Annals of Surgical Oncology

, Volume 19, Issue 4, pp 1089–1099 | Cite as

Sentinel Lymph Nodes Containing Very Small (<0.1 mm) Deposits of Metastatic Melanoma Cannot Be Safely Regarded as Tumor-Negative

  • Rajmohan Murali
  • Chitra DeSilva
  • Stanley W. McCarthy
  • John F. Thompson
  • Richard A. Scolyer
Melanomas

Abstract

Background

Some authors have suggested that patients with very small (<0.1 mm) deposits of metastatic melanoma in sentinel lymph nodes (SLNs) should be considered SLN-negative, whereas others have reported that such patients can have adverse long-term outcomes. The aims of the present study were to determine whether extensive sectioning of SLNs resulted in more accurate categorization of histologic features of tumor deposits and to assess prognostic associations of histologic parameters obtained using more intensive sectioning protocols.

Methods

From patients with a single primary cutaneous melanoma who underwent SLN biopsy between 1991 and 2008, those in which the maximum size of the largest tumor deposit (MaxSize) in SLNs was <0.1 mm in the original sections were identified. Five batches of additional sections were cut from the SLN tissue blocks at intervals of 250 μm. The 1st batch was cut from the blocks without any trimming; these sections were therefore immediately adjacent to the original sections. Each batch included 5 sequential sections, the 1st and 5th stained with hematoxylin-eosin, and the 2nd, 3rd, and 4th stained immunohistochemically with S-100, HMB-45, and Melan-A, respectively. In each batch of sections, the following histologic features of tumor deposit(s) in the SLNs were evaluated: MaxSize; tumor penetrative depth (TPD) (defined as the maximum depth of tumor deposit(s) from the inner margin of the lymph node capsule), and intranodal location (classified as subcapsular if the tumor deposit(s) were confined to the subcapsular zone or parenchymal if there was any involvement of the nodal parenchyma beyond the subcapsular zone). The measured histologic parameters were compared in each batch of sections. The association of histologic parameters with overall survival was assessed for the parameters measured in each batch of sections.

Results

There were 20 eligible patients (15 females, 5 males, median age 60 years). After a median follow-up duration of 40 months, 4 patients had died from melanoma and 2 patients of unknown causes. Completion lymph node dissection (CLND) was performed in 13 cases (65%) and was negative in all cases. Relative to the measured values on the original sections, all 3 parameters were upstaged in subsequent batches of sections, but no further upstaging of MaxSize, TPD, or location was seen beyond batch 3, batch 4, and batch 2, respectively. Increasing MaxSize was associated with significantly poorer overall survival in batches 1, 2, and 3. Parenchymal involvement was significantly associated with poorer survival in batches 2–5. TPD was not significantly associated with overall survival.

Conclusions

The results of this study indicate that very small (<0.1 mm) deposits of melanoma in SLNs may be associated with adverse clinical outcomes and that this is due, at least in part, to the underestimation of SLN tumor burden in the initial sections. Our evidence does not support clinical decision-making on the assumption that patients with very small melanoma deposits in SLNs have the same outcome as those who are SLN-negative.

Notes

Acknowledgment

We acknowledge the support of the Cancer Institute New South Wales, the Australian National Health and Medical Research Council, and colleagues at Melanoma Institute Australia and the Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital.

Disclosure

Professor Scolyer is a Cancer Institute New South Wales ClinicalResearch Fellow

References

  1. 1.
    Reeves ME, Delgado R, Busam KJ, Brady MS, Coit DG. Prediction of nonsentinel lymph node status in melanoma. Ann Surg Oncol. 2003;10:27–31.PubMedCrossRefGoogle Scholar
  2. 2.
    Lee JH, Essner R, Torisu-Itakura H, Wanek L, Wang H, Morton DL. Factors predictive of tumor-positive nonsentinel lymph nodes after tumor-positive sentinel lymph node dissection for melanoma. J Clin Oncol. 2004;22:3677–84.PubMedCrossRefGoogle Scholar
  3. 3.
    Scolyer RA, Li LX, McCarthy SW, Shaw HM, Stretch JR, Sharma R, et al. Micromorphometric features of positive sentinel lymph nodes predict involvement of nonsentinel nodes in patients with melanoma. Am J Clin Pathol. 2004;122:532–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Vuylsteke RJ, Borgstein PJ, van Leeuwen PA, Gietema HA, Molenkamp BG, Statius Muller MG, et al. Sentinel lymph node tumor load: an independent predictor of additional lymph node involvement and survival in melanoma. Ann Surg Oncol. 2005;12:440–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Pearlman NW, McCarter MD, Frank M, Hurtubis C, Merkow RP, Franklin WA, et al. Size of sentinel node metastases predicts other nodal disease and survival in malignant melanoma. Am J Surg. 2006;192:878–81.PubMedCrossRefGoogle Scholar
  6. 6.
    Debarbieux S, Duru G, Dalle S, Béatrix O, Balme B, Thomas L. Sentinel lymph node biopsy in melanoma: a micromorphometric study relating to prognosis and completion lymph node dissection. Br J Dermatol. 2007;157:58–67.PubMedCrossRefGoogle Scholar
  7. 7.
    Govindarajan A, Ghazarian DM, McCready DR, Leong WL. Histological features of melanoma sentinel lymph node metastases associated with status of the completion lymphadenectomy and rate of subsequent relapse. Ann Surg Oncol. 2007;14:906–12.PubMedCrossRefGoogle Scholar
  8. 8.
    Scheri RP, Essner R, Turner RR, Ye X, Morton DL. Isolated Tumor cells in the sentinel node affect long-term prognosis of patients with melanoma. Ann Surg Oncol. 2007;14:2861–6.PubMedCrossRefGoogle Scholar
  9. 9.
    Gershenwald JE, Andtbacka RH, Prieto VG, Johnson MM, Diwan AH, Lee JE, et al. Microscopic tumor burden in sentinel lymph nodes predicts synchronous nonsentinel lymph node involvement in patients with melanoma. J Clin Oncol. 2008;26:4296–303.PubMedCrossRefGoogle Scholar
  10. 10.
    Rossi CR, De Salvo GL, Bonandini E, Mocellin S, Foletto M, Pasquali S, et al. Factors predictive of nonsentinel lymph node involvement and clinical outcome in melanoma patients with metastatic sentinel lymph node. Ann Surg Oncol. 2008;15:1202–10.PubMedCrossRefGoogle Scholar
  11. 11.
    Satzger I, Volker B, Meier A, Kapp A, Gutzmer R. Criteria in sentinel lymph nodes of melanoma patients that predict involvement of nonsentinel lymph nodes. Ann Surg Oncol. 2008;15:1723–32.PubMedCrossRefGoogle Scholar
  12. 12.
    van Akkooi AC, Nowecki ZI, Voit C, Schäfer-Hesterberg G, Michej W, de Wilt JH, et al. Sentinel node tumor burden according to the Rotterdam criteria is the most important prognostic factor for survival in melanoma patients: a multicenter study in 388 patients with positive sentinel nodes. Ann Surg. 2008;248:949–55.PubMedCrossRefGoogle Scholar
  13. 13.
    Francischetto T, Spector N, Neto Rezende JF, de Azevedo Antunes M, de Oliveira Romano S, Small IA, et al. Influence of sentinel lymph node tumor burden on survival in melanoma. Ann Surg Oncol. 2010;17:1152–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Starz H, Balda BR, Kramer KU, Büchels H, Wang H. A micromorphometry-based concept for routine classification of sentinel lymph node metastases and its clinical relevance for patients with melanoma. Cancer. 2001;91:2110–21.PubMedCrossRefGoogle Scholar
  15. 15.
    Starz H, Siedlecki K, Balda BR. Sentinel lymphonodectomy and s-classification: a successful strategy for better prediction and improvement of outcome of melanoma. Ann Surg Oncol. 2004;11:162S–8S.PubMedGoogle Scholar
  16. 16.
    Fink AM, Weihsengruber F, Spangl B, Feichtinger H, Lilgenau N, Rappersberger K, et al. S-classification of sentinel lymph node biopsy predicts the results of complete regional lymph node dissection. Melanoma Res. 2005;15:267–71.PubMedCrossRefGoogle Scholar
  17. 17.
    van der Ploeg IM, Nieweg OE, Valdes Olmos RA, et al. Is completion lymph node dissection needed in case of minimal melanoma metastasis in the sentinel node? Ann Surg Oncol 2008;15(Suppl 1):17.Google Scholar
  18. 18.
    van der Ploeg IM, Kroon BB, Antonini N, Valdés Olmos RA, Nieweg OE. Comparison of three micromorphometric pathology classifications of melanoma metastases in the sentinel node. Ann Surg. 2009;250:301–4.PubMedCrossRefGoogle Scholar
  19. 19.
    Franco R, Cantile M, Scala S, Catalano E, Cerrone M, Scognamiglio G, et al. Histomorphologic parameters and CXCR4 mRNA and protein expression in sentinel node melanoma metastasis are correlated to clinical outcome. Cancer Biol Ther. 2010;9:423–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Younan R, Bougrine A, Watters K, Mahboubi A, Bouchereau-Eyeque M, Loutfi A, et al. Validation study of the S classification for melanoma patients with positive sentinel nodes: the Montreal experience. Ann Surg Oncol. 2010;14:1414–21.CrossRefGoogle Scholar
  21. 21.
    Dewar DJ, Newell B, Green MA, Topping AP, Powell BW, Cook MG. The microanatomic location of metastatic melanoma in sentinel lymph nodes predicts nonsentinel lymph node involvement. J Clin Oncol. 2004;22:3345–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Cascinelli N, Bombardieri E, Bufalino R, Camerini T, Carbone A, Clemente C, et al. Sentinel and nonsentinel node status in stage IB and II melanoma patients: two-step prognostic indicators of survival. J Clin Oncol. 2006;24:4464–71.PubMedCrossRefGoogle Scholar
  23. 23.
    Wright EH, Stanley PR, Roy A. Evaluation of sentinel lymph nodes positive for melanoma for features predictive of non-sentinel nodal disease and patient prognosis: A 49 patient series. J Plast Reconstr Aesthet Surg. 2009;63:e500–2.PubMedCrossRefGoogle Scholar
  24. 24.
    Murali R, Desilva C, Thompson JF, Scolyer RA. Non-Sentinel Node Risk Score (N-SNORE): a scoring system for accurately stratifying risk of non-sentinel node positivity in patients with cutaneous melanoma with positive sentinel lymph nodes. J Clin Oncol. 2010;28:4441–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Flaherty KT, Hodi FS, Bastian BC. Mutation-driven drug development in melanoma. Curr Opin Oncol. 2010;22:178–83.PubMedCrossRefGoogle Scholar
  26. 26.
    Murali R, Thompson JF, Scolyer RA. Sentinel lymph node biopsy for melanoma: aspects of pathologic assessment. Future Oncol. 2008;4:535–51.PubMedCrossRefGoogle Scholar
  27. 27.
    Scolyer RA, Murali R, McCarthy SW, Thompson JF. Pathologic examination of sentinel lymph nodes from melanoma patients. Semin Diagn Pathol. 2008;25:100–11.PubMedCrossRefGoogle Scholar
  28. 28.
    Scolyer RA, Murali R, Satzger I, Thompson JF. The detection and significance of melanoma micrometastases in sentinel nodes. Surg Oncol. 2008;17:165–74.PubMedCrossRefGoogle Scholar
  29. 29.
    van Akkooi AC, de Wilt JH, Verhoef C, Schmitz PI, van Geel AN, Eggermont AM, et al. Clinical relevance of melanoma micrometastases (< 0.1 mm) in sentinel nodes: are these nodes to be considered negative? Ann Oncol. 2006;17:1578–85.PubMedCrossRefGoogle Scholar
  30. 30.
    Scolyer RA, Murali R, Gershenwald JE, Cochran AJ, Thompson JF. Clinical relevance of melanoma micrometastases in sentinel nodes: too early to tell. Ann Oncol. 2007;18:806–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Abrahamsen HN, Hamilton-Dutoit SJ, Larsen J, Steiniche T. Sentinel lymph nodes in malignant melanoma: extended histopathologic evaluation improves diagnostic precision. Cancer. 2004;100:1683–91.PubMedCrossRefGoogle Scholar
  32. 32.
    Gietema HA, Vuylsteke RJ, de Jonge IA, van Leeuwen PA, Molenkamp BG, van der Sijp JR, et al. Sentinel lymph node investigation in melanoma: detailed analysis of the yield from step sectioning and immunohistochemistry. J Clin Pathol. 2004;57:618–20.PubMedCrossRefGoogle Scholar
  33. 33.
    Riber-Hansen R, Sjoegren P, Hamilton-Dutoit SJ, Steiniche T. Extensive pathological analysis of selected melanoma sentinel lymph nodes: high metastasis detection rates at reduced workload. Ann Surg Oncol. 2008;15:1492–501.PubMedCrossRefGoogle Scholar
  34. 34.
    Spanknebel K, Coit DG, Bieligk SC, Gonen M, Rosai J, Klimstra DS. Characterization of micrometastatic disease in melanoma sentinel lymph nodes by enhanced pathology: recommendations for standardizing pathologic analysis. Am J Surg Pathol. 2005;29:305–17.PubMedCrossRefGoogle Scholar
  35. 35.
    Riber-Hansen R, Nyengaard JR, Hamilton-Dutoit SJ, Steiniche T. Stage migration after minor changes in histologic estimation of tumor burden in sentinel lymph nodes: the protocol trap. Cancer. 2009;115:2177–87.PubMedCrossRefGoogle Scholar
  36. 36.
    Carlson GW, Murray DR, Lyles RH, Staley CA, Hestley A, Cohen C. The amount of metastatic melanoma in a sentinel lymph node: does it have prognostic significance? Ann Surg Oncol. 2003;10:575–81.PubMedCrossRefGoogle Scholar
  37. 37.
    Cochran AJ, Wen DR, Huang RR, Wang HJ, Elashoff R, Morton DL. Prediction of metastatic melanoma in nonsentinel nodes and clinical outcome based on the primary melanoma and the sentinel node. Mod Pathol. 2004;17:747–55.PubMedCrossRefGoogle Scholar
  38. 38.
    Guggenheim M, Dummer R, Jung FJ, Mihic-Probst D, Steinert H, Rousson V, et al. The influence of sentinel lymph node tumour burden on additional lymph node involvement and disease-free survival in cutaneous melanoma–a retrospective analysis of 392 cases. Br J Cancer. 2008;98:1922–8.PubMedCrossRefGoogle Scholar
  39. 39.
    Murali R, Desilva C, Thompson JF, Scolyer RA. Factors predicting recurrence and survival in sentinel lymph node-positive melanoma patients. Ann Surg. 2011;253:1155–64.PubMedCrossRefGoogle Scholar
  40. 40.
    Satzger I, Volker B, Al Ghazal M, Meier A, Kapp A, Gutzmer R. Prognostic significance of histopathological parameters in sentinel nodes of melanoma patients. Histopathology. 2007;50:764–72.PubMedCrossRefGoogle Scholar
  41. 41.
    Satzger I, Volker B, Meier A, Schenck F, Kapp A, Gutzmer R. Prognostic significance of isolated HMB45 or Melan A positive cells in melanoma sentinel lymph nodes. Am J Surg Pathol. 2007;31:1175–80.PubMedCrossRefGoogle Scholar
  42. 42.
    Cook MG, Green MA, Anderson B, Eggermont AM, Ruiter DJ, Spatz A, et al. The development of optimal pathological assessment of sentinel lymph nodes for melanoma. J Pathol. 2003;200:314–9.PubMedCrossRefGoogle Scholar
  43. 43.
    Riber-Hansen R, Nyengaard JR, Hamilton-Dutoit SJ, Steiniche T. The nodal location of metastases in melanoma sentinel lymph nodes. Am J Surg Pathol. 2009;33:1522–8.PubMedCrossRefGoogle Scholar
  44. 44.
    Yee VS, Thompson JF, McKinnon JG, Scolyer RA, Li LX, McCarthy WH, et al. Outcome in 846 cutaneous melanoma patients from a single center after a negative sentinel node biopsy. Ann Surg Oncol. 2005;12:429–39.PubMedCrossRefGoogle Scholar
  45. 45.
    Li LX, Scolyer RA, Ka VS, McKinnon JG, Shaw HM, McCarthy SW, et al. Pathologic review of negative sentinel lymph nodes in melanoma patients with regional recurrence: a clinicopathologic study of 1152 patients undergoing sentinel lymph node biopsy. Am J Surg Pathol. 2003;27:1197–202.PubMedCrossRefGoogle Scholar
  46. 46.
    Karim RZ, Scolyer RA, Li W, Yee VS, McKinnon JG, Li LX, et al. False negative sentinel lymph node biopsies in melanoma may result from deficiencies in nuclear medicine, surgery, or pathology. Ann Surg. 2008;247:1003–10.PubMedCrossRefGoogle Scholar
  47. 47.
    Scolyer RA, Li LX, McCarthy SW, Shaw HM, Stretch JR, Sharma R, et al. Immunohistochemical stains fail to increase the detection rate of micrometastatic melanoma in completion regional lymph node dissection specimens. Melanoma Res. 2004;14:263–8.PubMedCrossRefGoogle Scholar

Copyright information

© Society of Surgical Oncology 2012

Authors and Affiliations

  • Rajmohan Murali
    • 1
    • 2
    • 3
    • 5
  • Chitra DeSilva
    • 2
  • Stanley W. McCarthy
    • 1
    • 2
    • 3
  • John F. Thompson
    • 2
    • 4
  • Richard A. Scolyer
    • 1
    • 2
    • 3
  1. 1.Tissue Pathology and Diagnostic OncologyRoyal Prince Alfred HospitalSydneyAustralia
  2. 2.Melanoma Institute AustraliaSydneyAustralia
  3. 3.Discipline of Pathology, Sydney Medical SchoolThe University of SydneySydneyAustralia
  4. 4.Discipline of Surgery, Sydney Medical SchoolThe University of SydneySydneyAustralia
  5. 5.Human Oncology and Pathogenesis Program and Department of PathologyMemorial Sloan-Kettering Cancer CenterNew YorkUSA

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