs with curative intent were randomized into 2 groups: stained and unstained. The sample size was calculated as 66. In all patients, details of disease stage, history of neoadjuvant therapy, and number of isolated lymph nodes were recorded. The mean number of lymph nodes extracted from the stained group was significantly higher than that from the unstained group (15.9±5.2 vs 9.1±5.7, respectively; P<.001). Among the patients who had received neoadjuvant therapy, the yield was higher in the stained group (P<.001). The yield was found to be greater in patients who had undergone upfront surgery than in those who had undergone neoadjuvant therapy, even in the stained group (100% vs 66.7%, respectively). The use of methylene blue injection into resected specimens of left-sided CRCs significantly improved the lymph node yield.

Association of serum superoxide dismutase activity and the incidence of colorectal cancer in a nested case-control study

BackgroundSuperoxide dismutase (SOD) is an antioxidant enzyme that degrades superoxide, a major causative factor in carcinogenesis. We assessed associations between serum SOD activities and incidence of colorectal carcinoma (CRC) in a case-control study nested in the Japan Collaborative Cohort (JACC) study. MethodsAt baseline, 39,242 subjects donated serum samples. Participants diagnosed with CRC during follow-up were regarded as cases. Odds ratios (ORs) for CRC incidence associated with SOD were evaluated with conditional logistic regression models. In the current study, 176 cases and 524 controls were analyzed. ResultsFor the overall cohort, a decreasing trend in risk of CRC with increasing SOD was observed (P for trend=0.054) and the fourth quartile of SOD level showed the lowest risk compared to the first (OR=0.52, 95% confidence interval [CI]=0.29–0.93). This was significant in men (P for trend=0.001), with the fourth quartile of SOD level showing the lowest risk compared to the first (OR, 0.23; 95%CI, 0.09–0.60). It was also exclusively observed for rectal cancer and left-sided CRC (P for trend, 0.037 and 0.020, respectively), with the fourth quartile again showing the lowest risk compared to the first (OR, 0.28 and 0.38; 95%CI, 0.09–0.84 and 0.16–0.91, respectively). Limiting subjects to those followed-up over 2 years, all trends remained unchanged. ConclusionsOur findings suggest that serum SOD activity correlates inversely with risk of CRC, particularly in men and individuals with rectal cancer/left-sided CRC.

Prognostic significance of mucinous histology in left‑sided metastatic colorectal cancers with wild‑type RAS and evaluation of backbone chemotherapy regimens.

Mucinous colorectal adenocarcinoma (MCAC) is a distinct subtype of colorectal carcinoma (CRC). The prognostic and predictive significance of mucinous histology remains controversial. It was aimed to investigate the prognostic and/or predictive role of mucinous histology in left-sided metastatic CRC (mCRC) with wild-type RAS. This is a retrospective multicenter study of mCRC treated with first line anti-EGFR combined 5-fluorouracil based chemotherapy (CT). Patients were stratified according to presence (>50% extracellular mucin) or absence of mucinous histology. Survival analyses were performed firstly regardless of treatment options and then performed as separating according to CT regimens. Additional analyses were performed for MCAC patients considering backbone CT regimens. A total of 125 patients were included, consisting of 40 (32.0%) patients with MCAC and 85 (68.0%) patients with non-MCAC. Median follow-up time was 19.7 months. Median progression-free survival (PFS) was 10.7 months in all patients, and PFS was lower in MCAC than non-MCAC (9.9 vs. 12.0 months, respectively, P=0.005). Median overall survival (OS) was 25.7 months in all patients. OS was lower in MCAC than non-MCAC (22.8 vs. 29.7 months, respectively, P=0.005). When considering backbone CT regimens, in multivariate analyses, mucinous histology was an independent prognostic factor for OS in both for mFOLFOX6 (HR: 1.92, P=0.04) and FOLFIRI (HR: 2.04, P=0.04) groups and was associated with poor PFS in only mFOLFOX6 (HR: 3.86, P<0.001) group. When outcomes were analyzed for the MCAC group, median OS of MCAC patients receiving mFOLFOX6 and FOLFIRI was 22.47 and 14.22 months, respectively (P=0.41). Median PFS of MCAC patients receiving mFOLFOX6 and FOLFIRI was 10.15 and 8.11 months, respectively (P=0.73). The study revealed poor prognosis of mucinous histology, both in whole study population and in backbone CT groups. Moreover, lower PFS of MCAC patients was revealed in only mFOLFOX6 group and this finding may be a valuable issue for the future research. However, considering all analyses, the present results did not indicate a special benefit of any backbone CT regimen for MCAC patients.

Risk factors for anastomotic leakage and its impact on long-term survival in left-sided colorectal cancer surgery

BackgroundAnastomotic leakage (AL) significantly impairs short-term outcomes. The impact on the long-term outcomes remains unclear. This study aimed to identify the risk factors for AL and the impact on long-term survival in patients with left-sided colorectal cancer.MethodsNine-hundred patients with left-sided colorectal carcinoma who underwent sigmoid or rectal resection were enrolled in the study. Risk factors for AL after sigmoid or rectal resection were identified, and long-term outcomes of patients with and without AL were compared.ResultsAL rates following sigmoid and rectal resection were 5.1% and 10.7%, respectively. Higher ASA score (III–IV; OR = 10.54, p = 0.007) was associated with AL in patients undergoing sigmoid surgery on multivariable analysis. Male sex (OR = 2.40, p = 0.004), CCI score > 5 (OR = 1.72, p = 0.025), and T3/T4 stage tumors (OR = 2.25, p = 0.017) were risk factors for AL after rectal resection on multivariable analysis. AL impaired disease-free and overall survival in patients undergoing sigmoid (p = 0.009 and p = 0.001) and rectal (p = 0.003 and p = 0.014) surgery.ConclusionASA score of III–IV is an independent risk factor for AL after sigmoid surgery, and male sex, higher CCI score, and advanced T stage are risk factors for AL after rectal surgery. AL impairs the long-term survival in patients undergoing left-sided colorectal surgery.

Prognostic Utility of Apical Lymph Node Metastasis in Patients With Left-sided Colorectal Cancer.

Unlike the tumor nodes metastasis (TNM) lymph node classification, based solely on counts of nodal metastases, the Japanese system of classifying colorectal carcinoma (CRC) focuses on regional lymph node spread. In this study, we explored the prognostic utility of inferior mesenteric artery (IMA) apical lymph node (APN) metastasis. This was a retrospective study of patients with stage III left-sided CRC. All enrollees were subjected to D3 resection between April 2007 and December 2016 at the International Medical Center of Saitama Medical University and then stratified by histologic presence (APN+ group) or absence (APN- group) of tumor in APNs examined postoperatively. Ultimately, propensity score matching was invoked (1:2) and COX regression analysis was conducted, determining group rates of relapse-free survival (RFS) and cancer-specific survival (CSS). A total of 498 patients were studied, grouped as APN+ (19/498, 3.8%) or APN- (479/498, 96.2%). Prior to matching, the APN+ (vs. APN-) group showed significantly more lymphatic involvement (73.7% vs. 47.8%; p=0.023), deep (T3/T4) tumor infiltration (100% vs. 78.9%; p=0.024), and nodal metastasis (N2: 84.2% vs. 27.6%; p<0.001). In addition, para-aortic nodal recurrences were significantly increased (15.7% vs. 2.0%; p<0.001), conferring worse RFS (p<0.001) and CSS (p=0.014) rates. Once baseline factors were matched, the two groups appeared similar in RFS (p=0.415) and CSS (p=0.649). Multivariate regression analysis indicated that elevated carcinoembryonic antigen (CEA) level and deep tumor infiltration were independent risk factors for RFS, whereas postoperative complications and tumor-positive node counts were independent risk factors for CSS. APN+ status was not a significant risk factor for RFS or CSS. APN positivity may thus constitute a regional rather than systemic manifestation. The TNM staging based on the number of metastatic lymph nodes seems to be more reasonable than the regional lymph node classification method.

SATB1 Expression of Colorectal Adenomatous Polyps is Higher than that of Colorectal Carcinomas.

"Special AT-rich sequence-binding protein-1" (SATB1) is a global genome organizer and is found to have effects on carcinogenesis and progression of various malignancies including colorectal carcinoma (CRC). We aimed to investigate the expression of SATB1 in CRC and colorectal adenomatous polyps (CAP), the correlation between clinicopathologic parameters, and overall survival. We examined 227 CRCs and 129 CAPs. SATB1 protein expression was evaluated by immunohistochemistry. We found higher SATB1 expression in adenomatous epithelium than in CRC tissues (55.0% vs. 42.7%, respectively) (P<0.05). None of the adjacent normal colorectal mucosa stained positive in CRC cases, and only one of the adjacent normal mucosa of the CAP cases was positive. SATB1 expression of left-sided CRC was higher than that of right-sided CRC (46.3% vs. 28.6%, respectively) (P<0.05), and SATB1 expression of conventional adenocarcinomas was higher than that of mucinous carcinomas (45.5% vs. 6.3%, respectively) (P<0.05). SATB1 expression was higher in CAPs consisting of high-grade dysplasia than in polyps with low-grade dysplasia (77.8% vs. 51.4%) (P<0.05). SATB1 expression did not correlate with patients' overall survival. In conclusion, due to the higher expression of SATB1 in CAP than in CRC, we think SATB1 may have a role in the early stages of carcinogenesis of CRCs. This is the first study investigating SATB1 expression in CAPs. Besides this is the first report that shows different SATB1 expressions in conventional colorectal adenocarcinoma and mucinous carcinoma, and also in right-sided and left-sided CRC. Our results, with supporting new studies, can provide SATB1 as a possible candidate for targeted therapy for CRC patients.

DNA mismatch repair and CD133-marked cancer stem cells in colorectal carcinoma.

BackgroundExcept for a few studies with contradictory observations, information is lacking on the possibility of association between DNA mismatch repair (MMR) status and the presence of cancer stem cells in colorectal carcinoma (CRC), two important aspects in colorectal carcinogenesis.MethodsEighty (40 right-sided and 40 left-sided) formalin-fixed, paraffin-embedded primary CRC were immunohistochemically studied for CD133, a putative CRC stem cell marker, and MMR proteins MLH1, MSH2, MSH6 and PMS2. CD133 expression was semi-quantitated for proportion of tumor immunopositivity on a scale of 0–5 and staining intensity on a scale of 0–3 with a final score (units) being the product of proportion and intensity of tumor staining. The tumor was considered immunopositive only when the tumor demonstrated moderate to strong intensity of CD133 staining (a decision made after analysis of CD133 expression in normal colon). Deficient MMR (dMMR) was interpreted as unequivocal loss of tumor nuclear staining for any MMR protein despite immunoreactivity in the internal positive controls.ResultsCD133 was expressed in 36 (90.0%) left-sided and 28 (70.0%) right-sided tumors (p < 0.05) and CD133 score was significantly higher in left- (mean ± SD = 9.6 ± 5.3 units) compared with right-sided tumors (mean ± SD = 6.8 ± 5.6 units) p < 0.05). dMMR was noted in 14 (35%) right-sided and no (0%) left-sided CRC. When stratified according to MMR status, dMMR cases showed a lower frequency of CD133 expression (42.9%) and CD133 score (mean ± SD = 2.5 ± 3.6 units) compared with pMMR tumors on the right (frequency = 84.6%; mean score ± SD = 9.2 ± 5.0 units) as well as pMMR tumors on the left (frequency = 90.0%; mean score ± SD = 9.6 ± 5.3 units) (p < 0.05). Interestingly, frequencies of CD133 immunoreactivity and CD133 scores did not differ between pMMR CRC on the right versus the left (p > 0.05).ConclusionProficient MMR correlated with high levels of CD133-marked putative cancer stem cells in both right- and left-sided tumors, whereas significantly lower levels of CD133-marked putative cancer stem cells were associated with deficient MMR status in colorectal carcinomas found on the right.

The Case Files

Figure: Image A.FigureFigureA 41-year-old woman presented to the emergency department with abdominal pain, noting multiple episodes over the past year of intermittent right upper quadrant pain that she described as “achy” and “fullness.” These episodes occurred sporadically with no identifiable exacerbating factors. Associated symptoms included a 20-pound unintentional weight loss over two months with occasional nausea and vomiting. She was a former smoker of 10-pack years and had stopped two months prior to arrival, and she reported drinking two to three glasses of wine a week. She did not have a primary care physician. Her vital signs on arrival were a temperature of 97.7°F, blood pressure of 132/97 mm Hg, heart rate of 98 bpm, 99% pulse ox on room air, respirations of 18 bpm, and weight of 76 kg. A physical exam revealed mild tenderness to deep palpation in the RUQ with appreciable hepatomegaly. Laboratory values were remarkable for a hemoglobin of 12.7 g/dL, mean corpuscular volume of 92, gamma-glutamyl transferase of 382 (9-48 U/L), total bilirubin of 0.6, alkaline phosphatase of 205 (44-147), aspartate aminotransferase of 55 U/L (10-37 U/L), alanine aminotransferase of 33 U/L (8-37 U/L). She was hemoccult-positive on rectal exam. Ultrasound showed multiple lobulated ill-defined masses throughout the liver. (Images A and B.) A CT abdomen/pelvis showed multiple heterogeneously enhancing irregular hepatic masses, with the largest measuring 10.6 x 10.1 x 11.1 cm. (Images C and D.) She was admitted for further evaluation. High Mortality Colorectal carcinoma is a common and lethal disease with around 140,000 cases diagnosed annually in the United States. (UpToDate, May 2, 2018; http://bit.ly/2IPlAS5.) About 56,000 patients die of the disease. Clinical research has shown that patients with a primary care physician have better management of chronic disease, access to preventive care, including cancer screenings, and chronic care of a multitude of medical problems. Advanced cases, like our patient's demonstrated, commonly present with iron-deficient anemia, rectal bleeding, abdominal pain, change in bowel habits, and sometimes an intestinal obstruction or perforation. A study of 388 patients diagnosed with colorectal carcinoma from 2011-2014 found the most common symptoms leading to a diagnostic colonoscopy to be rectal bleeding (37%), abdominal pain (34%), and anemia (23%). (UpToDate, May 2, 2018; http://bit.ly/2IPlAS5.) Clinical manifestations will differ depending on the location of the tumor. A change in bowel habits is more common in left-sided colorectal carcinoma, as is hematochezia. Iron-deficient anemia has been found to be more common in right-sided colorectal carcinoma. (UpToDate, May 2, 2018, http://bit.ly/2IPlAS5; Clin Colorectal Cancer 2016;15[1]:67; http://bit.ly/2KDxe7F.)Figure: Image B.Figure: Image C.The goal of laboratory evaluation is to assess patients' organ function for potential diagnostic and therapeutic procedures, as well as tumor burden. A baseline carcinoembryonic antigen carries a prognostic value. Patients with highly elevated values are associated with more advanced disease. (Anticancer Res 2001;21[4B]:3031.) Colorectal carcinoma metastases are most commonly found in the liver and the lung. Chemotherapy and radiation therapy following surgical resection of the primary tumor, when indicated, remain the mainstay of adjuvant therapy. Approximately 20 percent of patients are diagnosed with metastatic disease at their initial presentation. (UpToDate, May 2, 2018; http://bit.ly/2IPlAS5.) Our patient's colonoscopy showed an ulcerated sigmoid mass. The tumor marker carbohydrate Ag 19-9 was 670 U/mL (0-35). The confirmed diagnosis of metastatic adenocarcinoma with primary colorectal carcinoma was made based on subsequent CT-guided biopsy of the liver, followed by pathological report and a biopsy at the ulcerated sigmoid mass showing high-grade dysplasia. Given the extent and bilobar nature of the metastases, our patient's best option was to start systemic chemotherapy, followed by fully restaging after 12 cycles to determine if she would benefit from liver-directed therapy.Figure: Image D.

PD-018 - Comparing survival in left-sided and right-sided colorectal carcinoma: A Belgian population-based study

PD-018 - Comparing survival in left-sided and right-sided colorectal carcinoma: A Belgian population-based study

CD9 Expression in Colorectal Carcinomas and Its Prognostic Significance.

BackgroundCD9, a member of the tetraspanin superfamily, is a tumor suppressor in many malignancies. The aim of this study was to evaluate the immunohistochemical expression of CD9 in colorectal carcinomas (CRCs) and determine clinicopathological and prognostic significance of its expression.MethodsThe CD9 expression status of 305 CRCs was evaluated using a semi-quantitative scoring system in tumor cells (T-CD9) and immune cells (I-CD9) by classifying the results as high and low expression.ResultsHigh T-CD9 (T-CD9 [+]) expression was detected in 175 samples (57.6%) and high I-CD9 (I-CD9 [+]) expression was detected in 265 samples (86.9%). Using Kaplan-Meier survival analysis, the T-CD9 (+) group showed a tendency for better disease-free survival (DFS) (p = .057). In left-sided tumors, DFS was significantly longer in the T-CD9 (+) group (p = .021) but no statistical significance was observed with right-sided tumors (p = .453). I-CD9 (+) CRCs significantly correlated with well/moderately differentiation (p = .014). In Kaplan-Meier analysis, the I-CD9 (+) group had a tendency towards worse DFS compared to the I-CD9 (–) group (p = .156). In combined survival analysis of T-CD9 and I-CD9, we found that the longest DFS was among patients in the T-CD9 (+)/I-CD9 (–) group, whereas the T-CD9 (–)/I-CD9 (+) group showed the shortest DFS (p = .054).ConclusionsHigh expression of T-CD9 was associated with a favorable DFS, especially in left-sided CRCs. Combined evaluation of T-CD9 and I-CD9 is required to determine the comprehensive prognostic effect of CD9 in CRCs.

Colorectal Carcinomas in Uyo City, Southern Geopolitical Zone of Nigeria: A Review of Clinicopathological Characteristics and Literature

Colorectal carcinomas (CRC) were initially thought to be rare in Africa including Nigeria, but recent studies have shown a reverse trend in our environment. This study is aimed to identify the clinical and pathological characteristics of CRC diagnosed between July 2006 and June 2015 in the University of Uyo Teaching Hospital, and a Private Specialist Laboratory, Uyo, Akwa Ibom State, Nigeria. All histological diagnosed cases of CRC seen in the two laboratories (University teaching and a private facility) in Uyo, Akwa-Ibom state, Nigeria during the study period were retrieved noting their bio-data, pathological and clinical variables. A total of 45 patients of age range 26-80 years with a mean of 55.9 years (SD 3.9) and a male to female ratio of 1.4:1 were seen. The two most common age groups affected in CRCs were 61-70 years (28.9%) and 51-60 years (24.4%) respectively. Majority of CRC patients were older than 40 years (86.7%) with identifiable predisposing factors being tubulo-villous adenoma (4 cases, 8.8%), villous adenoma (2 cases 4.4%), polyposis syndromes (2 cases, 4.4%) and schistosomiasis (1 case, 2.2%). Features of large intestinal obstruction were the most common presenting symptom of CRC (53.3%). Rectal bleeding, alteration in bowel habit and fecal incontinence were other symptoms, accounting for 33.3%, 8.9% and 4.4% of cases respectively. Left-sided CRCs were commoner (68.9%) with the majority appearing as annular-constricting type macroscopically (60.0%). Recto-sigmoid region was the preponderant site involved in CRC (29 cases, 64.5%). Adenocarcinoma (84.4%) was the most frequent histological subtype. Mucinous carcinoma, signet ring carcinoma and carcinoid tumor were other histologic subtypes seen in 8.9, 4.4 and 2.2% of cases respectively. The 22.0% of CRC patients presented at advanced stages of the disease. It can be concluded that majority of CRC patients were older than 40 years (86.7%) with features of intestinal obstruction (53.3%) and adenocarcinoma (84.4%) being the predominant mode of clinical presentation and histological subtype respectively.

Interaction of KRAS somatic mutation and colorectal carcinoma and its association with differential DNA methylation.

577 Background: We examined if KRAS somatic mutation in colorectal carcinoma (CRC) is associated with differential tumor DNA methylation. Methods: We did a genome-wide methylation assay (450K) for a total of 250 paired samples from 125 CRC patients (m = 72, f = 53) at different stages (stage 1: 25, stage II: 33 and stage III: 67). Of them 101 had left-sided CRC (descending colon to rectum); 30 had MSI, and 34 had somatic mutation in KRAS (rs112445441). Results: Frequency of KRAS mutation was not different between right and left-sided CRC (29% vs. 27%). But, like other series, MSI was more frequent in the right-sided tumor (54% vs. 17%, p = 0.003). In patients with wild type KRAS tumor (n = 91), paired comparison between tumor and corresponding normal tissue identified a total of 1244 tumor-specific differential methylation loci (DML) covering 532 genes that were significant at FDR 0.001 and magnitude of difference ≥ 20%; But similar analysis in patients with KRAS mutation (n = 34) revealed 7612 tumor-specific DML covering 2357 genes - suggesting an association of KRAS mutation and DNA methylation. We also found that MSI in tumor tissue was associated with DNA methylation change too. Next, we identified 726 genes that are markedly differentially methylated in tumor compared to corresponding normal tissue only in presence of KRAS mutation, irrespective of MSI status, staging, and location of tumor (KRAS mutation associated tumor-specific genes – list enriched in GO ontology “developmental process”, “biological regulation”). We also identified 241 genes that are differentially methylated in tumor compared to normal tissue irrespective of KRAS mutation, MSI status, staging, and location of tumor. (common tumor-specific genes) Conclusions: KRAS somatic mutation is independently associated with methylation changes in a number of genes related to carcinogenesis in CRC.

A national population-based study provides insight in the origin of malignancies metastatic to the ovary.

A significant proportion of ovarian malignancies consists of metastatic tumors, with a wide variety in site of origin. Differentiating between a primary and metastatic malignancy of the ovaries can be difficult and misdiagnosis might have considerable impact on both treatment and prognosis. To further examine the origin of malignancies metastatic to the ovary, we performed a large-scale, nationwide search for ovarian metastases in the Dutch Pathology Registry (PALGA). All pathology reports concerning malignancies metastatic to the ovary and associated primary tumors in the Netherlands between 2000 and 2010 were collected. Age, year of diagnosis, tumor type, location of the primary tumor, and side of the ovarian tumor were extracted from the database. We identified 2312 patients fulfilling our selection criteria. The most common primary malignancy sites were colon (33.2 %), endometrium (17.1 %), breast (14.3 %), appendix (7.3 %), and stomach (4.5 %). The metastases were most frequently bilateral (46.3 %) followed by unilateral metastases in the right (26.7 %) and left ovary (19.8 %), while side was unknown in 7.2 % of cases. Of colorectal carcinomas, only 40.2 % metastasized bilaterally, compared to 63.9 % of breast, 62.9 % of gastric, and 58.9 % of appendix carcinomas. Left-sided colorectal carcinomas most often metastasized to the left ovary (p < 0.0001). We found colon carcinomas to be most frequently responsible for metastases to the ovaries, followed by endometrial and breast carcinomas. Metastases from breast, stomach, and appendix carcinomas were mostly bilateral, whereas metastases from colorectal carcinomas were mostly unilateral. The mechanisms underlying preferred sites for metastasis or side remain unclear.

Left-sided early-onset vs late-onset colorectal carcinoma: histologic, clinical, and molecular differences.

Carcinomas of the left colon represent a neoplasm of older patients (late onset), but epidemiologic evidence has been showing an increasing incidence in patients 50 years or younger (early onset). In this study, we investigate pathologic and molecular features of early- and late-onset carcinoma of the left colon. We selected 22 patients 50 years or younger and 21 patients 70 years or older with left-sided colorectal carcinoma (CRC). All samples were evaluated for pathologic features, microsatellite instability, and KRAS and BRAF mutations. Moreover, both groups were analyzed to identify CpG island methylator phenotype features and assessed with restriction landmark genome scanning (RLGS) to unveil differential DNA methylation patterns. Early-onset patients had advanced pathologic stages compared with late-onset patients (P = .0482). All cases showed a microsatellite stable profile and BRAF wild-type sequence. Early-onset patients (43%) more frequently had mutations at KRAS codon 12 compared with late-onset patients (14%) (P =.0413). RLGS showed that patients younger than 50 years who had CRC had a significantly lower percentage of methylated loci than did patients 70 years or older (P = .04124), and differential methylation of several genomic loci was observed in the two groups. Our results suggest that left-sided CRCs may present differential patterns of aberrant DNA methylation when they are separated by age.

A comparison of right versus left-sided colorectal carcinoma for DNA mismatch repair and presence of putative CD133-stem cells

Right and left-sided colorectal carcinoma (CRC) are generally observed to differ in pathogenetic mechanisms, with deficiency of DNA mismatch repair (dMMR) leading to microsatellite instability occurring more commonly on the right. A study to assess the DNA mismatch repair status and presence of CD133-putative stem cells in 40 consecutive right and 40 left-sided formalin-fixed, paraffin-embedded CRC was carried out at the Department of Pathology, University of Malaya Medical Centre. Immunohistochemical staining for DNA mismatch repair gene products, MLH1, MSH2, MSH6 and PMS2 and CD133 were carried out on a Ventana XT autostainer. dMMR was significantly increased in right-sided (35%) compared with left-sided (0%) CRC. Of the dMMR cases, 10 had concomitant loss of MLH1 and PMS2, two concomitant loss of MSH2 and MSH6, one isolated loss of MSH6 and another of PMS2. CD133 immunoexpression score, arbitrarily computed as the semi-quantitative estimation of proportion of CRC immunopositive cells multiplied by intensity of staining was significantly lower (<i>p</i><0.05) in right (mean score=7.0) compared with left-sided tumours (mean score=9.9). The observations of a higher frequency of dMMR and lower CD133 expression in right-sided CRC further support the notion of dissimilar mechanisms involved in aetiology and evolution of right and left-sided tumours.

Lynch syndrome–associated colorectal carcinoma: frequent involvement of the left colon and rectum and late-onset presentation supports a universal screening approach

The optimal strategy for screening patients with colorectal carcinoma for Lynch syndrome (LS) is a subject of continued debate in the literature with some advocating universal screening while others arguing for selective screening. We evaluated 1292 colorectal carcinomas for DNA mismatch repair protein abnormalities and identified 150 (11.6%) tumors demonstrating high-levels of microsatellite instability (MSI-H). MSI-H colorectal carcinomas were divided into sporadic (112/1292, 8.7%) and LS/probable LS-associated (38/1292, 2.9%) groups based on BRAF V600E mutation, MLH1 promoter hypermethylation, cancer history, and germline mismatch repair gene mutation. All MSI-H colorectal carcinomas were analyzed for grade, location, and tumor histology. The utility of the revised Bethesda guidelines and published predictive pathology models for MSI-H colorectal carcinomas (PREDICT and MSPath) were evaluated. Left-sided MSI-H colorectal carcinomas were more frequently associated with LS compared with right-sided MSI-H colorectal carcinomas (12/21, 57% versus 26/129, 20%, P = .0008). There was no significant difference in histology between sporadic MSI-H and LS/probable LS-associated colorectal carcinomas except for a slightly higher proportion of sporadic MSI-H tumors demonstrating tumor-infiltrating lymphocytes (81% versus 61%, P = .015). Neither pathology predictive model identified all LS-associated colorectal carcinomas (PREDICT: 33/38, 87%; MSPath: 35/38, 92%). 12/117 (10%) MSI-H colorectal carcinomas identified in patients >60 years were LS/probable LS-associated. Our results demonstrate that models of predicting MSI-H fail to identify LS-associated colorectal carcinoma given their reliance on right-sided location. A significant proportion (32%) of LS-associated colorectal carcinoma is identified in patients >60 years. Finally, our results demonstrate similar morphologic features between LS-associated and sporadic MSI-H colorectal carcinomas.

TROP2 expression and its evolving role in tumor pathogenesis in systemic tumors

To the Editor: I read with great interest the recent article by Fang et al. [1]. TROP2 may play a major role in tumor pathogenesis in a number of systemic malignancies. Pulmonary squamous cell carcinomas tend to show increased expression of TROP2. A close association exists between the pathological T stage and TROP2 overexpression in pulmonary squamous cell carcinomas [2]. Poorly differentiated lung tumors tend to exhibit increased expression of TROP2. TROP2 also influences and alters IGF-1R signaling in these tumors [3]. Patients with pulmonary adenocarcinomas, especially those in stage II or III that overexpressTROP2, tend to have a better clinical outcome. They also exhibit better survival rates. Thus, TROP2 overexpression is an important independent marker of prognosis in lung carcinomas. A similar relationship is seen in colorectal carcinomas [4]. Decreased overall survival and increased invasiveness is seen in stage IIB colorectal carcinomas that show upregulation of TROP2. Interestingly, there is differential expression of TROP2 and tumor aggressiveness in between rightand left-sided colorectal carcinomas [5]. For instance, left-sided colorectal carcinomas show significantly higher TROP2 expression in contrast to TROP2 expression in right-sided colon carcinomas. Recent data suggest that TROP2 is an independent parameter influencing prognosis in left-sided colon carcinomas. Tumors with accentuated TROP2 expression also demonstrate more lymph node metastases as well as deeper depth of invasion. In patients with left-sided squamous cell carcinoma and low TROP2 expression, the median survival time is 63.1months in contrast to 45.9months in those with high TROP2 expression [5–7]. TROP2 expression is also an important parameter that influences the risk of developing hepatic metastasis. About 56 % of gastric malignancies, especially the intestinal type, exhibit TROP2 overexpression [8]. Assessment of TROP2 in intestinal type gastric malignancies is highly significant. In these tumors, TROP2 is an independent parameter that influences cancer recurrence. In lymph nodepositive patients, a negative relationship exists between TROP2 overexpression and disease-free survival as well as overall survival. It promotes cancerogenesis by activating the ERK MAPK pathway [9]. Fifty-five percent of pancreatic malignancies exhibit TROP2 overexpression [10]. In pancreatic malignancies that demonstrate accentuated levels of TROP2, a poor clinical outcome is seen typically. A positive relationship exists between lymph node metastasis and TROP2 overexpression. Similarly, a positive relationship exists between tumor grade and TROP2 overexpression. In the end, TROP2 overexpression is associated with decreased progression-free survival as well as decreased overall survival. The above examples clearly illustrate the role of TROP2 in systemic carcinogenesis and the need for further studies in this regard.

Helicobacter pylori infection and colorectal carcinoma: pathologic aspects.

Helicobacter pylori infection and colorectal carcinoma: pathologic aspects.