Colorectal cancer in the very young: a comparative study of tumor markers, pathology and survival in early onset and adult onset patients.

INTRODUCTION: Colorectal cancer (CRC) diagnosed before age 30 years is a fatal disease whose biology remains poorly understood. To understand its pathogenesis, we compared molecular and clinical data in surgically treated early-age onset and adult onset patients. MATERIALS AND METHODS: Clinical data and tumor tissue were collected retrospectively for 94 patients with early-age onset CRC (age ≤30 years) and compared to 275 adult CRC patients (age ≥50 years). Tumor morphology, microsatellite instability (MSI) and stability (MSS), KRAS and BRAF mutations, and mismatch repair (MMR) expression (MSH2, MLH1, MSH6, PMS2) were assessed. RESULTS: Early-age CRC was distinguished from adult CRC by advanced stage presentation (P<0.001), frequent high grade cancers (P<0.001), and poor prognosis (P<0.001). MSI was associated with favorable survival and MMR loss in both groups. Compared to adults, MSI in early-onset CRC was more prevalent (P<0.01), not tightly linked to MLH1/PMS2 loss, and never associated with BRAFV600E mutations (P<0.01). MSS/BRAFV600E genotype had poor prognosis and was more prevalent in early-age CRC (9% vs. 3%). DISCUSSION: Specific genetic subtypes are found at different frequencies in early-age onset and adult onset CRC. Complete absence of the indolent MSI/BRAFV600E genotype and enrichment in the unfavorable MSS/BRAFV600E genotype help explain the poor prognosis of early onset CRC.

Isolated nasopharyngeal castleman disease: an uncommon diagnosis in an unusual location.

Localised nasopharyngeal Castleman disease has rarely been reported. We present a case involving a 23-year-old female, describe the clinical, imaging, and histopathologic features of this challenging diagnosis, and review the literature.

Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer.

PURPOSE: To determine the prognostic significance of FOXP3(+) lymphocyte (Treg) density in colorectal cancer compared with conventional histopathologic features and with CD8(+) and CD45RO(+) lymphocyte densities. PATIENTS AND METHODS: Tissue microarrays and immunohistochemistry were used to assess the densities of CD8(+), CD45RO(+), and FOXP3(+) lymphocytes in tumor tissue and normal colonic mucosa from 967 stage II and stage III colorectal cancers. These were evaluated for associations with histopathologic features and patient survival. RESULTS: FOXP3(+) Treg density was higher in tumor tissue compared with normal colonic mucosa, whereas CD8(+) and CD45RO(+) cell densities were lower. FOXP3(+) Tregs were not associated with any histopathologic features, with the exception of tumor stage. Multivariate analysis showed that stage, vascular invasion, and FOXP3(+) Treg density in normal and tumor tissue were independent prognostic indicators, but not CD8(+) and CD45RO(+). High FOXP3(+) Treg density in normal mucosa was associated with worse prognosis (hazard ratio [HR] = 1.51; 95% CI, 1.07 to 2.13; P = .019). In contrast, a high density of FOXP3(+) Tregs in tumor tissue was associated with improved survival (HR = 0.54; 95% CI, 0.38 to 0.77; P = .001). CONCLUSION: FOXP3(+) Treg density in normal and tumor tissue had stronger prognostic significance in colorectal cancer compared with CD8(+) and CD45RO(+) lymphocytes. The finding of improved survival associated with a high density of tumor-infiltrating FOXP3(+) Tregs in colorectal cancer contrasts with several other solid cancer types. The inclusion of FOXP3(+) Treg density may help to improve the prognostication of early-stage colorectal cancer.

Tumor-infiltrating lymphocytes and perforation in colon cancer predict positive response to 5-fluorouracil chemotherapy.

PURPOSE: The major pathologic markers of prognosis in colorectal cancer include vascular invasion by tumor cells, invasion of adjacent lymph nodes, and perforation of the serosal wall. Recent work suggests that a high density of tumor-infiltrating lymphocytes (TIL) is associated with good outcome independently of these established prognostic markers. The aim of the present study was to investigate the prognostic significance of TILs and other routinely reported pathologic features in colon cancer, particularly in relation to the use of adjuvant chemotherapy. EXPERIMENTAL DESIGN: Pathologic markers, disease-specific survival, and the use of adjuvant chemotherapy were recorded in a retrospective, population-based series of 1,156 stage III colon cancer patients with a median follow-up time of 52 months. RESULTS: In patients treated by surgery alone (n = 851), markers with significant prognostic value included poor histologic grade, T4 stage, N2 nodal status, vascular invasion, and perforation, but not the presence of TILs. In patients treated with 5-fluorouracil-based chemotherapy (n = 305), TILs were associated with significantly improved survival [hazard ratio (HR), 0.52; 95% confidence interval, 0.30-0.91; P = 0.02] and perforation with a trend for improved survival (HR, 0.67; 95% confidence interval, 0.27-1.05; P = 0.16). Patients with TILs or perforation seemed to gain more survival benefit from chemotherapy (HR, 0.22 and 0.21, respectively) than patients without these features (HR, 0.84 and 0.82, respectively). CONCLUSION: The apparent survival advantage from 5-fluorouracil associated with TILs and perforation requires confirmation in prospective studies. Because the presence of TILs reflects an adaptive immune response and perforation is associated with inflammatory response, these results suggest that there may be interactions between the immune system and chemotherapy leading to improved survival of colon cancer patients.

Surgical volume influences survival in patients undergoing resections for stage II colon cancers.

BACKGROUND: There is current interest in the correlation between surgical volume and outcomes. Survival in patients with rectal cancer appears to improve when carried out by surgeons who do high volumes of procedures. A similar correlation for patients with colon cancer has never been clearly established. The aim of this study was to determine whether surgical volume was an independent predictor for survival in patients undergoing surgery for stage II colon cancer. METHODS: Population-based findings were collected from all patients diagnosed with stage II colon cancer in Western Australia between 1993 and 2003. The Kaplan-Meier product limit estimate of survival was used to calculate overall and cancer-specific survival. The Cox proportional hazards model was used to define the correlation between a number of covariates and survival. The results are recorded as hazard ratio (HR) with 95% confidence intervals (CI). RESULTS: From 1993 to 2003, 1467 patients underwent resections for stage II colon cancers. Significant independent predictors for overall survival were surgeon carrying out more than 25 procedures (P = 0.0001, HR 0.657, 95%CI 0.532-0.811), surgery in a private hospital (P = 0.0001, HR 0.487, 95%CI 0.400-0.594), use of chemotherapy (P = 0.001, HR 0.664, 95%CI 0.496-0.837), age at diagnosis (P = 0.0001, HR 1.014, 95%CI 1.027-1.044) and T staging and vascular invasion (T4 and vascular positive P = 0.001, HR 1.850, 95%CI 1.294-2.645). CONCLUSIONS: Surgical volume was a significant independent predictor for survival in patients undergoing resections for stage II colon cancers. Surgeons carrying out only 25 procedures over a 10-year period outperformed surgeons doing fewer cases.

A population-based study of age-related variation in clinicopathological features, molecular. Markers and outcome from colorectal cancer.

BACKGROUND: To investigate age-related differences in clinicopathological features, molecular alterations and patient survival in a large, population-based series of CRC. PATIENTS AND METHODS: The study cohort consisted of 5,971 cases diagnosed between 1993 and 2003 representing over 90% of the CRCs diagnosed in the state of Western Australia. RESULTS: Patients aged < or =30, < or =40, < or =50 and < or =60 years comprised 0.9%, 3.1%, 10.6% and 27.8% of all cases, respectively. The proportion of rectal cancers and tumors with poor differentiation was higher in < or =30-year-old patients and decreased progressively with age. The incidence of tumors with microsatellite instability was significantly higher in patients aged 540 years (18.3%) compared to those aged 41-60 years (6.6%; p<0.0001). TP53 mutations were also more frequent (p=0.002), however K-ras mutations were less common (p =0.0001) when comparing the same age groups. CONCLUSION: These results provide evidence for major age-related differences in the clinical and molecular features of CRC.

Heterogeneous staining for mismatch repair proteins during population-based prescreening for hereditary nonpolyposis colorectal cancer.

The aim of this study was to determine the frequency of microsatellite instability (MSI(+)) in tumors from a population-based series of young colorectal cancer patients and its correlation with the loss of expression of mismatch repair (MMR) proteins. The BAT-26 mononucleotide repeat was used to screen for MSI(+) in all colorectal cancers diagnosed in Western Australia throughout a 5-year period in patients <60 years of age. MSI(+) was found in 75 of 1003 (7.5%) cases, of which six contained a concomitant mutation in BRAF and were therefore excluded from further investigations as possible hereditary nonpolyposis colorectal cancer. Immunohistochemistry was used to evaluate expression of the four major MMR proteins (MLH1, MSH2, MSH6, and PMS2) in the remaining 69 MSI(+) tumors. Complete loss of MLH1 and PMS2 expression or of MSH2 and MSH6 expression was found in 35 (51%) and 17 (25%) cases, respectively, whereas other patterns of complete loss were observed in eight cases (12%). Eight tumors (12%) were initially recorded as showing normal expression, but on review seven were reclassified as having abnormal staining because of heterogeneous patterns of MMR loss. Three of these seven cases had previously been found to have germline mutations. Because of possible misinterpretation of heterogeneous immunohistochemistry staining for MMR protein loss, MSI testing is recommended as the initial screen for population-based detection of hereditary nonpolyposis colorectal cancer.

Comparing survival outcomes for patients with colorectal cancer treated in public and private hospitals.

OBJECTIVE: To determine whether treatment in a private versus public hospital was an independent predictor of survival outcomes in patients with colorectal cancer. DESIGN: Retrospective, population-based study. SETTING: Tertiary care hospitals. PARTICIPANTS: All patients diagnosed with colorectal cancer in Western Australia between 1993 and 2003. INTERVENTIONS: Management in private versus public hospitals. MAIN OUTCOME MEASURES: Overall survival and cancer-specific survival rates. RESULTS: 5809 patients were treated for colorectal cancer. Of these, 1523 (26%) were managed in private hospitals. The 5-year overall survival rates for private and public hospital patients were 59.4% (95% CI, 56.9%-61.9%) and 48.6% (95% CI, 47.0%-50.2%), respectively. Significant independent predictors of overall survival were: treatment in a private hospital (P = 0.0001; relative risk [RR], 0.764; 95% CI, 0.696-0.839); younger age (P = 0.0001; RR, 1.032; 95% CI, 1.029-1.036); male sex (P = 0.001; RR, 1.148; 95% CI, 1.068-1.234); and cancer stage (eg, Stage II: P = 0.0001; RR, 1.508; 95% CI, 1.316-1.729). CONCLUSIONS: Treatment in a private hospital was a significant independent predictor of survival outcomes. Further validation of these results would have a significant bearing on how we approach health care delivery for patients with colorectal cancer.

Survival rates for stage II colon cancer patients treated with or without chemotherapy in a population-based setting.

BACKGROUND AND AIMS: There is considerable uncertainty as to whether adjuvant 5-fluorouracil-based chemotherapy provides survival benefit for colon cancer patients with stage II disease. Consequently, the current rates of chemotherapy use for this disease are low despite 5-year survival rates of only 70-80%. The aim of the present study is to compare the survival rate of stage II colon cancer patients treated by surgery alone with that of patients also treated by chemotherapy. PATIENTS AND METHODS: A population-based observational study was conducted on the survival of stage II colon cancer patients (n = 812) diagnosed in Western Australia from 1993 to 2003. The study was restricted to patients aged < or =75 years, of whom 18% (n = 142) were treated with chemotherapy. Only 0.9% of patients older than 75 years received chemotherapy. RESULTS: Patients who received chemotherapy were significantly younger (mean age 6 years) than those treated by surgery alone (65 years, P < 0.001), and their tumors were more often positive for vascular invasion (P = 0.007). Multivariate analysis that included all prognostic factors revealed adjuvant chemotherapy was associated with improved survival (HR = 0.62, 95% CI [0.39-0.98], P = 0.043), with women gaining more benefit (HR = 0.48, 95% CI [0.20-1.22], P = 0.09) than men (HR = 0.94, 95% CI [0.54-1.64], P = 0.8). CONCLUSIONS: In view of the apparent survival benefit from chemotherapy for stage II colon cancer, the present study raises concerns about the current low rates of adjuvant treatment for this disease in the community, particularly for female patients.