Top

Published in:

01-04-2009 | Review

The clinical significance of sentinel lymph node micrometastasis in breast cancer

Authors: Neill Patani, Kefah Mokbel

Published in: Breast Cancer Research and Treatment | Issue 3/2009

Abstract

Introduction The advent of sentinel lymph node biopsy (SLNB) and improvements in histopathological and molecular analysis have increased the rate at which micrometastases (MM) are identified. However, their significance has been the subject of much debate. In this article we review the literature concerning axillary lymph node (ALN) MM, with particular reference to SLNB. The controversies regarding histopathological assessment, clinical relevance and management implications are discussed. Methods Literature review facilitated by Medline and PubMed databases. Results Published studies have reported divergent results regarding the significance and implications of ALN MM in general and sentinel lymph node (SLN) MM in particular. Some studies demonstrate no associations, whilst others have found these to be indicators of poor prognosis, associated with non-SLN involvement, in addition to local and distant failure. Absolute consensus regarding the optimal analytical technique for SLNs has yet to be reached, particularly concerning immunohistochemical (IHC) techniques targeting cytokeratins and the utility of contemporary molecular analysis. Conclusion SLN MM are likely to represent an incremental detriment to prognosis and increased risk of non-SLN involvement, despite only modest up-staging within current classification systems. In the absence of level-1 guidance concerning the management of women with SLN MM, each case requires discussion with regard to other tumour and patient related factors in the context of the multidisciplinary team. Randomized studies are required to evaluate the prognostic significance and optimal management of each category of tumour burden within the SLN. The identification of MM remains highly dependent on the analytical technique employed and there exists potential for stage migration and impact on management decisions.

Carter CL, Allen C, Henson DE (1989) Relation of tumor size, lymph node status, and survival in 24, 740 breast cancer cases. Cancer 63:181–187PubMedCrossRef

Veronesi U, Paganelli G, Viale G (2003) A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. N Engl J Med 349:546–553PubMedCrossRef

Patani N, Cutuli B, Mokbel K. Current management of DCIS: a review. Breast Cancer Res Treat 2007 Sep 28; [Epub ahead of print]

International Agency for Research on Cancer (IARC) (2003) WHO histological classification of tumours of the breast. In: Tavassoli FA, Devilee P (eds) World health organization classification of tumours, pathology & genetics tumours of the breast and female genital organs. IARC Press, Lyon, pp 10–12

Greene FL, Page DL, Fleming ID, Fritz A, Balch CM et al (eds) (2002) AJCC Cancer Staging Manual, 6th edn

Khalifa K, Pereira B, Thomas VA, Mokbel K (2004) The accuracy of intraoperative frozen section analysis of the sentinel lymph nodes during breast cancer surgery. Int J Fertil Womens Med 49(5):208–211PubMed

Tew K, Irwig L, Matthews A, Crowe P, Macaskill P (2005) Meta-analysis of sentinel node imprint cytology in breast cancer. Br J Surg 92(9):1068–1080PubMedCrossRef

Schoenfeld A, Luqmani Y, Smith D, O’Reilly S, Shousha S, Sinnett HD, Coombes RC (1994) Detection of breast cancer micrometastases in axillary lymph nodes by using polymerase chain reaction. Cancer Res 54(11):2986–2990PubMed

Kurosumi M, Takei H (2007) Significance and problems of histopathological examination and utility of real-time reverse transcriptase-polymerase chain reaction method for the detection of sentinel lymph node metastasis in breast cancer. Breast Cancer 14(4):342–349PubMedCrossRef

10.

Tsujimoto M, Nakabayashi K, Yoshidome K, Kaneko T et al (2007) One-step nucleic acid amplification for intraoperative detection of lymph node metastasis in breast cancer patients. Clin Cancer Res 13(16):4807–4816PubMedCrossRef

11.

Ishikawa T, Miyajima E, Sasaki T, Tanabe M et al (2007) Transcription-reverse transcription concerted reaction and minimal residual disease in axillary sentinel nodes of breast cancer. Eur J Surg Oncol 33(4):430–434PubMedCrossRef

12.

Treseler P (2006) Pathologic examination of the sentinel lymph node what is the best method? Breast J 12(5 Suppl 2):S143–S151PubMedCrossRef

13.

Carter B, Jensen R, Simpson J et al (2000) Benign transport of breast epithelium into axillary lymph nodes after biopsy. Am J Clin Pathol 113:259–265PubMedCrossRef

14.

European Working Group for Breast Screening Pathology (2003) Pathological work-up of sentinel lymph nodes in breast cancer. Review of current data to be considered for the formulation of guidelines. Eur J Cancer 39:1654–1667CrossRef

15.

Schwartz GF, Giuliano AE, Veronesi U (2002) Proceedings of the consensus conference on the role of sentinel lymph node biopsy in carcinoma of the breast, April 19–22, 2001, Philadelphia, Pensylvania. Cancer 94:2542–2551PubMedCrossRef

16.

Lyman GH, Giuliano AE, Somerfield MR et al (2005) American society of clinical oncology guideline recommendations for sentinel lymph node biopsy in early breast cancer. J Clin Oncol 23:7703–7720PubMedCrossRef

17.

Cserni C, Amendoeira I, Apostolikas N et al (2003) Pathologic work-up of sentinel lymph nodes in breast cancer: Review of current data to be considered for the formulation of guidelines. Eur J Cancer 39:1654–1667PubMedCrossRef

18.

Cserni G (2004) A model for determining the optimum histology of sentinel lymph nodes in breast cancer. J Clin Pathol 57(5):467–471PubMedCrossRef

19.

Dowlatshanhi K, Fan M, Anderson JM, Bloom KJ (2001) Occult metastases in sentinel nodes of 200 patients with operable breast cancer. Ann Surg Oncol 8:675–681CrossRef

20.

Cote R, Peterson H, Chaiwun B et al (1999) Role of immunohistochemical detection of lymph-node metastases in management of breast cancer. Lancet 354:896–900PubMedCrossRef

21.

Rivera M, Merlin S, Hoda R et al (2004) Minimal involvement of sentinel lymph node in breast carcinoma: prevailing concepts and challenging problems. Int J Surg Pathol 12:301–306PubMedCrossRef

22.

Mori M, Mimori K, Inoue H et al (1995) Detection of cancer micrometastases in lymph nodes by reverse transcriptase-polymerase chain reaction. Cancer Res 55:3417–3420PubMed

23.

Leers MP, Schoffelen RH, Hoop JG et al (2002) Multiparameter flow cytometry as a tool for the detection of micrometastatic tumour cells in the sentinel lymph node procedure of patients with breast cancer. J Clin Pathol 55(5):359–366PubMed

24.

Mesker WE, Torrenga H, Sloos WC et al (2004) Supervised automated microscopy increases sensitivity and efficiency of detection of sentinel node micrometastases in patients with breast cancer. J Clin Pathol 57(9):960–964PubMedCrossRef

25.

Weaver DL, Krag DN, Manna EA, Ashikaga T, Harlow SP, Bauer KD (2003) Comparison of pathologist-detected and automated computer-assisted image analysis detected sentinel lymph node micrometastases in breast cancer. Mod Pathol 16(11):1159–1163PubMedCrossRef

26.

Huvos AG, Hutter RV, Berg JW (1971) Significance of axillary macrometastases and micrometastases in mammary cancer. Ann Surg 173:44–46PubMedCrossRef

27.

Fisher B, Gebhardt MC (1978) The evolution of breast cancer surgery: past, present, and future. Semin Oncol 5:385–394PubMed

28.

Fisher ER, Palekar A, Rockette H, Redmond C, Fisher B (1978) Pathologic findings from the National Surgical Adjuvant Breast Project (Protocol No. 4). V. Significance of axillary nodal micro- and macrometastases. Cancer 42(4):2032–2038PubMedCrossRef

29.

Chen SL, Hoehne FM, Giuliano AE (2007) The prognostic significance of micrometastases in breast cancer: a SEER population-based analysis. Ann Surg Oncol Sep 26; [Epub ahead of print].

30.

Kuijt GP, Voogd AC, van de Poll-Franse LV, Scheijmans LJ, van Beck MW, Roumen RM (2005) The prognostic significance of axillary lymph-node micrometastases in breast cancer patients. Eur J Surg Oncol 31(5):500–505PubMedCrossRef

31.

Reed W, Bøhler PJ, Sandstad B, Nesland JM (2004) Occult metastases in axillary ymph nodes as a predictor of survival in node-negative breast carcinoma with long-term follow-up. Breast J 10(3):174–180PubMedCrossRef

32.

Susnik B, Frkovic-Grazio S, Bracko M (2004) Occult micrometastases in axillary lymph nodes predict subsequent distant metastases in stage I breast cancer: a case–control study with 15-year followup. Ann Surg Oncol 11:568–572PubMedCrossRef

33.

Rosen PP, Saigo PE, Braun DW, Weathers E, Fracchia AA, Kinne DW (1981) Axillary micro- and macrometastases in breast cancer: prognostic significance of tumor size. Ann Surg 194(5):585–591PubMedCrossRef

34.

Clayton F, Hopkins CL (1993) Pathologic correlates of prognosis in lymph node- positive breast carcinomas. Cancer 71(5):1780–1790PubMedCrossRef

35.

International (Ludwig) Breast Cancer Study Group (1990) Prognostic importance of occult axillary lymph node micrometastases from breast cancers. Lancet 335:1565–1568

36.

Colleoni M, Rotmensz N, Peruzzotti G et al (2005) Size of breast cancer metastases in axillary lymph nodes: clinical relevance of minimal lymph node involvement. J Clin Oncol 23:1379–1389PubMedCrossRef

37.

Umekita Y, Ohi Y, Sagara Y, Yoshida H (2002) Clinical significance of occult micrometastases in axillary lymph nodes in “node-negative” breast cancer patients. Jpn J Cancer Res 93(6):695–698PubMed

38.

Dowlatshahi K, Fan M, Snider HC, Habib FA (1997) Lymph node micrometastases from breast carcinoma. Reviewing the dilemma. Cancer 80:1188–1197PubMedCrossRef

39.

Sakorafas GH, Geraghty J, Pavlakis G (2004) The clinical significance of axillary lymph node micrometastases in breast cancer. Eur J Surg Oncol 30:807–816PubMedCrossRef

40.

Mullenix PS, Brown TA, Meyers MO, Giles LR et al (2005) The association of cytokeratin-only-positive sentinel lymph nodes and subsequent metastases in breast cancer. Am J Surg 189(5):606–609. Discussion 609PubMedCrossRef

41.

van Rijk MC, Peterse JL, Nieweg OE, Oldenburg HS, Rutgers EJ, Kroon BB (2006) Additional axillary metastases and stage migration in breast cancer patients with micrometastases or submicrometastases in sentinel lymph nodes. Cancer 107(3):467–471PubMedCrossRef

42.

Viale G, Maiorano E, Pruneri G et al (2005) Predicting the risk for additional axillary metastases in patients with breast carcinoma and positive sentinel lymph node biopsy. Ann Surg 241:319–325PubMedCrossRef

43.

Turner RR, Chu KU, Qi K, Botnick LE, Hansen NM, Glass EC et al (2000) Pathologic features associated with nonsentinel lymph node metastases in patients with metastatic breast carcinoma in a sentinel lymph node. Cancer 89:574–581PubMedCrossRef

44.

Viale G, Maiorano E, Mazzarol G, Zurrida S, Galimberti V, Luini A et al (2001) Histologic detection and clinical implications of micrometastases in axillary sentinel lymph nodes for patients with breast carcinoma. Cancer 92:1378–1384PubMedCrossRef

45.

Dabbs DJ, Fung M, Landsittel D, McManus K, Johnson R (2004) Sentinel lymph node micrometastasis as a predictor of axillary tumor burden. Breast J 10(2):101–105PubMedCrossRef

46.

Leidenius MH, Vironen JH, Riihela MS, Krogerus LA, Toivonen TS, von Smitten KA, Heikkila PS (2005) The prevalence of non-sentinel node metastases in breast cancer patients with sentinel node micrometastases. Eur J Surg Oncol 31(1):13–18PubMedCrossRef

47.

Schrenk P, Konstantiniuk P, Wolfl S, Bogner S, Haid A, Nemes C, Jagoutz-Herzlinger M, Redtenbacher S (2005) Prediction of non-sentinel lymph node status in breast cancer with a micrometastatic sentinel node. Br J Surg 92(6):707–713PubMedCrossRef

48.

Giard S, Baranzelli MC, Robert D, Chauvet MP et al (2004) Surgical implications of sentinel node with micrometastatic disease in invasive breast cancer. Eur J Surg Oncol 30(9):924–929PubMed

49.

den Bakker MA, van Weeszenberg A, de Kanter AY, Beverdam FH, Pritchard C, van der Kwast TH, Menke-Pluymers M (2002) Non-sentinel lymph node involvement in patients with breast cancer and sentinel node micrometastasis; too early to abandon axillary clearance. J Clin Pathol 55(12):932–935CrossRef

50.

Houvenaeghel G, Nos C, Mignotte H, Classe JM, Giard S, Rouanet P, Lorca FP, Jacquemier J, Bardou VJ (2006) Groupe des Chirurgiens de la Federation des Centres de Lutte Contre le Cancer. Micrometastases in sentinel lymph node in a multicentric study: predictive factors of nonsentinel lymph node involvement–Groupe des Chirurgiens de la Federation des Centres de Lutte Contre le Cancer. J Clin Oncol 24(12):1814–1822 Epub 2006 Mar 27PubMedCrossRef

51.

Di Tommaso L, Arizzi C, Rahal D, Destro A et al (2006) Anatomic location of breast cancer micrometastasis in sentinel lymph node predicts axillary status. Ann Surg 243(5):706–707 author reply 706–7PubMedCrossRef

52.

Rutgers EJ (2004) Sentinel node micrometastasis in breast cancer. Br J Surg 91(10):1241–1242PubMedCrossRef

53.

Broekhuizen LN, Wijsman JH, Peterse JL, Rutgers EJ (2006) The incidence and significance of micrometastases in lymph nodes of patients with ductal carcinoma in situ and T1a carcinoma of the breast. Eur J Surg Oncol 32(5):502–506PubMedCrossRef

54.

Tjan-Heijen VCG, Bult P, de Widt-Levert LM, Ruers TJ, Beex LVAM (2001) Micro-metastases in axillary lymph nodes: an increasing classification and treatment dilemma in breast cancer due to the introduction of the sentinel lymph node procedure. Breast Cancer Res Treat 70:81–88CrossRef

55.

de Mascarel I, Bonichon F, Coindre JM, Trojani M (1992) Prognostic significance of breast cancer axillary lymph node micrometastases assessed by two special techniques: reevaluation with longer follow-up. Br J Cancer 66(3):523–527PubMed

56.

Colpaert C, Vermeulen P, Jeuris W et al (2001) Early distant relapse in “node- negative” breast cancer patients is not predicted by occult axillary lymph node metastases, but by features of the primary tumour. J Pathol 193:442–449PubMedCrossRef

57.

Millis RR, Springall R, Lee AH, Ryder K, Rytina ER, Fentiman IS (2002) Occult axillary lymph node metastases are of no prognostic significance in breast cancer. Br J Cancer 86:396–401PubMedCrossRef

58.

Kahn HJ, Hanna WM, Chapman JA et al (2006) Biological significance of occult micrometastases in histologically negative axillary lymph nodes in breast cancer patients using the recent American Joint Committee on Cancer breast cancer staging system. Breast J 12:291–293CrossRef

59.

Langer I, Marti WR, Guller U et al (2005) Axillary recurrence rate in breast cancer patients with negative sentinel lymph node (SLN) or SLN micrometastases. Ann Surg 241:152–158PubMed

60.

Guenther JM, Hansen NM, DiFronzo LA, Giuliano AE, Collins JC, Grube BL et al (2003) Axillary dissection is not required for all patients with breast cancer and positive sentinel nodes. Arch Surg 138:52–56PubMedCrossRef

61.

Fant JS, Grant MD, Knox SM, Livingston SA, Ridl K, Jones RC et al (2003) Preliminary outcome analysis in patients with breast cancer and a positive sentinel lymph node who declined axillary dissection. Ann Surg Oncol 10:126–130PubMedCrossRef

62.

Liang WC, Sickle-Santanello BJ, Nims TA (2001) Is a completion axillary dissection indicated for micrometastases in the sentinel lymph node? Am J Surg 182:365–368PubMedCrossRef

63.

Rutledge H, Davis J, Chiu R, Cibull M, Brill Y, McGrath P, Samayoa L (2005) Sentinel node micrometastasis in breast carcinoma may not be an indication for complete axillary dissection. Mod Pathol 18(6):762–768PubMedCrossRef

64.

Fournier K, Schiller A, Perry RR, Laronga C (2004) Micrometastasis in the sentinel lymph node of breast cancer does not mandate completion axillary dissection. Ann Surg 239(6):859–863 discussion 863–865PubMedCrossRef

65.

Wong S, Chao C, Edwards M et al (2001) The use of cytokeratin staining in sentinel lymph node biopsy for breast cancer. Am J Surg 182:330–334PubMedCrossRef

66.

Klauber-Demore N, Tan LK, Liberman L et al (2000) Sentinel lymph node biopsy: Is it indicated in patients with high-risk ductal carcinoma-insitu and ductal carcinoma-in-situ with microinvasion? Ann Surg Oncol 7:636–642PubMedCrossRef

67.

Lara JF, Young SM, Velilla RE, Santoro EJ, Templeton SF (2003) The relevance of occult axillary micrometastasis in ductal carcinoma in situ: a clinicopathologic study with long-term follow-up. Cancer 98(10):2105–2113PubMedCrossRef

68.

Bland CS (1981) The Halsted mastectomy: present illness and past history. West J Med 134(6):549–555PubMed

69.

Vaidya J, Vyas J, Chinoy R et al (1996) Multicentricity of breast cancer: whole organ analysis and clinical implications. Br J Cancer 74:820–824PubMed

70.

Baum M, Vaidya J, Mittra I (1997) Multicentricity and recurrence of breast cancer. Lancet 349(9046):208PubMedCrossRef

71.

Fisher B, Anderson S, Bryant J et al (2002) Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 347(16):1233–1241PubMedCrossRef

72.

Louis-Sylvestre C, Clough K, Asselain B et al (2004) Axillary treatment in conservative management of operable breast cancer: dissection or radiotherapy? Results of a randomized study with 15 years of follow-up. J Clin Oncol 22:97–101PubMedCrossRef

73.

Cserni G, Amendoeira I, Apostolikas N et al (2004) Discrepancies in current practice of pathological evaluation of sentinel lymph nodes in breast cancer. Results of a questionnaire based survey by the European Working Group for Breast Screening Pathology. J Clin Pathol 57:695–701PubMedCrossRef

74.

De Mascarel I, MacGrogan G, Picot V, Mathoulin-Pelissier S (2002) Prognostic significance of immunohistochemically detected breast cancer node metastases in 218 patients. Br J Cancer 87:70–74PubMedCrossRef

75.

Singletary S, Greene G, Sobin L (2003) Classification of isolated tumor cells: clarification of the 6th edition of the American Joint Committee on Cancer Staging Manual. Cancer 98:2740–2741PubMedCrossRef

76.

Hansen NM, Ye X, Grube BJ, Giuliano AE (2004) Manipulation of the primary breast tumor and the incidence of sentinel node metastases from invasive breast cancer. Arch Surg 139:634–640PubMedCrossRef

77.

Peters-Engl C, Konstantiniuk P, Tausch C et al (2004) The impact of preoperative breast biopsy on the risk of sentinel lymph node metastases: analysis of 2502 cases from the Austrian Sentinel Node Biopsy Group. Br J Cancer 91:1782–1786PubMedCrossRef

78.

Moore KH, Thaler HT, Tan LK et al (2004) Immunohistochemically detected tumor cells in the sentinel nodes of patients with breast carcinoma. Cancer 100:929–934PubMedCrossRef

79.

Kinoshita S, Uchida K, Kyoda S, Shioya H, Takeyama H, Morikawa T (2007) Impact of fine-needle aspiration on long-term survival rate and axillary lymph node micrometastasis in patients with early breast cancer. Breast J 13(2):216–217PubMedCrossRef

80.

Diaz NM, Cox CE, Ebert M, Clark JD, Vrcel V, Stowell N, Sharma A, Jakub JW, Cantor A, Centeno BA, Dupont E, Muro-Cacho C, Nicosia S (2004) Benign mechanical transport of breast epithelial cells to sentinel lymph nodes. Am J Surg Pathol 28(12):1641–1645PubMedCrossRef

81.

Chu KU, Turner RR, Hansen NM, Brennan MB, Bilchik A, Giuliano AE (1999) Do all patients with sentinel node metastasis from breast carcinoma need complete axillary node dissection? Ann Surg 229(4):536–541PubMedCrossRef

82.

Nagashima T, Sakakibara M, Nakano S, Tanabe N, Nakamura R, Nakatani Y, Nagai Y, Koda K, Miyazaki M (2006) Sentinel node micrometastasis and distant failure in breast cancer patients. Breast Cancer 13(2):186–191PubMedCrossRef

83.

Ganaraj A, Kuhn JA, Jones RC, Grant MD, Andrews VR, Knox SM, Netto GJ, Altrabulsi B, Livingston SA, McCarty TM (2003) Predictors for nonsentinel node involvement in breast cancer patients with micrometastases in the sentinel lymph node. Proc (Bayl Univ Med Cent) 16(1):3–6

Title: The clinical significance of sentinel lymph node micrometastasis in breast cancer
Authors: Neill Patani
Kefah Mokbel
Publication date: 01-04-2009
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 3/2009
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-008-0021-6

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2009

Molecular mechanisms of the D327N SHBG protective role on breast cancer development after estrogen exposure

A pilot genome-wide association study of early-onset breast cancer

Population-based estimates of the relation between breast cancer risk, tumor subtype, and family history

Time-varying pattern of recurrence risk for Chinese breast cancer patients

Analysis of the progression of intraductal proliferative lesions in the breast by PCR-based clonal assay

Optimal delivery of anthracycline-based chemotherapy in the adjuvant setting improves outcome of breast cancer patients

Keynote webinar | Spotlight on antibody–drug conjugates in cancer