Virchows Archiv

, Volume 443, Issue 6, pp 745–751 | Cite as

Immunostaining for the tumour suppressor gene p16 product is a useful marker to differentiate melanoma metastasis from lymph-node nevus

  • Daniela Mihic-Probst
  • Parvin Saremaslani
  • Paul Komminoth
  • Philipp U. Heitz
Original Article


Upon the introduction of extensive sampling protocols of sentinel node biopsies, pathologists are increasingly confronted with small melanoma metastases. Using conventional histology, it proves sometimes difficult or impossible to differentiate small melanoma metastases from lymph-node nevi. Loss of the tumour suppressor gene p16 has been shown to be associated with tumour progression of melanoma. We investigated nevus and melanoma cells for the presence of the product of the gene p16, using immunohistochemistry. All nevus cells, independent of their location (nodal or skin) displayed an extensive nuclear and cytoplasmic staining for p16. In contrast, all cells of melanoma metastases, except one skin metastasis, lacked nuclear staining for p16. These findings indicate that p16 is a reliable marker to distinguish lymph-node nevi from melanoma metastasis.


Nodal nevus Metastatic melanoma Sentinel lymph node Tumour suppressor gene p16 



We thank N. Wey for photographic and computer-assisted reproductions and Dr. W. Jochum, Department of Pathology, University Hospital Zürich, for critical reading of the manuscript.


  1. 1.
    Andreola S, Clemente C (1985) Nevus cells in axillary lymphnodes from radical mastectomy specimens. Pathol Res Pract 179:616–618PubMedGoogle Scholar
  2. 2.
    Carson KF, Wen DR, Li PX, Lana AM, Bailly C, Morton DL, Cochran AJ (1996) Nodal nevi and cutaneous melanomas. Am J Surg Pathol 20:834–840CrossRefPubMedGoogle Scholar
  3. 3.
    Castellano M, Pollock PM, Walters MK, Sparrow LE, Down LM, Gabrielle BG, Parson PG, Hayward NK (1997) CDKN2A/p16 is inactivated in most melanoma cell lines. Cancer Res 57:4868–4875Google Scholar
  4. 4.
    de Vries TJ, Smeets M, de Graaf R, Hou-Jensen K, Brocker EB, Renar N, Eggermont AM, van Muijen GN, Ruiter D (2001) Expression of gp100, MART-1, tyrosinase, and S100 in paraffin-embedded primary melanomas and locoregional, lymph node, and visceral metastases: implications for diagnosis and immunotherapy. A study conducted by the EORTC Melanoma Cooperative Group. J Pathol 193:13–20CrossRefPubMedGoogle Scholar
  5. 5.
    Fisher CJ, Hill S, Millis RR (1994) Benign lymph node inclusions mimicking metastatic carcinoma. J Clin Pathol 47:245–247PubMedGoogle Scholar
  6. 6.
    Fontaine D, Parkhill W, Greer W, Walsh N (2002) Nevus cells in lymph nodes: an association with congenital cutaneous nevi. Am J Dermatopathol 24:1–5CrossRefPubMedGoogle Scholar
  7. 7.
    Fujimoto A, Morita R, Hatta N, Takehara K, Takata M (1999) p16INK4a inactivation is not frequent in uncultured sporadic primary cutaneous melanoma. Oncogene 18:2527–2532CrossRefPubMedGoogle Scholar
  8. 8.
    Funk JO, Schiller PI, Barret MT, Wong DJ, Kind P, Sander CA (1998) p16INK4a expression is frequently decreased and associated with 9p21 loss of heterozygosity in sporadic melanoma. J Cutan Pathol 25:291–296PubMedGoogle Scholar
  9. 9.
    Hilton DA, Penney M, Evans B, Sanders H, Love S (2002) Evaluation of molecular markers in low-grade diffuse astrocytomas: loss of p16 and retinoblastoma protein expression is associated with short survival. Am J Surg Pathol 26:472–478CrossRefPubMedGoogle Scholar
  10. 10.
    Kamb A, Grius NA, Weaver-Feldhaus J, Liu Q, Harshman K, Tavtigian SV, Stockert E, Day RS 3rd, Johnson BE, Skolnick MH (1994) A cell cycle regulator potentially involved in genesis of many tumor types. Science 264:436–440PubMedGoogle Scholar
  11. 11.
    Kossard S, Wilkinson B (1997) Small cell (naevoid) melanoma: a clinicopathologic study of 131 cases. Australas J Dermatol 38[Suppl 1]:S54–S58Google Scholar
  12. 12.
    Lambert WC, Brodkin RH (1984) Nodal and subcutaneous cellular blue nevi. A pseudometastasizing pseudomelanoma. Arch Dermatol 120:367–370CrossRefPubMedGoogle Scholar
  13. 13.
    Lohmann CM, Iversen K, Jungbluth AA, Berwick M, Busam KJ (2002) Expression of melanocyte differentiation antigens and ki-67 in nodal nevi and comparison of ki-67 expression with metastatic melanoma. Am J Surg Pathol 26:1351–1357CrossRefPubMedGoogle Scholar
  14. 14.
    McCarthy SW, Palmer AA, Bale PM, Hirst E (1974) Naevus cells in lymph nodes. Pathology 6:351–358PubMedGoogle Scholar
  15. 15.
    Nobori T, Miura K, Wu DJ, Lois A, Takabayashi K, Carson DA (1994) Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature 368:753–756PubMedGoogle Scholar
  16. 16.
    Reed JA, Loganzo F Jr, Shea CR, Waker GJ, Flores FJ, Glendening JM, Bogdany JK, Shiel MJ, Haluska FG, Fountain JW (1995) Loss of expression of the p16/cyclin-dependent kinase inhibitor 2 tumor suppressor gene in melanocytic lesions correlates with invasive stage of tumor progression. Cancer Res 55:2713–2718PubMedGoogle Scholar
  17. 17.
    Ridolfi RL, Rosen PP, Thaler H (1977) Nevus cell aggregates associated with lymph nodes: estimated frequency and clinical significance. Cancer 39:164–171PubMedGoogle Scholar
  18. 18.
    Serrano M, Hannon GJ, Beach D (1993) A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 366:704–707PubMedGoogle Scholar
  19. 19.
    Sterchi JM, Muss HB, Weidner N (1987) Cellular blue nevus simulating metastatic melanoma: report of an unusually large lesion associated with nevus-cell aggregates in regional lymph nodes. J Surg Oncol 36:71–75PubMedGoogle Scholar
  20. 20.
    Subramony C, Lewin JR (1985) Nevus cells within lymph nodes. Possible metastases from a benign intradermal nevus. Am J Clin Pathol 84:220–223PubMedGoogle Scholar
  21. 21.
    Zembowicz A, McCusker M, Chiarelli C, Dei Tos AP, Granter SR, Calonje E, McKee PH (2001) Morphological analysis of nevoid melanoma: a study of 20 cases with a review of the literature. Am J Dermatopathol 23:167–175CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Daniela Mihic-Probst
    • 1
    • 3
  • Parvin Saremaslani
    • 1
  • Paul Komminoth
    • 2
  • Philipp U. Heitz
    • 1
  1. 1.Department of PathologyUniversity HospitalZürich
  2. 2.Institute of PathologyCantonal HospitalBadenSwitzerland
  3. 3.Department of PathologyUniversity HospitalZürichSwitzerland

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