Garrett M. Nash

Long-term results of local excision for rectal cancer

ObjectiveTo review the authors’ experience with local excision of early rectal cancers to assess the effectiveness of initial treatment and of salvage surgery. Summary Background DataLocal excision for rectal cancer is appealing for its low morbidity and excellent functional results. However, its use is limited by inability to assess regional lymph nodes and uncertainty of oncologic outcome. MethodsPatients with T1 and T2 adenocarcinomas of the rectum treated by local excision as definitive surgery between 1969 to 1996 at the authors’ institution were reviewed. Pathology slides were reviewed. Among 125 assessable patients, 74 were T1 and 51 were T2. Thirty-one patients (25%) were selected to receive adjuvant radiation therapy. Fifteen of these 31 patients received adjuvant radiation in combination with 5-fluorouracil chemotherapy. Median follow-up was 6.7 years. One hundred fifteen patients (92%) were followed until death or for greater than 5 years, and 69 patients (55%) were followed until death or for greater than 10 years. Recurrence was recorded as local, distant, and overall. Survival was disease-specific. ResultsTen-year local recurrence and survival rates were 17% and 74% for T1 rectal cancers and 26% and 72% for T2 cancers. Median time to relapse was 1.4 years (range 0.4–7.0) for local recurrence and 2.5 years (0.8–7.5) for distant recurrence. In patients receiving radiotherapy, local recurrence was delayed (median 2.1 years vs. 1.1 years), but overall rates of local and overall recurrence and survival rates were similar to patients not receiving radiotherapy. Among 26 cancer deaths, 8 (28%) occurred more than 5 years after local excision. On multivariate analysis, no clinical or pathologic features were predictive of local recurrence. Intratumoral vascular invasion was the only significant predictor of survival. Among 34 patients who developed tumor recurrence, the pattern of first clinical recurrence was predominantly local: 50% local only, 18% local and distant, and 32% distant only. Among the 17 patients with isolated local recurrence, 14 underwent salvage resection. Actuarial survival among these surgically salvaged patients was 30% at 6 years after salvage. ConclusionsThe long-term risk of recurrence after local excision of T1 and T2 rectal cancers is substantial. Two thirds of patients with tumor recurrence have local failure, implicating inadequate resection in treatment failure. In this study, neither adjuvant radiotherapy nor salvage surgery was reliable in preventing or controlling local recurrence. The postoperative interval to cancer death is as long as 10 years, raising concern that cancer mortality may be higher than is generally appreciated. Additional treatment strategies are needed to improve the outcome of local excision.

Nonoperative management of rectal cancer with complete clinical response after neoadjuvant therapy.

Introduction:Nonoperative management (NOM) of rectal cancer after a complete clinical response (cCR) to neoadjuvant therapy is controversial. In this article, we retrospectively reviewed the outcomes of patients managed with selective NOM after a cCR to neoadjuvant treatment and compared these with patients who underwent standard rectal resection with a pathological complete response (pCR). Methods:Patients completing neoadjuvant chemoradiotherapy (CRT) for stage I to III rectal cancer between January 2006 and August 2010 were retrospectively reviewed. Median follow-up was calculated in months after completion of CRT. Results:Thirty-two patients (median follow-up 28 months) were treated by NOM after a cCR. Among 265 treated by CRT and rectal resection, 57 patients (22%) had a pCR and formed the control group (median follow-up 43 months). Factors associated with selective use of NOM included lower pretreatment stage, older age, and distal tumor location (P < 0.05). In the NOM group, 6 recurred locally (median 11 months, range 7–14), 3 of whom also had concurrent distant recurrence. All 6 local failures were controlled by salvage rectal resection with no further local recurrence of disease (median follow-up 17 months). In the rectal resection/pCR group, there were no local failures. The 2-year distant disease-free survival (88% vs 98%, P = 0.27) and overall survival (96% vs 100%, P = 0.56) were similar for NOM and rectal resection/pCR groups. Conclusions:Rectal resection was successfully avoided in 81% of patients selected for NOM. When combined with salvage surgery, NOM appears to achieve similar local and distant disease control compared with patients with a pCR treated by rectal resection. Longer follow-up and prospective trials are warranted to evaluate this promising treatment option.

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.

c-Met gene amplification is associated with advanced stage colorectal cancer and liver metastases ☆

The c-Met proto-oncogene encodes a receptor tyrosine kinase (TK) that promotes invasive tumor growth and metastasis. Recent studies show that the presence of c-Met gene amplification is predictive for selective c-Met TK inhibitors in gastric cancer and lung cancer. In this study, we utilized a highly quantitative PCR/ligase detection reaction technique to quantify c-Met gene copy number in primary colorectal cancer (CRC) (N=247), liver metastases (N=147), and paired normal tissues. We identified no differences in c-Met gene copy number between normal colonic mucosa and liver tissue. However, mean c-Met gene copy number was significantly elevated in CRC compared with normal mucosa (P<0.001), and in liver metastases compared with normal liver (P<0.001). Furthermore, a significant increase in c-Met was seen in liver metastases compared with primary CRC (P<0.0001). c-Met gene amplification was observed in 2% (3/177) of localized cancers, 9% (6/70) of cancers with distant metastases (P<0.02), and 18% (25/147) of liver metastases (P<0.01). Among patients treated by liver resection, there was a trend toward poorer 3-year survival in association with c-Met gene amplification (P=0.07). Slight increases in c-Met copy number can be detected in localized CRCs, but gene amplification is largely restricted to Stage IV primary cancers and liver metastases. c-Met gene amplification is linked to metastatic progression, and is a viable target for a significant subset of advanced CRC.

Lymph node metastasis in T1 adenocarcinoma of the colon and rectum.

The biology of colorectal cancer differs according to location within the large intestine. To evaluate the clinical significance of tumor location as a risk factor for lymph node metastasis (LNM), we performed a detailed pathological review of T1 adenocarcinomas of the colon and rectum. T1 adenocarcinomas of the colon and rectum treated by radical resection (n = 428) were identified from prospective clinical databases at two institutions. Tumor location was assigned as right colon (cecum to transverse), left colon (splenic flexure to sigmoid), or rectum (0–18 cm from AV). Pathology slides were reviewed, extent of submucosal invasion (sm width, sm depth) was quantified using an optical micrometer, and morphologic features of the cancer and its infiltrating margin were recorded. The overall rate of LNM was 10%. On univariate analysis, LNM was significantly more common in the rectum (27/176, 15%) compared to the left colon (13/160, 8%, p = .04) or right colon (3/92, 3%, p = .003). However, on multivariate analysis, deep submucosal invasion and lymphovascular invasion were independent and significant risk factors, whereas tumor location was not. T1 colorectal cancers have a progressively higher risk of LNM as their location becomes more distal. However, the increasing rate of LNM observed in cancers of the left colon and rectum is explained by a higher prevalence of high-risk pathologic features. In early colorectal cancers, tumor morphology is the strongest clinical predictor of metastatic behavior.

Long-term survival after transanal excision of T1 rectal cancer.

PURPOSE: Several series report higher recurrence after transanal excision of T1 rectal cancer than after radical resection. However, the impact of transanal excision on cancer mortality has not been adequately studied. The purpose of this study was to compare oncologic outcomes of transanal excision with those of radical resection. METHODS: Patients with transanal excision or radical resection for T1 rectal cancer treated between 1985 and 2004 were identified from a prospective database. Patients receiving preoperative chemotherapy or radiation or with tumors >12 cm from the anal verge were excluded. RESULTS: The final cohort comprised 145 radical resections and 137 transanal excisions. The transanal excision group was notable for older mean age (64 vs. 59 years), shorter mean distance from anal verge (5.9 vs. 7.8 cm), and smaller tumor size (2.3 vs. 3.1 cm). Lymphovascular invasion and poor differentiation were similar in both groups. Twenty percent of radical resection specimens had lymph node metastasis. Median follow-up was 5.6 years. Local recurrence was noted in a higher proportion of transanal excision patients (13.2 vs. 2.7 percent, P = 0.001). After transanal excision the hazard ratio for local recurrence was 11.3 (95 percent confidence interval, 2.6-49.2), and disease-specific survival was inferior (87 vs. 96 percent at 5 years, P = 0.03, hazard ratio 2.8 [range, 1.04-7.3]). CONCLUSIONS: Transanal excision offers inferior oncologic results, including greater risk of cancer-related death. This procedure should be restricted to patients who have prohibitive medical contraindications to major surgery or have made an informed decision to accept the oncologic risks of local excision and avoid the functional consequences of rectal resection.

HER 2/neu expression and gene amplification in colon cancer

HER 2/neu is an important oncogene in breast cancer, but the prevalence and significance of HER 2/neu gene amplification in colon cancer have been poorly documented. We have evaluated HER 2/neu gene amplification and protein overexpression in a series of colon cancers to assess the frequency, concordance and clinical significance of these events. HER 2/neu gene copy number was measured in 154 primary colon tumors, 15 liver metastases and matched normal tissues using a quantitative PCR/ligase detection reaction (LDR) technique developed and validated in our laboratory. HER 2/neu copy number was confirmed by fluorescent in situ hybridization (FISH) in all tumors found to have gene amplification. In an independent and blinded fashion, HER 2/neu expression was assessed in paraffin sections from 139 of the tumor specimens using the HercepTest kit. HER 2/neu gene amplification was observed in 4 (2.4%) of the 169 tumor specimens and in none of the normal tissues. There was no apparent association with stage of disease, tumor grade or patient survival. Among 139 cases evaluated by immunohistochemistry (IHC), HER 2/neu overexpression was seen in 5 cases (3.6%). There was extremely high concordance (kappa = 0.852) between gene amplification and protein overexpression. The low prevalence of HER 2/neu gene amplification and protein overexpression suggests that this oncogene plays an infrequent role in the development and progression of colon cancer. These data indicate that the primary mechanism of dysregulated HER 2/neu expression in colon cancer, as in breast cancer, is gene amplification.

Immunohistochemistry as first-line screening for detecting colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome: a 2-antibody panel may be as predictive as a 4-antibody panel.

The utility of immunohistochemical detection of DNA mismatch repair proteins in screening colorectal cancer for hereditary nonpolyposis colorectal cancer (HNPCC) is being widely investigated. Currently, in both research and clinical settings, a 4-antibody panel that includes the 4 most commonly affected proteins (MLH1, MSH2, MSH6, and PMS2) is being used generally. On the basis of the biochemical properties of these proteins, we hypothesized that a 2-antibody panel, comprising MSH6 and PMS2, would be sufficient to detect abnormalities in all 4 proteins. We tested this hypothesis on a series of 232 colorectal carcinoma samples derived from 2 patient cohorts: (1) a prospectively accrued series of patients who were judged to carry a higher-than-average risk for HNPCC based on the revised Bethesda guidelines (n=190); and (2) a retrospective series of patients who were 40 years of age or younger (n=42). Immunohistochemical stains were regarded as negative (protein lost), when there was no nuclear labeling in tumor cells (with positive internal control). Overall, 70 of the 232 tumors demonstrated loss of at least one protein. The most common abnormality was concurrent loss of MLH1 and PMS2 (observed in 17% of the cases), followed by concurrent loss of MSH2 and MSH6 (6%). All MLH1 and MSH2-abnormal cases were also abnormal for PMS2 and MSH6, respectively, whereas 9 of 50 (18%) PMS2 and 6 of 20 (30%) MSH6-abnormal cases showed only isolated loss of PMS2 or MSH6 (with normal staining for MLH1 and MSH2). As such, our findings provide evidence that a 2-antibody panel (PMS2 and MSH6) is as effective as the current 4-antibody panel in detecting DNA mismatch repair protein abnormalities. Such a cost-effective approach carries significant implication, as immunohistochemistry is being widely used as first-line screening for HNPCC.

Neither FDG-PET nor CT can distinguish between a pathological complete response and an incomplete response after neoadjuvant chemoradiation in locally advanced rectal cancer: A prospective study

Objective: To prospectively compare the ability of flourodeoxyglucose-positron emission tomography (FDG-PET) and computed tomography (CT) to identify a pathological complete response (pCR) in patients with rectal cancer treated by chemoradiation. Background: A major obstacle in pursuing nonoperative management in patients with rectal cancer after chemoradiation is the inability to identify a pCR preoperatively. Methods: A total of 121 patients with rectal cancer were prospectively enrolled. FDG-PET scans and helical CT scans were obtained before and after neoadjuvant chemoradiation. Consensus readings of PET and CT scans were used to classify certainty of disease (5-point confidence rating scale). The ability of PET and CT scans to accurately distinguish a pCR (ypT0) from an incomplete response (ypT1–4) was estimated using the area under the receiver operating characteristic curve (AUC). Results: Of the 121 patients, 26 (21%) had a pCR. PET and CT scans were equally inadequate at distinguishing a pCR from an incomplete response (AUC = 0.64 for both, P = 0.97). Among the 26 patients with a pCR, 14 (54%) and 5 (19%) were classified as complete responders on PET and CT scans, respectively. Among the 95 patients with an incomplete pathological response, 63 (66%) and 90 (95%) were classified as incomplete responders on PET and CT scans, respectively. None of the individual PET parameters, including visual response score, mean standard uptake value (SUVmean), maximum SUV (SUVmax), and total lesion glycolysis, accurately distinguished a pCR (AUCs = 0.57–0.73). Conclusions: Neither PET nor CT scans have adequate predictive value to be clinically useful in distinguishing a pCR from an incomplete response and, therefore, should not be obtained for the purpose of attempting to predict a pCR after neoadjuvant chemoradiation for rectal cancer.

Significance of acellular mucin pools in rectal carcinoma after neoadjuvant chemoradiotherapy

The presence of mucin pools lacking neoplastic epithelium (“acellular” mucin) in resection specimens of rectal carcinoma after neoadjuvant chemoradiotherapy (CRT) is a well-recognized phenomenon. The current recommendation by the College of American Pathologists is to regard acellular mucin as a type of treatment response and not as residual tumor. However, data-based evidence for or against such an approach is incomplete. In this study, we systematically analyzed the pattern and significance of mucin pools in 108 consecutive, prospectively collected resection specimens from patients who had uT3-4 and/or uN1 rectal cancer and were treated with preoperative long-course CRT. The 108 patients, 39 female and 69 male, had a median age of 58.5 years. With every tumor entirely examined in whole-mount sections, mucin pools were identified in 33 cases (33 of 108, 31%); in 16 (15%) they were all acellular. The mucin pools were focal (10% to 50% of the entire lesion) in 25 cases and extensive (>50%) in 8 cases. Mucin pools were also noted in the lymph nodes in 6 cases (6%); 3 of these were entirely acellular. Five cases had mucin pools in both the primary site and the lymph nodes. When acellular mucin was considered as “no residual tumor,” the complete pathologic response rate for the entire cohort was 22% (24 of 108). The pathologic stage of the residual tumor (ypT) was 0 or 1 for 27 cases (25%) and 2 to 4 for 81 cases. The pathologic stage of nodal disease (ypN) was 0 for 83 (77%) and 1 or 2 for 25 cases. When acellular mucin was considered as “residual tumor,” the complete pathologic response rate dropped to 17%; ypT was upstaged in 10 tumors and ypN was upstaged in 2 tumors. With a median follow-up of 31 months, the 3-year recurrence-free survival (RFS) was 73% for the entire group. Advanced pathologic response and low pathologic stage of the residual tumor (determined based on the depth of only viable tumor cells) correlated significantly with better RFS. However, the correlation between pathologic response and RFS became insignificant when acellular mucin pools were considered as residual tumor. Neither the presence of mucin pools nor their extent or cellularity had an impact on RFS. Furthermore, none of the 12 patients whose ypT or ypN was upstaged by acellular mucin had recurrent disease (3-y RFS of 100%). Thus, our results suggest that mucin pools in rectal carcinoma after neoadjuvant CRT do not have a significant impact on patient outcome, supporting the College of American Pathologists recommendation that only viable tumor cells, not acellular mucin, are to be interpreted as residual disease in the tumor pathologic staging.