Detection of Lymphatic Micrometastases in Patients With Stages I and II Colorectal Cancer: Impact on Five-Year Survival

PURPOSE: Despite having removed the whole macroscopic disease (curative intent surgery), one of five patients with Stages I and II colorectal cancer will develop recurrence. Lymphatic micrometastases detected by immunohistochemistry could be one of explanation for recurrence and cancer-related death in patients without lymph node involvement at light microscopy. However, the biologic importance of micrometastases remains unclear. This study was designed to determine the impact of micrometastases in five-year survival in patients with Stages I and II colorectal cancer.METHODS: This retrospective study included patients operated on between May 1989 and January 1999 for colorectal cancer without histopathologic lymph node involvement. Patients who received any adjuvant therapy were excluded. Immunohistochemical staining of the lymph nodes was performed with antipancytokeratin antibodies. Follow-up data were obtained from the clinical database and death certificates. Survival was estimated by the Kaplan-Meier method and compared by the log-rank test.RESULTS: Micrometastases were observed in 26 of 90 patients (28.9 percent). The mean follow-up time was 90.7 (range, 11–160) months. Seventeen cancer-related deaths occurred during follow-up (18.9 percent), 6 of them in patients with micrometastases (23.1 percent) and 11 in patients without micrometastases (17.2 percent; P = 0.559). Cancer-specific five-year survival was 87 percent in the whole group and 81 percent in patients positive for micrometastases vs. 90 percent in negative patients (P = 0.489).CONCLUSIONS: The presence of micrometastases in patients with Stages I and II colorectal cancer seems not to have any impact on cancer-specific survival.Supported by the Apertus Research Program (Andromaco Pharmaceutical Company) and by The National Public Grant (FONDECYT #1000556).     

The detection of cytokeratins in lymph nodes of Duke's B colorectal cancer subjects predicts a poor outcome

OBJECTIVES: The objectives of this study were to examine the frequency of lymph node micrometastases detected by keratin immunohistochemistry and their relationship with survival behaviour. METHODS: A total of 133 consecutive patients staged as Duke's B, who had curative resection for colorectal cancer (CRC), comprised the study population. Patients who had died of a non-CRC-related cause or who became lost to follow-up were excluded, resulting in an amended population of 100. Study end-points were defined as disease-free survival of 5 years or CRC-related death. Paraffin-embedded lymph node sections were stained with a commercial cytokeratin antibody using a standard avidin-biotin technique. RESULTS: One quarter of subjects had micrometastases. Fifty-six per cent of subjects with positive lymph nodes had an adverse outcome, compared with 11% of subjects with negative nodes. A highly significant association was found between lymph node cytokeratin expression and mortality in both the univariate (log rank P = 0.0001) and multivariate (Cox proportional hazards P = 0.0123) analysis. CONCLUSIONS: Lymph node micrometastases detected by this inexpensive and simple technique are significantly associated with mortality in Duke's B CRC. This technique may be used to select patients for adjuvant chemotherapy.     

Tumour-derived mutated K-ras codon 12 expression in regional lymph nodes of stage II colorectal cancer patients is not associated with increased risk of cancer-related death

This study examined the frequency of lymph node micrometastases detected by expression of mutant K-ras oncogene present in the respective primary tumour. The study population consisted of consecutive patients with stage II colorectal cancer (CRC) undergoing curative resection and with disease-free survival of 60 months or longer or CRC-related death. Of 27 patients found to have K-ras mutations at codon 12, 17 had genomic DNA suitable for PCR recovered from corresponding regional lymph node tissue. The same K-ras mutation was identified in the lymph nodes of 13 patients (76%), four of whom (30%) died of CRC recurrence within 5 years. A single patient in the negative group (25%) also died. Lymph node micrometastases detected by this technique thus show no relationship to mortality in stage II CRC. Further study of this technique is necessary before it can be used in the selection of patients for adjuvant chemotherapy.     

Analysis of micrometastatic disease in histologically negative lymph nodes of patients with adenocarcinoma of the distal esophagus or gastric cardia

SUMMARY. Lymphatic dissemination is the most important prognostic factor in patients with esophageal carcinoma. However, the clinical significance of lymph node micrometastases is still debated due to contradictory results. The aim of the present study was to identify the incidence of potentially relevant micrometastatic disease in patients with histologically node‐negative esophageal adenocarcinoma and to analyze the sensitivity and specificity of three different immunohistochemical assays. From a consecutive series of 79 patients who underwent a transthoracic resection with extended 2‐field lymphadenectomy, all 20 patients with pN0 esophageal adenocarcinoma were included in this study. A total of 578 lymph nodes were examined for the presence of micrometastases by immunohistochemical analysis with the antibodies Ber‐EP4, AE1/AE3 and CAM 5.2. Lymph node micrometastases were detected in five of the 20 patients (25%). They were identified in 16 of the 578 lymph nodes examined (2.8%) and most frequently detected with the Ber‐EP4 and AE1/AE3 antibody (sensitivity 95% and 79% respectively). In 114 of the 559 negative lymph nodes (20.4%), positive single cells were found that did not demonstrate malignant characteristics. These false‐positive cells were more frequently found with the AE1/AE3 staining (specificity of the Ber‐Ep4 and AE1/AE3 antibody 94% and 84% respectively). The presence of nodal micrometastases was associated with the development of locoregional recurrences (P=0.01), distant metastases (P=0.01), and a reduced overall survival (log rank test, P=0.009). For the detection of clinically relevant micrometastatic disease in patients operated upon for adenocarcinoma of the distal esophagus or gastric cardia, Ber‐EP4 is the antibody of first choice because of its high sensitivity and specificity. Immunohistochemically detected micrometastases in histologically negative lymph nodes have potential prognostic significance and are associated with a high incidence of both locoregional and systemic recurrence. Therefore, this technique has the potential to refine the staging system for esophageal cancer and to help identify patients who will not be cured by surgery alone.     

Prognostic Significance of Lateral Lymph Node Micrometastases in Lower Rectal Cancer

PURPOSE: The aims of this study were to determine the rate of lymph node micrometastases and to evaluate their prognostic value in lateral lymph nodes in lower rectal cancer at or below the peritoneal reflection. METHODS: A retrospective analysis was made of 892 lymph nodes from 66 consecutive patients who had undergone radical resection with lateral lymph node dissection. These lymph nodes were examined immunohistochemically with an antibody against cytokeratins 7 and 8, CAM5.2. RESULTS: Routine hematoxylin-eosin staining revealed 9 patients with positive lateral lymph nodes that were stained consistently with CAM5.2. Among 57 patients in whom lateral lymph node metastases were not detected by hematoxylin-eosin staining, cytokeratin staining was positive in 19 nodes (2.7 percent) from 11 patients (19.3 percent). These 11 patients with micrometastases in lateral nodes showed a significantly high recurrence rate (P = 0.048) and worse overall survival (P = 0.01) than the 46 patients without lateral node metastases. The recurrence rate and overall survival of patients with micrometastases did not differ significantly from those of patients with positive lateral nodes with hematoxylin-eosin staining. Local recurrence developed in 6 of 66 patients, but neither the presence nor the absence of micrometastases in lateral nodes influenced the local recurrence rate. CONCLUSION: The presence of nodal micrometastases leads to a poor prognosis. The survival of patients with micrometastases was not different from that of patients with overt metastases. Therefore, patients with cytokeratin-positive cells in lateral lymph nodes should be regarded as having overt metastases.     

Number of lymph node metastases influences survival in patients with thoracic esophageal carcinoma: therapeutic value of radiation treatment for recurrence

We retrospectively investigated whether the number of involved lymph nodes and the radiation therapy for recurrence affect survival in patients with thoracic esophageal carcinoma. Eighty-nine patients underwent surgical resection and reconstruction for thoracic esophageal squamous cell carcinoma beyond the mucosal layer. Patients were classified into three groups: group 1 comprised 40 patients without lymph node involvement; group 2 comprised 34 patients with 1-3 positive nodes; and group 3 comprised 15 patients with > or = 4 involved lymph nodes. The 3-year and 5-year survival rates were 77.5% and 73.2% respectively in group 1, 64.8% and 55.8% respectively in group 2, and 28.1% and 0% respectively in group 3. The mean survival time (MST) mean +/- SD of the patients in group 3 (772.1 +/- 146.2 days) was significantly shorter than that of patients in group 1 (3728.5 +/- 320.7 days, p < 0.0001) and group 2 (2330.4 +/- 344.3 days, p = 0.0130). The MST of the patients in group 2 was also significantly shorter than that of patients in group 1 (p = 0.0366). Patients with recurrent lymph nodes that were localized were treated effectively with radiation therapy. We conclude that the number of lymph node metastases influences survival in thoracic esophageal cancer. Early detection as well as radiation therapy for recurrent lymph node metastases is effective in improving long-term survival.     

癌胚抗原在结直肠癌淋巴结微转移检测中的应用

目的 探讨Ⅰ和Ⅱ期结直肠癌术后病理因素及淋巴结微转移对术后5年无瘤生存率的影响.方法 Ⅰ和Ⅱ期结直肠癌患者共126例,均行结直肠癌根治术.每例结直肠癌患者的淋巴结数平均为16枚(10～28枚),用癌胚抗原(CEA)指标对所有淋巴结进行免疫组化染色.统计分析临床病理因素及微转移对术后5年无瘤生存率的影响.结果 术后平均随访64.11(64～106)个月.淋巴管侵犯和肿瘤侵袭深度与淋巴结的CEA表达呈正相关,而其他临床病理因素与淋巴结CEA表达无明显相关性.10项临床病理因素对5年无瘤生存率的影响差异均无统计学意义(P＞0.05).淋巴结CEA表达阴性、孤立肿瘤细胞巢和微转移患者的5年无瘤生存率分别为75.4%、68.2%和46.2%.孤立肿瘤细胞巢患者与CEA阴性患者5年无瘤生存率比较差异无统计学意义(P=0.245).微转移患者与CEA阴性患者比较,前者5年无瘤生存率明显较低(P=0.003).结论 对于Ⅰ和Ⅱ期结直肠癌,若淋巴结中检测到微转移,其预后较差,术后复发率较高,应予以积极的术后辅助化学治疗.     

Management of inguinal lymph node metastases from adenocarcinoma of the rectum

Forty patients with inguinal lymph node metastases from rectal adenocarcinoma were reviewed. Patients were divided into three groups based on the extent of their disease: (1) patients with unresectable primary tumors; (2) patients with recurrent disease after abdominoperineal resection; and (3) patients with isolated inguinal lymph node metastases after abdominoperineal resection. Patients in Groups 1 and 2 underwent biopsy of their nodal metastases. Patients in Group 3 were treated by inguinal node dissection. Survival data were examined for each group, and four clinical and pathologic features were analyzed to determine their impact on prognosis: depth of invasion of the primary tumor (T1-2 vs. T3-4), number of positive lymph nodes in the rectal specimen (0-2 vs. greater than 2), extent of the inguinal lymph node metastases (unilateral vs. bilateral), and timing of the inguinal lymph node metastases (less than 1 vs. greater than 1 year after abdominoperineal resection). There were no five-year survivors in any group. Median survival was highest in those with isolated lymph node metastases, with 2 patients remaining free of disease, and was lowest in those with unresectable primary disease (7 months). Median survival was increased when inguinal LNM were unilateral (17 vs. 6 months; P less than 0.01) and when they occurred more than 1 year after abdominoperineal resection (21 vs. 7 months; P = 0.02). Stage of the primary lesion (depth of invasion and number of positive lymph nodes) did not affect survival. Of the 32 patients who underwent biopsy alone, only 1 developed a tumor-related groin complication. For patients with isolated inguinal lymph node metastases, inguinal node dissection is recommended for the purposes of local control and possible cure. For patients with extranodal disease, prophylactic excision of inguinal lymph node metastases is not warranted.     

Micrometastases in the cervical lymph nodes in esophageal squamous cell carcinoma

Few studies have investigated the presence of lymph node micrometastases (MM) in the cervical region of patients with esophageal squamous cell cancer. The present study examines the presence of cervical MM and attempts to determine a way to predict the occurrence and site of such micrometastases. A total of 2203 cervical lymph nodes and 118 mediastinal recurrent nerve nodes obtained from 86 patients with esophageal carcinoma were examined immunohistochemically using cytokeratins. Cervical lymph nodes and mediastinal recurrent nerve nodes metastases were detected histologically in 33 and 41 of the 86 patients respectively. Cervical lymph node and mediastinal recurrent nerve node MM were immunohistochemically detected in 16 (18.6%) and 6 (7.0%) patients respectively. Of these 16 patients with cervical MM, seven were found to have lymph node metastases in different cervical regions, whereas cervical MM only were detected in nine patients. Among the former group of patients, five were diagnosed by ultrasound examination as having cervical lymph node metastases. Mediastinal recurrent nerve node metastases and MM correlated with the presence of cervical MM in all but one patient. Cervical lymph node metastasis, including micrometastasis, can be predicted by preoperative ultrasonography and the routine histologic examination of mediastinal recurrent nerve nodes.     

Clinicopathological features of skip metastasis in colorectal cancer

BACKGROUND/AIMS: Japanese general rules for the staging of colorectal cancer conventionally classify lymph node metastasis into three groups according to location with respect to the primary tumor. Skip metastasis, in which distant nodes are positive but regional nodes are negative, is often encountered but poorly understood. We studied the clinicopathological features of skip metastasis in colorectal cancer. METHODOLOGY: The location of positive nodes was classified in 323 patients with Dukes' stage C colorectal cancer. Skip n2 lymph node metastasis was defined as positive N2 metastasis without negative N1 or N3 metastasis. Clinicopathological findings and survival were compared between the patients with skip n2 metastasis (skip n2 group) and those with n1 (n1 group) or n2 metastasis (n2 group). RESULTS: There were 211 patients in the n1 group, 91 in the n2 group, and 21 in the skip n2 group. Pathological examination showed that the skip n2 group had fewer positive nodes than the n1 and n2 groups, but was positioned between these groups with respect to the degree of lymphatic invasion. Cumulative survival was significantly poorer in the n2 group than in the skip n2 group (p = 0.039 by log-rank test). Survival was similar in the skip n2 group and n1 group. There was also no difference in survival between patients in the skip n2 group and patients with one, two, or three N1 metastases. CONCLUSIONS: Lymph nodes with skip n2 metastasis are most likely sentinel nodes of the primary tumor in patients with colorectal cancer. The prognosis of patients with skip n2 metastasis is therefore better than that of patients with n2 metastasis and similar to that of patients with n1 metastasis.     

Sentinel lymph node detection in colorectal cancer: importance, techniques and results

BACKGROUND AND AIM: Considering that lymph node status is a key factor in colorectal cancer staging, and the main determinant for adjuvant therapy of colorectal cancer being this therapy, responsible for a significant increase in colorectal cancer patients survival, the staging methods should be the most accurate possible in order to offer this individuals the opportunity to be adequate treated in order to achieve the best survival possible. Sentinel lymph node study is progressively being popularized as a method that increases sensibility in detect positive nodes to reveal a more accurate stage and prognosis in colorectal cancer patients. PATIENTS AND METHODS: Thirty one colorectal cancer patients were prospectively studied and sentinel lymph node was identified in 100% of the cases utilizing either patent blue alone, or in association with radiotracer based on technetium 99m colloid solution in a randomized fashion. RESULTS: The mean number of sentinel nodes per patient was 1.96 ranging from 1 to 3 nodes. With the addition of transoperative lympho-scintigraphy five extra sentinel nodes, not identified by the blue dye alone, were identified and considered for histopathology study. In four cases (12.9%) the sentinel lymph node was the only site of metastasis, all of them being detected by association of hematoxylin and eosin and immunohistochemical examination. CONCLUSION: Sentinel lymph node detection and analysis is feasible, technique is relatively simple and is able to produce upstage in colorectal cancer. Blue staining and radio guided techniques are both safe and their superposition has shown good results in terms of increase accuracy in our experience. There was no aberrant lymph drainage that would alter resection margins in patients studied. Upstaging rate, identifying potential candidates for adjuvant therapy was 12.9% (4/31). To this individuals chemotherapy could be a chance to increase their global survival.     

Lack of Influence of Cytokeratin-Positive Mini Micrometastases in ”Negative Node” Patients With Colorectal Cancer: Findings From the National Surgical Adjuvant Breast and Bowel Projects Protocols R-01 and C-01

PURPOSE: Results of the few extant reports concerning the clinical significance of so-called occult micrometastases of lymph nodes of patients with Dukes A and B colorectal cancer have been variable. We examined the presumably negative nodes of a larger cohort of such patients who were enrolled in the National Surgical Adjuvant Breast and Bowel Project clinical trials R-01 and C-01 for the influence of what we preferably designate as nodal mini micrometastases on parameters of survival. METHODS: Mini micrometastases were detected by immunohistochemical staining of the original lymph node sections with anticytokeratin A1/A3 in a total of 241 Dukes A and B patients with rectal and 158 with colonic cancers. Their frequency, as well as that of nuclear and histologic grades, and an estimation of their relationship to relative risks were correlated with overall and recurrence-free survival by univariate and multivariate analyses. RESULTS: Nodal mini micrometastases were detected in 73 of 399 (18.3 percent) patients of this cohort. They failed to exhibit any significant relationship to overall or recurrence-free survival. No association between the assessments of tumor differentiation and mini micrometastases was found. Nuclear and histologic grades also failed to further discriminate overall or recurrence-free survival in patients with A or B stages of colonic or rectal cancers in this cohort. CONCLUSION: The immunohistochemical demonstration of nodal mini micrometastases failed to discriminate high- and low-risk groups of patients with colorectal cancer who were designated as being node-negative after routine pathologic examination.     

Lack of influence of cytokeratin-positive mini micrometastases in "Negative Node" patients with colorectal cancer: findings from the national surgical adjuvant breast and bowel projects protocols R-01 and C-01

PURPOSE: Results of the few extant reports concerning the clinical significance of so-called "occult micrometastases" of lymph nodes of patients with Dukes A and B colorectal cancer have been variable. We examined the presumably negative nodes of a larger cohort of such patients who were enrolled in the National Surgical Adjuvant Breast and Bowel Project clinical trials R-01 and C-01 for the influence of what we preferably designate as nodal mini micrometastases on parameters of survival. METHODS: Mini micrometastases were detected by immunohistochemical staining of the original lymph node sections with anticytokeratin A1/A3 in a total of 241 Dukes A and B patients with rectal and 158 with colonic cancers. Their frequency, as well as that of nuclear and histologic grades, and an estimation of their relationship to relative risks were correlated with overall and recurrence-free survival by univariate and multivariate analyses. RESULTS: Nodal mini micrometastases were detected in 73 of 399 (18.3 percent) patients of this cohort. They failed to exhibit any significant relationship to overall or recurrence-free survival. No association between the assessments of tumor differentiation and mini micrometastases was found. Nuclear and histologic grades also failed to further discriminate overall or recurrence-free survival in patients with A or B stages of colonic or rectal cancers in this cohort. CONCLUSION: The immunohistochemical demonstration of nodal mini micrometastases failed to discriminate high- and low-risk groups of patients with colorectal cancer who were designated as being node-negative after routine pathologic examination.     

How many lymph nodes should be examined in Dukes' B colorectal cancer? Determination on the basis of cumulative survival rate

BACKGROUND/AIMS: We analyzed how many lymph nodes should be examined to establish the presence or absence of lymph node metastasis, a staging factor, based on cumulative survival rate in colorectal cancer. METHODOLOGY: Among those who had undergone curative resection of colorectal cancer and lymphadenectomy exceeding D2, 94 patients with Dukes' B colorectal cancer (group B) and 108 patients with Dukes' C colorectal cancer (group C) were investigated, excluding obvious deaths from other diseases. Group B was divided into two groups by the number of lymph nodes examined, and the minimum number of retrieved lymph nodes yielding significant difference in survival rate was determined. RESULTS: Dividing group B into two groups by the number of lymph nodes examined, survival rate was studied. The minimum number of retrieved lymph nodes yielding significant difference in survival rate between the two groups was observed when group B was divided into one group with 9 or more lymph nodes (72 patients) and the other with less than 9 (22 patients), with cumulative five-year survival rate of 86.7% and 66.7%, respectively. More favorable prognoses were observed in the 9 or more group compared with the less than 9 group or Dukes' C group (p=0.0284, p=0.0032, respectively). On the other hand, survival rate of the less than 9 group was similar to that of the Dukes' C group (p=0.8167). CONCLUSIONS: Based on survival rate, 9 or more lymph nodes should be examined in order to correctly ascertain nodal negativity in lymphadenectomy exceeding D2 for Dukes' B colorectal cancer.     

Sentinel lymph nodes of colorectal carcinoma: reappraisal of 123 cases

AIMS: Results concerning the usefulness of the sentinel lymph node (SLN) in colorectal carcinoma have been discordant. The SLN technique may be used to guide surgical resection (lymph mapping), restrict the lymph node analysis solely to the SLN (accuracy) and upgrade tumor staging when micrometastases are specifically detected in the SLN. METHODS: The blue dye injection technique was used. Serial sections of the SLNs were analyzed after hematoxylin-eosin (HES) staining. RESULTS: The SLN technique was tested in 123 patients, successfully in 112/118 (feasibility 95%) (five intraoperative exclusions). On average, twenty lymph nodes (range: 5-74) and two SLNs (range: 1-5) were identified. Lymph mapping was used in 11% of patients to guide surgical resection; the SLN was negative in 14 of 36 N+ patients (39% false-negatives); HES staining enabled detection of micrometastases in 8 of 84 initially N0 patients (10% secondary upgrading to N+). CONCLUSION: Limiting node analysis to the SLN cannot replace a complete pathology examination of all resected lymph nodes. Careful examination of serial sections of the SLN can however affect therapeutic decision making since staging may be upgraded in up to 10% of initially N0 patients.     

The novel combination of fat clearance and immunohistochemistry improves prediction of the outcome of patients with colorectal carcinomas: a preliminary study

To evaluate the significance of micrometastases in relation to survival rate, specimens from 48 colorectal carcinoma patients were analysed after fat clearance. The number and size of the lymph nodes harbouring metastases and the significance of micrometastases for patients' survival were assessed. We found that although the majority of metastatic lymph nodes (71.8%) were 5 mm or less in diameter, their size had no effect on survival. Immunohistochemical staining of lymph nodes revealed that 15 of 25 patients with Dukes' stage B diagnosed by routine staining had micrometastases, 86% of these lymph nodes being less than 5 mm in diameter. The survival rate of this subgroup was found to be considerably poorer than that of Dukes' stage B patients with no micrometastases. None of the three patients with Dukes' stage A carcinoma had micrometastases. Since most of the metastases and micrometastases occur in lymph nodes of 5 mm and less and can be easily missed by routine examination, we suggest that fat clearance and routine immunohistochemical analysis of Dukes' stage B improve the prediction of outcome of colorectal cancer patients. Accepted: 10 February 1998