Use of immunohistochemistry in the diagnosis of melanocytic lesions: applications and pitfalls.

The accurate diagnosis of melanocytic lesions is essential for the adequate clinical management of the patients. Besides the histopathologic examination, immunohistochemical studies are often used as an adjunct in distinguishing melanocytic lesions from tumors with different origin or between benign and malignant melanocytic lesions. In the first part of this article, we analyze data on currently used immunohistochemical markers, with special emphasis on their applicability to clinical practice, and underline their potential pitfalls. The pathogenesis of malignant transformation of melanocytes is not completely understood. Recent studies report that various melanoma progression markers are preferentially expressed in benign or malignant melanocytic lesions or show different expression in subsequent stages of tumor development. Furthermore, in recent years, emerging genetic studies suggest that there are distinctive patterns of chromosomal aberrations in different subtypes of melanoma that can be altered by newly developed targeted therapies. In the second part of our article, we will discuss the most significant progression markers in melanoma that can be detected by immunohistochemistry and their potential usefulness for diagnosis, prognosis, staging or as therapeutic targets.

[1]  D. Dabbs,et al.  Diagnostic immunohistochemistry : theranostic and genomic applications , 2010 .

[2]  J. Gershenwald,et al.  Immunohistochemical detection of lymphovascular invasion with D2‐40 in melanoma correlates with sentinel lymph node status, metastasis and survival , 2009, Journal of cutaneous pathology.

[3]  S. Woodman,et al.  Correlation between KIT expression and KIT mutation in melanoma: a study of 173 cases with emphasis on the acral-lentiginous/mucosal type , 2009, Modern Pathology.

[4]  H. Kerl,et al.  Melan-a-positive "pseudomelanocytic nests": a pitfall in the histopathologic and immunohistochemical diagnosis of pigmented lesions on sun-damaged skin. , 2009, The American Journal of dermatopathology.

[5]  D. Ivan,et al.  Pigmented Paget Disease - A Diagnostic Pitfall Mimicking Melanoma , 2009, The American Journal of dermatopathology.

[6]  J. Fletcher,et al.  Imatinib Targeting of KIT-Mutant Oncoprotein in Melanoma , 2008, Clinical Cancer Research.

[7]  Susan Muller,et al.  KIT Gene Mutations and Copy Number in Melanoma Subtypes , 2008, Clinical Cancer Research.

[8]  C. Shea,et al.  Use of immunohistochemistry in melanocytic lesions , 2008, Journal of cutaneous pathology.

[9]  L. Chiriboga,et al.  Sox10: A Pan-Schwannian and Melanocytic Marker , 2008, The American journal of surgical pathology.

[10]  A. Cochran,et al.  Immunohistochemical characteristics of melanoma , 2008, Journal of cutaneous pathology.

[11]  L. From,et al.  Lymphatic invasion identified by monoclonal antibody D2-40, younger age, and ulceration: predictors of sentinel lymph node involvement in primary cutaneous melanoma. , 2008, Archives of dermatology.

[12]  M. Wick,et al.  Immunostaining for MART‐1 in the interpretation of problematic intra‐epidermal pigmented lesions , 2007, Journal of cutaneous pathology.

[13]  Narasimhan P. Agaram,et al.  L576P KIT mutation in anal melanomas correlates with KIT protein expression and is sensitive to specific kinase inhibition , 2007, International journal of cancer.

[14]  D. Pinkel,et al.  Somatic activation of KIT in distinct subtypes of melanoma. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  H. Skelton,et al.  Nuclear expression of the antiapoptotic protein survivin in malignant melanoma , 2006, Cancer.

[16]  A. H. Diwan,et al.  Loss of claudin‐1 expression in tumor‐associated vessels correlates with acquisition of metastatic phenotype in melanocytic neoplasms , 2005, Journal of cutaneous pathology.

[17]  G. Orchard,et al.  The use of LYVE-1 antibody for detecting lymphatic involvement in patients with malignant melanoma of known sentinel node status , 2005, Journal of Clinical Pathology.

[18]  R. Botella-Estrada,et al.  Prognostic factors in localized invasive cutaneous melanoma: high value of mitotic rate, vascular invasion and microscopic satellitosis , 2005, Melanoma research.

[19]  J. Teruya-Feldstein,et al.  Immunohistochemical Analysis of Novel Monoclonal Antibody PNL2 and Comparison With Other Melanocyte Differentiation Markers , 2005, The American journal of surgical pathology.

[20]  M. Martinka,et al.  Prognostic significance of activated Akt expression in melanoma: a clinicopathologic study of 292 cases. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[21]  D. Grossman.  Imatinib mesylate for melanoma: will a new target be revealed? , 2004, The Journal of investigative dermatology.

[22]  H. Kerl,et al.  Melan-A: Not a Helpful Marker in Distinction between Melanoma In Situ on Sun-Damaged Skin and Pigmented Actinic Keratosis , 2004, The American Journal of dermatopathology.

[23]  R. Vollmer.  Use of Bayes rule and MIB-1 proliferation index to discriminate Spitz nevus from malignant melanoma. , 2004, American journal of clinical pathology.

[24]  F. Esteva,et al.  Expression of cell cycle inhibitor p27Kip1 and its inactivator Jab1 in melanocytic lesions , 2004, Modern Pathology.

[25]  G. V. van Muijen,et al.  Immunohistochemistry in melanocytic proliferative lesions , 2004, Histopathology.

[26]  G. Orchard.  Comparison of Immunohistochemical Labelling of Melanocyte differentiation Antibodies Melan-A, Tyrosinase and HMB 45 with NKIC3 and S100 Protein in the Evaluation of Benign Naevi and Malignant Melanoma , 2000, The Histochemical Journal.

[27]  C. Qin.  Morphological and immunophenotypic variations in malignant melanoma , 2004 .

[28]  M. Piris,et al.  Progression in cutaneous malignant melanoma is associated with distinct expression profiles: a tissue microarray-based study. , 2004, The American journal of pathology.

[29]  M. Mihm,et al.  PTEN expression in normal skin, acquired melanocytic nevi, and cutaneous melanoma. , 2003, Journal of the American Academy of Dermatology.

[30]  Y. Natkunam,et al.  Expression of the B-Cell Proliferation Marker MUM1 by Melanocytic Lesions and Comparison with S100, gp100 (HMB45), and MelanA , 2003, Modern Pathology.

[31]  V. Prieto,et al.  Intraparenchymal Nevus Cell Aggregates in Lymph Nodes: A Possible Diagnostic Pitfall With Malignant Melanoma and Carcinoma , 2003, The American journal of surgical pathology.

[32]  C. Cordon-Cardo,et al.  HDM2 protein overexpression and prognosis in primary malignant melanoma. , 2002, Journal of the National Cancer Institute.

[33]  A. Offidani,et al.  Immunohistochemical expression of vascular endothelial growth factor, matrix metalloproteinase 2, and matrix metalloproteinase 9 in cutaneous melanocytic lesions , 2002, Cancer.

[34]  O. Larsson,et al.  Tissue distribution and differential expression of melanocortin 1 receptor, a malignant melanoma marker , 2002, British Journal of Cancer.

[35]  C. Cordon-Cardo,et al.  Evaluation of the proliferation marker MIB‐1 in the prognosis of cutaneous malignant melanoma , 2002, Cancer.

[36]  R. Barr,et al.  S100-Positive Spindle Cells in Scars: A Diagnostic Pitfall in the Re-Excision of Desmoplastic Melanoma , 2002, The American Journal of dermatopathology.

[37]  V. Prieto,et al.  Atypical cells in human cutaneous re‐excision scars for melanoma express p75NGFR, C56/N‐CAM and GAP‐43: evidence of early Schwann cell differentiation , 2002, Journal of cutaneous pathology.

[38]  D. Fisher,et al.  Role for Microphthalmia Transcription Factor in the Diagnosis of Metastatic Malignant Melanoma , 2002, Applied immunohistochemistry & molecular morphology : AIMM.

[39]  D. Elder,et al.  Immunoprofile of MITF, Tyrosinase, Melan-A, and MAGE-1 in HMB45-Negative Melanomas , 2002, The American journal of surgical pathology.

[40]  J. Nesland,et al.  Cyclin A expression in superficial spreading malignant melanomas correlates with clinical outcome , 2001, The Journal of pathology.

[41]  C. Cordon-Cardo,et al.  HDM2 protein overexpression, but not gene amplification, is related to tumorigenesis of cutaneous melanoma. , 2001, Cancer research.

[42]  M. Nosrati,et al.  Vascular involvement in the prognosis of primary cutaneous melanoma. , 2001, Archives of dermatology.

[43]  M. Miettinen,et al.  Low-affinity nerve growth factor receptor (p75) in dermatofibrosarcoma protuberans and other nonneural tumors: a study of 1,150 tumors and fetal and adult normal tissues. , 2001, Human pathology.

[44]  S. N. Agoff,et al.  The p75 Neurotrophin Receptor, Relative to Other Schwann Cell and Melanoma Markers, Is Abundantly Expressed in Spindled Melanomas , 2001, The American Journal of dermatopathology.

[45]  K Satyamoorthy,et al.  N-cadherin-mediated intercellular interactions promote survival and migration of melanoma cells. , 2001, Cancer research.

[46]  K. Franssila,et al.  Microphthalmia Transcription Factor in the Immunohistochemical Diagnosis of Metastatic Melanoma: Comparison With Four Other Melanoma Markers , 2001, The American journal of surgical pathology.

[47]  S. Moretti,et al.  Correlation of Ki-67 expression in cutaneous primary melanoma with prognosis in a prospective study: different correlation according to thickness. , 2001, Journal of the American Academy of Dermatology.

[48]  K. Busam,et al.  Analysis of Microphthalmia Transcription Factor Expression in Normal Tissues and Tumors, and Comparison of Its Expression With S-100 Protein, gp100, and Tyrosinase in Desmoplastic Malignant Melanoma , 2001, The American journal of surgical pathology.

[49]  M. Mihm,et al.  Microphthalmia Transcription Factor Expression in Cutaneous Benign, Malignant Melanocytic, and Nonmelanocytic Tumors , 2001, The American journal of surgical pathology.

[50]  A. Folpe,et al.  Microphthalmia Transcription Factor and Melanoma Cell Adhesion Molecule Expression Distinguish Desmoplastic/Spindle Cell Melanoma From Morphologic Mimics , 2001, The American journal of surgical pathology.

[51]  R. Henrique,et al.  Prognostic value of Ki-67 expression in localized cutaneous malignant melanoma. , 2000, Journal of the American Academy of Dermatology.

[52]  J. Kril,et al.  A Zonal Comparison of MIB1-Ki67 Immunoreactivity in Benign and Malignant Melanocytic Lesions , 2000, The American Journal of dermatopathology.

[53]  Yanjun Liu,et al.  SM5-1: a new monoclonal antibody which is highly sensitive and specific for melanocytic lesions , 2000, Archives of Dermatological Research.

[54]  S. Hinrichs,et al.  Inhibition of tumor growth and metastasis of human melanoma by intracellular anti-ATF-1 single chain Fv fragment , 2000, Oncogene.

[55]  L. Akslen,et al.  Loss of nuclear p16 protein expression correlates with increased tumor cell proliferation (Ki-67) and poor prognosis in patients with vertical growth phase melanoma. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[56]  R. Halaban.  The regulation of normal melanocyte proliferation. , 2000, Pigment cell research.

[57]  C. Shea,et al.  Desmoplastic (sclerotic) nevus: an underrecognized entity that resembles dermatofibroma and desmoplastic melanoma. , 1999, The American journal of surgical pathology.

[58]  V. Kosma,et al.  p21WAF1/CIP1expression in stage I cutaneous malignant melanoma: its relationship with p53, cell proliferation and survival , 1999, British Journal of Cancer.

[59]  Yao-Tseng Chen,et al.  Expression of melan-A (MART1) in benign melanocytic nevi and primary cutaneous malignant melanoma. , 1998, The American journal of surgical pathology.

[60]  F. Marincola,et al.  Comparison of melanoma antigen recognized by T cells (MART-1) to HMB-45: additional evidence to support a common lineage for angiomyolipoma, lymphangiomyomatosis, and clear cell sugar tumor. , 1998, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.

[61]  J. Nesland,et al.  Protein expression of the cell-cycle inhibitor p27Kip1 in malignant melanoma: inverse correlation with disease-free survival. , 1998, The American journal of pathology.

[62]  W. Gerald,et al.  A103: An anti-melan-a monoclonal antibody for the detection of malignant melanoma in paraffin-embedded tissues. , 1998, The American journal of surgical pathology.

[63]  R. Dummer,et al.  Tyrosinase immunoreactivity in formalin‐fixed, paraffin‐embedded primary and metastatic melanoma: frequency and distribution , 1998, Journal of cutaneous pathology.

[64]  J. A. Burch,et al.  The SCF/KIT pathway plays a critical role in the control of normal human melanocyte homeostasis. , 1998, The Journal of investigative dermatology.

[65]  J. Kusari,et al.  Regulation of Growth Factor-Induced Signaling by Protein-Tyrosine-Phosphatases , 1997, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[66]  A. Schauer,et al.  Differential expression of growth arrest, DNA damage genes and tumour suppressor gene p53 in naevi and malignant melanomas. , 1997, Anticancer research.

[67]  D J Ruiter,et al.  Transition of horizontal to vertical growth phase melanoma is accompanied by induction of vascular endothelial growth factor expression and angiogenesis , 1997, Melanoma research.

[68]  R. Barnhill,et al.  The prognostic significance of basic fibroblast growth factor in cutaneous malignant melanoma , 1996, Journal of cutaneous pathology.

[69]  L. Akslen,et al.  Independent prognostic importance of vascular invasion in nodular melanomas , 1996, Cancer.

[70]  A. Cochran,et al.  Nodal nevi and cutaneous melanomas. , 1996, The American journal of surgical pathology.

[71]  Yao-Tseng Chen,et al.  Serological analysis of Melan-A(MART-1), a melanocyte-specific protein homogeneously expressed in human melanomas. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[72]  M. Yaar,et al.  p75 nerve growth factor receptor staining helps identify desmoplastic and neurotropic melanoma , 1996, Journal of cutaneous pathology.

[73]  M. Herlyn,et al.  Shifts in cadherin profiles between human normal melanocytes and melanomas. , 1996, The journal of investigative dermatology. Symposium proceedings.

[74]  Y. Collan,et al.  Immunohistochemical expression of p53 protein, mitotic index and nuclear morphometry in primary malignant melanoma of the skin. , 1996, Pathology, research and practice.

[75]  P. Duray,et al.  Analysis of expression of the melanoma-associated antigens MART-1 and gp100 in metastatic melanoma cell lines and in in situ lesions. , 1996, Journal of immunotherapy with emphasis on tumor immunology : official journal of the Society for Biological Therapy.

[76]  N. S. Mcnutt,et al.  Nevoid malignant melanoma: morphologic patterns and immunohistochemical reactivity , 1995, Journal of cutaneous pathology.

[77]  C. Saenz‐Santamaría,et al.  p53 Expression Is Rare in Cutaneous Melanomas , 1995, The American Journal of dermatopathology.

[78]  A. Schauer,et al.  Significance of P-53 antigen in malignant melanomas and naevi of the head and neck area. , 1995, Anticancer research.

[79]  A. Houghton.  Cancer antigens: immune recognition of self and altered self , 1994, The Journal of experimental medicine.

[80]  J. Renauld,et al.  A new gene coding for a differentiation antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas , 1994, The Journal of experimental medicine.

[81]  S. Rosenberg,et al.  Cloning of the gene coding for a shared human melanoma antigen recognized by autologous T cells infiltrating into tumor. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[82]  M. Ueda,et al.  PCNA expression and nucleolar organizer regions in malignant melanoma and nevus cell nevus. , 1994, The Kobe journal of medical sciences.

[83]  T. Hunter,et al.  Receptor protein-tyrosine kinases and their signal transduction pathways. , 1994, Annual review of cell biology.

[84]  H. Kerl,et al.  Comparison of proliferative activity as assessed by proliferating cell nuclear antigen (PCNA) and Ki‐67 monoclonal antibodies in melanocytic skin lesions , 1993, Journal of cutaneous pathology.

[85]  C. Bacchi,et al.  S‐100 protein: Is it useful as a tumour marker in diagnostic immunocytochemistry? , 1989, Histopathology.

[86]  X. Ji,et al.  Comparison of HMB-45 monoclonal antibody and S-100 protein in the immunohistochemical diagnosis of melanoma. , 1988, American journal of clinical pathology.

[87]  P. Swanson,et al.  Recognition of malignant melanoma by monoclonal antibody HMB‐45. An immunohistochemical study of 200 paraffin‐embedded cutaneous tumors , 1988, Journal of cutaneous pathology.

[88]  A. Gown,et al.  Monoclonal antibodies specific for melanocytic tumors distinguish subpopulations of melanocytes. , 1986, The American journal of pathology.

[89]  A. Cochran,et al.  S‐100 PROTEIN AS A MARKER FOR MELANOCYTIC AND OTHER TUMOURS , 1985, Pathology.

[90]  I. Campbell,et al.  Use of NK1 C3 monoclonal antibody in the assessment of benign and malignant melanocytic lesions. , 1984, Journal of clinical pathology.