Tumor Biology and Immunology of Head and Neck Cancer

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Tumor Biology and Immunology of Head and Neck Cancer

Head and Neck Surgery
Author Credentials 

Tammara L. Watts, MD, PhD
Medical College of Georgia
1120 15th Street, BP-4109
Augusta, GA 30912-4060

Subinoy Das, MD
Medical College of Georgia
1120 15th Street, BP-4109
Augusta, GA 30912-4060

Michael G. Moore, MD
University of California at Davis Medical Center
2521 Stockton Blvd.  #7200
Sacramento, CA 95817

Module Summary
  1. Define the TNM staging for each of the subsets of head and neck cancer as defined by the AJCC.
  2. Outline the major risk factors for the development of squamous cell carcinoma of the head and neck and the current trends in epidemiology.
  3. Describe the multiple-hit theory of tumorigenesis and its implications for diagnosis and treatment.
  4. Outline with the current mechanisms for targeted therapies for use in the treatment of head and neck squamous cell carcinoma.
  5. Describe the role of HPV infection in the pathogenesis of head and neck cancer and cite the current indications for HPV vaccination.
  6. Define the concept of de-escalation trials and their role in the management of HPV-related oropharyngeal cancer.
Module Learning Objectives 
  1. Classify tumors according to subsite (anatomy) and stage all forms of head and neck cancer.
  2. Describe the basic biology of tumorigenesis in head and neck cancer.
  3. List the common carcinogens and genetic abnormalities that promote head and neck tumorigenesis.
  4. Outline the targets of therapeutic modalities that treat head and neck cancer.
  5. Be familiar with the ongoing clinical trials and current research efforts to treat and cure head and neck cancer. 

Anatomy

Learning Objectives 
  1. Describe the importance of anatomical subsite and its relevance to tumor biology.
  2. Define the concepts simultaneous, synchronous, and metachronous tumors. 
  3. Outline the differences between the 7th and 8th Editions of the AJCC TNM staging for head and neck cancer.
References 
  1. National comprehensive cancer network: practice guidelines in clinical oncology.
  2. American Joint Committee on Cancer. 8th Edition, Springer.
  3. Gourin CG. Terris DJ. Carcinoma of the hypopharynx. Surg Oncol Clin N Am. 2004;13(1):81-98. 
  4. Janfaza P, Nadol JB, Galla RJ, Fabian RL, and Montgomery, WW.  Surgical anatomy of the head and neck.  Lippincott Williams and Wilkins 2001.

Pathogenesis

Learning Objectives 
  1. Outline the basic concepts of tumor biology as it is related to squamous cell carcinoma of the head and neck.  Specifically, be able to define the concept of field cancerization and the role of carcinogen exposure.  
  2. Describe the difference between tumor suppressor genes and oncogenes.
  3. Define tumor complexity and intratumoral heterogeneity and their significance in tumor response to therapy.
  4. Outline with the role of genes in the development of squamous cell carcinoma, specifically p53, retinoblastoma gene, INK4 gene family, Cyclin D1, and P21.
  5. Define the basic concepts of apoptosis (programmed cell death), immortalization, and angiogenesis and how these pathophysiologic changes affect tumor development.
  6. Recognize the role of viruses (i.e. HPV and EBV), environmental exposures (i.e. heavy metal exposure, ionizing radiation, etc.) and social influences (alcohol and tobacco use) on the development and head and neck cancer.  
  7. Cite the current indications for vaccination against high right HPV.
References 
  1. Lentsch, EJ, and Myers, JN.  Pathogenesis and Progression of Squamous Cell Carcinoma of the Head and Neck.  In Myers, EN et al. Cancer of the Head and Neck. 4th ed. Philadelphia, PA:  Saunders; 2003:5-28.
  2. Richtsmeier WJ. Tumor biology and immunology of head and neck cancer. In: Bailey, BJ, editor. Head and neck surgery – otolaryngology. Vol. 2. Philadelphia: Lippincott Williams & Wilkins; 2001:1211-21.
  3. Sharpless NE, DePinho RA. p53: good cop/bad cop. Cell. 2002;110(1):9-12. 
  4. Stransky N, Egloff AM, TwardAD, Kostic AD, Cibulskis K, Sivachenko A, et al. The mutational landscape of head and neck squamous cell carcinoma. Science 2011 Aug 26;333(6046):1157-60.
  5. Wiseman SM, Stoler DL,  Anderson GR. The role of genomic instability in the pathogenesis of squamous cell carcinoma of the head and neck. Surgi Oncol Clin N Am. 2004;13(1):1-11.
  6. Boscolo-Rizzo P, RampazzoE, Perissinotto E, Piano MA, Giunco S, Baboci L. et al. Telomere shortening in mucosa surrounding the tumor: biosensor of field cancerization and prognostic marker of mucosal failure in head and neck squamous cell carcinoma. Oral Oncol. 2015 May;51(5):500-7.
  7. Meites E, Kempe A, Markowitz LE.  Use of a 2-Dose Schedule for Human Papillomavirus Vaccination – Updated Recommendations of the Advisory Council of Immunization Practices. MMWR.  2016 Dec;65(49):1405-8.
  8. Ausoni S, Boscolo-Rizzo P, Singh B, et al.  Targeting cellular and molecular drivers of head and neck squamous cell carcinoma: current opinions and emerging perspectives. Cancer and Metastasis Rev. 2016 Sep;35(3):413-26.
  9. Mroz, E. A., Tward, A. M., Hammon, R. J., Ren, Y., & Rocco, J. W. Intra-tumor genetic heterogeneity and mortality in head and neck cancer: analysis of data from the cancer genome Atlas.  PLoS Med. 2015 Feb 10;12(2):e1001786.
  10. Network CGA. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015 Jan 29;517(7536):576-82.

Basic Science

Learning Objectives 
  1. Describe the mechanism of checkpoint inhibitors that act through the CTLA-4 and PD-1/PD-1L pathways. 
  2. Outline the mechanism of action of monoclonal antibodies such as nivolumab and pembrolizumab as immunotherapy and targeted therapy in head and neck cancer.
  3. Understand the mechanism of action of iressa, cetuximab. 
References 
  1. Ciardiello F, Caputo R, Bianco R, et al.  Antitumor Effect and Potentiation of Cytotoxic Drugs Activity in Human Cancer Cells by ZD-1839 (Iressa), an Epidermal Growth Factor Receptor-selective Tyrosine Kinase Inhibitor.  Clinical Cancer Research.  2000 May;6(5):2053-63.
  2. Baselga, J. The EGFR as a target for anticancer therapy—focus on cetuximab.  Eur J Cancer. 2001 Sep;37 Suppl 4:S16-22.
  3. Tosoni A, Franceschi E, Pasquini E, et al. Immunotherapy in head and neck cancer: evidence and perspectives. Immunotherapy.  2017 Dec;9(16):1351-8.

Incidence

Learning Objectives 
  1. Know the basic epidemiology of head and neck cancer.
  2. The most prevalent tumor types (squamous cell, adenocarcinoma, melanoma).
  3. The associations with advanced stage: tumor grade (poorly differentiated), race (African American), and income level (low).
  4. Be familiar with the role of skin cancer in the head and neck, with particular attention to melanoma, incidence, pathophysiology, staging, unique surgical challenges in tumor resections of the head and neck.
References 
  1. Hoffman HT, Karnell LH, Funk GF, Robinson RA, Menck HR. The National Cancer Data Base report on cancer of the head and neck. Arch Otolaryngol Head Neck Surg. 1998;124(9):951-62.
  2. Sankaranarayanan R, Masuyer E, Swaminathan R, et al.  Head and neck cancer: a global perspective on epidemiology and prognosis. Anticancer Res.1998;18(6B):4779-86.
  3. Schmalbach CE, Nussenbaum B, Rees RS, et al.  Reliability of Sentinel Lymph Node Mapping With Biopsy for Head and Neck Cutaneous Melanoma. Arch Otolaryngol Head Neck Surg. 2003; 129(1): 61-65.
  4. Stanley P,  Leong L, Accortt NA, et al. Impact of Sentinel Node Status and Other Risk Factors on the Clinical Outcome of Head and Neck Melanoma Patients. Arch Otolaryngol Head Neck Surg. 2006;132:370-373.
  5. Stein A, Saha S, Kraniger J, et al. Prevalence of human papillomavirus in oropharyngeal cancer: a systematic review.  Cancer Journal of Sudbury Mass. 2015;21:138-46.

Patient Evaluation

Learning Objectives 
  1. Be familiar with the prognostic consequences of various genetic mutations and biological findings in head and neck cancers, including ploidy,lymphovascular invasion, perineural invasion, BRAF mutations.
  2. Understand the role of HPV infection and P16 in the pathogenesis of head and neck cancer patients with respect to prognosis and response to treatment.
References 
  1. Gillison ML. Human Papillomavirus and Prognosis of Oropharyngeal Squamous Cell Carcinoma: Implications for Clinical Research in Head and Neck Cancers. J Clin Oncol. 2006; 24:(36)5623-5625.
  2. Temam S, et al. p53 gene status as a predictor of tumor response to induction chemotherapy of patients with locoregionally advanced squamous cell carcinomas of the head and neck. J Clin Oncol. 2000;18 385.
  3. Zatterstrom UK, Wennerberg J, Ewers SB, Willen R, Attewell R. Prognostic factors in head and neck cancer: histologic grading, DNA ploidy, and nodal status. Head Neck. 1991;13(6):477-87. 
  4. Xing M, Alzahrani AS, Carson KA, et al.  Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer. JAMA. 2013 Apr;309(14):1493-501.

Measurement of Functional Status

Learning Objectives 
  1. Outline the ECOG performance status and how it might impact treatment decisions.
  2. Describe the different categroeis of the Karnofsky score.
References 
  1. Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655.
  2.  Karnofsky DA, Abelmann WH, Craver LF, Burchenal JH. The Use of the Nitrogen Mustards in the Palliative Treatment of Carcinoma – with Particular Reference to Bronchogenic Carcinoma. Cancer. 1948;1(4):634-56.

Imaging

Learning Objectives 
  1. Understand the indications and limitations of computed tomography (CT), ultrasound, and magnetic resonance imaging (MRI) in the management of head and neck cancers.
  2. Understand the use of positron emission tomography (PET) versus PET-CT in the pre and post treatment management of head and neck cancer.
  3. Outline the role of PET/CT imaging in the evaluation of well differentiated thyroid cancer.  In particular, describe the relationship of PET avidity and RAI uptake.
References 
  1. Aygun F, Oliverio PJ, and Zinreich SJ. Overview of Diagnostic Imaging of the head and neck. In Cummings CW. eds. Otolaryngology head and neck surgery.  Vol. 1. Philadelphia:  Elsevier; 2005:25-92. 
  2. 9790297 Mendenhall WM, Mancuso AA, Parsons JT, et. al. Diagnostic evaluation of squamous cell carcinoma metastatic to cervical lymph nodes from an unknown head and neck primary site. Head Neck. 1998;(8):739-44.
  3. Wechalekar K, Sharma B, and Cook G. PET/CT in oncology-a major advance. Clin Radiol. 2005;60(11):1143-55.

Treatment

Learning Objectives 
  1. Describe how radiation kills tumor cells.  Know what tumors in the head and neck are uniquely radiosensitive and which tumors are not, and therefore treated with primary surgery.
  2. Outline which stage tumors require multimodality therapy and how, when, and why chemotherapy is added to a treatment regimen.
  3. Understand the concept of adverse pathologic features, and when postoperative radiation therapy is appropriate.
  4. Understand the concept of salvage surgery.
  5. Outline the appropriate timing of post treatment imaging (PET/CT) and what criteria should be used to consider salvage neck dissection for residual lymphadenopathy.
  6. Outline which patients are candidates for post-treatment neck dissection, the timing of surgery, and why.
  7. Read, know, and be able to reference the VA laryngeal preservation trial and how this impacted treatment of larynx cancer.
  8. Outline indications for the use of adjuvant radiation and chemoradiation therapy.
References 
  1. Ang KK, Milas L, and Shiu AS.  General Principles of Radiation Therapy for Cancer of the Head and Neck. In: Myers, et al, eds.,Cancer of the Head and Neck, 4th ed. Philadelphia: Saunders; 2003:717-745. 
  2. Brown, JM. Exploiting the hypoxic cancer cell: mechanisms and therapeutic strategies. Mol Med Today. 2000;6(4):157-62.
  3. Head and neck neoplasms in: http://www.clinicaltrials.gov
  4. Hussey DH and Wen BC.  Principles of Radiation Oncology. In: Bailey BJ, et al, eds., Head and Neck Surgery-Otolaryngology, 3rd ed. Philadelphia: Lipincott Williams &Wilkins; 2001:1199-1210.  
  5. Meyers, EN, Suen JY, Myers JN, Hanna EYN. Cancer of the Head and Neck. 4th ed. Saunders. 2003.
  6. PMID: 2034244 Wolf, GT. The Department of Veterans Affairs Laryngeal Cancer Study Group. Induction Chemotherapy Plus Radiation Compared with Surgery Plus Radiation in Patients with Advanced Laryngeal Cancer. N Engl J Med. 1991.324:1685-90.
  7. Bernier J, Cooper JS, Pajak TF, van Glabbeke M, Bourhis J, Forastiere A, et al. Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head and neck. 2005;27(10):843-50.
  8. Puram SV, Rocco JW.  Molecular Aspects of Head and Neck Cancer Therapy.  Hematol Oncol Clin North Am. 2015 Dec:29(6):971-82.
  9. Ferris R, Blumenschein Jr. G, Fayette J, et al. Nivolumab for Recurrent Squamous Cell Carcinoma of the Head and Neck. N Eng J Med. 2016;375(19):1856-67.
  10. Chow LQM, Haddad R, Gupta S, et al.  Antitumor Activity of Pembrolizumab in Biomarker-Unselected Patients with Recurrence and/or Metastatic Head and Neck Squamous Cell Carcinoma:  Results from the Phase 1b KEYNOTE-012 Expansion Cohort. J Clin Oncol. 2016 Nov 10;34(32):3838-3845.

Staging

Learning Objectives 

Outline the differences between the 7th Edition and the 8th Edition of the AJCC Staging Systems.

References 
  1. American Joint Committee on Cancer. 7th and 8th Edition, Springer.

Complications

Learning Objectives 

Outline the commonly observed side effects of cisplatin, cetuximab, and approved immunotherapeutic agents.

Review

Review Questions 
  1. Define a T3N1M0 of the hypopharynx.
  2. Is alcohol a carcinogen? How does alcohol increase the incidence of squamous cell carcinoma of the head and neck?
  3. What is the difference between a synchronous and metachronous form of recurrence?
  4. What are the functions of p16, EGFR, and p53?
  5. What are the indications for PET-CT in head and neck cancer?
  6. What is INGN-201 (p53 gene transfer) and how does it work?
  7. What is the mechanism of action of iressa and what tumors are responsive to this therapy?
  8. How do nivolumab and pembrolizumab impart their therapeutic effects on patients and what are the current indications for their use?
Resources 

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