Pathology of Head and Neck Tumors



The chapter on head and neck surface epithelial-derived lesions presents recent developments in the classification of premalignant and malignant entities at different anatomical sites. Emphasis on close clinician and pathologist interactions in intraoperative consultation for both diagnosis and margins is stressed. The chapter provides a practical and simplified approach to the assessment of premalignant and dysplastic lesions in both oral and laryngeal sites. Emphasis on the significance of grading and morphologic subtypes is highlighted. The chapter also introduces and addresses the issues associated with the development of oropharyngeal carcinoma as an etiologic and clinical subtype. The HPV high-risk association, the morphologic manifestations, and the diagnosis of this entity are concisely presented with emphasis on biomarker integration.


Premalignancy Squamous carcinoma Squamous tumorigenesis Risk factors Viral etiology Squamous carcinoma phenotypes 


  1. 1.
    El-Naggar AK. Pathobiology of head and neck squamous tumorigenesis. Curr Cancer Drug Targets. 2007;7:606–12.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Mao L, El-Naggar AK. Molecular changes in the multistage pathogenesis of head and neck cancer. In: Srivastava S, et al., editors. Molecular pathology of early cancer: IOS Press; 1999.Google Scholar
  3. 3.
    Mandal M, Myers JN, Lippman SM, et al. Epithelial to mesenchymal transition in head and neck squamous carcinoma: association of Src activation with E-cadherin down-regulation, vimentin expression, and aggressive tumor features. Cancer. 2008;112:2088–100.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Choi HR, Roberts DB, Johnigan RH, et al. Molecular and clinicopathologic comparisons of head and neck squamous carcinoma variants: common and distinctive features of biological significance. Am J Surg Pathol. 2004;28:1299–310.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Shear M, Pindborg JJ. Verrucous hyperplasia of the oral mucosa. Cancer. 1980;46:1855–62.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Begum S, Westra WH. Basaloid squamous cell carcinoma of the head and neck is a mixed variant that can be further resolved by HPV status. Am J Surg Pathol. 2008;32:1044–50.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Choi HR, Sturgis EM, Rosenthal DI, et al. Sarcomatoid carcinoma of the head and neck: molecular evidence for evolution and progression from conventional squamous cell carcinomas. Am J Surg Pathol. 2003;27:1216–20.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Dahlstrand H, Nasman A, Romanitan M, et al. Human papillomavirus accounts both for increased incidence and better prognosis in tonsillar cancer. Anticancer Res. 2008;28:1133–8.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Dahlstrom KR, Adler-Storthz K, Etzel CJ, et al. Human papillomavirus type 16 infection and squamous cell carcinoma of the head and neck in never-smokers: a matched pair analysis. Clin Cancer Res. 2003;9:2620–6.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Kumar B, Cordell KG, Lee JS, et al. Response to therapy and outcomes in oropharyngeal cancer are associated with biomarkers including human papillomavirus, epidermal growth factor receptor, gender, and smoking. Int J Radiat Oncol Biol Phys. 2007;69:S109–11.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Nichols AC, Faquin WC, Westra WH, et al. HPV-16 infection predicts treatment outcome in oropharyngeal squamous cell carcinoma. Otolaryngol Head Neck Surg. 2009;140:228–34.Google Scholar
  12. 12.
    Sand L, Jalouli J, Larsson PA, et al. Human papilloma viruses in oral lesions. Anticancer Res. 2000;20:1183–8.Google Scholar
  13. 13.
    Westra WH, Taube JM, Poeta ML, et al. Inverse relationship between human papillomavirus-16 infection and disruptive p53 gene mutations in squamous cell carcinoma of the head and neck. Clin Cancer Res. 2008;14:366–9.Google Scholar
  14. 14.
    Barnes L, Eveson JW, Reichart P, et al. World Health Organization classification of tumours. Pathology & genetics. Head and neck tumours. International Agency for Research on Cancer (IARC). Lyon: IARC Press; 2005.Google Scholar
  15. 15.
    Janot F, Klijanienko J, Russo A, et al. Prognostic value of clinicopathological parameters in head and neck squamous cell carcinoma: a prospective analysis. Br J Cancer. 1996;73:531–8.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Braakhuis BJ, Tabor MP, Kummer JA, et al. A genetic explanation of Slaughter's concept of field cancerization: evidence and clinical implications. Cancer Res. 2003;63:1727–30.Google Scholar
  17. 17.
    Forastiere A, Koch W, Trotti A, et al. Head and neck cancer. N Engl J Med. 2001;345:1890–900.Google Scholar
  18. 18.
    Jang SJ, Chiba I, Hirai A, et al. Multiple oral squamous epithelial lesions: are they genetically related? Oncogene. 2001;20:2235–42.Google Scholar
  19. 19.
    Coombes MM, Briggs KL, Bone JR, et al. Resetting the histone code at CDKN2A in HNSCC by inhibition of DNA methylation. Oncogene. 2003;22:8902–11.Google Scholar
  20. 20.
    Papadimitrakopoulou VA, Izzo J, Mao L, et al. Cyclin D1 and p16 alterations in advanced premalignant lesions of the upper aerodigestive tract: role in response to chemoprevention and cancer development. Clin Cancer Res. 2001;7:3127–34.Google Scholar
  21. 21.
    Wang D, Grecula JC, Gahbauer RA, et al. p16 gene alterations in locally advanced squamous cell carcinoma of the head and neck. Oncol Rep. 2006;15:661–5.Google Scholar
  22. 22.
    Nakahara Y, Shintani S, Mihara M, et al. Alterations of Rb, p16(INK4A) and cyclin D1 in the tumorigenesis of oral squamous cell carcinomas. Cancer Lett. 2000;160:3–8.Google Scholar
  23. 23.
    Thurfjell N, Coates PJ, Uusitalo T, et al. Complex p63 mRNA isoform expression patterns in squamous cell carcinoma of the head and neck. Int J Oncol. 2004;25:27–35.Google Scholar
  24. 24.
    Weber A, Bellmann U, Bootz F, et al. Expression of p53 and its homologues in primary and recurrent squamous cell carcinomas of the head and neck. Int J Cancer. 2002;99:22–8.Google Scholar
  25. 25.
    Hazan RB, Norton L. The epidermal growth factor receptor modulates the interaction of E-cadherin with the actin cytoskeleton. J Biol Chem. 1998;273:9078–84.Google Scholar
  26. 26.
    Rubin Grandis J, Melhem MF, Gooding WE, et al. Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival. J Natl Cancer Inst. 1998;90:824–32.Google Scholar
  27. 27.
    Temam S, Kawaguchi H, El-Naggar AK, et al. Epidermal growth factor receptor copy number alterations correlate with poor clinical outcome in patients with head and neck squamous cancer. J Clin Oncol. 2007;25:2164–70.Google Scholar
  28. 28.
    Ang KK, Berkey BA, Tu X, et al. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res. 2002;62:7350–6.Google Scholar
  29. 29.
    Gallo O, Franchi A, Magnelli L, et al. Cyclooxygenase-2 pathway correlates with VEGF expression in head and neck cancer. Implications for tumor angiogenesis and metastasis. Neoplasia. 2001;3:53–61.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Janot F, El-Naggar AK, Morrison RS, et al. Expression of basic fibroblast growth factor in squamous cell carcinoma of the head and neck is associated with degree of histologic differentiation. Int J Cancer. 1995;64:117–23.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Joo YH, Jung CK, Kim MS, et al. Relationship between vascular endothelial growth factor and Notch1 expression and lymphatic metastasis in tongue cancer. Otolaryngol Head Neck Surg. 2009;140:512–8.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Li J, Huang H, Sun L, et al. MiR-21 indicates poor prognosis in tongue squamous cell carcinomas as an apoptosis inhibitor. Clin Cancer Res. 2009;15:3998–4008.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Montag M, Dyckhoff G, Lohr J, et al. Angiogenic growth factors in tissue homogenates of HNSCC: expression pattern, prognostic relevance, and interrelationships. Cancer Sci. 2009;100:1210–8.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Rafii S, Avecilla ST, Jin DK. Tumor vasculature address book: identification of stage-specific tumor vessel zip codes by phage display. Cancer Cell. 2003;4:331–3.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Schultz-Hector S, Haghayegh S. Beta-fibroblast growth factor expression in human and murine squamous cell carcinomas and its relationship to regional endothelial cell proliferation. Cancer Res. 1993;53:1444–9.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Williams JK, Carlson GW, Cohen C, et al. Tumor angiogenesis as a prognostic factor in oral cavity tumors. Am J Surg. 1994;168:373–80.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Qiu W, Schonleben F, Li X, et al. PIK3CA mutations in head and neck squamous cell carcinoma. Clin Cancer Res. 2006;12:1441–6.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Chan G, Boyle JO, Yang EK, et al. Cyclooxygenase-2 expression is up-regulated in squamous cell carcinoma of the head and neck. Cancer Res. 1999;59:991–4.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Papadimitrakopoulou VA, Hong WK. Biology of oral premalignant lesions: concepts and implications for chemoprevention. Eur J Cancer Prev. 1996;5(Suppl 2):87–93.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Avizienyte E, Wyke AW, Jones RJ, et al. Src-induced de-regulation of E-cadherin in colon cancer cells requires integrin signalling. Nat Cell Biol. 2002;4:632–8.Google Scholar
  41. 41.
    Batlle E, Sancho E, Franci C, et al. The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol. 2000;2:84–9.Google Scholar
  42. 42.
    Chen YJ, Lin SC, Kao T, et al. Genome-wide profiling of oral squamous cell carcinoma. J Pathol. 2004;204:326–32.Google Scholar
  43. 43.
    Christiansen JJ, Rajasekaran AK. Reassessing epithelial to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis. Cancer Res. 2006;66:8319–26.Google Scholar
  44. 44.
    Chung CH, Parker JS, Karaca G, et al. Molecular classification of head and neck squamous cell carcinomas using patterns of gene expression. Cancer Cell. 2004;5:489–500.PubMedPubMedCentralGoogle Scholar
  45. 45.
    El-Naggar AK, Hurr K, Huff V, et al. Microsatellite instability in preinvasive and invasive head and neck squamous carcinoma. Am J Pathol. 1996;148:2067–72.PubMedPubMedCentralGoogle Scholar
  46. 46.
    El-Naggar AK, Hurr K, Huff V, et al. Allelic loss and replication errors at microsatellite loci on chromosome 11p in head and neck squamous carcinoma: association with aggressive biological features. Clin Cancer Res. 1996;2:903–7.PubMedPubMedCentralGoogle Scholar
  47. 47.
    El-Naggar AK, Hurr K, Luna MA, et al. Intratumoral genetic heterogeneity in primary head and neck squamous carcinoma using microsatellite markers. Diagn Mol Pathol. 1997;6:305–8.PubMedPubMedCentralGoogle Scholar
  48. 48.
    El-Naggar AK, Lai S, Clayman GL, et al. p73 gene alterations and expression in primary oral and laryngeal squamous carcinomas. Carcinogenesis. 2001;22:729–35.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Giri U, Ashorn CL, Ramdas L, et al. Molecular signatures associated with clinical outcome in patients with high-risk head-and-neck squamous cell carcinoma treated by surgery and radiation. Int J Radiat Oncol Biol Phys. 2006;64:670–7.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Lopez-Graniel CM, Tamez de Leon D, Meneses-Garcia A, et al. Tumor angiogenesis as a prognostic factor in oral cavity carcinomas. J Exp Clin Cancer Res. 2001;20:463–8.Google Scholar
  51. 51.
    Maeda M, Shintani Y, Wheelock MJ, et al. Src activation is not necessary for transforming growth factor (TGF)-beta-mediated epithelial to mesenchymal transitions (EMT) in mammary epithelial cells. PP1 directly inhibits TGF-beta receptors I and II. J Biol Chem. 2006;281:59–68.Google Scholar
  52. 52.
    Maruya S, Issa JP, Weber RS, et al. Differential methylation status of tumor-associated genes in head and neck squamous carcinoma: incidence and potential implications. Clin Cancer Res. 2004;10:3825–30.Google Scholar
  53. 53.
    Ramdas L, Giri U, Ashorn CL, et al. miRNA expression profiles in head and neck squamous cell carcinoma and adjacent normal tissue. Head Neck. 2009;31:642–54.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Roepman P, Wessels LF, Kettelarij N, et al. An expression profile for diagnosis of lymph node metastases from primary head and neck squamous cell carcinomas. Nat Genet. 2005;37:182–6.Google Scholar
  55. 55.
    Viswanathan M, Tsuchida N, Shanmugam G. Promoter hypermethylation profile of tumor-associated genes p16, p15, hMLH1, MGMT and E-cadherin in oral squamous cell carcinoma. Int J Cancer. 2003;105:41–6.Google Scholar
  56. 56.
    Wong TS, Liu XB, Wong BY, et al. Mature miR-184 as potential oncogenic microRNA of squamous cell carcinoma of tongue. Clin Cancer Res. 2008;14:2588–92.Google Scholar

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© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Department of PathologyUniversity of Texas M.D. Anderson Cancer CenterHoustonUSA

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