Craig A. Messick

Genetic and molecular diversity of colon cancer hepatic metastases

BACKGROUND Colon cancer arises through distinct molecular pathways resulting in diverse tumor populations demonstrated by differences in microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and mutations in oncogenes KRAS and BRAF. Although these molecular differences are well-described for primary neoplasms, the molecular nature of hepatic metastases is not well-characterized. This study seeks to describe molecular characteristics of colon cancer hepatic metastases in terms of oncogenic pathway. METHODS Tumor DNA was isolated from fresh frozen hepatic metastases from colon cancer and analyzed for MSI by polymerase chain reaction (PCR)-based microsatellite analysis and for CIMP using MethyLight quantitative PCR. KRAS and BRAF oncogenes were analyzed for DNA mutations. Metastases were classified by their molecular and genetic features. Unfortunately, tissue from the primary neoplasms from these patients were not available RESULTS Thirty patients with liver metastases from colon cancer were studied. Molecular analysis revealed 10% (3/30) were MSI-H, 10% (3/30) were CIMP positive, 33% (10/30) had KRAS mutations, and none had BRAF mutations. Literature describing primary colon cancers reports an incidence of approximately 20% MSI-H, 20% CIMP-positive, 35% KRAS mutants, and 17% BRAF mutants. CONCLUSION Hepatic metastases from colon cancer, like primary colon adenocarcinomas, show genetic and molecular diversity. Furthermore, hepatic metastases may have a different incidence of MSI and methylation compared with primary neoplasms. These differences could impact treatment decisions.

Identification of the Methylator (serrated) Colorectal Cancer Phenotype Through Precursor Serrated Polyps

PURPOSE: Colorectal cancers arise via cumulative genetic and molecular changes that cause mucosal instability, premalignant polyps, and malignant transformation. Distinct neoplastic pathways characterized by chromosomal instability, genetic mutation, and epigenetic methylation have been described, but their associated precursor polyps have not. This study analyzes characteristics of precursor polyps occurring within different molecular subtypes of sporadic colorectal cancer. METHODS: Colorectal cancers from a prospectively maintained frozen tissue bank were analyzed for microsatellite stability and promoter methylation, defined by the CpG island methylator phenotype. Patients with tumors meeting the following criteria were included: microsatellite stable and methylator-negative; microsatellite stable and methylator-positive; and microsatellite unstable and methylator-positive. Hereditary cancers were excluded. Patient demographics, colonoscopic and histologic polyp characteristics, operative reports, and pathology reports were reviewed. RESULTS: One hundred seven patients were included: 65, 20, and 22 patients in each group, respectively. The proportion of patients with synchronous polyps and polyp number, size, and location were similar. However, associated polyp histology varied according to tumor classification. Microsatellite stable tumors, regardless of methylator status, had a greater proportion of adenomas than microsatellite unstable tumors, which had an increased proportion of serrated polyps (P = 0.029). CONCLUSIONS: Patients with microsatellite unstable colorectal cancers demonstrate an increased serrated polyp-to-adenoma ratio compared with microsatellite stable cancers regardless of methylator status. Loss of microsatellite stability appears to be a key event in serrated polyp and cancer formation. An increased proportion of serrated polyps to adenomas discovered in patients on colonoscopy should arouse suspicion that cancers arising in these patients are probably microsatellite unstable.

CEACAM-7: A predictive marker for rectal cancer recurrence

BACKGROUND The identification of rectal cancer patients predisposed to developing recurrent disease could allow directed adjuvant therapy to improve outcomes while decreasing unnecessary morbidity. This study evaluates carcinoembryonic antigen cellular adhesion molecule-7 (CEACAM-7) expression in rectal cancer as a predictive recurrence factor. METHODS A single-institution colorectal cancer database and a frozen tissue biobank were queried for rectal cancer patients. CEACAM-7 messenger RNA (mRNA) expression from normal rectal mucosa and rectal cancers was analyzed using quantitative real-time polymerase chain reaction (PCR). Expression-level differences among normal tissue, disease-free survivors, and those that developed recurrence were analyzed. RESULTS Eighty-four patients were included in the study, which consisted of 37 patients with nonrecurrent disease (median follow-up, 170 months), 29 patients with recurrent disease, and 18 patients with stage IV disease. CEACAM-7 expression was decreased 21-fold in rectal cancers compared with normal mucosa (P = .002). The expression levels of CEACAM-7 were relatively decreased in tumors that developed recurrence compared with nonrecurrence, significantly for stage II patients (14-fold relative decrease, P = .002). For stages I-III, disease-free survival segregates were based on relative CEACAM-7 expression values (P = .036), specifically for stage II (P = .018). CONCLUSION CEACAM-7 expression is significantly decreased in rectal cancer. Expression differences between long-term survivors and those with recurrent disease introduce a potential tumor marker to define a subset of patients who benefit most from adjuvant therapy.

Impact of recurrence and salvage surgery on survival after multidisciplinary treatment of rectal cancer

Purpose After preoperative chemoradiotherapy followed by total mesorectal excision for locally advanced rectal cancer, patients who experience local or systemic relapse of disease may be eligible for curative salvage surgery, but the benefit of this surgery has not been fully investigated. The purpose of this study was to characterize recurrence patterns and investigate the impact of salvage surgery on survival in patients with rectal cancer after receiving multidisciplinary treatment. Patients and Methods Patients with locally advanced (cT3-4 or cN+) rectal cancer who were treated with preoperative chemoradiotherapy followed by total mesorectal excision at our institution during 1993 to 2008 were identified. We examined patterns of recurrence location, time to recurrence, treatment factors, and survival. Results A total of 735 patients were included. Tumors were mostly midrectal to lower rectal cancer, with a median distance from the anal verge of 5.0 cm. The most common recurrence site was the lung followed by the liver. Median time to recurrence was shorter in liver-only recurrence (11.2 months) than in lung-only recurrence (18.2 months) or locoregional-only recurrence (24.7 months; P = .001). Salvage surgery was performed in 57% of patients with single-site recurrence and was associated with longer survival after recurrence in patients with lung-only and liver-only recurrence ( P < .001) but not in those with locoregional-only recurrence ( P = .353). Conclusion We found a predilection for lung recurrence in patients with rectal cancer after multidisciplinary treatment. Salvage surgery was associated with prolonged survival in patients with lung-only and liver-only recurrence, but not in those with locoregional recurrence, which demonstrates a need for careful consideration of the indications for resection.

Metachronous serrated neoplasia is uncommon after right colectomy in patients with methylator colon cancers with a high degree of microsatellite instability

BACKGROUND: Right-sided serrated polyps are precursors to sporadic microsatellite unstable colon cancers via the methylator pathway and have a high rate of synchronous and metachronous lesions. Serrated polyps also occur in Lynch syndrome, where right-sided microsatellite unstable cancers arise from germline mutations in mismatch repair genes. OBJECTIVE: The aim of this study was to compare serrated neoplasia in patients with sporadic and hereditary microsatellite unstable colon cancer and to examine the effect of right colectomy on the risk of metachronous polyps and cancers. DESIGN: This is a retrospective, descriptive, cohort study from database and chart review. SETTING: This study was conducted at a tertiary care hospital with a center for hereditary colorectal cancer. PATIENTS: Patients who had colon cancers with a high degree of microsatellite instability, methylator cancers, and Lynch syndrome cancers, were included. INTERVENTIONS: Interventions included colectomy, surveillance colonoscopy, and polypectomy. MAIN OUTCOME MEASURES: The primary outcomes measured were the incidence and location of metachronous polyps and cancers. RESULTS: Eighty-five patients were included: 47 with methylator cancers and 38 with Lynch syndrome. Median ages at surgery were 75 years (range, 41–90) and 48 years (range, 27–77), p < 0.0001. Forty-six (98%) patients with methylator cancers and 17 (45%) patients with Lynch syndrome underwent a right colectomy, p < 0.0001. Metachronous cancers occurred in 19/60 (32%) of patients with Lynch syndrome and no patients with methylator cancers, p < 0.0001. Thirty-four patients with methylator cancers had colonoscopic follow-up, with a median of 2 colonoscopies per patient over a 32-month follow-up (range, 1–136). Sixty-three percent of patients with Lynch syndrome had colonoscopic follow-up, median of 4 colonoscopies per patient over 102 months (range, 1–462), p < 0.0001. Four (9%) patients with methylator cancers each had 1 metachronous serrated polyp, compared with 10/37 (27%) patients with Lynch syndrome (p = 0.049), whose median number of polyps was 2 (range, 1–8). Characteristics of other associated polyps were similar between cohorts. LIMITATIONS: This study is somewhat limited by potential inherent bias from its retrospective design. Also, a high number of deaths in the CIMP+ cohort could have contributed to the low number of serrated polyps detected on colonoscopy surveillance, but given current understanding of serrated polyp growth, this may truly represent the left colons tendency not to develop serrated polyps. CONCLUSIONS: Cancers with a high degree of microsatellite instability arise through 2 different molecular mechanisms. Metachronous serrated neoplasia, benign and malignant, following right colectomy in patients with the CpG-island methylator phenotype of colorectal cancer is uncommon. However, the colons of patients with Lynch syndrome are at high risk after segmental colectomy.

Presacral tumors: how do they compare in pediatric and adult patients?

UNLABELLED Presacral tumors are rare with few published studies in the literature. It is unknown whether the course of the disease and the required treatment differs between pediatric and adult patients. The aim of the study was to compare presenting symptoms, surgical treatment, pathology, and recurrence rates of presacral tumors in these two groups. MATERIAL AND METHODS An IRB-approved chart review was conducted for patients diagnosed with a presacral tumor at the Cleveland Clinic between 1981 and 2011. Symptoms, physical exam, surgical details, tumor histology, and outcomes were collected as part of the review. Patients were divided into two groups: pediatric (< 18 years n=14) and adult (≥ 18 years n=50). RESULTS The most common symptom was a mass in pediatric and pain in adult patients. The most common pediatric primary tumor was a teratoma (n=5, 36%) versus Hamartoma/tailgut cyst (n=17, 34%) in adult patients. Three pediatric and nine adult patients developed tumor recurrences, and 2/14 (14%) pediatric and 4/50 (8%) adult patients developed metastases. CONCLUSIONS This study summarizes the presentation, evaluation and management of pediatric and adult presacral tumors at tertiary referral center. The presentation, histology, and management of presacral tumors vary depending upon whether they occur in pediatric or adult patients and recognition of potential differences may influence management.

Presacral (Retrorectal) Tumors: Optimizing the Management Strategy

151 DISEASES OF THE COLON & RECTUM VOLUME 61: 2 (2018) CASE SUMMARY: A 67-year-old healthy man presents with a recent history of an elevated prostate-specific antigen that resulted in biopsies (negative for malignancy) and imaging of the pelvis with MRI that revealed 2 tumors in the presacral space low in the pelvis. He admits to constipation for the past year that has resolved with stool softeners. He endorses a history of Parkinson disease, throat cancer (remote) treated with chemoradiation therapy, and asbestos exposure; he carries no additional diagnoses and denies any reports specifically to pain, rectal bleeding, or other defecatory dysfunction. On examination, he has a palpable mass that is soft to touch, nontender, and mobile, and it has components that exist both above and below the levator ani located right posterior-laterally. The top of the tumor is not palpable. Additional workup included an MRI of the pelvis with true coronals and 3-mm slices that demonstrate 2 large, homogeneous, cystic masses that may represent a single mass that is connected traversing the levator ani muscle and does not involve the rectal wall (Fig. 1).

Do precursor polyp burdens help distinguish Lynch versus non-Lynch microsatellite unstable colorectal cancers?

Background Microsatellite instability (MSI) within colorectal cancers (CRC) may develop through inherited germline mutations in mismatch repair (MMR) genes (Lynch Syndrome) or sporadic epigenetic methylation of tumor suppressor or repair genes (methylator pathway). Although the molecular mechanisms in each pathway have been described, their associated precursor polyp burdens are not well-defined. This study analyzes precursor polyp burdens occurring within patients with MSI-H colorectal cancers associated with Lynch Syndrome (LS) or those with a methylator pathway cancer phenotype.