The feasibility and reliability of sentinel node mapping in colorectal cancer.

AIMS: Sentinel node mapping (SNM) has been introduced in colorectal cancer (CRC) to improve staging by facilitating occult tumour cell (OTC) assessment in lymph nodes that are most likely to be tumour-positive. In this paper, studies on the feasibility and reliability of SNM in CRC are reviewed. METHODS: A literature search was conducted in the National Library of Medicine by using the keywords colonic, rectal, colorectal, neoplasm, adenocarcinoma, cancer and sentinel. Additional articles were identified by cross-referencing from papers retrieved in the initial search. RESULTS: There is a large variation in identification rates and false-negative rates mainly due to the learning curve effect, differences in SNM technique and tumour stage. CONCLUSIONS: We conclude that SNM in CRC is technically feasible. Standardization of SNM procedures is mandatory to resolve the debate on the reliability of sentinel node status for predicting the tumour status of all lymph nodes. Only then can adjuvant treatment of patients upstaged by OTC detection in sentinel nodes be justified.     

无淋巴结转移的结直肠癌患者淋巴结切除数目对预后的影响

结直肠癌是我国最常见的癌症死亡原因之一。术中切除的淋巴结数目与结直肠癌患者的预后密切相关,特别是对无淋巴结转移的患者具有重要的临床意义。其机制可能包括淋巴结错误病理分期及淋巴结微转移等。因此,术中规范地进行淋巴结清扫,术后对高危患者进行强化治疗,提高微转移检测手段等对结直肠癌患者的预后具有重要作用。     

无淋巴结转移的结直肠癌患者淋巴结切除数目对预后的影响

结直肠癌是我国最常见的癌症死亡原因之一。术中切除的淋巴结数目与结直肠癌患者的预后密切相关,特别是对无淋巴结转移的患者具有重要的临床意义。其机制可能包括淋巴结错误病理分期及淋巴结微转移等。因此,术中规范地进行淋巴结清扫,术后对高危患者进行强化治疗,提高微转移检测手段等对结直肠癌患者的预后具有重要作用。     

Number of lymph nodes examined and prognosis of TNM stage II colorectal cancer

The diagnosis of a lymph node-negative colorectal carcinoma should imply a good prognosis; however, the outcomes for TNM stage II patients remain variable. Few studies have examined the relationship of the number of lymph nodes examined to the prognosis of this stage. The aim of this study was to determine whether the number of lymph nodes examined has an effect on prognosis of a relatively large sample of patients undergoing curative surgery for stage II colorectal cancer at a single institution. Data on patients who underwent surgery for colorectal cancer between January 1980 and April 2000 were prospectively collected in a database. Patients with TNM stage II or stage III tumours who were treated with curative intent were removed. Patients over 80 years of age were excluded from the survival analysis. Survival comparisons were made using Kaplan-Meier curves and the log-rank test. Multivariate analysis was performed using a Cox regression model. A total of 625 cases of TNM stage II cases and, for comparison purposes, 415 stage III cases, were analysed. Lymph node retrieval in stage II cases was affected by the patient's age (P=0.04) and gender (P=0.02), tumour grade (P<0.0001), tumour site (P<0.0001), and necessity to carry out extended resection (P<0.0001). In stage III cases, lymph node retrieval was affected by patient age (P<0.0001), tumour grade (P=0.02), and tumour site (P=0.002). Decreased lymph node detection was associated with increasing hazard ratios among the 480 TNM stage II patients under 80 years of age, but not among the 345 patients with TNM stage III tumours. Five year survival rate for patients with stage III tumours with only 1-3 positive lymph nodes (52.6%) was similar to that of patients with stage II tumour who had nine or fewer lymph nodes examined (51.3%). These results demonstrate that the prognosis of TNM stage II colorectal cancer is dependent on the number of lymph nodes examined. Patients with few nodes examined have a poorer prognosis. It is possible that a smaller number of lymph nodes examined reflects a diminished immune response. It can be presumed that those patients with stage II tumour with only a few nodes examined should be offered postoperative chemotherapy on a routine basis.     

The prognostic significance of total lymph node number in patients with axillary lymph node-negative breast cancer.

AIM: In node-negative breast cancer patients, several factors for survival have been evaluated and currently, some of them are accepted for their prognostic and/or predictive values after validation in the separate data sets. The prognostic significance of increases in the number of pathologically detectable axillary lymph nodes in the node-negative patients could not been established clearly. To address this question, we have reviewed our patients' records. METHODS: A retrospective cohort study was conducted in pathologically node-negative patients who underwent modified radical mastectomy for stage I and II breast cancer. Survival and multivariate prognostic factor analyses were carried out to determine whether the number of tumour-free lymph nodes in complete axillary dissection material in addition to known factors was significant for the outcomes. RESULTS: Two hundred and seventy consecutive patients were eligible to enter the trial. The median observation time and the median number of tumour-free lymph nodes were 61 (from 30 to 120) months and 18 (from 10 to 44), respectively. The cohort was divided into the groups according to the number of nodes. The 5-year event-free and overall survivals were 92.5 and 98.3% for patients who had 18 lymph nodes or less, and 70 and 86.7% for those who had more than 18 negative nodes, respectively (P < 0.00001). Multivariate analysis for event-free survival demonstrated that the number of lymph nodes (Relative risk: 3.2 and 95% confidence interval: 1.7 to 5.9) in addition to the pathological tumour size and age was the most important independent prognosticator. In similar, multivariate analysis for overall survival showed that the number of lymph nodes together with the tumour size was the significant indicator (RR of cancer-specific dying in patients who had more than 18 nodes: 3.1 and 95% CI: 1.2 to 8.5). CONCLUSION: The increases in number of tumour-free lymph nodes are clinically important and this parameter should be taken into consideration in the breast cancer patients without metastatic lymph nodes.     

Immunohistochemical assessment of localization and frequency of micrometastases in lymph nodes of colorectal cancer.

PURPOSE: Micrometastases are often found in regional lymph nodes of colorectal cancer (CRC). The aim of this study is to examine the extent and distribution of such lymph nodes. EXPERIMENTAL DESIGN: We immunohistochemically assessed localization and frequency of micrometastases in 878 lymph nodes from 98 patients with CRC. The anatomical position of lymph nodes was defined as level 1 to level 3 according to distance from the main tumor. RESULTS: The frequency of micrometastasis increased through observation of the 4-microm-thick lymph node sections, from one to two to five slices. With five slices, micrometastasis was frequently and extensively present in 49.1, 35.7, and 53.3% patients of histologically node-negative patients, node-positive patients at level 1, and node-positive patients at level 2, respectively. We then assessed the value of the presence of micrometastasis in node-negative patients with regard to prognosis, but no significant impact was obtained. To examine the reproducibility of the results obtained with immunohistochemistry, serial sectioning (four consecutive slices at seven different levels) of lymph nodes was additionally performed in lymph nodes initially diagnosed as micrometastasis positive. Immunohistochemical detection revealed that the sectioning level highly affected the results. CONCLUSIONS: Our results indicated frequent presence of micrometastasis in lymph nodes of CRC and that micrometastasis in node-negative CRC patients did not help in predicting the outcome, in part because of the limited reproducibility with immunohistochemistry.     

A qualitative synthesis of the evidence behind elective lymph node irradiation in oesophageal cancer

Background and purpose: Oesophageal cancer is the sixth leading cause of cancer death worldwide and radiotherapy plays a prominent role in its treatment. The presence of lymph node (LN) metastasis has been demonstrated to be one of the most significant prognostic factors related to oesophageal cancer. The use of elective lymph node irradiation (ENI) is still a topic of persistent controversy. The conservative school is to irradiate positive lymph nodes only; the other school is to prophylactically irradiate the regional lymph node area according to different tumour sites. This review investigated the justification for including ENI in the treatment of patients with oesophageal cancer. Material and methods: We performed a systematic literature search to find surgical data about lymph node distribution depending on different tumour subgroups: early, cervical, thoracic and gastroesophageal junction cancer. Furthermore, we performed a qualitative assessment of recurrence patterns in patients treated with or without ENI to derive estimates of the potential area at risk for lymph node harvest. Results: We identified and reviewed 49 studies: 10 in early, 8 in cervical, 10 in thoracic and the remaining 21 in gastroesophageal junction cancer. In general, these studies were conclusive in incidence and location of pathologic lymph nodes for different subgroups. Data for lymph node recurrence patterns are scarce and contributed little to our review. Conclusions: This review resulted in five recommendations for radiation oncologists in daily practice. We used the available evidence about metastatic lymph node distribution to develop a careful reasonable radiation protocol for the corresponding tumour subgroups.     

腋窝淋巴结微小转移与肿瘤微血管计数对乳腺癌患者预后的影响

目的:通过对腋窝淋巴结阴性乳腺癌患者的淋巴结进一步分析,研究淋巴结微小转移灶及肿瘤微血管计数(MVD)对预后的影响.方法:选取1993年564例乳腺癌中腋窝淋巴结阴性患者48例(24例死亡,24例生存),分别用HE、EMA和CK19对原淋巴结病理切片进行复染,确定微小转移灶.将肿瘤病理切片用FVIII因子染色,确定微血管数目.结果:48例共882枚淋巴结中发现微小转移灶为9.0%(79/882),死亡组与对照组之间无显著差异(P＞0.05);微血管计数两组之间差异有显著性意义(P＜0.001),经统计学分析微血管计数对患者预后的判别能力大于淋巴结微小转移灶.结论:本研究中淋巴结微小转移灶未显示出对生存的明显影响,而肿瘤的微血管计数与腋窝淋巴结阴性乳腺癌患者的生存时间呈负相关.     

Sentinel lymph node mapping in colorectal cancer: a feasibility study

AIMS AND BACKGROUND: Sentinel lymph node (SLN) biopsy is currently used and investigated in melanoma and in breast cancer. Its utility in gastrointestinal malignancies is still under debate. The prognosis of colorectal cancer patients is strongly related to the lymphatic involvement. The aim of this study was to evaluate the feasibility of SLN mapping in colorectal cancer and to assess its impact on pathological staging and treatment. METHODS AND STUDY DESIGN: We injected blue dye in 11 colorectal cancer patients during surgery. After resection the tumor specimen was examined to identify blue-stained lymph nodes and these lymph nodes were sent separately to the pathologist. Routine hematoxylin-eosin examination was performed on all nodes (including blue ones). No other techniques (eg immunohistochemistry or PCR) were performed. RESULTS: Sentinel lymph nodes were successfully identified in 10 of the 11 patients. We observed only one false negative result (10%) and the agreement between SLN and other lymph node status was 80% (8/10). One patient was upstaged: SLN was positive for metastases while the other lymph nodes were negative. CONCLUSIONS: Lymphatic mapping using patent blue dye is feasible in colorectal cancer. The identification of lymph nodal metastases by this technique led to upstaging of one patient, who may benefit from adjuvant therapy. These initial results prompt further investigation of this procedure as an accurate, minimally invasive staging approach in early colorectal cancer. We proceed with our study to evaluate the role of SLN mapping in colorectal cancer management.     

淋巴结转移阴性结直肠癌的临床病理特点及预后多因素分析

目的探讨淋巴结转移阴性结直肠癌的临床病理特点及其预后因素,为临床治疗提供依据.方法以我院1996至1999年间施行结直肠癌根治手术,检取5个以上淋巴结均无转移的247例患者为研究对象,总结临床病理特点;采用Kaplan-Meier法进行单因素分析,COX比例风险模型进行多因素分析,判定淋巴结转移阴性结直肠癌的独立预后因素.结果淋巴结转移阴性结直肠癌浸润深度较浅,肿瘤小,血清CEA值低.5年生存率为73.8%(175/237).结论淋巴结转移阴性结直肠癌施行根治术后预后较好,浸润深度和术前血清CEA值是其独立预后因素.     

Outcomes of a population-based series of early breast cancer patients with micrometastases and isolated tumour cells in axillary lymph nodes

BackgroundAxillary lymph node staging is traditionally important to provide prognostic information to guide further treatment. However, the relevance of isolated tumour cells (ITC) or micrometastases in axillary nodes and the need for adjuvant treatment remain uncertain.Patients and methodsData from 18 370 patients with pT1–2 breast cancer with pN0, pN0i+ or pN1mi were analysed. The primary end point was 5-year disease-free survival (locoregional recurrence, distant metastases or contralateral breast cancer).ResultsFive-year disease-free survival was 89.9% [95% confidence interval 89.5% to 90.4%]; and did not differ significantly between groups. After adjusting for prognostic factors (including treatment), patients with ITC had a comparable risk (hazard ratio = 1.12) as patients with node-negative disease, while patients with micrometastases had a 38% higher risk of recurrence.Conclusion(s)Patients with ITC and node-negative breast cancer appear to have similar prognosis, and those with micrometastases have a 38% higher risk of tumour recurrence. However, considering that disease-free survival is already high, we are reluctant to advise chemotherapy in all patients with ITC or micrometastases. In future, genomic tumour characteristics might predict the propensity of dissemination from the primary cancer better than the status of the axillary lymph nodes.     

Clinical significance of micrometastasis to lymph nodes in gastrointestinal tract cancers]

Surgery is the main therapy for malignancies of the gastrointestinal tract. Lymph node metastasis is one of the major factors in predicting patients' clinical course and choosing appropriate adjuvant therapy after surgery. The concept of micrometastasis to regional lymph nodes emerged over 10 years ago, but its significance has been controversial. To clarify the relevance of micrometastasis of gastrointestinal tract cancers, we have established RT-PCT based-diagnostic methods using multi-markers such as CEA, CK20, and Mage 3. Prospective studies have shown that not a few micrometastasis-positive patients with carcinoma of the colon, stomach, and esophagus suffered disease recurrence, even though they did not show histologically positive lymph node metastasis. They were initially diagnosed as node-negative, and thus predicted to be disease free. A retrospective study of 62 patients with stage II node-negative colorectal cancer showed that 5-year overall survival was 78.2% among micrometastasis-positive patients, against 95.3% micrometastasis-negative patients. Moreover, there was a marked difference in 5-year disease-free survival, with 61.4% versus 88.4%, respectively. These data warrant further prospective study with a large population since RT-PCR based detection systems for micrometastasis appear to have the potential to improve conventional diagnosis and therapy for colorectal cancer.     

Impact of number of nodes retrieved on outcome in patients with rectal cancer.

PURPOSE: We postulated that the pathologic evaluation of the lymph nodes of surgical specimens from patients with rectal cancer can have a substantial impact on time to relapse and survival. PATIENTS AND METHODS: We analyzed data from 1,664 patients with T3, T4, or node-positive rectal cancer treated in a national intergroup trial of adjuvant therapy with chemotherapy and radiation therapy. Associations between the number of lymph nodes found by the pathologist in the surgical specimen and the time to relapse and survival outcomes were investigated. RESULTS: Patients were divided into groups by nodal status and the corresponding quartiles of numbers of nodes examined. The number of nodes examined was significantly associated with time to relapse and survival among patients who were node-negative. For the first through fourth quartiles, the 5-year relapse rates were 0.37, 0.34, 0.26, and 0.19 (P: = .003), and the 5-year survival rates were 0.68, 0.73, 0.72, and 0.82 (P: = .02). No significant differences were found by quartiles among patients determined to be node-positive. We propose that observed differences are primarily related to the incorrect determination of nodal status in node-negative patients. Approximately 14 nodes need to be studied to define nodal status accurately. CONCLUSION: These results suggest that the pathologic assessment of lymph nodes in surgical specimens is often inaccurate and that examining greater number of nodes increases the likelihood of proper staging. Some patients who might benefit from adjuvant therapy are misclassified as node-negative due to incomplete sampling of lymph nodes.     

Clinical utility of urokinase-type plasminogen activator and plasminogen activator inhibitor-1 determination in primary breast cancer tissue for individualized therapy concepts

Invasion factors urokinase-type plasminogen activator (uPA) and its plasminogen activator inhibitor (PAI-1) are the only novel tumor biological prognostic factors validated at the highest level of evidence with regard to their clinical utility in breast cancer. Antigen levels of both factors present in extracts of primary tumor tissue are determined by standardized, quality-assured enzyme-linked immunosorbent assays. Numerous studies showed that patients with low levels of uPA and PAI-1 have a significantly better survival than patients with high levels of either factor. Recently, these data have been validated by a European Organization for Research and Treatment of Cancer pooled analysis comprising more than 8000 breast cancer patients. The particular combination of both factors, uPA/PAI-1 (both low vs. either or both factors high), outperforms the single factors as well as other traditional prognostic factors with regard to risk group assessment, particularly in node-negative breast cancer. Node-negative breast cancer patients with low levels of uPA and PAI-1 have a very good prognosis and, as such, may be candidates for being spared the burden of adjuvant chemotherapy. In contrast, node-negative patients with high uPA/PAI-1 are at a substantially increased risk of relapse, comparable to that of patients with > or = 3 involved axillary lymph nodes. First results from a multicenter prospective randomized therapy trial in node-negative breast cancer (Chemo N(0)) as well as recent retrospective analyses indicate that these high-risk patients benefit from adjuvant chemotherapy. Thus, combined determination of the invasion factors uPA and PAI-1 supports risk-adapted individualized therapeutic strategies in patients with primary breast cancer, particularly in those with node-negative breast cancer.     

One-step nucleic acid amplification (OSNA): where do we go with it?

The one-step nucleic acid amplification (OSNA) assay was initially developed for the intraoperative assessment of sentinel lymph node metastases in breast cancer. This assay measures cytokeratin 19 (CK19) mRNA copy number and is widely used in hospitals. The results of the IBCSG 23-01, ACOSOG Z0011, and AMAROS trials demonstrated that no further axillary dissection is required for patients with sentinel lymph nodes that tested positive for cancer, which has led to a decreasing trend in the need for intraoperative assessment of lymph nodes. Here, I review studies relevant to OSNA and discuss perspectives on future applications of OSNA in cancer surgery. The studies reviewed were identified by carrying out a search on PubMed for all articles pertaining to OSNA and published prior to the end of June 2016 using the keywords “OSNA” or “one-step nucleic acid amplification” in the title or abstract. Method comparison studies between OSNA and pathological assessment for the detection of lymph node metastasis in breast cancer revealed that in a pooled assessment OSNA had a high specificity (94.8 %), high concordant rate (93.8 %), and a negative predictive value (97.6 %). Similar results have been found for gastric, colorectal, and lung cancers in multicenter studies. These results demonstrate that OSNA can serve as an alternative method to pathological assessment for examining lymph node metastasis. Multicenter prospective studies with a large sample size are needed to definitively reveal the superiority of OSNA over pathological assessment to predict prognosis. Technical refinements to improve the assay are essential to its further development as a new standard for testing in place of pathological examination.     

Molecular detection of neoplastic cells in lymph nodes of metastatic colorectal cancer patients predicts recurrence.

Disseminated disease, especially to the liver, constitutes the major risk of recurrence for colorectal cancer patients. However, successful resection can still be achieved in 25-35% of colorectal cancer patients with isolated metastases. To evaluate the clinical value of occult micrometastatic disease detection in lymph nodes, we tested genetic (K-ras and p53 gene mutations) and epigenetic (p16 promoter hypermethylation) molecular markers in the perihepatic lymph nodes from colorectal cancer patients with isolated liver metastases. DNA was extracted from 21 paraffin-embedded liver metastases and 80 lymph nodes from 21 colorectal cancer patients. K-ras and p53 gene mutations were identified in DNA from liver metastases by PCR amplification followed by cycle sequencing. A sensitive oligonucleotide-mediated mismatch ligation assay was used to search for the presence of K-ras and p53 mutations to detect occult disease in 68 lymph nodes from tumors positive for these gene mutations. Promoter hypermethylation at the p16 tumor suppressor gene was examined in both liver lesions and lymph nodes by methylation-specific PCR. Sixteen of the 21 (76%) liver metastases harbored either gene point mutations or p16 promoter hypermethylation. Twelve of the 68 lymph nodes were positive for tumor cells by molecular evaluation and negative for tumor cells by histopathology and cytokeratin immunohistochemistry, whereas none were positive for tumor cells by histopathology or negative for tumor cells by molecular analysis (P = 0.0005, McNemar's test). Moreover, in three patients with lymph nodes that were histologically negative at all sites, molecular screening detected tumor DNA at one or more lymph nodes. Survival analysis showed a median survival of 1056 days for patients without evidence of lymph node involvement by molecular analysis and 165 days for patients with positive lymph nodes by this approach (P = 0.0005). These results indicate that lymph node metastasis screening in colorectal cancer patients by molecular-based techniques increases the sensitivity of tumor cell detection and can be a good predictor of recurrence in colorectal cancer patients with resectable liver metastases.     

Determination of TGFbeta1 protein level in human primary breast cancers and its relationship with survival

Transforming growth factor-beta (TGFbeta)1 is thought to be implicated in breast cancer progression. However, data about the influence of TGFbeta1 on breast cancer development are conflicting. To clarify the clinical relevance of TGFbeta1, TGFbeta1 protein level has been measured by enzyme-immunoassay in 193 breast tumour samples. We found that 94.3% of patients expressed TGFbeta1 with a range of 0-684 pg mg(-1) protein. In the overall population, an increase of tumoral TGFbeta1 was observed in premenopausal patients when compared to postmenopausal subgroup (P=0.0006). When patients were subdivided according to nodal status, TGFbeta1 was correlated to type-1 plasminogen activator inhibitor in the node-negative subgroup (P=0.040). Multivariate analysis revealed that, after lymph node status (P=0.0002) and urokinase-type plasminogen activator (P=0.004), TGFbeta1 was an independent prognostic marker for DFS (P=0.005) in the overall population. In the node-negative population, TGFbeta1 was the prominent prognostic factor (P=0.010). In the same population, Kaplan-Meier curves demonstrated that high TGFbeta1 level was correlated with a shorter disease-free survival (P=0.020). These data suggest that the measurement of tumoral TGFbeta1 protein level, especially for node-negative patients, might help to identify a high-risk population early in tumour progression.     

Predicting the recurrence/metastasis of stage I and II breast cancer without lymph node metastasis

Prediction of the recurrence of primary breast cancer was attempted by detection of occult neoplastic cells (ONCs) in lymph nodes or by using the high-risk criteria for recurrence/metastasis of gastric and colorectal cancer. The subjects were 70 patients with stage I or II node-negative primary breast cancer. Prediction of recurrence using ONCs had a sensitivity of 60.0% (3/5) and a false-negative rate of 40.0% (2/5) in the recurrence group, while the specificity was 96.9% (63/65) and the false-positive rate was 3.1% (2/65) in the non-recurrence group. The accuracy of ONCs was 78.5%. Prediction of recurrence based on positivity for at least 2 of the high-risk criteria showed a sensitivity of 60.0% (3/5) and a false-negative rate of 40.0% (2/5) in the recurrence group, while the specificity was 95.4% (62/65) and the false-positive rate was 4.6% (3/65) in the non-recurrence group. The accuracy of the high-risk criteria was 77.7%. These results suggest that ONCs show the same accuracy as the high-risk criteria for predicting recurrence/metastasis of stage I and II node-negative breast cancer with a high specificity.