The role of sentinel lymph node mapping in colon cancer: detection of micro-metastasis, effect on survival, and driver of a paradigm shift in extent of colon resection.

Unlike in breast cancer and melanoma, sentinel lymph node mapping in colon cancer is primarily used as an aid to the pathologist for accurate nodal staging. The study was undertaken to review the incidence of micro-metastasis and its impact on survival when treated with chemotherapy. The study was also undertaken to see if SLNM could guide limited colon resection in early T stage tumor as a paradigm shift. SLNM was done by subserosal injection of a blue dye. SLNs were ultra-staged by multilevel sectioning and remaining Specimen was then examined by conventional method. For the last 245 patients the specimen was divied ex vivo into two segments as segment A containing the tumor bearing portion of the colon and SLNs with attached mesentery, while segment B include distal part of the colon with attached mesentery. Nodal staging was separately examined. Of the 354 Pts, SLNM was successful in 99.9% of Pts with an average no of SLN/ Pt = 2.8 and total nodes 17.8/pt. Survival was directly related negatively with stage and nodal status. Pts with +ve LN did much better with chemotherapy than without chemotherapy. With 245 Pts, specimen A Vs B, no Pts had +ve node in specimen B with -ve LN in specimen A. SLNM results in more node/Pt, more positive node/Pt ,and more micro-metastasis who when treated with chemotherapy survive longer. Limited segmental resection in early T stage is possible when done with guidance by SLNM without compromising biology.

Challenging the conventional treatment of colon cancer by sentinel lymph node mapping and its role of detecting micrometastases for adjuvant chemotherapy.

All colon cancer patients with lymph node (LN) positive disease are treated with chemotherapy. Patients with node negative disease are usually cured by surgery alone. Yet about 20% of patients develop recurrence within 5 years despite node negative status. This may often be the result of missed micrometastases by conventional examination. Sentinel lymph node (SLN) mapping was developed to find those nodes detected by blue dye which was ultrastaged to detect micrometastases. Consecutive patients, underwent SLN mapping with the blue dye with success rate of 99.2%. Average number of LN was 18.3, average number of SLN was 3/patient and overall nodal positivity was 45%. Ten patients had skip metastases. Overall survival of 235 patients was 84 months with survival of node negative patients 97 months versus 68 months for node positive patients. For stage I-IV patients, overall survival was as follows: stage I-115 months, stage II-90 months, stage III-84 months and stage IV-24 months respectively. Patients with micrometastases after chemotherapy had average survival of 108 months versus those without chemotherapy was 50 months. Thus, SLN mapping techniques is highly successful, easily reproducible and finds micrmoetastases in over 15% of patients which could have been missed by conventional pathological examination. These patients when treated with adjuvant chemotherapy have similar survival as those of node negative disease. Similarly, patients without any nodal metastases after SLN mapping and ultrastaging, may be considered as true node negative disease and may avoid further adjuvant chemotherapy.

Effect of Axillary Dissection vs No Axillary Dissection on 10-Year Overall Survival Among Women With Invasive Breast Cancer and Sentinel Node Metastasis: The ACOSOG Z0011 (Alliance) Randomized Clinical Trial.

Importance: The results of the American College of Surgeons Oncology Group Z0011 (ACOSOG Z0011) trial were first reported in 2005 with a median follow-up of 6.3 years. Longer follow-up was necessary because the majority of the patients had estrogen receptor-positive tumors that may recur later in the disease course (the ACOSOG is now part of the Alliance for Clinical Trials in Oncology). Objective: To determine whether the 10-year overall survival of patients with sentinel lymph node metastases treated with breast-conserving therapy and sentinel lymph node dissection (SLND) alone without axillary lymph node dissection (ALND) is noninferior to that of women treated with axillary dissection. Design, Setting, and Participants: The ACOSOG Z0011 phase 3 randomized clinical trial enrolled patients from May 1999 to December 2004 at 115 sites (both academic and community medical centers). The last date of follow-up was September 29, 2015, in the ACOSOG Z0011 (Alliance) trial. Eligible patients were women with clinical T1 or T2 invasive breast cancer, no palpable axillary adenopathy, and 1 or 2 sentinel lymph nodes containing metastases. Interventions: All patients had planned lumpectomy, planned tangential whole-breast irradiation, and adjuvant systemic therapy. Third-field radiation was prohibited. Main Outcomes and Measures: The primary outcome was overall survival with a noninferiority hazard ratio (HR) margin of 1.3. The secondary outcome was disease-free survival. Results: Among 891 women who were randomized (median age, 55 years), 856 (96%) completed the trial (446 in the SLND alone group and 445 in the ALND group). At a median follow-up of 9.3 years (interquartile range, 6.93-10.34 years), the 10-year overall survival was 86.3% in the SLND alone group and 83.6% in the ALND group (HR, 0.85 [1-sided 95% CI, 0-1.16]; noninferiority P = .02). The 10-year disease-free survival was 80.2% in the SLND alone group and 78.2% in the ALND group (HR, 0.85 [95% CI, 0.62-1.17]; P = .32). Between year 5 and year 10, 1 regional recurrence was seen in the SLND alone group vs none in the ALND group. Ten-year regional recurrence did not differ significantly between the 2 groups. Conclusions and Relevance: Among women with T1 or T2 invasive primary breast cancer, no palpable axillary adenopathy, and 1 or 2 sentinel lymph nodes containing metastases, 10-year overall survival for patients treated with sentinel lymph node dissection alone was noninferior to overall survival for those treated with axillary lymph node dissection. These findings do not support routine use of axillary lymph node dissection in this patient population based on 10-year outcomes. Trial Registration: clinicaltrials.gov Identifier: NCT00003855.

Systematic development of an abbreviated protocol for screening breast magnetic resonance imaging.

RATIONALE & OBJECTIVES: We sought to develop an abbreviated protocol (AP) for breast MRI that maximizes lesion detection by assessing each lesion not seen on mammography by each acquisition from a full diagnostic protocol (FDP). MATERIALS & METHODS: 671 asymptomatic women (mean 55.7 years, range 40-80) with a negative mammogram were prospectively enrolled in this IRB approved study. All lesions on MRI not visualized on mammography were analyzed, reported, and suspicious lesions biopsied. In parallel, all FDP MRI acquisitions were scored by lesion to eventually create a high-yield AP. RESULTS: FDP breast MRI detected 452 findings not visible on mammography, including 17 suspicious lesions recommended for biopsy of which seven (PPV 41.2%) were malignant in six women. Mean size of the four invasive malignancies was 1.9 cm (range 0.7-4.1), all node negative; three lesions in two women were ductal carcinoma in situ. Nine biopsied lesions were benign, mean size 1.2 cm (range 0.6-2.0). All biopsied lesions were in women with dense breasts (heterogeneously or extremely dense on mammography, n = 367), for a cancer detection rate of 16.3/1000 examinations in this subpopulation. These data were used to identify four high-yield acquisitions: T2, T1-pre-contrast, T11.5, and T16 to create the AP with a scan time of 7.5 min compared to 24 min for the FDP. CONCLUSIONS: Our analysis of a FDP MRI in a mammographically negative group identified four high-yield acquisitions that could be used for rapid screening of women for breast cancer that retains critical information on morphology, histopathology, and kinetic activity to facilitate detection of suspicious lesions.

Locoregional Recurrence After Sentinel Lymph Node Dissection With or Without Axillary Dissection in Patients With Sentinel Lymph Node Metastases: Long-term Follow-up From the American College of Surgeons Oncology Group (Alliance) ACOSOG Z0011 Randomized Trial.

BACKGROUND AND OBJECTIVE: The early results of the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial demonstrated no difference in locoregional recurrence for patients with positive sentinel lymph nodes (SLNs) randomized either to axillary lymph node dissection (ALND) or sentinel lymph node dissection (SLND) alone. We now report long-term locoregional recurrence results. METHODS: ACOSOG Z0011 prospectively examined overall survival of patients with SLN metastases undergoing breast-conserving therapy randomized to undergo ALND after SLND or no further axillary specific treatment. Locoregional recurrence was prospectively evaluated and compared between the groups. RESULTS: Four hundred forty-six patients were randomized to SLND alone and 445 to SLND and ALND. Both groups were similar with respect to age, Bloom-Richardson score, Estrogen Receptor status, adjuvant systemic therapy, histology, and tumor size. Patients randomized to ALND had a median of 17 axillary nodes removed compared with a median of only 2 SLNs removed with SLND alone (P < 0.001). ALND, as expected, also removed more positive lymph nodes (P < 0.001). At a median follow-up of 9.25 years, there was no statistically significant difference in local recurrence-free survival (P = 0.13). The cumulative incidence of nodal recurrences at 10 years was 0.5% in the ALND arm and 1.5% in the SLND alone arm (P = 0.28). Ten-year cumulative locoregional recurrence was 6.2% with ALND and 5.3% with SLND alone (P = 0.36). CONCLUSION: Despite the potential for residual axillary disease after SLND, SLND without ALND offers excellent regional control for selected patients with early metastatic breast cancer treated with breast-conserving therapy and adjuvant systemic therapy.

The prognostic value of additional malignant lesions detected by magnetic resonance imaging versus mammography.

BACKGROUND: Nodal positivity is correlated with a poorer prognosis in breast cancer. A study was composed to compare nodal positivity in patients with single versus multiple lesions found on magnetic resonance imaging (MRI) and mammogram (MMG). METHODS: A retrospective study of breast cancer patients undergoing MRI and MMG was performed. Nodal positivity was compared in patients with additional invasive lesions found on MRI versus single invasive lesions found on MRI and MMG. RESULTS: A total of 425 patients were included. The overall nodal positivity was 23.8%. Patients with single versus multiple malignant lesions had nodal positivity of 20.9% vs 31.1% (P = .04). MRI detected multiple lesions in 120 patients, 80 of which were not detected by MMG (18.8%). Comparing single lesions with additional malignant lesions detected by MRI only, nodal positivity increased from 20.9% to 51.6% (P = .0002). CONCLUSIONS: Patients with additional invasive lesions on MRI had significantly higher nodal positivity than single invasive lesions. Hence, addition of MRI in early-stage breast cancer may have prognostic value because of detection of potential node-positive patients.

Tumor size predicts long-term survival in colon cancer: an analysis of the National Cancer Data Base.

BACKGROUND: American Joint Committee on Cancer uses tumor size for "T" staging of many solid tumors for its effect on prognosis. However, tumor size has not been incorporated in tumor (T), nodal status (N), metastasis (M) staging for colon cancer. Hence, the National Cancer Data Base was used to determine whether tumor size correlates with TNM staging and survival. METHODS: For the 300,386 patients, tumor size was divided into S1 (0 to 2 cm), S2 (>2 to 4 cm), S3 (>4 to 6 cm), and S4 (>6 cm). Statistical comparison was done for TNM stage, grade, and nodal status with tumor size. Kaplan-Meier survival analysis was done for each "S" stage. RESULTS: Of the 300,386 patients, 13% were classified as S1, 39% S2, 30% S3 and 18% as S4. Right colon was the most common site (48%). Tumor size positively correlated with grade, T stage, and nodal stage. Tumor size was inversely associated with survival. CONCLUSION: Tumor size is positively correlated with important prognostic factors and negatively impacted survival.

Aberrant drainage of sentinel lymph nodes in colon cancer and its impact on staging and extent of operation.

BACKGROUND: The role of aberrant lymphatic drainage in changing operations for patients undergoing sentinel lymph node mapping in colon cancer has not been described on a large scale. METHODS: Patients with colon cancer underwent sentinel lymph node mapping and standard oncologic resection. Aberrant lymphatic drainage was identified outside the standard resection margin, requiring change of the extent of operation. Objectives were to identify the frequency of aberrant lymphatic drainage leading to changes of operation and staging. RESULTS: Among 192 patients undergoing standard oncologic resection, 42 (22%) had extended surgery because of aberrant lymphatic drainage. Nodal positivity was higher in patients undergoing change of operation, at 62% compared with 43% of those undergoing only standard oncologic resection. In 19 of 192 patients (10%), positive sentinel nodes were found in aberrant locations. CONCLUSIONS: Sentinel node mapping in patients with colon cancer detects aberrant drainage in 22% of patients, changing the extent of operation.

Meeting the biologic challenge of colorectal metastases.

An overview of colorectal cancer discussed (Philip Paty) the good outcome after primary management with local control in 90-95 % of colon and 85 % in rectal cancer patients with major progression to metastases and to death related to hematogenous dissemination. The major disease pathways include the APC, aneuploid pathway involving mutations of P53, KRAS, SMAD 4, or the CMP/MSI pathway, mismatched repair defect as characterized by Lynch syndrome, the major hereditary form which may also have KRAS and P53 mutations. The common sporadic colorectal cancers are MS1 high, with many patients having BRAF and KRAS mutations. The sentinel node biopsy in colorectal cancer surgery may provide more definitive staging and perhaps modification of the extent of resection with better outcome as suggested by Dr. Saha. The identification of sentinel lymph nodes outside of the planned bowel resection may increase the resection biologically indicated by the sentinel lymph node location leading to better outcome. In a small study by Dr. Saha, the operation was enhanced in 21 % by extending the length of bowel resection, which increased node recovery to 18.5 nodes versus 12 nodes with the more conventional resection, increasing nodal recovery, and positivity to 60 % with reduction to five year recurrence rate to 9 % versus 27 % with the conventional resection. A new (Swiss) technique for pathologic node examination, the OSNA (the One Step Nucleic Acid diagnostic system), was presented which demonstrated increased detection of micro-metastases in a focused pathology study of 22 patients (Zuber) to 11 out of 15 patients versus the 7 micro-metastases identified by the standard single slide per node, and compared to 14 out of 15 with an intensive multi-slide technique. This suggests value in pursuing OSNA study by other centers with relevant clinical trials to establish its true value. An analysis of liver resection for metastatic colorectal cancer (CRC) emphasized the value of 10-year follow-up (DeAngelica). The 10-year survival of 102 patients among 612 patients was 17 % (Memorial Sloan Kettering data). At the five-year point 99 of 102 survivors were NED and 86 have been free of disease since the resection. The usual five-year figure after hepatic resection reveals that one-third of five-year survivors die from recurrence of distant disease suggesting the value of longer term follow-up in these patients. An additional question reviewed related to the role of neoadjuvant systemic chemotherapy (with response rates in the 50 % range) to produce down staging of the hepatic metastases and allow one to retrieve these patients with possible residual disease. In a series of 116 patients who had hepatic resection of CRC metastases in presence of regional node metastases, post neoadjuvant chemotherapy (normally not candidates for resection) these patients were demonstrated to have a 95 % recurrence at median time of 9 months. This raises a cautionary note to the literature report of five-year survivals in the 20-30 % range for hepatic metastases in presence of extra hepatic disease. Such may reflect patient selection rather than a true measure of the biology of disease, and warrant clinical trial evaluation. Lastly, regional therapy and overall systemic therapy were addressed by Dr. Kemeny. The CALGB study of hepatic artery infusion (HAI) with FUDR, dexamethasone versus 5FU leucovorin showed an overall survival of 24.4 months with HAI versus 20 months with systemic therapy (P = 0.0034). An adjuvant trial of HAI at MSK in 156 patients showed an overall survival benefit at 2 year and recent long term 10yr follow-up showing a significant overall survival of 41 % with HAI versus 27 % with systemic therapy (5FU leucovorin). In the neoadjuvant Nordlinger trial for hepatic metastases, there was a significant outcome differences-the preoperative therapy group had 9.2 % increase of progression free survival versus the surgery alone group which suggests the value of combining neoadjuvant surgery in good risk liver resection candidates. Conclude the final lesson from this well presented mini symposium confirms the need for continued evaluation of the numerous discussion points by clinical trial.

Impact of nodal status and tumor burden in sentinel lymph nodes on the clinical outcomes of cancer patients.

The validation of sentinel lymph node (SLN) concept in melanoma and breast cancer has established a new paradigm in cancer metastasis that, in general, cancer cells spread in a orderly fashion from the primary site to the SLNs in the regional nodal basin and then to the distant sites. In this review article, we examine the development of SLN concept in penile carcinoma, melanoma and breast carcinoma and its application to other solid cancers with emphasis of the relationship between micrometastasis in SLNs and clinical outcomes.

Detection and prognostic impact of micrometastasis in colorectal cancer.

Review of literature was performed on studies with prognostic impact of micrometastasis in colorectal cancer. Among 16 studies included, micrometastasis was detected in 26.5% of patients. Most analysis revealed that micrometastasis carries a poorer prognosis compared to node negative disease (NND). The results of those studies were compared with our pilot study of 109 patients with colon cancer, showing improved prognosis of micrometastasis after being upstaged and treated with chemotherapy when compared with NND.

Nodal positivity in breast cancer correlated with the number of lesions detected by magnetic resonance imaging versus mammogram.

BACKGROUND: Magnetic resonance imaging (MRI) in breast cancer can detect more than 15% additional lesions than mammography. We investigated lymph node metastases rates in patients with multifocal or multicentric disease detected by MRI compared with patients with a single lesion detected by mammography and magnetic resonance imaging. METHODS: A retrospective analysis of breast cancer patients undergoing MRI and mammography was performed. The objective was to compare lymph node metastases rates in patients with additional lesions detected by MRI versus a single lesion detected by mammography or MRI. RESULTS: Of 413 patients, 318 were included for the study. The overall nodal metastases rate was 24.8%. MRI detected multiple lesions in 83 (26.1%) patients; 67 (21.1%) patient MRI findings were not detected by mammography. The lymph node metastases rate was 37.3% when ≥ 2 lesions were detected compared with 20.2% when a single malignant lesion was detected (P = .01). The evaluation of the 67 patients with additional lesions detected by MRI revealed 32 patients with invasive lesions, 29 with benign lesions, and 6 with in situ disease. Comparing patients with single malignant lesions with patients with additional malignant lesions detected by MRI, the lymph node metastases rate increased from 20.2% to 50% (P = .002). CONCLUSIONS: Our study shows a significant increase in the lymph node metastases rate in patients with additional malignant lesions detected by MRI. This finding suggests that MRI-detected malignant lesions are biologically significant and may predict more aggressive disease.

Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial.

CONTEXT: Sentinel lymph node dissection (SLND) accurately identifies nodal metastasis of early breast cancer, but it is not clear whether further nodal dissection affects survival. OBJECTIVE: To determine the effects of complete axillary lymph node dissection (ALND) on survival of patients with sentinel lymph node (SLN) metastasis of breast cancer. DESIGN, SETTING, AND PATIENTS: The American College of Surgeons Oncology Group Z0011 trial, a phase 3 noninferiority trial conducted at 115 sites and enrolling patients from May 1999 to December 2004. Patients were women with clinical T1-T2 invasive breast cancer, no palpable adenopathy, and 1 to 2 SLNs containing metastases identified by frozen section, touch preparation, or hematoxylin-eosin staining on permanent section. Targeted enrollment was 1900 women with final analysis after 500 deaths, but the trial closed early because mortality rate was lower than expected. INTERVENTIONS: All patients underwent lumpectomy and tangential whole-breast irradiation. Those with SLN metastases identified by SLND were randomized to undergo ALND or no further axillary treatment. Those randomized to ALND underwent dissection of 10 or more nodes. Systemic therapy was at the discretion of the treating physician. MAIN OUTCOME MEASURES: Overall survival was the primary end point, with a noninferiority margin of a 1-sided hazard ratio of less than 1.3 indicating that SLND alone is noninferior to ALND. Disease-free survival was a secondary end point. RESULTS: Clinical and tumor characteristics were similar between 445 patients randomized to ALND and 446 randomized to SLND alone. However, the median number of nodes removed was 17 with ALND and 2 with SLND alone. At a median follow-up of 6.3 years (last follow-up, March 4, 2010), 5-year overall survival was 91.8% (95% confidence interval [CI], 89.1%-94.5%) with ALND and 92.5% (95% CI, 90.0%-95.1%) with SLND alone; 5-year disease-free survival was 82.2% (95% CI, 78.3%-86.3%) with ALND and 83.9% (95% CI, 80.2%-87.9%) with SLND alone. The hazard ratio for treatment-related overall survival was 0.79 (90% CI, 0.56-1.11) without adjustment and 0.87 (90% CI, 0.62-1.23) after adjusting for age and adjuvant therapy. CONCLUSION: Among patients with limited SLN metastatic breast cancer treated with breast conservation and systemic therapy, the use of SLND alone compared with ALND did not result in inferior survival. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00003855.

Comparison of nodal positivity between SLNM vs conventional surgery in colon cancer patients with <12 and ≥12 lymph nodes harvested.

BACKGROUND: Examination of ≥12 lymph nodes (LNs) ensures accurate staging in colon cancer. The aim of this study was to compare nodal positivity between sentinel LN mapping (SLNM) and conventional surgery in patients with <12 and ≥12 LNs harvested. METHODS: From 1993 to 2008, 407 and 380 patients with colon cancer underwent SLNM and conventional surgery, respectively. Total LNs harvested and nodal positivity were analyzed. Patients were grouped according to number of LNs harvested: 2 to 11, 12 to 25, or >25. RESULTS: The average numbers of LNs harvested in the groups with 2 to 11, 12 to 25, and >25 LNs harvested for SLNM and conventional surgery, respectively, were 8.3 and 7.1 (P < .0001), 17.2 and 16.5 (P = .09), and 34.2 and 32.1 (P = .40). Nodal positivity for SLNM and conventional surgery in the groups with <12 and ≥12 LNs harvested was 42% and 29% (P = .01) and 50% and 36% (P = .003), respectively. Overall nodal positivity was 47% for SLNM and 32% for conventional surgery (P < .0001). When SLNM with 2 to 11 LNs was compared with conventional surgery with 12 to 25 LNs, nodal positivity was 42% versus 36% (P = .35). CONCLUSIONS: SLNM possessed higher nodal positivity compared with conventional surgery. SLNM is a valuable adjunct to accurate nodal staging in colon cancer.

Locoregional recurrence after sentinel lymph node dissection with or without axillary dissection in patients with sentinel lymph node metastases: the American College of Surgeons Oncology Group Z0011 randomized trial.

BACKGROUND AND OBJECTIVE: Sentinel lymph node dissection (SLND) has eliminated the need for axillary dissection (ALND) in patients whose sentinel node (SN) is tumor-free. However, completion ALND for patients with tumor-involved SNs remains the standard to achieve locoregional control. Few studies have examined the outcome of patients who do not undergo ALND for positive SNs. We now report local and regional recurrence information from the American College of Surgeons Oncology Group Z0011 trial. METHODS: American College of Surgeons Oncology Group Z0011 was a prospective trial examining survival of patients with SN metastases detected by standard H and E, who were randomized to undergo ALND after SLND versus SLND alone without specific axillary treatment. Locoregional recurrence was evaluated. RESULTS: There were 446 patients randomized to SLND alone and 445 to SLND + ALND. Patients in the 2 groups were similar with respect to age, Bloom-Richardson score, estrogen receptor status, use of adjuvant systemic therapy, tumor type, T stage, and tumor size. Patients randomized to SLND + ALND had a median of 17 axillary nodes removed compared with a median of only 2 SN removed with SLND alone (P < 0.001). ALND also removed more positive lymph nodes (P < 0.001). At a median follow-up time of 6.3 years, there were no statistically significant differences in local recurrence (P = 0.11) or regional recurrence (P = 0.45) between the 2 groups. CONCLUSIONS: Despite the potential for residual axillary disease after SLND, SLND without ALND can offer excellent regional control and may be reasonable management for selected patients with early-stage breast cancer treated with breast-conserving therapy and adjuvant systemic therapy.

Ultrastaging of sentinel lymph nodes (SLNs) vs. non-SLNs in colorectal cancer--do we need both?

BACKGROUND: The aim of this study to analyze whether ultrastaging of initially negative nonsentinel lymph nodes (non-SLNs) would increase nodal positivity in colon cancer and rectal cancer. METHODS: After SLN mapping (SLNM), SLNs were ultrastaged by 4 hematoxylin and eosin and 1 immunohistochemistry sections. A blinded pathologist reexamined initially negative non-SLNs by 3 additional hematoxylin and eosin and 1 immunohistochemistry sections. RESULTS: In 156 colon cancer and 44 rectal cancer patients, 2,755 nodes were identified (494 SLNs and 2,261 non-SLNs). Metastases were detected in 20.9% of SLNs and 8.6% of non-SLNs (P<.0001). After ultrastaging non-SLNs, only .58% became positive for metastases in 12 patients. Of these, 10 already had positive lymph nodes, hence no change of staging occurred. Ultrastaging upstaged only 2 of 200 patients (1%). CONCLUSIONS: The chance of finding additional metastases by ultrastaging of all non-SLNs is extremely low (<1%) and of little benefit.

Predictors of occult nodal metastasis in colon cancer: results from a prospective multicenter trial.

BACKGROUND: The relationship between primary colon cancer and occult nodal metastases (OMs) detected by cytokeratin immunohistochemistry (CK-IHC) is unknown. We sought to investigate the correlation of clinicopathologic features of colon cancer with OMs and to identify predictors of OM. METHODS: Patients with colon cancer from 5 tertiary referral cancer centers enrolled in a prospective trial of staging had standard pathologic analysis performed on all resected lymph nodes (using hematoxylin and eosin staining [H&E]). Nodes negative on H&E underwent CK-IHC to detect OMs, which were defined as micrometastases (N1mic) or isolated tumor cells (N0i+). Patients who were negative on both H&E and CK-IHC were defined as node negative (NN), and those positive on H&E were node positive (NP). The relationships between tumor characteristics and OMs were analyzed using the Kruskal-Wallis and the Fisher exact test. RESULTS: OMs were identified in 23.4% (25/107) of patients. No significant differences were found in demographics, tumor location, tumor size, and number of nodes examined between groups. Compared with the NN group, patients with OMs had more tumors that were T3/T4 (72% vs 57%; P < .001), had tumors of higher grade (28% vs 12%; P = .022), and had tumors with lymphovascular invasion (16% vs 3%; P < .001). CONCLUSION: Adverse primary pathologic colon cancer characteristics correlate with OMs. In patients with negative nodes on H&E and stage T3/T4 colon cancer, lymphovascular invasion, or high tumor grade, consideration should be given to performing CK-IHC. The detection of OMs in this subset may influence decisions regarding adjuvant chemotherapy and risk stratification.

Intraperitoneal virtual biopsy by fibered optical coherence tomography (OCT) at natural orifice transluminal endoscopic surgery (NOTES).

INTRODUCTION: Fibered optical coherence tomography (OCT) in conjunction with natural orifice transluminal endoscopic surgery (NOTES) could provide a facility for rapid, in situ pathological diagnosis of intraperitoneal tissues in a truly minimally invasive fashion. MATERIALS AND METHODS: A large porcine model was established to test this hypothesis. A standard double channel gastroscope (Olympus) was used to achieve a transgastric access to the peritoneum and initiate the pneumoperitoneum. Magnetic retraction was used to display the sigmoid colon along with its mesentery. A commercially available fibered OCT probe (NIRIS system, Imalux) was inserted via a working channel of the gastroscope and used to assess intraperitoneal tissues. Separately, OCT images of human tissue specimens ex vivo were contrasted with representative standard histopathological slides. RESULTS: Intraperitoneal OCT provided clear real-time images of both the serosal and muscularis propria mural layers as well as the submucosal-muscularis interface. Examination of mesenteric lymph nodes (including sentinel nodes) allowed visualization of their subcapsular sinus. Comparison of representative cross-sections however failed to evince sufficient resolution for confident diagnosis. CONCLUSION: This approach is technically feasible and, if the technology is advanced and proven accurate in human patients, could potentially be used to individualize operative extent prior to definitive resection.

A prospective trial comparing 1% lymphazurin vs 1% methylene blue in sentinel lymph node mapping of gastrointestinal tumors.

BACKGROUND: Methylene blue (M), as a dye in sentinel lymph node mapping (SLNM), has been introduced as an alternative to lymphazurin (L) after the recent shortage of L. M has been evaluated in breast cancer in multiple studies with favorable results. Our study compares L with M in the SLNM of gastrointestinal (GI) tumors. METHODS: Between Jan 2005 and Aug 2008, 122 consecutive patients with GI tumors were enrolled. All patients (pts) underwent SLNM with either L or M by subserosal injection of 2-5 mL of dye. Efficacy and rates of adverse reactions were compared between the two dyes. Patients were prospectively monitored for adverse reactions including anaphylaxis, development of blue hives, and tissue necrosis. RESULTS: Of 122 pts, 60 (49.2%) underwent SLNM using L and 62 (50.8%) underwent SLNM using M. Colon cancer (CrCa) was the most common site in both groups. The success rate of L and M in SLNM was 96.6% and 96.7%, respectively, with similar numbers of total number of lymph nodes per pt, SLNs per pt (<3), nodal positivity, skip metastasis, and accuracy. The only adverse reaction in the L group was oxygen desaturation >5% in 5% (3/60) of pts, compared with none in the M group. Cost per vial of L was $210 vs $7 for M. CONCLUSION: The success rate, nodal positivity, average SLNs per patient, and overall accuracy were similar between L and M. Absence of anaphylaxis and lower cost make M more desirable than L in SLNM of GI tumors.

Sentinel node biopsy for the individualization of surgical strategy for cure of early-stage colon cancer.

INTRODUCTION: The requirement for nodal analysis currently confounds the oncological propriety of focused purely endoscopic resection for early-stage colon cancer and complicates the evolution of innovative alternatives such as natural orifice transluminal endoscopic surgery (NOTES) and its hybrids. Adjunctive sentinel node biopsy (SNB) deserves consideration as a means of addressing this shortfall. METHODS: Data from two prospectively maintained databases established for multicentric studies of SNB in colon cancer that employed similar methodologies were pooled to establish technique potency selectively in T1/T2 disease (both overall and under optimized conditions) and to project potential clinical impact. RESULTS: Of 891 patients with T1-4, M0 intraperitoneal colon cancer, 225 had T1/T2 disease. Sentinel nodes were either not found or were falsely negative in 18 patients with T1/T2 cancers (8%) as compared with 17% (112/646) in those with T3/T4 disease (P = 0.001). Negative predictive value (NPV) in the former exceeded 95%, while sensitivity [including immunohistochemistry (IHC)] was 81%. In the 193 patients with T1/T2 disease recruited from those centers contributing >22 patients, sensitivity was 89% and NPV 97%. Thus, in this cohort, SNB could have correctly prompted localized resection (obviating en bloc mesenteric dissection) in 75% (144) of patients, including 59 with T1 lesions potentially amenable to intraluminal resection alone as their definitive treatment. Forty-four patients (23.4%) would still have conventional resection, leaving three patients (1.6% overall) understaged (11% false-negative rate). CONCLUSION: These findings support the further investigation of SNB as oncological augment for localized resective techniques. Specific prospective study should pursue this goal.