Arnold J. Markowitz

Value of histopathology in predicting microsatellite instability in hereditary nonpolyposis colorectal cancer and sporadic colorectal cancer

Identification of colorectal carcinomas with high levels of DNA microsatellite instability (MSI-H) is important because of the suggested prognostic and therapeutic significance associated with MSI. The role of histology in identifying MSI-H colorectal carcinomas has been suggested by some studies but not confirmed by others. Furthermore, previous studies assumed that hereditary nonpolyposis colorectal cancer (HNPCC)-associated MSI-H tumors and sporadic MSI-H tumors have similar histology. This assumption, however, has been challenged by more recent studies. In this report, we first analyzed the value of various histologic features in predicting MSI-H in a series of 218 colorectal carcinomas containing mixed HNPCC and sporadic cases [77 tumors (35%) were MSI-H by polymerase chain reaction (PCR) method]. Then, we evaluated the various histologic features comparatively in two groups extracted from the 218 cases. Group A was composed of 84 tumors from 82 patients obtained based on a strong family history (HNPCC/HNPCC-like group) (male to female ratio, 42:40; age range, 23–80 years, median, 53.5 years). Thirty-one of the 84 tumors (41.7%) were MSI-H by PCR, and all 31cases were HNPCC by Amsterdam criteria. Group B was composed of 109 patients with no family history of colorectal cancer or HNPCC-associated cancer, obtained from surgical clinics (sporadic group) (male to female ratio, 65:69; age range, 31–84 years, median, 65 years). Thirty-five of the 109 tumors (32.1%) were MSI-H by PCR. Our results showed that, overall, poor tumor differentiation, medullary type, mucinous type, signet-ring cell component, histologic heterogeneity, and increased tumor-infiltrating lymphocytes (TILs) were features more commonly seen in MSI-H tumors than in non-MSI-H tumors. Comparative analyses showed that the overall TIL count was significantly higher in HNPCC/HNPCC-like group, and mucinous type appeared to be more frequent in HNPCC MSI-H tumors than in sporadic MSI-H tumors. However, there was no significant difference in the odds ratio for predicting MSI-H status for any of the analyzed histologic features between HNPCC/HNPCC-like group and sporadic group, indicating that differences between HNPCC and sporadic MSI-H tumors did not significantly impact on the informative value of histology in predicting MSI in the two different clinical settings. TIL counts followed by histologic heterogeneity provided the greatest sensitivity and specificity in predicting MSI status in both HNPCC/HNPCC-like and sporadic cases. Using a stepwise logistic regression model, a formula was generated that could be used to calculate the probability of a colorectal carcinoma being MSI-H based on morphologic features.

Correlates of colorectal cancer screening compliance and stage of adoption among siblings of individuals with early onset colorectal cancer

Concepts from the health belief, transtheoretical, and dual process models were used to examine how siblings of individuals diagnosed with colorectal cancer (CRC) before age 56 made decisions about CRC screening. Siblings (N = 504) were assessed for CRC screening practices and intentions, pros, cons, processes-of-change, perceived risk of CRC, perceived severity of CRC, preventability of CRC, cancer-related distress, and sibling relationship closeness. Physician and family recommendation and knowledge were also assessed. Fifty-seven percent of participants (n = 287) were compliant with CRC screening. Logistic regression indicated that perceived pros and cons, perceived risk, commitment to screening, health care avoidance, and sibling closeness were associated with screening compliance. Physician and family recommendation were also strong correlates. A similar set of factors was associated with stage of adoption of CRC screening.

Value of immunohistochemical detection of DNA mismatch repair proteins in predicting germline mutation in hereditary colorectal neoplasms.

The utility of immunohistochemistry (IHC) as a screening method for the identification of persons with mutations in the DNA mismatch repair (MMR) genes in hereditary nonpolyposis colorectal cancer (HNPCC) remains to be defined. In this study, we analyzed the value of IHC versus that of microsatellite instability (MSI) testing in predicting mutation status of the MLH1, MSH2, and MSH6 genes in colorectal carcinomas and adenomas, and explored the frequency and significance of immunohistochemical staining variability. The study samples included 83 carcinomas and 29 adenomas derived from 110 patients who had strong family histories of colorectal cancer. Our results showed that IHC correctly predicted MSI status in 76% of the cases with a specificity of 100%. The overall sensitivity of IHC in predicting a germline mutation was 79% (30 of 38) with a specificity of 89% (48 of 54), whereas that of MSI testing was 97% (30 of 31) with a specificity of 83% (35 of 42). Six of 31 analyzable cases that had a disease-causing mutation and exhibited MSI showed normal IHC. The lower sensitivity of IHC was caused mainly by its low sensitivity in detecting MLH1 gene mutation (4 of 9). Coexisting adenomas and carcinomas observed in the same slide (n = 12) showed a similar or identical staining pattern for all three proteins. No significant difference was detected in the sensitivity of IHC or MSI in detecting a germline mutation between isolated adenomas and carcinomas. In IHC-positive cases, heterogeneous staining was noted in 30% to 40% of the cases with the three different antibodies, and cytoplasmic staining in 5% to 13%. Weak IHC (defined as positive staining in <10% of the tumor with weak intensity) was noted in 14 tumors: 5 for the MLH1 antibody, 1 for MSH2, and 8 for MSH6. One of the 5 MLH1 cases exhibited MSI and had an MLH1 germline mutation. Five of the 8 MSH6 cases exhibited MSI and had MSH2 germline mutations. In conclusion, our study shows that 1) IHC identifies a significant portion of colorectal tumors derived from MMR gene germline mutation carriers and can be used as an adjunct measure in the identification of HNPCC families, but IHC cannot replace MSI testing; 2) adenomas have similar MMR protein expression patterns as carcinomas and may serve as an adequate sample for screening purposes in the identification of patients with MMR mutations; 3) not all IHC-positive cases show uniform positivity throughout the tumor; and 4) weak and focal staining of an MMR protein may be associated with MSI or gene mutation or both, suggesting the need to incorporate staining intensity in further IHC studies.

The Founder Mutation MSH2*1906G→C Is an Important Cause of Hereditary Nonpolyposis Colorectal Cancer in the Ashkenazi Jewish Population

Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by mutations in the mismatch-repair genes. We report here the identification and characterization of a founder mutation in MSH2 in the Ashkenazi Jewish population. We identified a nucleotide substitution, MSH2*1906G-->C, which results in a substitution of proline for alanine at codon 636 in the MSH2 protein. This allele was identified in 15 unrelated Ashkenazi Jewish families with HNPCC, most of which meet the Amsterdam criteria. Genotype analysis of 18 polymorphic loci within and flanking MSH2 suggested a single origin for the mutation. All colorectal cancers tested showed microsatellite instability and absence of MSH2 protein, by immunohistochemical analysis. In an analysis of a population-based incident series of 686 Ashkenazi Jews from Israel who have colorectal cancer, we identified 3 (0.44%) mutation carriers. Persons with a family history of colorectal or endometrial cancer were more likely to carry the mutation than were those without such a family history (P=.042), and those with colorectal cancer who carried the mutation were, on average, younger than affected individuals who did not carry it (P=.033). The mutation was not detected in either 566 unaffected Ashkenazi Jews from Israel or 1,022 control individuals from New York. In hospital-based series, the 1906C allele was identified in 5/463 Ashkenazi Jews with colorectal cancer, in 2/197 with endometrial cancer, and in 0/83 with ovarian cancer. When families identified by family history and in case series are included, 25 apparently unrelated Ashkenazi Jewish families have been found to harbor this mutation. Although this pathogenic mutation is not frequent in the Ashkenazi Jewish population (accounting for 2%-3% of colorectal cancer in those whose age at diagnosis is <60 years), it is highly penetrant and accounts for approximately one-third of HNPCC in Ashkenazi Jewish families that fulfill the Amsterdam criteria.

EUS-guided fiducial placement for image-guided radiation therapy in GI malignancies by using a 22-gauge needle (with videos )

BACKGROUND Image-guided radiation therapy (IGRT) is dependent on the presence of fiducial markers for target localization and tracking. EUS-guided placement of fiducial markers with a 19-gauge needle has been reported. However, the size and stiffness of the 19-gauge needle may compromise the safety and ease of fiducial placement. OBJECTIVE The aim of this study was to evaluate the safety and feasibility of EUS-guided placement of thin flexible gold coil fiducials by using a 22-gauge needle. DESIGN Retrospective study. SETTING Memorial Sloan-Kettering Cancer Center, between December 2008 and November 2009. PATIENTS A total of 30 patients with GI malignancies of the mediastinum and upper abdomen who were to undergo IGRT. INTERVENTIONS EUS evaluation with a curvilinear-array echoendoscope was performed. The target lesion was identified, a 22-gauge needle preloaded with a gold coil fiducial was inserted into the lesion, and the fiducial was deployed under EUS guidance. MAIN OUTCOME MEASUREMENTS Technical success was defined as the ability to place fiducials in the desired location. Immediate and delayed complications were also noted. RESULTS A total of 69 fiducials were placed in 12 different sites in the mediastinum and upper abdomen. Technical success was achieved in 29 out of 30 cases (97%). No intraprocedural complications were encountered. One patient developed a fever and abnormal liver function tests 12 hours after fiducial placement. LIMITATIONS Retrospective design, small case series. CONCLUSIONS EUS-guided placement of thin flexible gold coil fiducials by using a 22-gauge needle is both safe and feasible for upper GI malignancies.

Quality of Life and Symptom Control after Stent Placement or Surgical Palliation of Malignant Colorectal Obstruction

BACKGROUND Emergent surgical management of malignant large bowel obstruction (LBO) carries a high rate of morbidity and mortality. Self-expanding metal stents have emerged as an alternative for palliation of malignant LBO. However, there are few long-term studies documenting the effect of surgical palliation or colonic stents on symptoms or quality of life (QoL). STUDY DESIGN Between 2003 and 2006, patients with unresectable-for-cure malignancies presenting with LBO were enrolled in this prospective study. Patients elected to undergo stent placement or surgical palliation. Patients completed a symptom questionnaire and a QoL instrument (Functional Assessment of Cancer Therapy-Colorectal [FACT-C]) at weeks 1, 2, 4, 8, 12, and 24 after palliation. Symptoms were assessed using the Colon Obstruction Score, a novel instrument comprising nausea, vomiting, pain, distension, and bowel movement frequency scores. RESULTS Thirty patients had successful stent placement; 14 underwent surgical diversion. Colon Obstruction Scores immediately improved after both stent placement and surgery (p < 0.05 for all time points). Composite FACT-C scores progressively improved after stent placement (p = NS), with the colon symptoms subscale improving after 1 month (p < 0.05). FACT-C scores declined initially after surgery and then returned to baseline, with modest improvements seen in the Colon Symptoms subscale (p = NS). CONCLUSIONS Both stent placement and surgical diversion provide durable improvement in symptoms from LBO, as readily assessed by the Colon Obstruction Score. QoL is difficult to assess in terminal cancer patients, but colon stent placement is associated with improved overall QoL and QoL related to gastrointestinal symptoms.

MSH6 germline mutations are rare in colorectal cancer families

Germline mutations in MSH6 can cause HNPCC, which is associated with a tumor phenotype featuring MSI. However, tumors arising in persons with disease‐causing mutations of MSH6 may or may not exhibit MSI. We used D‐HPLC to screen for germline mutations in the promoter region, the coding region and the 3′‐UTR of MSH6. Eighty‐four families, enrolled on the basis of Amsterdam I and II criteria (HNPCC families) and less stringent criteria (HNPCC‐like families), were tested for MMR gene mutations; 27 families had a disease‐causing mutation in MLH1 or MSH2, and the remaining 57 families were tested for mutations in MSH6. Two protein‐truncating mutations were identified in each of 2 families fulfilling the Amsterdam I criteria, being present in persons affected with early‐onset colorectal cancers exhibiting MSI. Immunohistochemical analysis showed that expression of both MSH2 and MSH6 proteins was lost in the cancer cells of the 2 mutation carriers but only MSH6 protein expression was lost in 2 adenomatous polyps. A third possibly disease‐causing mutation was found in a person affected with a tumor that did not exhibit MSI. In addition, we found 4 new polymorphisms and determined that neither of the 2 studied by association analysis conferred susceptibility to colorectal or endometrial cancer. Altogether, our results indicate that disease‐causing germline mutations of MSH6 are rare in HNPCC and HNPCC‐like families.

Endoscopic Ultrasound Can Improve the Selection for Laparoscopy in Patients with Localized Gastric Cancer

BACKGROUND The majority of newly diagnosed patients with gastric cancer have disease that is not resectable because of local extension or metastatic (M1) disease. Laparoscopy is a recommended staging evaluation to identify occult peritoneal metastatic disease. We determined if endoscopic ultrasound (EUS) could improve the selection of patients for laparoscopy. STUDY DESIGN Gastric cancer patients being screened for a preoperative chemotherapy clinical trial were prospectively examined. Patients underwent standard preoperative assessment. Those without obvious metastatic disease were referred for EUS and laparoscopy. EUS divided patients into risk categories for metastatic disease: low risk (T1-2, N0) and high risk (T3-4, N+, or both). Laparoscopy categories were M1 and M0. The ability of EUS to predict subradiographic peritoneal metastatic disease was evaluated. RESULTS Ninety-four patients were studied. The majority were EUS high risk (72%). Occult metastatic disease was identified in 19 patients, 18 of whom had high-risk EUS stage. The yields of identifying M1 disease by laparoscopy in EUS high- and low-risk patients were 25% (95% CI, 15% to 37%) and 4% (95% CI, 0.1% to 20%), respectively. The negative predictive value of low-risk EUS for laparoscopy and pathologic M0 was 96% (exact 95% CI, 80% to 100%). CONCLUSIONS This study suggested that laparoscopy can be avoided in patients with EUS early-stage gastric cancer. Patients with more advanced disease are at higher risk of occult peritoneal disease and require laparoscopy. Validation with greater numbers is warranted, but, based on these data, we propose a new staging algorithm allowing EUS low-risk patients to proceed directly to resection.

Hepatitis C and non-Hodgkin lymphoma: The clinical perspective

Hepatitis C virus (HCV) is a commonly transmitted infection that has both hepatic and extrahepatic repercussions. These range from the inflammatory to the oncologic with an undisputed link to hepatitis, liver cirrhosis, and hepatocellular carcinoma. Its role in the development of B cell non‐Hodgkin lymphoma (B‐NHL) is becoming better understood, leading to opportunities for research, therapy, and even prevention. Research in the field has progressed significantly over the last decade, with the number of patients diagnosed with HCV and B‐NHL rising incrementally. It is therefore becoming crucial to fully understand the pathobiologic link of HCV in B cell lymphomagenesis and its optimal management in the oncologic setting. (HEPATOLOGY 2012)

Carcinomatosis is not a contraindication to enteral stenting in selected patients with malignant gastric outlet obstruction

BACKGROUND Endoscopically inserted self-expandable metal stents (SEMSs) are used to palliate malignant gastric outlet obstruction (GOO). Peritoneal disease is considered a relative contraindication to SEMS placement given the risk of multifocal obstruction. OBJECTIVE To evaluate the success of SEMSs placed in patients with GOO with carcinomatosis. DESIGN Retrospective review of patients who underwent SEMS placement for malignant GOO. SETTING Large, urban cancer center. PATIENTS A total of 215 patients who were scheduled for SEMS placement for GOO. INTERVENTIONS SEMS placement. MAIN OUTCOME MEASUREMENTS Technical success, clinical success, early and late SEMS failure, and complications. RESULTS Technical success was achieved in 192 of 201 patients (95.5%). Of the 9 patients who did not achieve technical success, 6 had carcinomatosis. Among the 116 patients (60%) with carcinomatosis, clinical success was achieved 94 of them (81%). Of these 94 patients, 17 (18%) required reinterventions: 4 for early SEMS failure and 13 for late SEMS failure. Among the 76 patients (40%) without carcinomatosis, clinical success was achieved in 64 of them (84%). Of these 64 patients, 17 (27%) required reinterventions: 4 for early SEMS failure and 13 for late SEMS failure. Complication rates were similar for both groups. LIMITATIONS This was a retrospective review with experienced clinicians selecting patients whom they thought would benefit from SEMS placement. CONCLUSIONS This is the first study to evaluate the effect of carcinomatosis on the technical and clinical success of SEMSs in the palliation of malignant GOO. We found clinical outcomes comparable to those without peritoneal disease. Carcinomatosis should not be considered a contraindication to SEMS placement in selected patients with malignant GOO.