Bianchi V

Boni L

Chiappa C

Dionigi G

Dionigi R.

Frattini F

Piscopo C

Rausei S

Rovera F

ROVERA, FRANCESCA  ANGELA

FRATTINI, FRANCESCO

CHIAPPA, CORRADO

PISCOPO, CRISTIANO

BIANCHI, VERONICA

DIONIGI, GIANLORENZO

BONI, LUIGI

DIONIGI, RENZO

Archivio istituzionale della ricerca - Università dell'Insubria

ORIGINAL ARTICLEThe role of Micrometastatic Disease in Sentinel LymphNode in Breast CancerFrancesca Rovera, MD, Francesco Frattini, MD, Corrado Chiappa, MD,Cristiano Piscopo, MD, Veronica Bianchi, MD, Gianlorenzo Dionigi, MD,FACS, Stefano Rausei, MD, Luigi Boni, MD, FACS,and Renzo Dionigi, MD, FACSDepartment of Surgical Sciences, University of Insubria, Varese, Italyn Abstract: Sentinel lymph node (SLN) biopsy is the standard procedure for axillary node staging in breast cancer.Improvements in histopathological analysis and immunohistochemistry have recently increased the rate of detection oflymph nodal micrometastases. The clinical implications and prognostic significance of micrometastases in SLN still remaina controversial issue. Literature review was analyzed by searches of Medline and PubMed data bases. Whereas most stud-ies carried on small groups of patients did not show differences in survival, recently some studies with longer follow-up andwith larger populations demonstrated that prognosis of patients with micrometastases is worse compared to that of patientswith SLN free of disease. To date, completion axillary dissection remains the standard option when a macro or micrometas-tasis (0.2–2 mm) in the SLN is found. However, in absence of level-1 evidence guidelines, each case requires discussion inthe context of a multi-disciplinary team. nKey Words: axillary surgery, micrometastases, sentinel lymph node biopsyAxillary lymph node status represents the most sig-nificant prognostic factor in breast cancer. Senti-nel node biopsy has been validated as the standardtechnique in lymph nodal staging in breast cancer pre-senting high accuracy and minimal morbidity.The development in the anatomopathological tech-niques of evaluation of sentinel lymph node (SLN)with serial sectioning and immunohistochemistry(ICH) has increased the identification rate of microm-etastatic disease.DEFINITIONDefinition of micrometastasis is still controversial.The V Edition of the American Joint Committee(AJCC) Cancer Staging Manual defined ‘‘micrometas-tasis’’ a single cluster of metastases till 2 mm of size.The VI Edition of AJCC considered micrometastases asingle cluster of metastatic cells of 2.0 mm or less andlarger than 0.2 mm. Moreover, the same edition intro-duced the term of ‘‘Isolated Tumor Cells’’ (ITC) toconsider single cells or small groups of cells of 0.2 mmor less (1).The prevalence of micrometastatic disease in SLNranges from 8% to 59% (mean 38%) (2).DETECTION OF MICROMETASTASESTo date, most guidelines recommend a detailed anal-ysis of SLN through multilevel sectioning coupled withcytokeratin ICH (2). However, a recent review byCserni et al. (3) from about 240 pathology laboratoriesin Europe revealed a great variability in the work-up ofnodes. On the basis of the survey by the EuropeanWorking Group for Breast Screening Pathology (3), themost common methods, consisting of the evaluation ofsix levels separated by 150 lm, were used by only eightdepartments. A systematic and complete sampling iscarried out in 25% of cases. The distance between sec-tions also shows great variability, ranging from 2 to500 lm. The immunohistochemical technique is notconsidered mandatory, but may be performed when thehematoxylin and eosin-stained slides have suspiciousAddress correspondence and reprint requests to: Francesca Rovera,MD, Director, Senology Research Center, Department of Surgical Sciences,University of Insubria, Via Guicciardini 21100 Varese, Italy, or e-mail:francesca.rovera@uninsubria.it.DOI: 10.1111/j.1524-4741.2010.00999.x 2010 Wiley Periodicals, Inc., 1075-122X/10The Breast Journal, Volume 16 Suppl. 1, 2010 S26–S28cells that are equivocal. With the introduction of amore detailed and intensive use of SLN, an upstagingwould be expected. In a recent review (3,4), the upstag-ing rate ranged between 9% and 47% and upstagingwas seen to be enhanced by the use of ICH staining foranticytokeratin. ICH seems to increase the ability ofdetecting metastatic cells in lymph node tissue. In addi-tion, in recent years, advances in molecular biologyhave enabled highly sensitive techniques to be appliedto SLN analysis. Reverse transcriptase polymerasechain reaction (RT-PCR) method is capable of detect-ing trace amounts of keratin messenger RNA producedby epithelial cells. RT-PCR has recently been reportedto reach a sensitivity of 89.5% and a specificity of96.7% on frozen sections (5). RT-PCR is even moresensitive than cytokeratin ICH and may identify verylow-volume nodal involvement but, on the contrary,may also condition false signals. The VI AJCC CancerStaging system considers a pN0 (mol+) (sn) a SNLfound to be positive only by molecular methods (1).PREDICTION OF NONSENTINEL LYMPH NODEMETASTASESPrevalence of micrometastases in nonsentinel lymphnode in patients with sentinel node positive formicrometastases ranges from 0% to 57%. Severalstudies evidenced in multifactorial analysis that size ofmetastases in SLN is the most powerful risk factor ofmetastases in nonsentinel lymph nodes (6).Viale and colleagues (7) published a study specificaddressing the risk of further axillary metastases inpatients with ITC-positive SLN. In this large single-institution series, 1228 patients with positive SLN werereclassified according to the VI AJCC Cancer Staging asfollows: 64.6% macrometastases, 26% micrometasta-ses, and 9.4% ITC. Interestingly, further nonsentinelmetastases after axillary lymph node dissection (ALND)have been found in 50.3%, 21.4%, and 14.4% of thesegroups, respectively. Therefore, the finding of ITC inSLN is associated with a small (14.4%) but not negligi-ble risk of further axillary involvement, as well as mi-crometastases of up to 1 mm in size (17%). If bothgroups are considered together, patients with ITC onlyor SLN metastasis smaller than 1 mm have the lowestrisk of additional metastases compared with those withmicrometastases 1–2 mm and those with SLN macrom-etastases.Of 2929 cases with breast carcinoma not largerthan 15 mm and staged with SLN biopsy, Cserniet al. (8) found no further axillary involvement in theother nodes dissected if the SLN had ITC (26 cases of71 had ALND). In cases with micrometastases, 12%had further axillary node involvement (178 cases of234 cases had ALND). SLN macrometastases werefollowed by axillary node involvement in 37% ofcases (299 of 335 cases had ALND). In a predictivemodel considering the size of metastasis in the SLNcombined with other significant predictors (number ofpositive SLNs and presence of vascular invasion of theprimary tumor), patients with the most favorablecombination of predictive factors still have a 13% riskof developing nonsentinel node metastases. So, even ifmost surgeons would not recommend completion axil-lary dissection in ITC-positive SLN, in others’ opin-ions, it should be offered outside clinical trials.PROGNOSTIC IMPLICATIONS OFMICROMETASTATIC DISEASEDespite intensive working on the prognostic signifi-cance of micrometastases and ITC in the SLN, theirclinical implications remain unknown.Whereas the first studies on small groups ofpatients did not evidence differences in survival,recently several studies with longer follow-up(4–25 years) and with larger populations demon-strated that prognosis of patients with micrometasta-ses is quite different from patients with SLN free ofdisease. The International Breast Cancer Study Groupon 921 patients evidenced an increased risk of localrecurrence in patients with micrometastases (9). Thestudy of Grabau et al. (10), to date that with the larg-est population, has demonstrated a significantly worseoverall survival in patients with micrometastases (RR1.20, 95% CI, p = 0.04) compared with node-negativepatients. Similar results have been reported by Colle-oni (11) and Kujit (12). Chen et al. (13) reportedSEER data of 209720 cases among which, in multivar-iate analysis of overall survival, cases with microme-tastases had a HR of 1.35 compared with node-negative patients and of 0.82 compared with caseswith macrometastases.PRACTICAL APPROACH TO MICROMETASTATICDISEASEIt is still a controversial issue what is the best pro-cedure to perform in case of micrometastatic diseasein SLN. In approximately 80% of patients with SLNMicrometastases in Sentinel Lymph Node in Breast Cancer • S27micrometastases, the SLN is the only involved axillarylymph node; therefore, further axillary surgery may beconsidered an overtreatment. The guidelines of theAmerican Society of Clinical Oncology (ASCO) (14)recommend ALND in patients with micrometastasesin SLN. To date, completion axillary dissectionremains the standard option when a macrometastasisor micrometastasis (0.2–2 mm) in the SLN is found,while in the case of detection of ITC-positiveSLN axillary dissection may be omitted, even if thelow risk of further axillary involvement should beconsidered.ONGOING RANDOMISED CLINICAL TRIALSIn the few next years, the ongoing large randomisedtrials will issue their preliminary results, both in Eur-ope (Trial 23-01 of the International Breast CancerStudyGroup [IBCSG]) and the USA (the ACOGSOGstudy Z0010 and NSABP study B-32). Results fromthese trials are expected to give an important contri-bution to clarify the prognostic value of micrometa-stasis and ITCs in SLN and whether sparing anaxillary dissection in micrometastatic SLN is safe.REFERENCES1. Greene GL, Page DL, Fletcher C, editors. AJCC Cancer Stag-ing Manual. 6th edn. New York: Springer; 2002.2. Cserni G, Gregori D, Merletti F, et al. Meta-analysis of non-sentinel node metastases associated with micrometastatic sentinelnodes in breast cancer. Br J Surg 2004;91:1245–52.3. Cserni G, Amendoeira I, Apostolikas N, et al.; EuropeanWorking Group for Breast Screening Pathology Pathological work-up of sentinel nodes in breast cancer. Review of current data to beconsidered for the formulation of guidelines. Eur J Cancer2003;39:1654–67.4. Ryden L, Chebil G, Sjostrom L, Pawlowski R, Jonsson PE.Determination of sentinel lymph node status in primary breast can-cer by prospective use of immunohistochemistry increases the rateof micrometastases and isolated tumor cells: analysis of 174 patientsafter SLN biopsy. Eur J Surg Oncol 2007;33:33–8.5. Kurosumi M, Takei H. Significance and problems of histo-pathological examination and utility of real-time reverse transcrip-tase-polymerase reaction method for the detection of sentinel lymphnode metastasis in breast cancer. Breast Cancer 2007;14:342–9.6. Cserni G. Histopathologic examination of the sentinel lymphnodes. Breast J 2006;12(Suppl 2):S153–6.7. Viale G, Maiorano E, Pruneri G, et al. Predicting the riskfor additional axillary metastases in patients with breast carcinomaand positive sentinel lymph node biopsy. Ann Surg 2005;241:319–25.8. Cserni G, Bianchi S, Vezzosi V, et al. Sentinel lymph nodebiopsy in staging small (up to 15 mm) breast carcinomas. Resultsfrom a European multi-institutional study. Pathol Oncol Res2007;13:5–14.9. International (Ludwig) Breast Cancer Study Group. Prognos-tic importance of occult axillary lymph node micrometastases frombreast cancers. Lancet 1990;335:1565–8.10. Grabau D, Jensen MB, Rank F, Blichert-Toft M. Axillarylymph node micrometastases in invasive breast cancer: national fig-ures on incidence and overall survival. APMIS 2007;115:828–37.11. Colleoni M, Rotmensz N, Peruzzotti G, et al. Size of breastcancer metastases in axillary lymph nodes: clinical relevance of min-imal lymph node involvement. J Clin Oncol 2005;23:1379–89.12. Kuijt GP, Voogd AC, van de Poll_franse LV, Scheijmans LJ,van Beek MW, Roumen RM. The prognostic significance of axillarylymph-node micrometastases in breast cancer patients. Eur J SurgOncol 2005;31:500–5.13. Chen SL, Hoehne FM, Giuliano AE. The prognostic signifi-cance of micrometastases in breast cancer: a SEER population-basesanalysis. Ann Surg Oncol 2007;14:3378–94.14. Lyman GH, Giuliano AE, Somerfield MR, et al. AmericanSociety of Clinical Oncology Guideline Recommendations for senti-nel lymph node biopsy in early-stage breast cancer. J Clin Oncol2005;23:7703–20.S28 • rovera et al.

The role of micrometastatic disease in sentinel limph node in breast cancer

The role of micrometastatic disease in sentinel limph node in breast cancer

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