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Kang BM, Park JS, Kim HJ, Park SY, Yoon G, Choi GS. Prognostic Value of Mesorectal Lymph Node Micrometastases in ypN0 Rectal Cancer After Chemoradiation. J Surg Res 2022; 276:314-322. [DOI: 10.1016/j.jss.2022.02.040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 02/11/2022] [Accepted: 02/17/2022] [Indexed: 11/24/2022]
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Yamamoto H. Micrometastasis in lymph nodes of colorectal cancer. Ann Gastroenterol Surg 2022; 6:466-473. [PMID: 35847437 PMCID: PMC9271024 DOI: 10.1002/ags3.12576] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 04/21/2022] [Indexed: 11/11/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common cancers worldwide. Postoperative adjuvant chemotherapy is recommended for node-positive stage III patients. A systematic meta-analysis reported that the presence of micrometastases in regional lymph nodes (LNs) was associated with poor survival in patients with node-negative CRC. Because most data employed in the meta-analysis were based on retrospective studies, we conducted a prospective clinical trial and concluded that stage II is a transitional zone between stage I and stage III, where CRC tumors continuously increase the micrometastasis volume in LNs and proportionally raise the risk for tumor recurrence. The one-step nucleic acid amplification (OSNA) assay is a simple and rapid technique to detect CK19 mRNA using the reverse-transcription loop-mediated isothermal amplification (RT-LAMP) method. Using the OSNA assay, we and colleagues reported that the upstaging rates of pStages I, IIA, IIB, and IIC were 2.0%, 17.7%, 12.5%, and 25%, respectively, in 124 node-negative patients. Survival analysis indicated that OSNA positive stage II CRC patients had a shorter 3-y disease-free survival rate than OSNA negative stage II CRC patients. In 2017, AJCC TNM staging (the 8th version) revised the definition of LN metastasis in colon cancer and it is stated that micrometastasis should be considered as a standard LN metastasis. To our surprise, this revision was based on a meta-analysis to which our previous study on micrometastasis largely contributed. The remaining questions to be addressed are how to find micrometastases efficiently and whether postadjuvant chemotherapy is effective to prevent disease recurrence and to contribute to longer survival.
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Affiliation(s)
- Hirofumi Yamamoto
- Department of Surgery, Gastroenterological Surgery, Graduate School of MedicineOsaka UniversityOsakaJapan
- Department of Molecular Pathology, Division of Health Sciences, Graduate School of MedicineOsaka UniversityOsakaJapan
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Biswas A, Jantz MA, Mehta HJ. Pretreatment identification of micro-metastasis in mediastinal lymph node by endobronchial ultrasound-guided transbronchial needle aspiration for early-stage non-small cell lung cancer-is it time yet? J Thorac Dis 2019; 11:4096-4100. [PMID: 31737291 DOI: 10.21037/jtd.2019.09.41] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Abhishek Biswas
- Director of Interventional Pulmonology, Parkview Regional Medical Center, Fort Wayne, IN, USA
| | - Michael A Jantz
- Division of Pulmonary and Critical Care Medicine, University of Florida, Gainesville, FL, USA
| | - Hiren J Mehta
- Division of Pulmonary and Critical Care Medicine, University of Florida, Gainesville, FL, USA
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Liu H, Liu Z, Li K, Li S, Song L, Gong Z, Shi W, Yang H, Xu Y, Ning S, Ismail S, Chen Y. TBL1XR1 predicts isolated tumor cells and micrometastasis in patients with TNM stage I/II colorectal cancer. J Gastroenterol Hepatol 2017; 32:1570-1580. [PMID: 28127799 DOI: 10.1111/jgh.13749] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Revised: 01/05/2017] [Accepted: 01/24/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM A considerable number of early-stage colorectal cancer (CRC) patients may develop cancer relapse or metastasis after curative surgery. Isolated tumor cells (ITC) and micrometastasis in lymph nodes (LNMM), which are undetectable by conventional pathological examination, may be one primary reason. Detection of ITC/LNMM is time-consuming and cost-ineffective; we aimed to find biomarkers in primary CRC tissues to help predicting ITC/LNMM status. METHODS We enrolled 137 node-negative patients with early-stage CRC in this study. Existence of ITC/LNMM was identified by immunohistological staining with cytokeratin 20 in resected lymph nodes. Expression of transducin (β)-like 1 X-linked receptor 1 (TBL1XR1) in primary CRC tissues was also investigated. Chi-squared test was performed to reveal the correlations between ITC/LNMM and clinicopathological characteristics. Univariate and multivariate analyses were used to determine independent prognostic factors. Knockdown experiment together with proliferation and invasion assays were carried out to explore molecular mechanisms between TBL1XR1 and ITC/LNMM. RESULTS About 29.2% (40/137) patients were identified as ITC/LNMM positive, and most of them (32/40 cases, 80%) showed high TBL1XR1 expression in primary CRC tissues. Both ITC/LNMM and TBL1XR1 expression were independent prognostic factors for disease relapse or metastasis. In vitro experiments demonstrated that TBL1XR1 can regulate the expression of vascular endothelial growth factor C and epithelial-mesenchymal transition proteins, thus mediate the process of lymph node metastasis. CONCLUSIONS Identification of ITC/LNMM is significant in evaluating clinical outcome and guiding adjuvant chemotherapy for early-stage CRC patients. TBL1XR1 overexpression in CRC tissues can serve as an efficient biomarker to predict the status of ITC/LNMM.
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Affiliation(s)
- Hongda Liu
- Department of General Surgery, Qilu Hospital Affiliated to Shandong University, Jinan, Shandong, China
| | - Zhaochen Liu
- Department of General Surgery, Qilu Hospital Affiliated to Shandong University, Jinan, Shandong, China
| | - Kangshuai Li
- Department of General Surgery, Qilu Hospital Affiliated to Shandong University, Jinan, Shandong, China
| | - Shuo Li
- 302 Military Hospital of China, Beijing, China
| | - Lei Song
- Department of Urological Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Zheng Gong
- Department of Biochemistry and Molecular Biology, School of Medicine, Shandong University, Jinan, Shandong, China
| | - Weichen Shi
- Department of Breast Surgery, Qianfoshan Hospital, Affiliated to Shandong University, Jinan, Shandong, China
| | - Hui Yang
- Department of Gastrointestinal Surgery, Qianfoshan Hospital, Affiliated to Shandong University, Jinan, Shandong, China
| | - Yunfei Xu
- Department of General Surgery, Qilu Hospital Affiliated to Shandong University, Jinan, Shandong, China
| | - Shanglei Ning
- Department of General Surgery, Qilu Hospital Affiliated to Shandong University, Jinan, Shandong, China
| | - Sayed Ismail
- Department of General Surgery, Qilu Hospital Affiliated to Shandong University, Jinan, Shandong, China
| | - Yuxin Chen
- Department of General Surgery, Qilu Hospital Affiliated to Shandong University, Jinan, Shandong, China
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Liu TP, Huang CC, Yeh KT, Ke TW, Wei PL, Yang JR, Cheng YW. Down-regulation of let-7a-5p predicts lymph node metastasis and prognosis in colorectal cancer: Implications for chemotherapy. Surg Oncol 2016; 25:429-434. [DOI: 10.1016/j.suronc.2016.05.016] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Revised: 03/15/2016] [Accepted: 05/19/2016] [Indexed: 02/06/2023]
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6
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Aldecoa I, Atares B, Tarragona J, Bernet L, Sardon JD, Pereda T, Villar C, Mendez MC, Gonzalez-Obeso E, Elorriaga K, Alonso GL, Zamora J, Planell N, Palacios J, Castells A, Matias-Guiu X, Cuatrecasas M. Molecularly determined total tumour load in lymph nodes of stage I-II colon cancer patients correlates with high-risk factors. A multicentre prospective study. Virchows Arch 2016; 469:385-94. [PMID: 27447172 PMCID: PMC5033997 DOI: 10.1007/s00428-016-1990-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Revised: 06/17/2016] [Accepted: 07/07/2016] [Indexed: 01/11/2023]
Abstract
Stage I–II (pN0) colorectal cancer patients are surgically treated although up to 25 % will eventually die from disease recurrence. Lymph node (LN) status is an independent prognostic factor in colorectal cancer (CRC), and molecular tumour detection in LN of early-stage CRC patients is associated with an increased risk of disease recurrence and poor survival. This prospective multicentre study aimed to determine the relationship between LN molecular tumour burden and conventional high-risk factors in stage I–II colon cancer patients. A total of 1940 LN from 149 pathologically assessed pN0 colon cancer patients were analysed for the amount of tumour cytokeratin 19 (CK19) messenger RNA (mRNA) with the quantitative reverse transcription loop-mediated isothermal amplification molecular assay One-Step Nucleic Acid Amplification. Patient’s total tumour load (TTL) resulted from the sum of all CK19 mRNA tumour copies/μL of each positive LN from the colectomy specimen. A median of 15 LN were procured per case (IQR 12;20). Molecular positivity correlated with high-grade (p < 0.01), mucinous/signet ring type (p = 0.017), male gender (p = 0.02), number of collected LN (p = 0.012) and total LN weight per case (p < 0.01). The TTL was related to pT stage (p = 0.01) and tumour size (p < 0.01) in low-grade tumours. Multivariate logistic regression showed independent correlation of molecular positivity with gender, tumour grade and number of fresh LN [AUC = 0.71 (95 % CI = 0.62–0.79)]. Our results show that lymph node CK19 mRNA detection correlates with classical high-risk factors in stage I–II colon cancer patients. Total tumour load is a quantitative and objective measure that may help to better stage early colon cancer patients.
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Affiliation(s)
- Iban Aldecoa
- Pathology Department, Centre de Diagnòstic Biomèdic (CDB), Hospital Clínic, University of Barcelona, Escala 3, Planta 5. Villarroel 170, Barcelona, 08036, Spain
| | - Begoña Atares
- Pathology Department, Alava University Hospital, Vitoria-Gasteiz, Spain
| | - Jordi Tarragona
- Pathology Department, Hospital Arnau de Vilanova, Lleida, Spain
| | - Laia Bernet
- Pathology Department, Hospital L. Alcanyis, Xativa, Spain
| | | | - Teresa Pereda
- Pathology Department, Hospital Costa del Sol, Marbella, Spain
| | - Carlos Villar
- Pathology Department, Hospital Reina Sofia, Cordoba, Spain
| | - M Carmen Mendez
- Pathology Department, Hospital Severo Ochoa, Leganes, Madrid, Spain
| | | | - Kepa Elorriaga
- Pathology Department, Hospital Onkologikoa, San Sebastian, Spain
| | | | - Javier Zamora
- Biostatistic Unit, Hospital Ramon y Cajal, Madrid, Spain
| | - Nuria Planell
- Gastroenterology Department and Bioinformatics Unit, CIBERehd, IDIBAPS, Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - Jose Palacios
- Pathology Department, Hospital Ramon y Cajal, Madrid, Spain
| | - Antoni Castells
- Gastroenterology Department, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | | | - Miriam Cuatrecasas
- Pathology Department, Centre de Diagnòstic Biomèdic (CDB), Hospital Clínic, University of Barcelona, Escala 3, Planta 5. Villarroel 170, Barcelona, 08036, Spain.
- CIBERehd, and Banc de Tumors-Biobanc Clinic-IDIBAPS-XBTC, Hospital Clinic, Barcelona, Spain.
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Yamamoto H, Murata K, Fukunaga M, Ohnishi T, Noura S, Miyake Y, Kato T, Ohtsuka M, Nakamura Y, Takemasa I, Mizushima T, Ikeda M, Ohue M, Sekimoto M, Nezu R, Matsuura N, Monden M, Doki Y, Mori M. Micrometastasis Volume in Lymph Nodes Determines Disease Recurrence Rate of Stage II Colorectal Cancer: A Prospective Multicenter Trial. Clin Cancer Res 2016; 22:3201-8. [DOI: 10.1158/1078-0432.ccr-15-2199] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2015] [Accepted: 01/10/2016] [Indexed: 01/11/2023]
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Bork U, Grützmann R, Rahbari NN, Schölch S, Distler M, Reissfelder C, Koch M, Weitz J. Prognostic relevance of minimal residual disease in colorectal cancer. World J Gastroenterol 2014; 20:10296-10304. [PMID: 25132746 PMCID: PMC4130837 DOI: 10.3748/wjg.v20.i30.10296] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Revised: 12/18/2013] [Accepted: 04/29/2014] [Indexed: 02/06/2023] Open
Abstract
Presence of occult minimal residual disease in patients with colorectal cancer (CRC) has a strong prognostic impact on survival. Minimal residual disease plays a major role in disease relapse and formation of metastases in CRC. Analysis of circulating tumor cells (CTC) in the blood is increasingly used in clinical practice for disease monitoring of CRC patients. In this review article the role of CTC, disseminated tumor cells (DTC) in the bone marrow and micrometastases and isolated tumor cells (ITC) in the lymph nodes will be discussed, including literature published until September 2013. Occult disease is a strong prognostic marker for patient survival in CRC and defined by the presence of CTC in the blood, DTC in the bone marrow and/or micrometastases and ITC in the lymph nodes. Minimal residual disease could be used in the future to identify patient groups at risk, who might benefit from individualized treatment options.
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Morimoto J, Tanaka H, Ohira M, Kubo N, Muguruma K, Sakurai K, Yamashita Y, Maeda K, Sawada T, Hirakawa K. The impact of the number of occult metastatic lymph nodes on postoperative relapse of resectable esophageal cancer. Dis Esophagus 2014; 27:63-71. [PMID: 23480452 DOI: 10.1111/dote.12043] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Clinical stage II/III esophageal cancer (EC), as defined by the Japanese Classification, relapses at a moderately high rate even after curative resection. The number of lymph node metastases is known to be associated with tumor relapse. Recently, the prognostic significance of occult metastatic lymph nodes (MLNs), as well as that of overt MLNs, has been reported. The aim of this study was to investigate the impact of the total number of MLNs including occult MLNs on postoperative relapse in clinical stage II/III EC. One hundred and five patients with clinical stage II/III EC who underwent esophagectomy accompanied by radical lymphadenectomy at the Department of Surgical Oncology in Osaka City University Hospital between January 2000 and October 2008 were included in this study. Occult MLNs, metastases not detected by hematoxylin-eosin staining, were identified by immunohistochemistry (IHC) using antipancytokeratin antibody AE1/AE3. The clinicopathological features of occult MLNs were compared between the relapse and no relapse groups. A total of 6558 lymph nodes (1357 from two-field dissection and 5201 from three-field dissection) were examined by IHC staining; 362 overt MLNs and 143 occult MLNs were detected. The number of occult MLNs increased in proportion to the International Union Against Cancer pathological (p)N-status and pStage. When the number of occult MLNs was added to the number of pNs, the number of total MLNs was associated with postoperative relapse. With respect to tumor, node, metastasis stage, 6 of 22 patients (27%) who were pathological node-negative converted to node-positive by considering total MLNs. The number of N3 patients with relapse increased markedly with restaging by total MLNs. The number of total MLNs, but not overt MLNs, was an independent prognostic factor on multivariate analysis. These results suggest that occult MLNs were often found, and they were associated with postoperative relapse of resectable esophageal cancer. The total number of MLNs including occult MLNs could contribute to evaluating the precise stage of patients with esophageal cancer.
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Affiliation(s)
- J Morimoto
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan
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Abstract
Evidence has now accumulated that colonoscopy and removal of polyps, especially during screening and surveillance programs, is effective in overall risk reduction for colon cancer. After resection of malignant pedunculated colon polyps or early stage colon cancers, long-term repeated surveillance programs can also lead to detection and removal of asymptomatic high risk advanced adenomas and new early stage metachronous cancers. Early stage colon cancer can be defined as disease that appears to have been completely resected with no subsequent evidence of involvement of adjacent organs, lymph nodes or distant sites. This differs from the clinical setting of an apparent “curative” resection later pathologically upstaged following detection of malignant cells extending into adjacent organs, peritoneum, lymph nodes or other distant sites, including liver. This highly selected early stage colon cancer group remains at high risk for subsequent colon polyps and metachronous colon cancer. Precise staging is important, not only for assessing the need for adjuvant chemotherapy, but also for patient selection for continued surveillance. With advanced stages of colon cancer and a more guarded outlook, repeated surveillance should be limited. In future, novel imaging technologies (e.g., confocal endomicroscopy), coupled with increased pathological recognition of high risk markers for lymph node involvement (e.g., “tumor budding”) should lead to improved staging and clinical care.
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Bouvier AM, Faivre J. Lymph node evaluation for resected colorectal cancer. COLORECTAL CANCER 2013. [DOI: 10.2217/crc.13.14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
SUMMARY The negative impact of regional lymph node metastasis on survival from nonmetastatic colorectal cancers is proportional to the number of nodes harvested. A thorough lymph node examination by the pathologist is essential for accurate staging. Recommendations in the USA and Europe stipulate that a minimum of 12–15 lymph nodes must be examined to accurately predict regional node negativity. The prognostic separation for stage III colorectal cancer obtained by the lymph node ratio is superior to that of the absolute number of positive nodes. The extent of mesenteric resection, pathologic technique, age or tumor location may influence lymph node yield. In the future, biological significance and clinical impact on outcome of very small amounts of tumor in regional nodes could help in staging patients. The current data are considered insufficient to recommend either the routine examination of multiple tissue levels of paraffin blocks or the use of special/ancillary techniques.
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Affiliation(s)
- Anne-Marie Bouvier
- Digestive Cancers Registry of Burgundy, University Hospital Dijon, Inserm U866, University of Burgundy, Dijon, France.
| | - Jean Faivre
- Digestive Cancers Registry of Burgundy, University Hospital Dijon, Inserm U866, University of Burgundy, Dijon, France
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Prognostic significance of EpCAM-positive disseminated tumor cells in rectal cancer patients with stage I disease. Am J Surg Pathol 2013; 36:1809-16. [PMID: 23060348 DOI: 10.1097/pas.0b013e318265288c] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Here we evaluated the prevalence and prognostic impact of epithelial cell adhesion molecule (EpCAM)-positive disseminated tumor cells (DTCs) in stage I rectal cancer. Further we tested the association of these single tumor cells or small tumor cell groups with the extent of peritumoral lymphangiogenesis. A total of 845 regional lymph nodes (LN) of 44 patients classified as negative on conventional histopathology were retrospectively reanalyzed with immunohistochemistry (IHC) using the monoclonal antibody Ber-Ep4 directed against EpCAM for the detection of DTCs. The degree of lymphangiogenesis in the primary tumors was assessed by IHC of the primary tumor tissue using the monoclonal antibody D2-40, which reacts with the lymphatic endothelium. The IHC results were correlated with clinico-pathologic parameters and clinical follow-up data. EpCAM-positive DTCs in LNs were detected in 8 (18.2%) of the 44 patients. During a median follow-up of 59 months, 3 (37.5%) of the 8 patients with EpCAM-positive DTCs relapsed, whereas none of the DTC-negative patients developed tumor recurrence (P=0.004). Survival analysis revealed a significant effect of the prevalence of DTCs on overall survival (P=0.0009) and on recurrence-free survival (P=0.0001). Finally, the prevalence of EpCAM-positive DTCs in perirectal LNs was significantly correlated with a high density of peritumoral lymphatic vessels (P=0.015). Our results show that DTCs may occur in stage I of rectal cancer and are associated with poor prognosis. Their occurrence seems to be linked to a high density of newly formed lymphatic vessel at the primary tumor site. According to our data, patients with DTCs in their LN might benefit from adjuvant therapy.
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Yamamoto N, Daito M, Hiyama K, Ding J, Nakabayashi K, Otomo Y, Tsujimoto M, Matsuura N, Kato Y. An optimal mRNA marker for OSNA (One-step nucleic acid amplification) based lymph node metastasis detection in colorectal cancer patients. Jpn J Clin Oncol 2013; 43:264-70. [PMID: 23293371 DOI: 10.1093/jjco/hys227] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND We previously reported that the one-step nucleic acid amplification assay is effective for lymph node metastasis detection in breast cancer patients. This paper describes the identification of CK19 mRNA as an optimal marker and its cut-off value for use in the detection of one-step nucleic acid amplification-based lymph node metastasis in colorectal cancer patients. METHODS Candidate mRNA markers selected from the genome-wide expressed sequence tag database were evaluated by quantitative RT-PCR using a mixture of metastasis-positive and another mixture of metastasis-negative lymph nodes (n = 5 each), followed by quantitative RT-PCR using metastasis-positive and -negative lymph nodes (n = 10 each) from 20 patients. The one-step nucleic acid amplification assay for mRNA markers selected above was examined using 28 positive lymph nodes from 19 patients and 38 negative lymph nodes from the 11 pN0 patients. RESULTS Quantitative RT-PCR analyses of the 98 mRNAs selected from the genome-wide expressed sequence tag database and the subsequent quantitative RT-PCR analyses of the nine mRNAs selected above indicated that CK19 and CEA mRNAs have the highest capability for distinguishing between positive and negative lymph nodes. CK19, CEA and CK20 mRNAs were evaluated by the one-step nucleic acid amplification assay. An area under a receiver-operating-characteristic curve for CK19 mRNA (0.999) was slightly larger than that for CEA mRNA (0.946; P = 0.062) and significantly larger that than for CK20 mRNA (0.875; P = 0.006). CONCLUSION We found that CK19 mRNA has the best diagnostic performance and its cut-off value for discriminating positive from negative lymph nodes can be set in the range of 75-500 copies/µl with 96.4% sensitivity and 100% specificity.
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Affiliation(s)
- Noriko Yamamoto
- Central Research Laboratories, Sysmex Corporation, 4-4-4 Takatsukadai, Kobe, Hyougo, Japan.
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Moghimi-Dehkordi B, Safaee A. An overview of colorectal cancer survival rates and prognosis in Asia. World J Gastrointest Oncol 2012; 4:71-5. [PMID: 22532879 PMCID: PMC3334382 DOI: 10.4251/wjgo.v4.i4.71] [Citation(s) in RCA: 126] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2011] [Revised: 03/03/2012] [Accepted: 03/10/2012] [Indexed: 02/05/2023] Open
Abstract
Colorectal cancer is a rapidly rising trend in Asia. The incidence in many Asian countries is on par with the West. Several studies have provided data regarding the survival of patients with colorectal cancer. In Asia, the overall cure rate of colorectal cancer has not improved dramatically in the last decade, 5-year survival remaining at approximately 60%. Colorectal cancer survival time has increased in recent years, but mortality rate remains high. Although studies have determined a number of factors that can predict survival of patients after diagnosis, life expectancy has not been increased dramatically. It seems that among the prognostic factors explored so far, the most important are those that relate to early diagnosis of cancer. Primary detection is feasible since efficient screening modalities are available. Colonoscopic surveillance is needed, especially in subjects at higher risk.
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Affiliation(s)
- Bijan Moghimi-Dehkordi
- Bijan Moghimi-Dehkordi, Azadeh Safaee, Research Center for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Science, Tehran 1985711151, Iran
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15
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Mescoli C, Albertoni L, Pucciarelli S, Giacomelli L, Russo VM, Fassan M, Nitti D, Rugge M. Isolated tumor cells in regional lymph nodes as relapse predictors in stage I and II colorectal cancer. J Clin Oncol 2012; 30:965-971. [PMID: 22355061 DOI: 10.1200/jco.2011.35.9539] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
PURPOSE Lymph node (LN) involvement is the most important prognostic factor in colorectal cancer (CRC), and pN-positive status identifies patients who require adjuvant chemotherapy. Approximately 15% to 20% of patients without nodal metastases (pN0) develop recurrent disease. In this study, we tested the prognostic significance of isolated tumor cells (ITCs) in LNs of patients with pN0 CRC (stages I and II). PATIENTS AND METHODS ITCs in LNs regional to CRC were assessed in 312 consecutive patients with pN0 CRC who were followed up clinically and/or endoscopically for at least 6 months after surgery (mean, 67 months; median, 64 months; range, 8 to 102 months). LNs were dissected from gross surgical specimens according to a standardized protocol (with a mean of 17 LNs per patient; range, five to 107 LNs). In all, 5,313 pN0 LNs were collected and assessed by using cytokeratin immunostaining in two serial histology sections from each LN, which amounting to a total of 10,626 specimens. The correlation between ITC status and cancer recurrence was tested by using univariate and multivariate statistics. RESULTS ITCs were documented in 185 of 312 patients (59%). CRC relapsed in 31 of 312 patients (10%), and 25 of 31 recurrences (81%) were documented among ITC-positive patients. CRC recurrence rates among ITC-positive and ITC-negative patients were 14% (25 of 185 patients) and 4.7% (six of 127 patients), respectively. In both univariate and multivariate analyses, ITC status was the only variable significantly associated with cancer relapse (Cox model; hazard ratio, 3.00; 95% CI, 1.23 to 7.32; P = .013). CONCLUSION In patients with pN0 CRC, cancer relapse was significantly associated with ITCs in regional LNs. ITCs should be considered among the clinicobiologic variables that identify high-risk patients who can benefit from adjuvant chemotherapy.
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Barresi V, Reggiani Bonetti L, Vitarelli E, Di Gregorio C, Ponz de Leon M, Barresi G. Immunohistochemical assessment of lymphovascular invasion in stage I colorectal carcinoma: prognostic relevance and correlation with nodal micrometastases. Am J Surg Pathol 2012; 36:66-72. [PMID: 21989343 DOI: 10.1097/pas.0b013e31822d3008] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Several studies have suggested that the presence of occult nodal metastases (micrometastases) is related to adverse clinical course in stage I colorectal carcinoma. Herein we analyzed the correlation between nodal micrometastases and lymphovascular invasion (LVI) or lymphatic vessel density (LVD) in a series of stage I colorectal carcinomas; the cohort included cases characterized or not characterized by disease progression during the follow-up. In these cases, LVI and LVD were evidenced through the immunohistochemical detection of the specific marker for lymphatic vessels, D2-40. LVI was significantly more frequent in colorectal carcinomas characterized by the presence of micrometastases (P<0.0001), high peritumoral LVD (P<0.0001), and disease progression (P<0.0001). The analysis for progression risk indicated that nodal micrometastases and LVI were significant, negative, independent prognostic parameters associated with shorter disease-free survival of stage I colorectal cancer (P=0.0001; P=0.0242). In conclusion, in this study we demonstrated for the first time that LVI is significantly associated with nodal occult metastases in stage I colorectal carcinoma. In the light of its significant, independent, prognostic value in this neoplasia, the detection of LVI may represent a faster and cheaper tool compared with the time-consuming evaluation of micrometastases to select high-risk patients who may benefit from adjuvant systemic treatment. Furthermore, the assessment of LVI may be applied to establish the likelihood of nodal involvement from carcinomas treated with conservative local excision techniques, which provide no regional nodes for histologic examination.
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Affiliation(s)
- Valeria Barresi
- Department of Human Pathology, University of Messina, Messina, Italy.
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Rahbari NN, Bork U, Motschall E, Thorlund K, Büchler MW, Koch M, Weitz J. Molecular detection of tumor cells in regional lymph nodes is associated with disease recurrence and poor survival in node-negative colorectal cancer: a systematic review and meta-analysis. J Clin Oncol 2011; 30:60-70. [PMID: 22124103 DOI: 10.1200/jco.2011.36.9504] [Citation(s) in RCA: 125] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
PURPOSE Up to 25% of patients with node-negative colorectal cancer (CRC) on conventional histopathologic analysis ultimately die of recurrent disease. We performed a systematic review with meta-analyses to clarify whether molecular detection of isolated tumor cells or micrometastases in regional lymph nodes indicates high risk of disease recurrence and poor survival in node-negative CRC. METHODS The following databases were searched in August 2011 to identify studies on the prognostic significance of molecular tumor-cell detection in regional lymph nodes of node-negative CRC: MEDLINE, BIOSIS, Science Citation Index, EMBASE, CCMed, and publisher databases. We extracted hazard ratios (HRs) and associated 95% CIs from the identified studies and performed random-effects model meta-analyses on overall survival, disease-specific survival, and disease-free survival. RESULTS A total of 39 studies with a cumulative sample size of 4,087 patients were included. Immunohistochemistry, reverse transcriptase polymerase chain reaction, and both techniques were applied in 30, seven, and two studies, respectively. Thirteen studies were graded with low risk of bias. Meta-analyses revealed that molecular tumor-cell detection in regional lymph nodes was associated with poor overall survival (HR, 2.20; 95% CI, 1.43 to 3.40), disease-specific survival (HR, 3.37; 95% CI, 2.31 to 4.93), and disease-free survival (HR, 2.24; 95% CI, 1.57-3.20). Subgroup analyses showed the prognostic significance of molecular tumor-cell detection of being independent of the applied detection method, molecular target, and number of retrieved lymph nodes. CONCLUSION Molecular detection of occult disease in regional lymph nodes is associated with an increased risk of disease recurrence and poor survival in patients with node-negative CRC.
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Affiliation(s)
- Nuh N Rahbari
- Department of General, Visceral and Transplant Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany.
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Reggiani Bonetti L, Di Gregorio C, De Gaetani C, Pezzi A, Barresi G, Barresi V, Roncucci L, Ponz de Leon M. Lymph node micrometastasis and survival of patients with Stage I (Dukes' A) colorectal carcinoma. Scand J Gastroenterol 2011; 46:881-886. [PMID: 21492052 DOI: 10.3109/00365521.2011.571708] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Although patients with Stage I colorectal cancer show an excellent prognosis, a few of them die of metastatic disease. In this subgroup of individuals, the search of occult metastasis might reveal that early dissemination of tumor cells could be the cause of cancer progression. MATERIAL AND METHODS Through a Cancer Registry, we selected all patients with Stage I disease who died of metastatic tumor; a total of 32 patients were identified and in 25 of them paraffin-embedded material was available. The group was matched to 70 Stage I patients with favorable prognosis (controls). In cases and controls resected lymph nodes were cut, and micrometastases were searched using pan-cytokeratin antibodies. RESULTS Micrometastases were detected in 18 of 25 (72%) Stage I patients who died of the disease, while they were almost absent among controls (1 of 70, p < 0.001 by χ(2) test). Vascular invasion and tumor budding were more frequent among Stage I patients with an unfavorable prognosis than in controls. By regression analyses, micrometastases (HR 12.3, CI 4.8-32) and vascular invasion (HR 3.5, CI 1.4-8.5) maintained an independent association with prognosis (cancer-specific survival). CONCLUSION Micrometastasis in the lymph nodes can be revealed in the majority of patients with early colorectal cancer who die of tumor progression, while they appear extremely rare in Stage I individuals with good prognosis. The selection of patients through histology (vascular invasion) and search of occult metastatic cells might represent a way to identify individuals who might benefit from adjuvant chemotherapy.
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Affiliation(s)
- Luca Reggiani Bonetti
- Dipartimento ad Attività Integrata di Laboratori, Anatomia Patologica e Medicina Legale, Sezione di Anatomia Patologica, Università di Modena e Reggio Emilia, Modena, Italy
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Lee SE, Jang JY, Kim MA, Kim SW. Clinical implications of immunohistochemically demonstrated lymph node micrometastasis in resectable pancreatic cancer. J Korean Med Sci 2011; 26:881-5. [PMID: 21738340 PMCID: PMC3124717 DOI: 10.3346/jkms.2011.26.7.881] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2011] [Accepted: 04/21/2011] [Indexed: 01/30/2023] Open
Abstract
The purpose of this study was to determine the clinical significance of nodal micrometastasis detected by immunohistochemistry in patients that had undergone curative surgery for pancreatic cancer. Between 2005 and 2006, a total of 208 lymph nodes from 48 consecutive patients with pancreatic cancer that had undergone curative resection were immunostained with monoclonal antibody against pan-ck and CK-19. Micrometastasis was defined as metastasis missed by a routine H&E examination but detected during an immunohistochemical evaluation. Relations between immunohistochemical results and clinical and pathologic features and patient survival were examined. Nodal micrometastases were detected in 5 (29.4%) patients of 17 pN0 patients. Nodal micrometastasis was found to be related to tumor relapse (P = 0.043). Twelve patients without overt nodal metastasis and micrometastasis had better prognosis than 5 patients with only nodal micrometastasis (median survival; 35.9 vs 8.6 months, P < 0.001). The Cox proportional hazard model identified nodal micrometastasis as significant prognostic factors. Although the number of patients with micrometastasis was so small and further study would be needed, our study suggests that the lymph node micrometastasis could be the predictor of worse survival and might indicate aggressive tumor biology among patients undergoing curative resection for pancreas cancer.
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Affiliation(s)
- Seung Eun Lee
- Department of Surgery, Chung-Ang University College of Medicine, Seoul, Korea
| | - Jin-Young Jang
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Min-A Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
| | - Sun-Whe Kim
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Leong SPL, Zuber M, Ferris RL, Kitagawa Y, Cabanas R, Levenback C, Faries M, Saha S. Impact of nodal status and tumor burden in sentinel lymph nodes on the clinical outcomes of cancer patients. J Surg Oncol 2011; 103:518-30. [PMID: 21480244 DOI: 10.1002/jso.21815] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
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.
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Affiliation(s)
- Stanley P L Leong
- Center for Melanoma Research and Treatment, Department of Surgery, California Pacific Medical and Research Institute, San Francisco, California 94115, USA.
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Sirop S, Kanaan M, Korant A, Wiese D, Eilender D, Nagpal S, Arora M, Singh T, Saha S. Detection and prognostic impact of micrometastasis in colorectal cancer. J Surg Oncol 2011; 103:534-7. [PMID: 21480246 DOI: 10.1002/jso.21793] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
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.
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Affiliation(s)
- Saad Sirop
- Department of Surgical Oncology, McLaren Regional Medical Center, Michigan State University, Flint, Michigan, USA
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22
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Yang H, Kim C, Kim MJ, Schwendener RA, Alitalo K, Heston W, Kim I, Kim WJ, Koh GY. Soluble vascular endothelial growth factor receptor-3 suppresses lymphangiogenesis and lymphatic metastasis in bladder cancer. Mol Cancer 2011; 10:36. [PMID: 21481239 PMCID: PMC3080348 DOI: 10.1186/1476-4598-10-36] [Citation(s) in RCA: 74] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2010] [Accepted: 04/11/2011] [Indexed: 01/17/2023] Open
Abstract
Background Most bladder cancer patients experience lymphatic metastasis in the course of disease progression, yet the relationship between lymphangiogenesis and lymphatic metastasis is not well known. The aim of this study is to elucidate underlying mechanisms of how expanded lymphatic vessels and tumor microenvironment interacts each other and to find effective therapeutic options to inhibit lymphatic metastasis. Results The orthotopic urinary bladder cancer (OUBC) model was generated by intravesical injection of MBT-2 cell lines. We investigated the angiogenesis, lymphangiogenesis, and CD11b+/CD68+ tumor-associated macrophages (TAM) by using immunofluorescence staining. OUBC displayed a profound lymphangiogenesis and massive infiltration of TAM in primary tumor and lymphatic metastasis in lymph nodes. TAM flocked near lymphatic vessels and express higher levels of VEGF-C/D than CD11b- cells. Because VEGFR-3 was highly expressed in lymphatic vascular endothelial cells, TAM could assist lymphangiogenesis by paracrine manner in bladder tumor. VEGFR-3 expressing adenovirus was administered to block VEGF-C/D signaling pathway and clodronate liposome was used to deplete TAM. The blockade of VEGF-C/D with soluble VEGF receptor-3 markedly inhibited lymphangiogenesis and lymphatic metastasis in OUBC. In addition, the depletion of TAM with clodronate liposome exerted similar effects on OUBC. Conclusion VEGF-C/D are the main factors of lymphangiogenesis and lymphatic metastasis in bladder cancer. Moreover, TAM plays an important role in these processes by producing VEGF-C/D. The inhibition of lymphangiogenesis could provide another therapeutic target to inhibit lymphatic metastasis and recurrence in patients with invasive bladder cancer.
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Affiliation(s)
- Hanseul Yang
- National Research Laboratory of Vascular Biology and Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 305-701, Republic of Korea
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Faerden AE, Sjo OH, Bukholm IRK, Andersen SN, Svindland A, Nesbakken A, Bakka A. Lymph node micrometastases and isolated tumor cells influence survival in stage I and II colon cancer. Dis Colon Rectum 2011; 54:200-6. [PMID: 21228669 DOI: 10.1007/dcr.0b013e3181fd4c7c] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE Lymph-node status is considered the most important prognostic factor in colorectal cancer. The aim of the present prospective study was to evaluate the influence of micrometastases and isolated tumor cells on recurrence and disease-free survival in colon cancer. METHODS A total of 193 patients with colon cancer, operated on between 2000 and 2005, were enrolled in the study. All lymph nodes were examined by routine microscopy in hematoxylin and eosin-stained sections. If no metastases were identified in any node, all nodes were examined immunohistochemically with monoclonal antibody CAM 5.2. RESULTS Ordinary metastases were found in 67 patients, leaving 126 patients in stage I/II. Immunohistochemistry showed that 5% (6/126) of these had micrometastases and 26% (33/126) had isolated tumor cells. A median of 5 years of follow-up revealed local or distant recurrence in 23% (9/39) of stage I/II patients with micrometastases or isolated tumor cells, compared with 7% (6/87) without micrometastases or isolated tumor cells (P = .010). Five-year disease-free survival for patients with and without micrometastases or isolated tumor cells was 75% and 93%, respectively (P = .012). When analyzed separately, patients with isolated tumor cells (excluding micrometastases) had also lower survival than node-negative patients (P = .012). CONCLUSION The presence of micrometastases and isolated tumor cells was found to be a prognostic factor for recurrence and disease-free survival. This may have implications for future treatment of stage I/II colon cancer.
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Affiliation(s)
- Arne E Faerden
- Department of Digestive Surgery, Akershus University Hospital, University of Oslo, Oslo, Norway.
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Mejia A, Waldmana SA. Previstage GCC test for staging patients with colorectal cancer. Expert Rev Mol Diagn 2009; 8:571-8. [PMID: 18785805 DOI: 10.1586/14737159.8.5.571] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
The presence of tumor cells in regional lymph nodes is the most important prognostic and predictive marker in staging patients with colorectal cancer. Cancer cells in lymph nodes are associated with a poorer prognosis and an increased risk of recurrent disease. Additionally, nodal metastases identify patients who derive maximum benefit from adjuvant therapy. However, traditional paradigms for staging patients with colorectal cancer underestimate the extent of metastases and patients whose lymph nodes are ostensibly free of tumor cells by histopathology (pN0) have a 25-30% risk of developing recurrent disease, reflected by the presence of occult nodal metastases. These observations underscore the unmet clinical need for molecular approaches to accurately detect metastatic disease and identify patients at risk for disease relapse that could benefit from adjuvant chemotherapy. Detection of disease-specific mRNA targets as prognostic and predictive markers employing quantitative reverse transcription (qRT)-PCR is an emerging technology that has become a benchmark for individualization of patient management. However, to date, applications of qRT-PCR to detecting occult nodal metastases in colorectal cancer have been equivocal, reflecting markers with suboptimal sensitivity and specificity; limitations of utilizing qualitative, rather than quantitative, RT-PCR; and underpowered study designs based on inadequate patient populations. In that context, guanylyl cyclase C (GCC) is the most sensitive and specific biomarker for metastatic colorectal cancer in extra-intestinal tissues. GCC qRT-PCR detects occult metastases in lymph nodes, providing the most powerful independent prognostic information for predicting disease recurrence in pN0 patients in prospective multicenter clinical trials. This technology forms the basis for the Previstagetrade mark GCC Colorectal Cancer Staging Test encompassing a proprietary multiplex qRT-PCR assay compatible with formalin-fixed, paraffin-embedded lymph nodes for detecting occult metastases. Previstage GCC is a new diagnostic tool that may improve the accuracy of staging, prognosis of clinical outcomes and prediction of therapeutic responses to adjuvant therapy, representing a key advance in the management of patients with colorectal cancer.
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Affiliation(s)
- Alex Mejia
- Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, 132 South 10th Street, 1170 Main, Philadelphia, PA 19107, USA.
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Govindarajan A, Baxter NN. Lymph node evaluation in early-stage colon cancer. Clin Colorectal Cancer 2008; 7:240-6. [PMID: 18650192 DOI: 10.3816/ccc.2008.n.031] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Accurate nodal staging is of crucial importance in patients with nonmetastatic colon cancer, because it affects patient prognosis and delivery of adjuvant chemotherapy. In this article, we review the role of 2 controversial aspects of lymph node staging in colon cancer: the number of lymph nodes evaluated and sentinel lymph node (SLN) biopsy. Although it is clear that the number of lymph nodes assessed correlates with patient survival, the underlying mechanisms are far more uncertain, and thus, more research is warranted to determine whether interventions to increase nodal assessment will lead to improved patient outcomes. Sentinel lymph node biopsy does not appear to have the same advantages in the treatment of patients with colon cancer as in the treatment of patients with breast cancer or melanoma. Also, it might not improve colon cancer staging above standard pathology, and should be restricted to use in research settings.
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Affiliation(s)
- Anand Govindarajan
- Division of General Surgery, Keenan Research Centre at the Li Ka Shing Knowledge Institute St Michael's Hospital, Toronto, Ontario, Canada
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27
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Prognostic value of the detection of lymph node micrometastases in colon cancer. Clin Transl Oncol 2008; 10:572-8. [DOI: 10.1007/s12094-008-0252-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Davies M, Arumugam PJ, Shah VI, Watkins A, Roger Morgan A, Carr ND, Beynon J. The clinical significance of lymph node micrometastasis in stage I and stage II colorectal cancer. Clin Transl Oncol 2008; 10:175-9. [PMID: 18321821 DOI: 10.1007/s12094-008-0176-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
AIM Recent advances in immunohistochemical techniques have made it possible to identify micrometastasis using antibodies to cytokeratins (CK). The aim of the study was to determine the prevalence and prognostic significance of immunohistochemically detected micrometastasis (IHM) in patients with localised colorectal cancer (CRC) (Dukes' A and B). A further aim was to study the prognostic role of histopathological factors such as vascular invasion. METHODS The original histology of 168 consecutive patients with Dukes' A or B tumours who had undergone curative resection was reviewed. Immunohistochemical staining was performed using CK antibodies, AE1/AE3 and MNF116 on all (n=898) lymph nodes. Survival analysis was performed on 105 cases that had been followed up until death or for at least 5 years. RESULTS IHM were detected in 17.3% of lymph nodes analysed. Adverse outcome (death/local recurrence) was recorded in 8/49 (16%) patients with IHD-positive nodes and in 10/56 (18%) patients negative for IHM. IHM was not associated with adverse outcome on either univariate (p=0.540) or multivariate analyses (p=0.673). There was no correlation of IHM with age, gender, site, size and grade of tumour, depth of tumour invasion or perineural and vascular invasion. Vascular invasion was the only independent prognostic factor identified. DISCUSSION We have shown that isolated CK-positive epithelioid cells are commonly found in morphologically benign pericolic lymph nodes of patients with localised (Dukes' A or B) CRC. These cells may represent occult micrometastasis but are not clinically significant. Vascular invasion identifies patients with localised CRC likely to develop recurrences or die of disease.
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Affiliation(s)
- Mark Davies
- Department of Colorectal Surgery and Pathology, Singleton Hospital, Sketty, Swansea SA2 8QA,Wales, UK
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Bembenek A, String A, Gretschel S, Schlag PM. Technique and clinical consequences of sentinel lymph node biopsy in colorectal cancer. Surg Oncol 2008; 17:183-93. [PMID: 18571920 DOI: 10.1016/j.suronc.2008.05.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Sentinel lymph node biopsy (SLNB) in colorectal cancer (CRC) is a controversial issue. Different detection techniques, various protocols for the histopathological work-up of the SLN and a greatly differing experience between the investigators make the comparison of the available studies problematic. Nevertheless, it is clear, that the successful clinical application of SLNB in breast cancer and melanoma cannot simply be transferred into colorectal cancer treatment. In this paper we try to define the current status of clinical application of this technique in CRC by means of a literature review and our own experience. Moreover, the background and the potential clinical implications of additionally small tumor deposits in the SLN (so-called "upstaging") is critically reviewed. Summarizing the results, it is clear, that the value of SLNB in CRC is still unclear. If current techniques are to be applied outside a study protocol and no patient selection is performed the correct identification of macrometastases needs further investigation. Although still under debate, there is otherwise growing evidence, that -at least if RT-PCR-techniques are used- the detection of small tumor deposits in the SLN may be of prognostic and therefore clinical value. Future studies should focus on two subjects: First, alternative detection techniques and careful patient selection may clarify, if an improvement of the sensitivity to detect macrometastases is feasible. Second, large prospective trials using a standardized histopathological lymph node assessment should compare SLN and Non-SLN for its incidence to bear small tumor deposits. If SLNB proves to be sensitive, the prognostic and predictive value of these additional findings should be clarified.
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Affiliation(s)
- Andreas Bembenek
- Department of Surgery and Surgical Oncology, Robert-Rössle-Klinik, Charité, Universitätsmedizin Berlin Campus Buch im Helios Klinikum Berlin, Schwanebecker Chaussee 50, 13125 Berlin, Germany.
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Sentinel node mapping does not improve staging of lymph node metastasis in colonic cancer. Dis Colon Rectum 2008; 51:891-6. [PMID: 18259817 DOI: 10.1007/s10350-007-9185-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2007] [Revised: 09/03/2007] [Accepted: 09/09/2007] [Indexed: 02/08/2023]
Abstract
PURPOSE This study was designed to evaluate the reliability of the sentinel node concept in colonic cancer. METHODS Patent blue was used as tracer. The four blue nodes closest to the tumor were defined as the sentinel node(s) by the pathologist. All nodes were examined by routine microscopy (hematoxylin-eosin staining). If no metastases were detected, all lymph nodes were examined immunohistochemically with antibody to cytokeratin. RESULTS Two hundred colon specimens were examined. Sentinel node(s) were identified in 93 percent. Sixty contained metastases in hematoxylin-eosin sections. In 32 these were found in sentinel nodes (sensitivity 53 percent). Twenty-eight patients had metastases in nonsentinel nodes only, giving a false-negative rate of 47 percent. Immunostaining revealed 39 (30 percent) micrometastases or submicrometastases in 131 TNM Stages I and II patients, and in 17 of these patients metastases were found in nonsentinel nodes only (false-negative rate 44 percent). CONCLUSIONS Sentinel lymph node mapping shows low sensitivity for detection of ordinary metastases, micrometastases, and submicrometastases. If only the sentinel nodes had been examined, approximately half of the metastases would have been lost after routine staining, as well as half of the micrometastases and submicrometastases when immunohistochemical examination was added.
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Iddings D, Bilchik A. The biologic significance of micrometastatic disease and sentinel lymph node technology on colorectal cancer. J Surg Oncol 2008; 96:671-7. [PMID: 18081169 DOI: 10.1002/jso.20918] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
The sentinel lymph node (SLN) technique has practical applications in multiple solid tumors including colorectal carcinoma. Identifying the SLN(s) provides better staging of the regional lymphatics beyond standard H&E analysis. This additional information assists in predicting biology and may be useful in guiding adjuvant therapy. We postulate the era of sentinel node has ushered in a new generation of node-negative patients; patients that have an exceptionally favorable outcome when compared to historic controls.
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Affiliation(s)
- Douglas Iddings
- Department of Surgical Oncology, John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, California 90404, USA
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Bilchik AJ. Current and emerging trends in the treatment of early-stage colorectal cancer: importance of a multidisciplinary approach. Hematol Oncol Clin North Am 2007; 21 Suppl 1:8-18. [PMID: 17916494 DOI: 10.1016/s0889-8588(07)80012-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Affiliation(s)
- Anton J Bilchik
- Department of Gastrointestinal Surgery, John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, California 90404, USA.
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Dionigi G, Castano P, Rovera F, Boni L, Annoni M, Villa F, Bianchi V, Carrafiello G, Bacuzzi A, Dionigi R. The application of sentinel lymph node mapping in colon cancer. Surg Oncol 2007; 16 Suppl 1:S129-32. [PMID: 18023573 DOI: 10.1016/j.suronc.2007.10.024] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Lymph node status is the most important prognostic factor for colorectal carcinoma. Complete lymph node dissection has historically been an integral part of the surgical treatment of these diseases. Sentinel lymph node mapping is a newer technology that allows selective removal of the first node draining a tumor. Sentinel node mapping is well accepted for the management of breast carcinoma and cutaneous melanoma, and has resulted in reduced morbidity without adversely affecting survival. Sentinel node mapping is currently being investigated for treatment of colorectal cancers. Recent studies show promise for incorporating the sentinel node mapping technique for treatment of several gastrointestinal malignancies.
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Affiliation(s)
- G Dionigi
- Department of Surgical Sciences, University of Insubria, Viale Borri 57, 21100 Varese, Italy.
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Turner RR, Li C, Compton CC. Newer Pathologic Assessment Techniques for Colorectal Carcinoma. Clin Cancer Res 2007; 13:6871s-6s. [DOI: 10.1158/1078-0432.ccr-07-1151] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Nicastri DG, Doucette JT, Godfrey TE, Hughes SJ. Is occult lymph node disease in colorectal cancer patients clinically significant? A review of the relevant literature. J Mol Diagn 2007; 9:563-71. [PMID: 17916603 DOI: 10.2353/jmoldx.2007.070032] [Citation(s) in RCA: 86] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
The clinical significance of micrometastasis of colorectal cancer (CRC) to regional lymph nodes remains controversial. In this review, we analyze publications that have evaluated the clinical significance of occult lymph node metastasis in CRC. An extensive literature search identified 19 publications that evaluated the clinical significance of micrometastatic CRC by various methods, including immunohistochemistry (IHC; n = 13) and reverse transcription-polymerase chain reaction (RT-PCR, n = 6). These studies were reviewed for methodology and findings. Significant limitations in methodology were identified, including inconsistent histological definitions of micrometastatic disease, poor sampling because of an inadequate number of lymph nodes or number of sections per lymph node analyzed, lack of conformity with respect to IHC antibody or RT-PCR marker, and inadequate power because of small sample size. Micrometastatic lymph node metastasis identified by RT-PCR was consistently found to be prognostically significant, but this was not true of micrometastatic disease identified by IHC. RT-PCR analysis of lymph nodes with specific markers can help identify pN0 (pathological-negative lymph node) CRC patients at increased risk for recurrence. The identification of occult disease by IHC techniques may also ultimately prove to be associated with worse outcome, but a number of inadequately powered studies have concluded conversely.
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Affiliation(s)
- Daniel G Nicastri
- University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA 15261, USA
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Hara M, Hirai T, Nakanishi H, Kanemitsu Y, Komori K, Tatematsu M, Kato T. Isolated tumor cell in lateral lymph node has no influences on the prognosis of rectal cancer patients. Int J Colorectal Dis 2007; 22:911-7. [PMID: 17318555 DOI: 10.1007/s00384-007-0280-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/23/2007] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS The aim of this study was to determine the incidence of isolated tumor cells (ITC) and micrometastasis in lateral lymph nodes of patients with rectal cancer and its possible correlation with prognosis. MATERIALS AND METHODS One hundred seventy-seven rectal cancer patients who underwent curative resection with lateral lymph node dissection were enrolled. Dissected lymph nodes were examined using hematoxylin-eosin staining (HE) and immunohistochemistry (IHC) with anti-keratin antibody (AE1/AE3). States of lymph node metastasis were divisible into three groups: detectable with HE (HE+), detectable with only IHC (HE-/IHC+), and undetectable even with IHC (IHC-). Almost all the HE-/IHC+ group was classified as ITC consisting of a few tumor cells according to the UICC criteria (ITC+). Survival rates were compared among HE+, ITC+, and IHC-. RESULTS ITC+ were detected in 24.1% of patients with HE-negative lateral lymph nodes. No significant difference in overall 5-year survival was observed between ITC+ and IHC- patients (76.1 and 82.9%, respectively, p = 0.25). Multivariate analysis showed that perirectal HE+ lymph nodes, but not ITC+ lateral lymph nodes, was an independent prognostic factor. CONCLUSIONS ITC in lateral lymph nodes does not contribute to the prognosis of rectal cancer in patients who undergo extended lateral lymph node dissection, unlike HE+ lateral lymph node metastasis.
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Affiliation(s)
- M Hara
- Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, 1-1 Kanokoden, Nagoya, Aichi, Japan
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Hriesik C, Ramanathan RK, Hughes SJ. Update for surgeons: recent and noteworthy changes in therapeutic regimens for cancer of the colon and rectum. J Am Coll Surg 2007; 205:468-78 (Quiz 524). [PMID: 17765164 DOI: 10.1016/j.jamcollsurg.2007.04.032] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2007] [Revised: 03/29/2007] [Accepted: 04/24/2007] [Indexed: 01/16/2023]
Affiliation(s)
- Claudia Hriesik
- Department of Surgery, Division of Surgical Oncology, University of Pittsburgh School of Medicine, and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15261, USA
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Stojadinovic A, Nissan A, Protic M, Adair CF, Prus D, Usaj S, Howard RS, Radovanovic D, Breberina M, Shriver CD, Grinbaum R, Nelson JM, Brown TA, Freund HR, Potter JF, Peretz T, Peoples GE. Prospective randomized study comparing sentinel lymph node evaluation with standard pathologic evaluation for the staging of colon carcinoma: results from the United States Military Cancer Institute Clinical Trials Group Study GI-01. Ann Surg 2007; 245:846-57. [PMID: 17522508 PMCID: PMC1876962 DOI: 10.1097/01.sla.0000256390.13550.26] [Citation(s) in RCA: 89] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND The principal role of sentinel lymph node (SLN) sampling and ultrastaging in colon cancer is enhanced staging accuracy. The utility of this technique for patients with colon cancer remains controversial. PURPOSE This multicenter randomized trial was conducted to determine if focused assessment of the SLN with step sectioning and immunohistochemistry (IHC) enhances the ability to stage the regional nodal basin over conventional histopathology in patients with resectable colon cancer. PATIENTS AND METHODS Between August 2002 and April 2006 we randomly assigned 161 patients with stage I-III colon cancer to standard histopathologic evaluation or SLN mapping (ex vivo, subserosal, peritumoral, 1% isosulfan blue dye) and ultrastaging with pan-cytokeratin IHC in conjunction with standard histopathology. SLN-positive disease was defined as individual tumor cells or cell aggregates identified by hematoxylin and eosin (H&E) and/or IHC. Primary end point was the rate of nodal upstaging. RESULTS Significant nodal upstaging was identified with SLN ultrastaging (Control vs. SLN: 38.7% vs. 57.3%, P = 0.019). When SLNs with cell aggregates < or =0.2 mm in size were excluded, no statistically significant difference in node-positive rate was apparent between the control and SLN arms (38.7% vs. 39.0%, P = 0.97). However, a 10.7% (6/56) nodal upstaging was identified by evaluation of H&E stained step sections of SLNs among study arm patients who would have otherwise been staged node-negative (N0) by conventional pathologic assessment alone. CONCLUSION SLN mapping, step sectioning, and immunohistochemistry (IHC) identifies small volume nodal disease and improves staging in patients with resectable colon cancer. A prospective trial is ongoing to determine the clinical significance of colon cancer micrometastasis in sentinel lymph nodes.
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Affiliation(s)
- Alexander Stojadinovic
- Department of Surgery, Division of Surgical Oncology, and United States Military Cancer Institute, Walter Reed Army Medical Center, 6900 Georgia Avenue N.W., Washington, D.C. 20307, USA.
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de Haas RJ, Wicherts DA, Hobbelink MGG, Borel Rinkes IHM, Schipper MEI, van der Zee JA, van Hillegersberg R. Sentinel lymph node mapping in colon cancer: current status. Ann Surg Oncol 2007; 14:1070-80. [PMID: 17206482 DOI: 10.1245/s10434-006-9258-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
BACKGROUND The primary role of sentinel lymph node (SLN) mapping in colon cancer is to increase the accuracy of nodal staging by identifying those lymph nodes with the greatest potential for harbouring metastatic disease. Ultrastaging techniques aim to identify the otherwise undetected metastases. Until now, no consensus exists as to the most optimal procedure in patients with colon cancer. METHODS A systematic literature search on the value of different SLN mapping techniques in patients with colon cancer was performed using the electronic search engine PubMed. Prospective studies published before 1 December 2005 were included and further articles were selected by cross-referencing. The results of different techniques using either blue dye or radiocolloid, were investigated. RESULTS The literature search yielded 17 relevant articles. SLN mapping using blue dye was described in 15 studies. Two studies reported the results of SLN mapping using a combination of blue dye and radiocolloid. The reported results on identification rate varied between 71 and 100%. Accuracy rates were between 78 and 100%, sensitivity rates between 25 and 100% and true upstaging rates between 0 and 26%. The results were not affected by the addition of radiocolloid to blue dye. CONCLUSIONS Sentinel lymph node mapping in patients with colon cancer remains an experimental procedure with varying results. Further evaluation may lead to a standardized technique that offers the potential for significant upstaging of stage II patients. This may have important implications as to tailor adjuvant chemotherapeutic regimens in these patients.
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Affiliation(s)
- Robbert J de Haas
- Department of Surgery, University Medical Center Utrecht, P.O. Box 85500, 3508, GA, Utrecht, The Netherlands
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Klebig F, Fischer C, Petri S, Gerull H, Wagener C, Tschentscher P. Limitations in Molecular Detection of Lymph Node Micrometastasis From Colorectal Cancer. ACTA ACUST UNITED AC 2007; 16:91-5. [PMID: 17525678 DOI: 10.1097/pdm.0b013e31803278ee] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Colorectal cancer patients with lymph node metastasis have a shorter survival and may require adjuvant therapy after surgery of the primary tumor. It is supposed that a more reliable diagnosis can be achieved using tumor-specific DNA mutations for the detection of metastasizing cells. To design a practical approach for a molecular diagnosis of micrometastasis, we applied direct DNA sequencing to screen 48 early stage colorectal carcinomas for the most frequent mutations of the KRAS, P53, and APC tumor genes. KRAS mutations were detected as frequently as described earlier. In contrast, the frequency of P53 and APC hot spot mutations was unexpectedly low, compared with previous studies using other screening methods or including advanced tumor stages. Not more than 31% of early stage tumors showed a mutation in at least 1 of the selected hot spot codons. Applying mutant-enriched polymerase chain reaction (PCR), the mutation of the primary tumor was detected in lymph node DNA from 2 of the KRAS-positive patients. In 1 patient, the result was not verified by subtractive iterative PCR, a principally different molecular method with high sensitivity and specificity. Our data suggest that screening for suitable markers for a molecular detection of occult lymph node metastasis cannot be restricted to small-sized hot spot regions of a few tumor genes and possibly must include tumor-specific epigenetic changes. Furthermore, restriction enzyme-based methods such as mutant-enriched PCR are not suitable to detect any mutation with equal efficiency and they should be carefully controlled to avoid false-positive detection of marker mutations in lymph node DNA.
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Affiliation(s)
- Felix Klebig
- Institute of Clinical Chemistry, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20251 Hamburg, Germany
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Tangoku A, Seike J, Nakano K, Nagao T, Honda J, Yoshida T, Yamai H, Matsuoka H, Uyama K, Goto M, Miyoshi T, Morimoto T. Current status of sentinel lymph node navigation surgery in breast and gastrointestinal tract. THE JOURNAL OF MEDICAL INVESTIGATION 2007; 54:1-18. [PMID: 17380009 DOI: 10.2152/jmi.54.1] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
Sentinel lymph node biopsy (SLNB) has been developed as a new diagnostic and therapeutic modality in melanoma and breast cancer surgery. The purpose of the SLNB include preventing the operative morbidity and improving the pathologic stage by focusing on fewer lymph nodes using immunocytochemic and molecular technology has almost achieved in breast cancer surgery. The prognostic meaning of immunocytochemically detected micrometastases is also evaluating in the SLN and bone marrow aspirates of women with early-stage breast cancer. SLNB using available techniques have suggested that the lymphatic drainage of the gastrointestinal tract is much more complicated than other sites, skip metastasis being rather frequent because of an aberrant lymphatic drainage outside of the basin exist. At the moment, the available data does not justify reduced extent of lymphadenectomy, but provides strong evidence for an improvement in tumor staging on the basis of SLNB. Two large scale prospective multi-center trials concerning feasibility of gamma-probe and dye detection for gastric cancer are ongoing in Japan. Recent studies have shown favorable results for identification of SLN in esophageal cancer. CT lymphography with endoscopic mucosal injection of iopamidol was applicable for SLN navigation of superficial esophageal cancer. The aim of surgical treatment is complete resection of the tumor-infiltrated organ including the regional lymph nodes. Accurate detection of SLN can achieve a selection of a more sophisticated tailor made approach. The patient can make a individualized choice from a broader spectrum of therapeutic options including endoscopic, laparoscopic or laparoscopy-assisted surgery, modified radical surgery, and typical radical surgery with lymph node dissection. Ultrastaging by detecting micrometastasis at the molecular level and the choice of an adequate treatment improve the postoperative quality of life and survival. However these issues require further investigation.
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Affiliation(s)
- Akira Tangoku
- Department of Oncological and Regenerative Surgery, Institute of Health Bioscience, The University of Tokushima Graduate School, Tokushima, Japan
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Horibe D, Ochiai T, Shimada H, Tomonaga T, Nomura F, Gun M, Tanizawa T, Hayashi H. Rapid detection of metastasis of gastric cancer using reverse transcription loop-mediated isothermal amplification. Int J Cancer 2007; 120:1063-9. [PMID: 17139607 DOI: 10.1002/ijc.22397] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Tailor-made surgeries for patients with solid malignancies have been under consideration on the basis of the development of new approaches for minor metastatic foci of malignant tumors. Accurate and reliable methods to detect metastases in biopsy specimens with certain rapidity are essential for the performance of these surgeries. The aim of this study was to develop a rapid and practical method to detect metastasis in specimens from patients with gastric carcinoma with the use of reverse transcription loop-mediated isothermal amplification (RT-LAMP) reaction, a novel technique for detecting mRNA expressions of targeted sequences with high sensitivity, specificity and rapidity under isothermal conditions. RT-LAMP primers to detect cytokeratin19 (CK19) mRNA were generated and 92 lymph nodes (LNs) obtained from 9 patients with gastric cancer were tested for tumor metastases with this technique. Among 92 LNs, 15 were metastasis-positive by routine histopathological examination. RT-LAMP reaction detected CK19 expression in all of the pathologically positive LNs and in 16 of 77 negative LNs. Nested RT-PCR assay for CK19 expression was also performed on 2 of the 9 cases including 32 LNs. The agreement rate of CK19 expression detection by RT-LAMP and RT-PCR analysis was 31/32 (97%). The RT-LAMP technique showed similar sensitivity to detect metastases as nested RT-PCR assay, with a rapidity comparable to that of intraoperative histopathological examination with frozen sectioning and hematoxylin and eosin staining. This method is expected to play an essential role in the performance of tailor-made surgeries in the near future.
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Affiliation(s)
- Daisuke Horibe
- Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
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Abstract
The purpose of this study was to prove the prognostic value of the sentinel node (SN) in colon tumors, and to validate radioguided surgery in identifying the SN. Nodal metastases are a strong prognostic factor in patients operated on for colon or rectal cancer, decreasing the 5-year survival rate by approximately 20 per cent and dropping it to 30 per cent. Unfortunately, of 50 per cent of patients judged to be nodal disease-free at surgery, about 20 to 30 per cent will die from a local tumor relapse or distant metastases within 5 years of diagnosis. These data suggest that other steps are needed for more precise staging of patients, and specifically, to accurately harvest and study the nodes on which to base the prognosis. Mapping lymph nodes predictive of the whole basin status, referred to as SN, may help focus the pathologist's attention on a small but representative target, and achieve correct nodal harvesting, which includes atypical drainage pathways, when present. Twenty selected patients with colon tumor were administered a subserosal, peritumoral, intraoperative injection of blue dye and 99mTc-marked colloidal particles. The SN was identified visually and with a handheld gamma probe and was subsequently stitch-labeled. The operation was then conducted after standard surgical procedures, and the required lymphadenectomy was performed. Later, the probe was used to confirm radioactivity in the excised specimen and the absence of radioactivity in the operative field after resection; the purpose of the latter was to exclude the presence of aberrant routes of lymphatic drainage. The labeled SN were stained with hematoxylin and eosin and, in case of negative findings, cytokeratin immunostaining was performed. The remaining resected nodes were stained with hematoxylin and eosin. The probe identification of SN was 95 per cent overall (19/20); in 13 patients, a single SN was labeled, and two were labeled in six patients, harvesting 25 SN. In the 19 patients in whom a radio-emitting SN was labeled, we recorded only one false-negative; in one case, a micrometastasis in the SN was the only extracolonic site. The blue dye identified the SN in 14 cases; in some of them, the number of nodes was overestimated (five single, seven double, and two triple SN) in comparison with the radioisotope, but at least one of the dyed nodes was also radioemitting. SN identification in colon cancers is a safe, fast, and easy procedure for ultrastaging the nodal basin. The technique involves a relatively flat learning curve and could become standard care for identifying the presence of nodal micrometastases at a low cost, thereby also making it affordable at small health centers.
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Yagci G, Unlu A, Kurt B, Can MF, Kaymakcioglu N, Cetiner S, Tufan T, Sen D. Detection of micrometastases and skip metastases with ex vivo sentinel node mapping in carcinoma of the colon and rectum. Int J Colorectal Dis 2007; 22:167-73. [PMID: 16721490 DOI: 10.1007/s00384-006-0132-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/05/2006] [Indexed: 02/04/2023]
Abstract
BACKGROUND The debate over sentinel lymph node mapping (SLNM) and focused pathologic examination to detect micrometastases in patients with colorectal cancer (CRC) continues. We present in this paper our experience with SLNM for CRCs to improve staging. In addition, we have detailed the mapping procedure on an anatomical basis to define skip metastasis. MATERIALS AND METHODS Forty-seven patients underwent ex vivo SLNM. Immediately after resection, 1 ml of patent blue VF was injected submucosally around the tumor. Lymph nodes harvested from the first 15 patients were mapped in a standard fashion as the blue-stained nodes (SLNs), and the others (non-SLNs) were dissected away. In the remaining 32 patients, the lymph nodes were also mapped separately in relation to their anatomic location and described as epicolic-paracolic, intermediate, and principal. The blue-stained nodes (SLNs) and non-SLNs, negative by hematoxylin and eosin stain, were further stained with cytokeratin immunohistochemical analysis and carcinoembryonic antigen. RESULTS A total of 873 histologically confirmed LNs were examined with a mean of 18.6+/-8.1 nodes per patient. In 46 of 47 patients (97.8%), SLNs were identified. Immunohistochemical staining revealed micrometastases in the lymph nodes of four patients, which were negative by conventional methods. Anatomical skip metastases were noted in 4 of 32 patients studied (12.5%). CONCLUSION Ex vivo SLNM in CRCs is a feasible technique with a high SLN identification rate. Results of anatomical mapping of lymph nodes correlates with the limited literature, suggesting that occult skip metastases can occur in the apical lymph node group and may occur outside the resected area.
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Affiliation(s)
- Gokhan Yagci
- Department of Surgery, Gulhane Military Medical Academy, 06018 Etlik, Ankara, Turkey.
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Madbouly KM, Senagore AJ, Mukerjee A, Delaney CP, Connor J, Fazio VW. Does immunostaining effectively upstage colorectal cancer by identifying micrometastatic nodal disease? Int J Colorectal Dis 2007; 22:39-48. [PMID: 16528541 DOI: 10.1007/s00384-006-0098-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/23/2005] [Indexed: 02/04/2023]
Abstract
PURPOSE Measure the association between the incidence of primary tumor staining and the identification of mediastinal lymph node (MLN) using cytokeratins, NM23, DCC-positive tumors, and vascular endothelial growth factor (VEGF) expression in T(2) and T(3)/N(0) colorectal cancers. The impact of MLN on both recurrence and survival was assessed. MATERIALS AND METHODS There were 153 CORC patients (T(2), T(3)/N(0)) selected from a prospectively accrued database. All patients had been staged by routine histopathology after a curative resection and no patients received adjuvant chemotherapy. The primary tumors (PT) were assessed with a panel of immunohistochemical stains (cytokeratin, DCC, Nm23, and VEGF). If the PT was positive, the regional nodes were assessed with that marker(s). For any positive tumor marker, all lymph nodes (LNs, mean of 12.6+/-4.2) were stained for this marker. RESULTS Patient age ranged from 38 to 86 years with a mean age of 61.56+/-25.56 years. Mean follow-up was 72.1+/-32.4 months. Recurrence rate of the whole group was 19/153 (12.4%) and the mean time to recurrence was 37.6+/-23.6 months (15 to 77 months). Crude mortality was 39.9%, while the cancer specific mortality was 11.2% after the whole follow-up period. The relationship between PT staining and MLNs was: cytokeratin-PT 143 (93.5%)/MLN 9 (6.3%); NM23-PT 51 (33.3%)/MLN 3 (5.9%); DCC-PT 79 (53%)/MLN 3 (3.8%); and VEGF-PT 72 (47%)/MLN 4 (5.6%). Nineteen (12.4%) patients experienced tumor recurrence. No correlation exist between PT and/or MLN staining and either recurrence or survival. No patient with MLN with any stain experienced a recurrence. There was no advantage to using an individual stain or all four stains. CONCLUSION Immunohistochemical stains for PT and focused analysis of regional nodes did not improve prediction of survival or recurrence. Sentinel LN evaluation and the provision of adjuvant chemotherapy in node-negative patients should be questioned and not be utilized outside of a research protocol.
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Yano H, Saito Y, Kirihara Y, Takashima J. Tumor invasion of lymph node capsules in patients with Dukes C colorectal adenocarcinoma. Dis Colon Rectum 2006; 49:1867-77. [PMID: 17080279 DOI: 10.1007/s10350-006-0733-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
PURPOSE The objective of this study was to investigate the correlation between the microscopic findings of positive lymph nodes, especially focusing on capsular invasion, and the outcome after curative surgical resection of colorectal cancer. METHODS We analyzed 480 positive lymph nodes from 155 consecutive patients with Stage III colorectal cancer to determine the frequency and significance of lymph node capsular invasion. Recurrence-free and cancer-specific survival rates were assessed in the patients with and without lymph node capsular invasion. RESULTS Between April 1995 and December 2000, 406 consecutive patients with primary colorectal cancer underwent curative resection. Regional lymph node metastases were present in 155 cases (38.2 percent). During the median follow-up period of 4.8 years, 41 patients (26.5 percent) developed recurrent disease and 28 patients died of cancer. Lymph node capsular invasion was detected in one or more lymph nodes from 75 cases (48.3 percent). The five-year recurrence-free rate was 56.1 percent in this group, whereas in the 80 patients without lymph node capsular invasion the rate was 88 percent (P<0.01). Features that were associated with recurrent disease were greater number of positive lymph nodes, venous invasion in primary tumor, infiltrative growth pattern of intranodal tumor, and presence of lymph node capsular invasion. Multivariate analysis identified lymph node capsular invasion as the only significant prognostic factor for recurrence. In multivariate analysis with regard to survival, lymph node capsular invasion, venous invasion, and number of positive nodes remained as significant prognostic factors. CONCLUSIONS Lymph node capsular invasion, determined by routine hematoxylin-eosin staining, is a potent prognostic factor in Stage III colorectal cancer.
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Affiliation(s)
- Hideaki Yano
- Department of Surgery, International Medical Center of Japan, 1-21-1, Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan.
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Gretschel S, Bembenek A, Schulze T, Kemmner W, Schlag PM. [Minimal residual tumor in gastrointestinal carcinoma. Relevance to prognosis and oncologic surgical consequences]. Chirurg 2006; 77:1104-17. [PMID: 17119886 DOI: 10.1007/s00104-006-1263-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Isolated tumor cells as a consequence of minimal residual disease are often not detectable by routine diagnostic procedures. However, before or after surgery, isolated tumor cells in lymph nodes, the peritoneal cavity, blood, or bone marrow can frequently be identified by immunohistochemical or molecular methods. Failure to reveal the presence of such cells results in under-staging of tumor patients and may constitute the source of unexpected tumor recurrence after radical surgery. These facts emphasize the importance of isolated tumor cells at least as a surrogate marker. The frequency of appearance of isolated tumor cells in different organ systems also depends on the type of primary tumor. Developments in modern detection methods have led to increasing sensitivity but at the expense of specificity. Isolated tumor cells demonstrate remarkable heterogeneity with respect to proliferative potential and tumorigenicity. This characteristic is also reflected by a striking variability in the expression of various genes conditioning the aforementioned biological behavior. Unfortunately there is also remarkable heterogeneity in methods used for sampling and processing patient material as well as for the enrichment and detection of isolated tumor cells. Despite the ongoing controversies concerning detection methods and biological significance of isolated tumor cells, several clinical trials providing data supporting the prognostic relevance of minimal residual disease should also be considered for gastrointestinal carcinoma. In future this finding should be integrated in the planning of trials in surgical oncology, and "minimal residual disease" should receive stronger attention as a stratification criterion in such clinical studies.
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Affiliation(s)
- S Gretschel
- Klinik für Chirurgie und Chirurgische Onkologie, Robert-Rössle-Klinik am Helios Klinikum Berlin, Universitätsmedizin Berlin, Charite Campus Buch, Lindenberger Weg 80, 13125 Berlin
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García-Sáenz JA, Sáenz MC, González L, Pérez-Segura P, Puente J, López-Tarruella S, Sastre J, Casado A, López-Asenjo JG, Díaz-Rubio E. Significance of the immunohistochemical detection of lymph node micrometastases in stage II colorectal carcinoma. Clin Transl Oncol 2006; 8:676-80. [PMID: 17005470 DOI: 10.1007/s12094-006-0038-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
BACKGROUND Survival results of stage II colorectal cancer patients have led to major efforts to identify the subset of patients at risk for disease relapse and adjuvant therapies benefit. Immunohistochemistry is being explored to detect undetectable microscopic lymph node micrometastases. MATERIAL AND METHODS A retrospective analysis of a 105 consecutive stage II colorectal cancer patients was performed. Two four-micres sections were obtained from each lymph node. These slides were stained with AE1-AE3 monoclonal antibodies against cytoskeleton using DAKO EnVision visualization system. Micrometastases were identified either as isolated cells or as well-defined glandular cell clusters with cytoplasm but not the nucleus stained with cytoskeleton antibodies. RESULTS 665 lymph nodes isolated from 105 patients were analyzed. Lymph nodes micrometastases were assessed in 26 out of the 105 patients. 42 (6.3%) out of 665 lymph nodes were infiltrated. Most of these metastases consisted of isolated cell cluster localized in marginal and interfollicular sinus of lymph nodes. The relapse rate was 23.1% among the patients with immunohistochemical detected lymph node micrometastes and 20.3% for the patients without lymph node involvement. This result lacked statistical significance (p = 0.759). DISCUSSION AE1/AE3 lymph node immunohistochemical staining in stage II colorectal cancer is an interesting biological phenomenon but it fails to identify patients at higher risk of relapse who deserve a more aggressive adjuvant attitude.
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Iddings D, Ahmad A, Elashoff D, Bilchik A. The prognostic effect of micrometastases in previously staged lymph node negative (N0) colorectal carcinoma: a meta-analysis. Ann Surg Oncol 2006; 13:1386-92. [PMID: 17009147 DOI: 10.1245/s10434-006-9120-y] [Citation(s) in RCA: 111] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2006] [Revised: 06/04/2006] [Accepted: 06/04/2006] [Indexed: 01/11/2023]
Abstract
BACKGROUND The prognostic relevance of lymphatic micrometastases in colorectal carcinoma is unclear. To determine the prognostic significance of micrometastases in colorectal cancer, a meta-analysis was performed on all studies, which reported 3-year disease-free survival (DFS) and overall survival (OS). METHODS Published studies selected for meta-analysis contained sufficient data from which to extrapolate estimates of 3-year DFS and/or OS. From 1991-2003, 25 studies re-examined N0 lymph nodes by serial sectioning and immunohistochemical (IHC) staining or reverse transcriptase-polymerase chain reaction (RT-PCR) assay. Eight studies (566 patients) with IHC detected micrometastases and three (173 patients) with RT-PCR micrometastases were used to determine DFS and OS. Weighted estimates of 3-year survival were combined across studies within each group, and the combined survival estimates were compared across groups using a binomial test. RESULTS Micrometastases were identified in all IHC studies; upstaging, including N1, N1mi and N0(i+), was achieved in 32% (179/566 patients). All RT-PCR studies identified micrometastases; upstaging to N0(mol+) was achieved in 37% (64/173 patients). There was a statistically significant difference in 3-year OS between RT-PCR positive N0(mol+) patients (77.8%) and those for whom micrometastases were not detected (96.6%) (P < .001). CONCLUSION The prognostic value of micrometastases detected retrospectively by RT-PCR is significant in AJCC stage II colorectal patients. Studies utilizing RT-PCR performed a more complete nodal analysis when compared to studies using IHC techniques. RT-PCR may also be more specific for the detection of clinically relevant micrometastases compared to IHC detected cytokeratins. Prospective studies are needed to evaluate the potential benefit of systemic chemotherapy in patients with molecular metastases.
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Affiliation(s)
- Douglas Iddings
- Department of Surgical Oncology, John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, CA 90404, USA
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Sasaki E, Nagino M, Ebata T, Oda K, Arai T, Nishio H, Nimura Y. Immunohistochemically demonstrated lymph node micrometastasis and prognosis in patients with gallbladder carcinoma. Ann Surg 2006; 244:99-105. [PMID: 16794394 PMCID: PMC1570614 DOI: 10.1097/01.sla.0000217675.22495.6f] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE To investigate whether immunohistochemically demonstrated lymph node micrometastasis has a survival impact in patients with advanced gallbladder carcinoma (pT2-4 tumors). SUMMARY BACKGROUND DATA The clinical significance of immunohistochemically detected lymph node micrometastasis recently has been evaluated in various tumors. However, few reports have addressed this issue with regard to gallbladder carcinoma. METHODS A total of 1476 lymph nodes from 67 patients with gallbladder carcinoma (pN0, n = 40; pN1, n = 27) who underwent curative resection were immunostained with monoclonal antibody against cytokeratins 8 and 18. The results were correlated with clinical and pathologic features and with patient survival. RESULTS Lymph node micrometastases were detected immunohistochemically in 23 (34.3%) of the 67 patients and in 37 (2.5%) of the 1476 nodes examined. Of the 37 nodal micrometastases, 21 (56.8%) were single-cell events, and the remaining 16 were clusters. Five micrometastases were detected in the paraaortic nodes. Clinicopathologic features showed no significant associations with the presence of lymph node micrometastases. Survival was worse in the 27 patients with pN1 disease than in the 40 with pN0 disease (5-year survival; 22.2% vs. 52.6%, P = 0.0038). Similarly, survival was worse in the 23 patients with micrometastasis than in the 44 without micrometastasis (5-year survival; 17.4% vs. 52.7%, P = 0.0027). Twenty-eight patients without any lymph node involvement had the best prognosis, whereas survival for the 11 patients with both types of metastasis was dismal. The grade of micrometastasis (single-cell or cluster) had no effect on survival. The Cox proportional hazard model identified perineural invasion, lymph node micrometastasis, and microscopic venous invasion as significant independent prognostic factors. CONCLUSIONS Lymph node micrometastasis has a significant survival impact in patients with pN0 or pN1 gallbladder carcinoma who underwent macroscopically curative resection. Extensive lymph node sectioning with keratin immunostaining is recommended for accurate prognostic evaluation for patients with gallbladder carcinoma.
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Affiliation(s)
- Eiji Sasaki
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
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