Negative HER2/neu Amplification Using Immunohistochemistry and Chromogenic in Situ Hybridization Techniques in Skin Melanoma Cases

  • Shayanfar, Nasrin (Oncopathology Research Center, Iran University of Medical Sciences) ;
  • Bahari, Leila (Department of Pathology, Iran University of Medical Sciences) ;
  • Safaie-Naraghi, Zahra (Department of Pathology, Razi Hospital, Tehran University of Medical Sciences) ;
  • Kamyab, Kambiz (Department of Pathology, Razi Hospital, Tehran University of Medical Sciences) ;
  • Gheytanchi, Elmira (Oncopathology Research Center, Iran University of Medical Sciences) ;
  • Rezaei, Nima (Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences)
  • Published : 2015.02.25


Background: This study was performed to evaluate the amplification of HER-2/neu in patients with melanoma. Materials and Methods: Amplification of HER-2/neu was evaluated in a group of patients with melanoma, referred to two referral centers in Tehran, using immunohistochemistry (IHC) and chromogenic in situ hybridization (CISH) techniques. Results: Forty patients with mean age $57.9{\pm}19.5years$ were enrolled in this study. The most frequent type of melanoma was acral, while lower limbs were the most frequent sites. The amplification of HER2/neu was negative in 97.5% of patients with IHC and in 100% of patients with CISH technique. Only one case (2.5%) shows weak positive staining (+2) in IHC method. Fifty five percent of melanoma was ulcerative, and the most common stages of tumors were stages 4b and 3b. More than 47% of cases were in Clark level III, while the mean of Breslow thickness was $3.56{\pm}2.87mm$. The stage of the case that showed weakly positive staining (2+) in IHC was 4b. Conclusions: The amplification of HER2/neu biomarker was negative in patients with melanoma, using both CISH and IHC techniques.


  1. Allgayer H, R. Babic, et al (2000). c-erbB-2 is of independent prognostic relevance in gastric cancer and is associated with the expression of tumor-associated protease systems. J Clin Oncol, 18, 2201-9.
  2. Bar-Sela G, Kuten A, Ben-Eliezer S, Gov-Ari E, Ben-Izhak O (2003). Expression of HER2 and C-KIT in nasopharyngeal carcinoma: implications for a new therapeutic approach. Mod Pathol, 16, 1035-40.
  3. Bodey B, Bodey Jr B, Groger AM, et al (1997). Clinical and prognostic significance of the expression of the c-erbB-2 and c-erbB-3 oncoproteins in primary and metastatic malignant melanomas and breast carcinomas. Anticancer Res, 17, 1319-30.
  4. Chenevix-Trench G, Martin NG, Ellem KA et al (1990). Gene expression in melanoma cell lines and cultured melanocytes: correlation between levels of c-src-1, c-myc and p53. Oncogene, 5, 1187-93.
  5. Cihan YB, Baykan H, Kavuncuoglu E, et al (2013). Relationships between skin cancers and blood groups--link between nonmelanomas and ABO/Rh factors. Asian Pac J Cancer Prev, 14, 4199-4203.
  6. Demierre MF, Chung C, Miller DR, Geller AC (2005). Early detection of thick melanomas in the United States: beware of the nodular subtype. Arch Dermatol, 141, 745-50.
  7. Easty DJ, Herlyn M, Bennett DC (1995). Abnormal protein tyrosine kinase gene expression during melanoma progression and metastasis. Int J Cancer, 60, 129-36.
  8. El-Sheikh S, El-Sheikh S, El-Morsy I (2009). Detection of c-Kit (CD117) and HER-2/neu in Oral and Cutaneous Malignant Melanomas. J Egypt Women DermatolSoc, 6, 66-73.
  9. Gershenson DM, Tortolero-Luna G, Malpica A, et al (1996). Ovarian intraepithelial neoplasia and ovarian cancer. Obstet Gynecol Clin North Am, 23, 475-543.
  10. Gheytanchi E, Mehrazma M, Madjd M (2014). Expression of Ki-67, p53 and VEGF in pediatric neuroblastoma. Asian Pac J Cancer Prev, 15, 3065-70.
  11. Gleeson G, Larkin A, Horgan N, Kennedy S (2014). Evaluation of chromogenic in situ hybridization for the determination of monosomy 3 in uveal melanoma. Arch Pathol Lab Med, 138, 664-70.
  12. Hetzel DJ, Wilson TO, Keeney GL, et al (1992). HER-2/neu expression: a major prognostic factor in endometrial cancer. Gynecol Oncol, 47, 179-85.
  13. Hiesiger EM, Hayes RL, Pierz DM, Budzilovich GN (1993). Prognostic relevance of epidermal growth factor receptor (EGF-R) and c-neu/erbB2 expression in glioblastomas (GBMs). J Neurooncol, 16, 93-104.
  14. Hoersch B, Leiter U, Garbe C (2006). Is head and neck melanoma a distinct entity? A clinical registry-based comparative study in 5702 patients with melanoma. Br J Dermatol, 155, 771-7.
  15. Hwang CC, Pintye M,Chang LC, et al (2011). Dual-colour chromogenic in-situ hybridization is a potential alternative to fluorescence in-situ hybridization in HER2 testing. Histopathology, 59, 984-92.
  16. Jerant AF, Johnson JT, Sheridan CD, Caffrey TJ (2000). Early detection and treatment of skin cancer. Am Fam Physician, 62, 357-68.
  17. Kanavy HE, Gerstenblith MR (2011). Ultraviolet radiation and melanoma. Semin Cutan Med Surg, 30, 222-8.
  18. Krahn G, Leiter U, Kaskel P, et al (2001). Coexpression patterns of EGFR, HER2, HER3 and HER4 in non-melanoma skin cancer. Eur J Cancer, 37, 251-9.
  19. Lens MB, Dawes M (2004). Global perspectives of contemporary epidemiological trends of cutaneous malignant melanoma. Br J Dermatol, 150, 179-85.
  20. Levi F, Randimbison L, La Vecchia C, Te VC, Franceschi S (1998). Prognostic factors for cutaneous malignant melanoma in Vaud, Switzerland. Int J Cancer, 78, 315-19.<315::AID-IJC10>3.0.CO;2-5
  21. Mayr D, Heim S, Weyrauch K, et al (2009). Chromogenic in situ hybridization for Her-2/neu-oncogene in breast cancer: comparison of a new dual-colour chromogenic in situ hybridization with immunohistochemistry and fluorescence in situ hybridization. Histopathology, 55, 716-23.
  22. Narin A, Tuncay O (2012). Relationships between malignant melanoma and chromosome damage in human peripheral blood lymphocytes. Asian Pac J Cancer Prev, 13, 5229-32.
  23. Parkin DM, Bray F, Ferlay J, Pisani P (2005). Global cancer statistics, 2002. CA Cancer J Clin, 55, 74-108.
  24. Pauletti G, Godolphin W, Press MF, Slamon DJ (1996). Detection and quantitation of HER-2/neu gene amplification in human breast cancer archival material using fluorescence in situ hybridization. Oncogene, 13, 63-72.
  25. Persons DL, Arber DA, Sosman JA, Borelli KA, Slovak ML (2000). Amplification and overexpression of HER-2/neu are uncommon in advanced stage melanoma. Anticancer Res, 20, 1965-8.
  26. Potti A, Hille R, Koch M (2003). Immunohistochemical determination of HER-2/neu in malignant melanoma. Anticancer Res, 23, 4067-9.
  27. Potti A, Moazzam N, Langness E, et al (2004). Immunohistochemical determination of HER-2/neu, c-Kit (CD117), and vascular endothelial growth factor (VEGF) overexpression in malignant melanoma. J Cancer Res Clin Oncol, 130, 80-6.
  28. Rongcun Y, Salazar-Onfray F, Charo J, et al (1999). Identification of new HER2/neu-derived peptide epitopes that can elicit specific CTL against autologous and allogeneic carcinomas and melanomas. J Immunol, 163, 1037-44.
  29. Safaie-Naraghi Z, Bahadori M, Ehsani AH, et al (2006). Evaluation of primary cutaneous malignant melanoma according to Breslow and Clarke pathological indices. Tehran University Medical Journal, 64, 79-85.
  30. Tanner M, Gancberg D, Di Leo A, et al (2000). Chromogenic in situ hybridization: a practical alternative for fluorescence in situ hybridization to detect HER-2/neu oncogene amplification in archival breast cancer samples. Am J Pathol, 157, 1467-72.
  31. Tsugawa K, Fushida S, Yonemura Y (1993). Amplification of the c-erbB-2 gene in gastric carcinoma: correlation with survival. Oncology, 50, 418-25.
  32. Ullrich A, Schlessinger J (1990). Signal transduction by receptors with tyrosine kinase activity. Cell, 61, 203-12.
  33. Yu D, Wang SS, Dulski KM, et al (1994). c-erbB-2/neu overexpression enhances metastatic potential of human lung cancer cells by induction of metastasis-associated properties. Cancer Res, 54, 3260-6.

Cited by

  1. Moringa oleifera fruit induce apoptosis via reactive oxygen species-dependent activation of mitogen-activated protein kinases in human melanoma A2058 cells vol.14, pp.2, 2017,