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image of Dermal Melanocytes Detectability for Distinguishing In Situ and Early Invasive Melanoma: A Narrative Review

Abstract

The melanoma incidence has been increasing over the past three decades, with a disproportionately high fraction of tumors. The diagnosis of melanoma at its earliest stages can be challenging. The detectability of tumor melanocytes in the dermis is of key importance for distinguishing from invasive melanomas. In this review, a total of 475 melanomas diagnosed as tumors by hematoxylin and eosin staining were analyzed. This diagnosis was confirmed for 68% of cases, but 15% of melanomas were reassessed as invasive lesions using immunohistochemistry. The cases were upstaged by Melan-A/Mart-1, S-100, and SOX-10 with frequencies of 14.6%, 11.7%, and 10.8%, respectively. Whereas, the diagnosis of melanoma was confirmed by SOX-10, Melan-A/Mart-1, and S-100 in 81.4%, 63.8%, and 59.1% of cases, respectively. Moreover, the analysis of immunohistochemical detectability of melanocyte markers in different types of dermal cells was carried out for 574 various skin lesions. The stainings of S-100, SOX-10, MITF, and PRAME in fibroblasts and histiocytes, as well as Melan-A/Mart-1, HMB-45, and MITF in melanophages, were noted. The diagnosis of melanoma based on hematoxylin and eosin staining is confirmed by immunohistochemistry in most cases. However, some tumors become reassessed as invasive malignancies. Although none of the currently used melanocyte markers is absolutely specific, simultaneous analysis of nuclear SOX-10 and cytoplasmic Melan-A/Mart-1 stainings can support the diagnosis. However, immunohistochemistry remains an auxiliary tool, and the results should be analyzed in association with the cytomorphological features.

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2025-02-18
2025-04-01

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References

  1. Ackerman A.B. Cerroni L. Kerl H. Pitfalls in Histopathologic Diagnosis of Malignant Melanoma. Malvern, Pennsylvania, USA Lea & Febiger 1994
    [Google Scholar]
  2. Higgins H.W. II Lee K.C. Galan A. Leffell D.J. Melanoma in situ: Part I. Epidemiology, screening, and clinical features. J. Am. Acad. Dermatol. 2015 73 2 181 190 10.1016/j.jaad.2015.04.014 26183967
    [Google Scholar]
  3. Higgins H.W. II Lee K.C. Galan A. Leffell D.J. Melanoma in situ: Part II. Histopathology, treatment, and clinical management. J. Am. Acad. Dermatol. 2015 73 2 193 203 10.1016/j.jaad.2015.03.057 26183968
    [Google Scholar]
  4. Saida T. Histogenesis of cutaneous malignant melanoma: The vast majority do not develop from melanocytic nevus but arise de novo as melanoma in situ. J. Dermatol. 2019 46 2 80 94 10.1111/1346‑8138.14737 30632197
    [Google Scholar]
  5. Dainese-Marque O. Garcia V. Andrieu-Abadie N. Riond J. Contribution of Keratinocytes in skin cancer initiation and progression. Int. J. Mol. Sci. 2024 25 16 8813 10.3390/ijms25168813 39201498
    [Google Scholar]
  6. Green K.J. Pokorny J. Jarrell B. Dangerous liaisons: Loss of keratinocyte control over melanocytes in melanomagenesis. BioEssays 2024 46 11 2400135 10.1002/bies.202400135 39233509
    [Google Scholar]
  7. Barnhill R.L. Busam K.J. Pathology of Melanocytic Nevi and Malignant Melanoma. Newton, Massachusetts, USA Butterworth-Heinemann 1995
    [Google Scholar]
  8. Lee J.A.H. The systematic relationship between melanomas diagnosed in situ and when invasive. Melanoma Res. 2001 11 5 523 529 10.1097/00008390‑200110000‑00013 11595891
    [Google Scholar]
  9. Olsen C.M. Pandeya N. Rosenberg P.S. Whiteman D.C. Incidence of in situ vs invasive melanoma: Testing the “obligate precursor” hypothesis. J. Natl. Cancer Inst. 2022 114 10 1364 1370 10.1093/jnci/djac138 36042554
    [Google Scholar]
  10. Sacchetto L. Zanetti R. Comber H. Bouchardy C. Brewster D.H. Broganelli P. Chirlaque M.D. Coza D. Galceran J. Gavin A. Hackl M. Katalinic A. Larønningen S. Louwman M.W.J. Morgan E. Robsahm T.E. Sanchez M.J. Tryggvadóttir L. Tumino R. Van Eycken E. Vernon S. Zadnik V. Rosso S. Trends in incidence of thick, thin and in situ melanoma in Europe. Eur. J. Cancer 2018 92 108 118 10.1016/j.ejca.2017.12.024 29395684
    [Google Scholar]
  11. Rimal R. Robsahm T.E. Green A.C. Ghiasvand R. Rueegg C.S. Bassarova A. Gjersvik P. Weiderpass E. Aalen O.O. Møller B. Perrier F. Veierød M.B. Trends in invasive melanoma thickness in Norway, 1983–2019. Acta Derm. Venereol. 2024 104 adv26110 10.2340/actadv.v104.26110 39221835
    [Google Scholar]
  12. Scalvenzi M. Megna M. Costa C. Fabbrocini G. Villani A. Greco V. Cutaneous melanoma associated with naevi prevalence: A 15-year cross-sectional retrospective study. Australas. J. Dermatol. 2020 61 1 39 42 10.1111/ajd.13171 31603538
    [Google Scholar]
  13. Gershenwald J.E. Scolyer R.A. Hess K.R. Sondak V.K. Long G.V. Ross M.I. Lazar A.J. Faries M.B. Kirkwood J.M. McArthur G.A. Haydu L.E. Eggermont A.M.M. Flaherty K.T. Balch C.M. Thompson J.F. Melanoma staging: Evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA. Cancer J. Clin. 2017 67 6 472 492
    [Google Scholar]
  14. Quintanilla-Dieck M.J. Bichakjian C.K. Management of early-stage melanoma. Facial Plast. Surg. Clin. North Am. 2019 27 1 35 42 10.1016/j.fsc.2018.08.003 30420071
    [Google Scholar]
  15. Tas F. Metastatic behavior in melanoma: Timing, pattern, survival, and influencing factors. J. Oncol. 2012 2012 1 9 10.1155/2012/647684 22792102
    [Google Scholar]
  16. Garbe C. Peris K. Hauschild A. Saiag P. Middleton M. Bastholt L. Grob J.J. Malvehy J. Newton-Bishop J. Stratigos A.J. Pehamberger H. Eggermont A.M. European Dermatology Forum (EDF) European Association of Dermato-Oncology (EADO) European Organisation for Research and Treatment of Cancer (EORTC) Diagnosis and treatment of melanoma. European consensus-based interdisciplinary guideline – Update 2016. Eur. J. Cancer 2016 63 201 217 10.1016/j.ejca.2016.05.005 27367293
    [Google Scholar]
  17. Santillan A.A. Messina J.L. Marzban S.S. Crespo G. Sondak V.K. Zager J.S. Pathology review of thin melanoma and melanoma in situ in a multidisciplinary melanoma clinic: impact on treatment decisions. J. Clin. Oncol. 2010 28 3 481 486 10.1200/JCO.2009.24.7734 20008627
    [Google Scholar]
  18. Patrawala S. Maley A. Greskovich C. Stuart L. Parker D. Swerlick R. Stoff B. Discordance of histopathologic parameters in cutaneous melanoma: Clinical implications. J. Am. Acad. Dermatol. 2016 74 1 75 80 10.1016/j.jaad.2015.09.008 26514601
    [Google Scholar]
  19. Eriksson H. Frohm-Nilsson M. Hedblad M. Hellborg H. Kanter-Lewensohn L. Krawiec K. Rozell B. Månsson-Brahme E. Hansson J. Interobserver variability of histopathological prognostic parameters in cutaneous malignant melanoma: Impact on patient management. Acta Derm. Venereol. 2013 93 4 411 416 10.2340/00015555‑1517 23306667
    [Google Scholar]
  20. Niebling M.G. Haydu L.E. Karim R.Z. Thompson J.F. Scolyer R.A. Pathology review significantly affects diagnosis and treatment of melanoma patients: An analysis of 5011 patients treated at a melanoma treatment center. Ann. Surg. Oncol. 2014 21 7 2245 2251 10.1245/s10434‑014‑3682‑x 24748128
    [Google Scholar]
  21. Elmore J.G. Barnhill R.L. Elder D.E. Longton G.M. Pepe M.S. Reisch L.M. Carney P.A. Titus L.J. Nelson H.D. Onega T. Tosteson A.N.A. Weinstock M.A. Knezevich S.R. Piepkorn M.W. Pathologists’ diagnosis of invasive melanoma and melanocytic proliferations: Observer accuracy and reproducibility study. BMJ 2017 357 j2813 10.1136/bmj.j2813 28659278
    [Google Scholar]
  22. Piepkorn M.W. Longton G.M. Reisch L.M. Elder D.E. Pepe M.S. Kerr K.F. Tosteson A.N.A. Nelson H.D. Knezevich S. Radick A. Shucard H. Onega T. Carney P.A. Elmore J.G. Barnhill R.L. Assessment of second-opinion strategies for diagnoses of cutaneous melanocytic lesions. JAMA Netw. Open 2019 2 10 e1912597 10.1001/jamanetworkopen.2019.12597 31603483
    [Google Scholar]
  23. Geller B.M. Frederick P.D. Knezevich S.R. Lott J.P. Nelson H.D. Titus L.J. Carney P.A. Tosteson A.N.A. Onega T.L. Barnhill R.L. Weinstock M.A. Elder D.E. Piepkorn M.W. Elmore J.G. Pathologists’ use of second opinions in interpretation of melanocytic cutaneous lesions: Policies, practices, and perceptions. Dermatol. Surg. 2018 44 2 177 185 10.1097/DSS.0000000000001256 28858936
    [Google Scholar]
  24. Bax M.J. Johnson T.M. Harms P.W. Schwartz J.L. Zhao L. Fullen D.R. Chan M.P. Detection of occult invasion in melanoma in situ. JAMA Dermatol. 2016 152 11 1201 1208 10.1001/jamadermatol.2016.2668 27533878
    [Google Scholar]
  25. Drabeni M. Lopez-Vilaró L. Barranco C. Trevisan G. Gallardo F. Pujol R.M. Differences in tumor thickness between hematoxylin and eosin and Melan-A immunohistochemically stained primary cutaneous melanomas. Am. J. Dermatopathol. 2013 35 1 56 63 10.1097/DAD.0b013e31825ba933 22688397
    [Google Scholar]
  26. Penneys N.S. Microinvasive lentigo maligna melanoma. J. Am. Acad. Dermatol. 1987 17 4 675 680 10.1016/S0190‑9622(87)70254‑0 3312317
    [Google Scholar]
  27. Suchak R. Hameed O.A. Robson A. Evaluation of the role of routine melan-A immunohistochemistry for exclusion of microinvasion in 120 cases of lentigo maligna. Am. J. Dermatopathol. 2014 36 5 387 391 10.1097/DAD.0b013e3182a3877a 24394300
    [Google Scholar]
  28. Parra-Medina R. Morales S.D. Diagnostic utility of epithelial and melanocitic markers with double sequential immunohistochemical staining in differentiating melanoma in situ from invasive melanoma. Ann. Diagn. Pathol. 2017 26 70 74 10.1016/j.anndiagpath.2016.07.010 27594302
    [Google Scholar]
  29. Dyson S.W. Bass J. Pomeranz J. Jaworsky C. Sigel J. Somach S. Impact of thorough block sampling in the histologic evaluation of melanomas. Arch. Dermatol. 2005 141 6 734 736 10.1001/archderm.141.6.734 15967919
    [Google Scholar]
  30. Stuart L.N. Rodriguez A.S. Gardner J.M. Foster T.E. MacKelfresh J. Parker D.C. Chen S.C. Stoff B.K. Utility of additional tissue sections in dermatopathology: Diagnostic, clinical and financial implications. J. Cutan. Pathol. 2014 41 2 81 87 10.1111/cup.12267 24251693
    [Google Scholar]
  31. Megahed M. Schön M. Selimovic D. Schön M.P. Reliability of diagnosis of melanoma in situ. Lancet 2002 359 9321 1921 1922 10.1016/S0140‑6736(02)08741‑X 12057558
    [Google Scholar]
  32. Danga M.E. Yaar R. Bhawan J. Melan-A positive dermal cells in malignant melanoma in situ. J. Cutan. Pathol. 2015 42 6 388 393 10.1111/cup.12473 25726939
    [Google Scholar]
  33. Pop A.M. Monea M. Olah P. Moraru R. Cotoi O.S. The importance of immunohistochemistry in the evaluation of tumor depth of primary cutaneous melanoma. Diagnostics 2023 13 6 1020 10.3390/diagnostics13061020 36980327
    [Google Scholar]
  34. Rodic N. Glusac E.J. Detection of occult invasion in melanoma in situ. JAMA Dermatol. 2017 153 6 611 10.1001/jamadermatol.2017.0196 28384663
    [Google Scholar]
  35. Kuźbicki Ł. Brożyna A.A. The detectability of intraepidermal melanocytes—A narrative review of immunohistochemical studies. J. Cutan. Pathol. 2022 49 12 1074 1089 10.1111/cup.14295 35851493
    [Google Scholar]
  36. Robson A. Allen P. Hollowood K. S100 expression in cutaneous scars: A potential diagnostic pitfall in the diagnosis of desmoplastic melanoma. Histopathology 2001 38 2 135 140 10.1046/j.1365‑2559.2001.01066.x 11207826
    [Google Scholar]
  37. Trejo O. Reed J.A. Prieto V.G. Atypical cells in human cutaneous re-excision scars for melanoma express p75NGFR, C56/N-CAM and GAP-43: evidence of early Schwann cell differentiation. J. Cutan. Pathol. 2002 29 7 397 406 10.1034/j.1600‑0560.2002.290703.x 12139634
    [Google Scholar]
  38. Ramos-Herberth F.I. Karamchandani J. Kim J. Dadras S.S. SOX10 immunostaining distinguishes desmoplastic melanoma from excision scar. J. Cutan. Pathol. 2010 37 9 944 952 10.1111/j.1600‑0560.2010.01568.x 20653825
    [Google Scholar]
  39. Chorny J.A. Barr R.J. S100-positive spindle cells in scars: A diagnostic pitfall in the re-excision of desmoplastic melanoma. Am. J. Dermatopathol. 2002 24 4 309 312 10.1097/00000372‑200208000‑00004 12142609
    [Google Scholar]
  40. Behrens E.L. Boothe W. D’Silva N. Walterscheid B. Watkins P. Tarbox M. SOX-10 staining in dermal scars. J. Cutan. Pathol. 2019 46 8 579 585 10.1111/cup.13468 30950082
    [Google Scholar]
  41. Donaldson M.R. Weber L.A. SOX10 commonly stains scar in Mohs sections. Dermatol. Online J. 2020 26 1 15 10.5070/D3261047196 32155034
    [Google Scholar]
  42. Tan C.L. Maheshwari P. Choo S.N. Chan Y.H. Ng S.B. Expression of melanocytic markers in melanophages across platforms: A potential diagnostic pitfall. Histopathology 2017 70 3 501 504 10.1111/his.13075 27598989
    [Google Scholar]
  43. Audrey-Bayan C. Trager M.H. Gartrell-Corrado R.D. Rizk E.M. Pradhan J. Silverman A.M. Lopez A. Marks D.K. Niedt G. Geskin L.J. Saenger Y.M. Distinguishing melanophages from tumor in melanoma patients treated with talimogene laherparepvec. Melanoma Res. 2020 30 4 410 415 10.1097/CMR.0000000000000661 32379409
    [Google Scholar]
  44. Harvey N.T. Acott N.J. Wood B.A. Sox10-positive cells within scars: A potential diagnostic pitfall. Am. J. Dermatopathol. 2017 39 10 791 793 10.1097/DAD.0000000000000756 27759704
    [Google Scholar]
  45. Febres-Aldana C.A. Alexis J. Normal expression of SRY-related HMG-BOX gene 10 (SOX-10) in recent and old cutaneous scars is a potential mimicker of desmoplastic malignant melanoma. Appl. Immunohistochem. Mol. Morphol. 2020 28 3 197 204 10.1097/PAI.0000000000000729 30672775
    [Google Scholar]
  46. Christensen K.N. Hochwalt P.C. Hocker T.L. Roenigk R.K. Brewer J.D. Baum C.L. Otley C.C. Arpey C.J. Comparison of MITF and melan-a immunohistochemistry during mohs surgery for lentigo maligna-type melanoma in situ and lentigo maligna melanoma. Dermatol. Surg. 2016 42 2 167 175 10.1097/DSS.0000000000000600 26771682
    [Google Scholar]
  47. Andres C. Flaig M.J. Pitfalls of Melan-A staining. J. Cutan. Pathol. 2010 37 8 917 918 10.1111/j.1600‑0560.2009.01442.x 19804418
    [Google Scholar]
  48. Hendi A. Brodland D.G. Zitelli J.A. Melanocytes in long-standing sun-exposed skin: Quantitative analysis using the MART-1 immunostain. Arch. Dermatol. 2006 142 7 871 876 10.1001/archderm.142.7.871 16847203
    [Google Scholar]
  49. Plotzke J.M. Zoumberos N.A. Hrycaj S.M. Harms P.W. Bresler S.C. Chan M.P. PRAME expression is similar in scar and desmoplastic melanoma. J. Cutan. Pathol. 2022 49 9 829 832 10.1111/cup.14286 35752877
    [Google Scholar]
  50. Fujimoto M. Jinnouchi K. Kaku Y. Hirata M. Nishitsuji K. Haga H. Investigation of PRAME expression in lipid-laden and non-lipid-laden cutaneous histiocytes. J. Cutan. Pathol. 2022 49 12 1011 1014 10.1111/cup.14334 36149230
    [Google Scholar]
  51. Wakefield C. Heffron C.C.B.B. PRAME immunoexpression in benign fibroblasts - A diagnostic pitfall. Histopathology 2022 80 6 1011 1013 10.1111/his.14615 35103337
    [Google Scholar]
  52. Rawson R.V. Shteinman E.R. Ansar S. Vergara I.A. Thompson J.F. Long G.V. Scolyer R.A. Wilmott J.S. Diagnostic utility of PRAME, p53 and 5-hmC immunostaining for distinguishing melanomas from naevi, neurofibromas, scars and other histological mimics. Pathology 2022 54 7 863 873 10.1016/j.pathol.2022.05.012 35987723
    [Google Scholar]
  53. Fritschy J.M. Is my antibody-staining specific? How to deal with pitfalls of immunohistochemistry. Eur. J. Neurosci. 2008 28 12 2365 2370 10.1111/j.1460‑9568.2008.06552.x 19087167
    [Google Scholar]
  54. Gown A.M. Diagnostic immunohistochemistry: What can go wrong and how to prevent it. Arch. Pathol. Lab. Med. 2016 140 9 893 898 10.5858/arpa.2016‑0119‑RA 27575264
    [Google Scholar]
  55. Kużbicki Ł. Lange D. Chwirot B.W. Cyclooxygenase-2 immunohistochemistry in human melanoma: Differences between results obtained with different antibodies. Melanoma Res. 2009 19 5 294 300 10.1097/CMR.0b013e32832e0bde 19543125
    [Google Scholar]
  56. Kuźbicki Ł. Urban J. Chwirot B.W. Different detectability of cyclooxygenase-2 (COX-2) protein in standard paraffin sections and tissue microarrays of human melanomas and naevi – Comparative study. Pathol. Res. Pract. 2014 210 9 591 595 10.1016/j.prp.2014.04.014 24878108
    [Google Scholar]
  57. Matoso A. Singh K. Jacob R. Greaves W.O. Tavares R. Noble L. Resnick M.B. DeLellis R.A. Wang L.J. Comparison of thyroid transcription factor-1 expression by 2 monoclonal antibodies in pulmonary and nonpulmonary primary tumors. Appl. Immunohistochem. Mol. Morphol. 2010 18 2 142 149 10.1097/PAI.0b013e3181bdf4e7 19887917
    [Google Scholar]
  58. Sawicka M. Pawlikowski J. Wilson S. Ferdinando D. Wu H. Adams P.D. Gunn D.A. Parish W. The specificity and patterns of staining in human cells and tissues of p16INK4a antibodies demonstrate variant antigen binding. PLoS One 2013 8 1 e53313 10.1371/journal.pone.0053313 23308192
    [Google Scholar]
  59. Borrisholt M. Nielsen S. Vyberg M. Demonstration of CDX2 is highly antibody dependant. Appl. Immunohistochem. Mol. Morphol. 2013 21 1 64 72 10.1097/PAI.0b013e318257f8aa 22595949
    [Google Scholar]
  60. Røge R. Nielsen S. Vyberg M. Carb-3 is the superior anti-CD15 monoclonal antibody for immunohistochemistry. Appl. Immunohistochem. Mol. Morphol. 2014 22 6 449 458 10.1097/PAI.0b013e318292b764 23846425
    [Google Scholar]
  61. Toriyama A. Mori T. Sekine S. Yoshida A. Hino O. Tsuta K. Utility of PAX 8 mouse monoclonal antibody in the diagnosis of thyroid, thymic, pleural and lung tumours: A comparison with polyclonal PAX 8 antibody. Histopathology 2014 65 4 465 472 10.1111/his.12405 24592933
    [Google Scholar]
  62. Singh K. Hanley L.C. Sung C.J. Quddus M.R. Comparison of PAX8 expression in breast carcinoma using MRQ50 and BC12 monoclonal antibodies. Appl. Immunohistochem. Mol. Morphol. 2020 28 7 558 561 10.1097/PAI.0000000000000796 31335489
    [Google Scholar]
/content/journals/cmc/10.2174/0109298673339877250210105022
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Dermal Melanocytes Detectability for Distinguishing In Situ and Early Invasive Melanoma: A Narrative Review
Bentham Science Publishers ; https://doi.org/10.2174/0109298673339877250210105022
/content/journals/cmc/10.2174/0109298673339877250210105022
/content/journals/cmc/10.2174/0109298673339877250210105022
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  • Article Type:     Review Article
Keywords: early invasive melanoma ; melanocyte marker ; hematoxylin and eosin staining ; immunohistochemistry ; In situ melanoma ; diagnosis

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