Virchows Archiv

, Volume 470, Issue 6, pp 695–701 | Cite as

Strong association of insulin-like growth factor 1 receptor expression with histologic grade, subtype, and HPV status in penile squamous cell carcinomas: a tissue microarray study of 112 cases

  • Sheila F. Faraj
  • Nilda Gonzalez-Roibon
  • Enrico Munari
  • Rajni Sharma
  • Arthur L. Burnett
  • Antonio L. Cubilla
  • George J. Netto
  • Alcides Chaux
Original Article


Insulin-like growth factor-1 receptor (IGF1R) plays a key role in cell growth and transformation. It is overexpressed in several solid tumors. This study evaluates IGF1R immunoexpression in penile squamous cell carcinoma (SCC). Four tissue microarrays were built from formalin-fixed, paraffin-embedded blocks of 112 penile SCC from Paraguay. Membranous IGF1R expression was evaluated by immunohistochemistry using two different approaches. An H-score was calculated in each spot (stain intensity by extent), and a median score per tumor was obtained. The second approach consisted of a score similar to the scoring system that was used for evaluating HER2 immunoexpression. For each case, the highest category obtained at any spot was used for statistical analyses. IGF1R expression was compared by histologic subtype, grade, and human papillomavirus (HPV) status. Median H-score was 22.5. The distribution of IGF1R expression by HER2 approach was as follows: 0 in 33.0% cases, 1+ in 46.4%, 2+ in 14.3%, and 3+ in 6.2%. IGF1R H-scores were associated with basaloid and warty/basaloid subtypes (p = 0.0026) and higher grade (p = 0.00052). Although weaker when using the HER2 approach, the association of IGF1R expression with subtype (p = 0.015) and grade (p = 0.015) remained significant. Furthermore, there was an association between IGF1R expression by HER2 approach and HPV status (p = 0.012). IGF1R was expressed in about two thirds of penile SCC cases, showing a strong positive association with histologic grade, subtype, and HPV status. Considering that grade is a predictor of outcome IGF1R expression may have prognostic relevance and could point to a potential role for IGF1R inhibitors in treating penile SCC.


IGF1R Penile carcinoma Squamous cell carcinoma 



We acknowledge the outstanding work of Helen Fedor and Marcella Southerland, from the TMA Lab Core at the Johns Hopkins University, in building the TMAs for the study.

Compliance with ethical standards

Support/financial disclosure

This study was partially supported by the Johns Hopkins Medicine—Patana Fund for Research. Dr. Alcides Chaux was partially supported by an award granted by the National Council of Science and Technology (CONACYT) dependent of the Presidency of the Republic of Paraguay, as an Active Researcher of Level 2 of the National Incentive Program for Researchers (PRONII).

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

428_2017_2110_Fig3_ESM.gif (74 kb)
Supplementary Figure 1

Histologic subtypes, grades, HPV status and IGF1R expression distribution. Bar plots showing distribution of A) histologic subtypes, B) histologic grades, C) HPV status, D) IGF1R expression by H-scores using histograms, and E) by HER2 approach using bar plots. (GIF 74 kb)

428_2017_2110_MOESM1_ESM.tif (43.2 mb)
High resolution images (TIFF 44245 kb)
428_2017_2110_Fig4_ESM.gif (84 kb)
Supplementary Figure 2

Association of A) histologic subtypes, B) histologic grades, and C) HPV status with IGF1R expression by H-score. Association of D) histologic subtypes, E) histologic grades, and F) HPV status with IGF1R expression by H-score, using base 10 logarithmic scale. (GIF 83 kb)

428_2017_2110_MOESM2_ESM.tif (44.2 mb)
High resolution images (TIFF 45283 kb)
428_2017_2110_Fig5_ESM.gif (49 kb)
Supplementary Figure 3

Association of A) histologic subtypes, B) histologic grades, and C) HPV status with IGF1R expression by HER2 approach. (GIF 49 kb)

428_2017_2110_MOESM3_ESM.tif (21.9 mb)
High resolution images (TIFF 22375 kb)


  1. 1.
    Cubilla AL, Amin MB, Ayala A et al (2016) Tumours of the penis. In: Moch H, Humphrey PA, Ulbright TM, Reuter VE (eds) WHO classification of tumours of the urinary system and male genital organs, 4th edn. IARC, Lyon, p 259–285Google Scholar
  2. 2.
    Backes DM, Kurman RJ, Pimenta JM, Smith JS (2009) Systematic review of human papillomavirus prevalence in invasive penile cancer. Cancer Causes Control 20:449–457. doi: 10.1007/s10552-008-9276-9 CrossRefPubMedGoogle Scholar
  3. 3.
    Ball MW, Bezerra SM, Chaux A, Faraj SF, Gonzalez-Roibon N, Munari E, Sharma R, Bivalacqua TJ, Netto GJ, Burnett AL (2016) Overexpression of insulin-like growth factor-1 receptor is associated with penile cancer progression. Urology 92:51–56. doi: 10.1016/j.urology.2016.02.006 CrossRefPubMedGoogle Scholar
  4. 4.
    Camp RL, Neumeister V, Rimm DL (2008) A decade of tissue microarrays: progress in the discovery and validation of cancer biomarkers. J Clin Oncol 26:5630–5637. doi: 10.1200/jco.2008.17.3567 CrossRefPubMedGoogle Scholar
  5. 5.
    Chaux A, Cubilla AL (2012) Advances in the pathology of penile carcinomas. Hum Pathol 43:771–789. doi: 10.1016/j.humpath.2012.01.014 CrossRefPubMedGoogle Scholar
  6. 6.
    Chaux A, Munari E, Cubilla AL, Hicks J, Lecksell K, Burnett AL, Netto GJ (2014) Immunohistochemical expression of the mammalian target of rapamycin pathway in penile squamous cell carcinomas: a tissue microarray study of 112 cases. Histopathology 64:863–871. doi: 10.1111/his.12338 CrossRefPubMedGoogle Scholar
  7. 7.
    Chaux A, Munari E, Katz B, Sharma R, Lecksell K, Cubilla AL, Burnett AL, Netto GJ (2013a) The epidermal growth factor receptor is frequently overexpressed in penile squamous cell carcinomas: a tissue microarray and digital image analysis study of 112 cases. Hum Pathol 44:2690–2695. doi: 10.1016/j.humpath.2013.07.012 CrossRefPubMedGoogle Scholar
  8. 8.
    Chaux A, Netto GJ, Rodriguez I, Barreto JE, Oertell J, Ocampos S, Boggino H, Codas R, Bosch FX, Sanjose S, Munoz N, Hildesheim A, Cubilla AL (2013b) Epidemiologic profile, sexual history, pathologic features, and human papillomavirus status of 103 patients with penile carcinoma. World J Urol 31:861–867. doi: 10.1007/s00345-011-0802-0 CrossRefPubMedGoogle Scholar
  9. 9.
    Chaux A, Torres J, Pfannl R, Barreto J, Rodriguez I, Velazquez EF, Cubilla AL (2009) Histologic grade in penile squamous cell carcinoma visual estimation versus digital measurement of proportions of grades, adverse prognosis with any proportion of grade 3 and correlation of a Gleason-like system with nodal metastasis. Am J Surg Pathol 33:1042–1048CrossRefPubMedGoogle Scholar
  10. 10.
    Cubilla AL, Lloveras B, Alejo M, Clavero O, Chaux A, Kasamatsu E, Velazquez EF, Lezcano C, Monfulleda N, Tous S, Alemany L, Klaustermeier J, Munoz N, Quint W, de Sanjose S, Bosch FX (2010) The basaloid cell is the best tissue marker for human papillomavirus in invasive penile squamous cell carcinoma: a study of 202 cases from Paraguay. Am J Surg Pathol 34:104–114CrossRefPubMedGoogle Scholar
  11. 11.
    Dale OT, Aleksic T, Shah KA, Han C, Mehanna H, Rapozo DCM, Sheard JDH, Goodyear P, Upile NS, Robinson M, Jones TM, Winter S, Macaulay VM (2015) IGF-1R expression is associated with HPV-negative status and adverse survival in head and neck squamous cell cancer. Carcinogenesis 36:648–655. doi: 10.1093/carcin/bgv053 CrossRefPubMedGoogle Scholar
  12. 12.
    Fedor H, De Marzo A (2005) Practical methods for tissue microarray construction. Methods Mol Med 103:89–101PubMedGoogle Scholar
  13. 13.
    Ferrandiz-Pulido C, Masferrer E, Toll A, Hernandez-Losa J, Mojal S, Pujol RM, Cajal SRY, de Torres I, Garcia-Patos V (2013) mTOR signaling pathway in penile squamous cell carcinoma: pmTOR and peIF4E over expression correlate with aggressive tumor behavior. J Urol 190:2288–2295. doi: 10.1016/j.juro.2013.06.015 CrossRefPubMedGoogle Scholar
  14. 14.
    Gonzalez-Roibon N, Kim JJ, Faraj SF, Chaux A, Bezerra SM, Munari E, Ellis C, Sharma R, Keizman D, Bivalacqua TJ, Schoenberg M, Eisenberger M, Carducci M, Netto GJ (2014) Insulin-like growth factor-1 receptor overexpression is associated with outcome in invasive urothelial carcinoma of urinary bladder: a retrospective study of patients treated using radical cystectomy. Urology 83:1444.e1441–1444.e1446. doi: 10.1016/j.urology.2014.01.028 CrossRefGoogle Scholar
  15. 15.
    Hammond ME, Hayes DF, Wolff AC (2011) Clinical notice for American Society of Clinical Oncology–College of American Pathologists guideline recommendations on ER/PgR and HER2 testing in breast cancer. J Clin Oncol 29:E458–E458. doi: 10.1200/jco.2011.35.2245 CrossRefPubMedGoogle Scholar
  16. 16.
    Iams WT, Lovly CM (2015) Molecular pathways: clinical applications and future direction of insulin-like growth factor-1 receptor pathway blockade. Clin Cancer Res 21:4270–4277. doi: 10.1158/1078-0432.ccr-14-2518 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Kakies C, Lopez-Beltran A, Comperat E, Erbersdobler A, Grobholz R, Hakenberg OW, Hartmann A, Horn LC, Höhn AK, Köllermann J, Kristiansen G, Montironi R, Scarpelli M, Protzel C (2014) Reproducibility of histopathologic tumor grading in penile cancer—results of a European project. Virchows Arch 464:453–461. doi: 10.1007/s00428-014-1548-z CrossRefPubMedGoogle Scholar
  18. 18.
    Kreimer AR, Clifford GM, Boyle P, Franceschi S (2005) Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomark Prev 14:467–475. doi: 10.1158/1055-9965.epi-04-0551 CrossRefGoogle Scholar
  19. 19.
    Kuklinski A, Kamocki Z, Koda M, Piotrowski Z, Sulkowski S, Lesniewicz R, Pawlak K, Mysliwiec P, Kedra B (2011) IGF-IR in patients with advanced colorectal cancer in correlation with certain clinico-morphological factors: initial report. Oncol Lett 2:1155–1159. doi: 10.3892/ol.2011.396 PubMedPubMedCentralGoogle Scholar
  20. 20.
    Lin SB, Zhou L, Liang ZY, Zhou WX, Jin Y (2017) Expression of GRK2 and IGF1R in hepatocellular carcinoma: clinicopathological and prognostic significance. J Clin Pathol. doi: 10.1136/jclinpath-2016-203998 Google Scholar
  21. 21.
    Matsumoto F, Fujimaki M, Ohba S, Kojima M, Yokoyama J, Ikeda K (2015) Relationship between insulin-like growth factor-1 receptor and human papillomavirus in patients with oropharyngeal cancer head and neck-journal for the sciences and specialties of the. Head Neck 37:977–981. doi: 10.1002/hed.23702 CrossRefPubMedGoogle Scholar
  22. 22.
    Matsumoto F, Valdecanas DN, Mason KA, Milas L, Ang KK, Raju U (2012) The impact of timing of EGFR and IGF-1R inhibition for sensitizing head and neck cancer to radiation. Anticancer Res 32:3029–3035PubMedGoogle Scholar
  23. 23.
    Rubin MA, Kleter B, Zhou M, Ayala G, Cubilla AL, Quint WGV, Pirog EC (2001) Detection and typing of human papillomavirus DNA in penile carcinoma—evidence for multiple independent pathways of penile carcinogenesis. Am J Pathol 159:1211–1218. doi: 10.1016/s0002-9440(10)62506-0 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Siegel RL, Miller KD, Jemal A (2016) Cancer statistics, 2016 Ca-a cancer. Journal for Clinicians 66:7–30. doi: 10.3322/caac.21332 CrossRefGoogle Scholar
  25. 25.
    Sonpavde G, Pagliaro LC, Buonerba C, Dorff TB, Lee RJ, Di Lorenzo G (2013) Penile cancer: current therapy and future directions. Ann Oncol 24:1179–1189. doi: 10.1093/annonc/mds635 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Stankiewicz E, Prowse DM, Ng M, Cuzick J, Mesher D, Hiscock F, Lu YJ, Watkin N, Corbishley C, Lam W, Berney DM (2011) Alternative HER/PTEN/Akt pathway activation in HPV positive and negative penile carcinomas. Plos One 6. doi:  10.1371/journal.pone.0017517
  27. 27.
    Team RC (2014) R: a language and environment for statistical computing. R Foundation for Statistical Computing, ViennaGoogle Scholar
  28. 28.
    Ueda Y, Enomoto T, Kimura T, Yoshino K, Fujita M (2011) Two distinct pathways to development of squamous cell carcinoma of the vulva. J Skin Cancer 2011:951250. doi: 10.1155/2011/951250 CrossRefPubMedGoogle Scholar
  29. 29.
    Verhoeven RHA, Janssen-Heijnen MLG, Saum KU, Zanetti R, Caldarella A, Holleczek B, Brewster DH, Hakulinen T, Horenblas S, Brenner H, Gondos A, Grp ESW (2013) Population-based survival of penile cancer patients in Europe and the United States of America: no improvement since 1990. Eur J Cancer 49:1414–1421. doi: 10.1016/j.ejca.2012.10.029 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Sheila F. Faraj
    • 1
  • Nilda Gonzalez-Roibon
    • 1
  • Enrico Munari
    • 1
  • Rajni Sharma
    • 1
  • Arthur L. Burnett
    • 2
  • Antonio L. Cubilla
    • 3
  • George J. Netto
    • 4
    • 5
  • Alcides Chaux
    • 6
  1. 1.Department of PathologyJohns Hopkins Medical InstitutionsBaltimoreUSA
  2. 2.Department of UrologyJohns Hopkins Medical InstitutionsBaltimoreUSA
  3. 3.Instituto de Patología e InvestigaciónAsunciónParaguay
  4. 4.Johns Hopkins Medical InstitutionsBaltimoreUSA
  5. 5.Department of PathologyThe University of Alabama at BirminghamBirminghamUSA
  6. 6.Centro para el Desarrollo de la Investigación Científica (CEDIC)AsunciónParaguay

Personalised recommendations