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A. Characteristicsnavigator

  1. Arise from Local Structures
    1. Mucous Membranes - squamous cell (SC-HNC) carcinomas (oral cavity, larynx, pharynx)
    2. Salivary glands (usually parotid) - adenomas, adenocarcinomas, mucoepidermoid cancer
    3. Skin Cancer - SC-HNC and basal cell carcinomas very common
    4. Pharynx - nasopharyngeal carcinomas
    5. Thyroid Cancer - papillary and follicular carcinomas
    6. Lymph Nodes - lymphomas
    7. HNC presentation of metastases from other primaries (such as lung, stomach)
  2. Accounts for ~5% of newly diagnosed cancers in the USA
    1. About 43,000 new cases and 12,000 deaths per year in USA)
    2. Worldwide, 650,000 new cases and 350,000 deaths per year
    3. Typically affects men >50 years old
    4. Most commonly oral cancer (~30,000 new cases annually)
    5. Worldwide, ~300,000 new cases of oral cancer per year
    6. About 65% of patients present with advanced satge disease (regional lymph nodes, LN)
  3. Types of HNC in Adults [1]
    1. Majority are squamous cell carcinomas (SC-HNC) in different locations in head and neck
    2. Tongue cancers most common - usually lateral tongue (~25%)
    3. Larygeal cancer ~9,500 cases per year (~20%) [3]
    4. Lip cancer - behaves more like skin cancer, good prognosis (~14%)
    5. Floor of mouth cancers (~14%)
    6. Tonsilar cancers (~12%)
    7. Other parts of mouth, total palate, pyriform sinus in ~8% each
    8. Nasopharyngeal cancer: ~5% of cases (~1/100,000 in general population) [7]
    9. Hypopharynx and oropharynx are least common (~4% each)
    10. Nasopharyngeal cancer is relatively common in people of Cantonese/Chinese Descent
    11. Rarely occurs as osteosarcoma in maxillofacial region [6]
  4. Risk Factors
    1. Tobacco (all forms) - smoking is major contributor to oropharyngeal cancers
    2. Increasing age
    3. Alcohol, when combined with smoking, leads to >15X increased risk
    4. Human papilloma virus (HPV) types 18 and 16 infection (~15X risk) [9]
    5. At least 25% of SC-HNC has HPV DNA in cells; maybe higher levels
    6. Occupational: nickel refining, woodworking, textile fibers (for sinonasal carcinoma)
    7. Oral leukoplakia, particularly aneuploid dysplastic form [17,18]
  5. Screening
    1. American Cancer Society and National Cancer Institute recommend screening
    2. Very careful screening physical exam by general internist and dentist recommended
    3. US Preventive Task Force says insufficient evidence for general screening
    4. For high risk patients (heavy smoking ± alcohol) is recommended
    5. Assess for leukoplakia, erythroplakia, frank neoplasms, lymphadenopathy
    6. Evaluate salivary glands carefully
  6. Protection
    1. Dietary carotenoids
    2. High intake fruits and vegetables
    3. Long term use of non-steroidal anti-inflammatory drugs (NSAIDS) reduced risk of oral cancers in smokers but increases risk of cardiovascular events [23]
  7. Head and Neck Masses in Children and Adolescents [5]
    1. Rhabdomyosarcoma
    2. Soft tissue sarcomas - synovial, fibrosarcoma, Ewing's, peripheral nerve sheath tumor, primitive neuroectodermal tumor
    3. Benign parotid gland tumors - pleomorphic adenoma, papillary cystadenoma (Warthin's)
    4. Malignant parotid gland tumors - mucoepidermoid, acinic cell, lymphoma, mucosa associated lymphoma of the salivary gland
    5. Lymphoma: Hodgkin's and Non-Hodgkin's
    6. Multisystem Inflammatory Disease: Castleman's Disease, sarcoidosis
    7. Cervical lymphadenopathy syndromes: Rosai-Dorfman, Kikuchi-Fujimoto
    8. Parotid gland infection
  8. Hoarseness Differential [22]
    1. Infection (URI in most cases)
    2. Rhinosinusitis with postnasal drip
    3. Allergies / Allergic Rhinitis
    4. LPR
    5. Benign or malignant vocal cord lesion (laryngeal tumor)

B. Development of SC-HNC in Adultsnavigator

  1. Etiology
    1. Chemical carcinogens - tobacco and/or alcohol are major contributors
    2. Human Papillomavirus (HPV) - particularly in those with >6 oral sex partners [9]
    3. Epstein-Barr Virus (EBV) in nasopharyngeal cancer
    4. Possible genetic predisposition
    5. HIV: oral Kaposi sarcoma, lymphomas
  2. Smoking [23]
    1. Major contributor to all forms of oropharyngeal, laryngeal cancers
    2. Quitting smoking reduces risk of developing oral cancer by >50%
    3. Long term use of non-steroidal anti-inflammatory drugs (NSAIDS) reduced risk of oral cancers
  3. HPV [1,9]
    1. Increasing numbers of oral sex partners associated with increased HPV and HNC
    2. With sensitive techniques, HPV 16 DNA found in 72% of HNC (15X risk for SC-HNC)
    3. Type 18 also a major risk factor
    4. In patients without heavy smoking or alcohol intake, HPV is probably most important risk
  4. Nasopharyngeal Carcinoma [7,21]
    1. EBV associated with particularly anaplastic type
    2. Certain anti-EBV responses are associated with highly increased risk
    3. IgA anti-viral capsid antigen and anti-DNAse Abs very high risk for development of nasopharyngeal carcinoma
    4. Plasma EBV levels detectable in >90% of patients with advanced nasopharyngeal cancers
    5. Patients with persistently detectable plasma EBV levels had worse overall prognosis than those with undetectable levels one week after completion of radiotherapy [21]
  5. Premalignant Lesions
    1. Leukoplakia
    2. Erythroplakia - carries ~40% risk of harboring malignancy
    3. Nasopharyngeal carcinoma in situ and dysplasia - EBV genome is very common
  6. Oral Leukoplakia [10,11,18]
    1. White patches of oral cavity
    2. Carry ~10% risk of harboring malignancy
    3. Squamous cell cancers developing from leukoplakia have very poor prognosis
    4. In leukoplakia cells, aneuploidy has 27X, tetraploidy 20X, risk of cancer versus diploid
    5. Aneuploid dysplastic oral leukoplakia carries worst prognosis, may reflect true cancer
    6. DNA ploidy is a better prognosticator than histologic grade of tumor
    7. Analysis of DNA ploidy in cells surrounding surgical resection may be useful
    8. Complete resection of aneuploid oral leukoplakia had no effect on outcomes [19]
    9. Aneuploid leukoplakia carried a 73% mortality at 5 years

C. Genetic Alterations [1,11] navigator

  1. Loss of chromosomal region 9p21 is most common early event in >75% of SC-HNC
    1. Leads to inactivation of p16 gene, a cyclic dependent kinase inhibitor
    2. p16 is an important regulator of the cell cycle
  2. ~50% of tumors have p53 (TP53) mutations (chr 17p13)
    1. Strongly associated with alcohol intake and tobacco
    2. Loss of p53 function results in progression from preinvasive to invasive lesions
    3. Disruptive mutations associated with 1.7X increased risk for death in SC-HNC [28]
  3. Amplification of proto-oncogene cyclin D1 expression
    1. Cyclic D1 constitutively activates cell cycle progression
    2. Observed in ~33% of HNC
  4. Overexpression of epidermal growth factor receptor family members and/or
    1. About 90% of SC-HNC have c-erbB/HER2 overexpression
    2. HER1 (EGFR1) is amplified in many SC-HNC as well
  5. Amplification of several oncogenes (such as int-2, bcl-1)
  6. Amplification of p63 (keratinocyte proliferation) gene

D. Symptoms and Diagnosisnavigator

  1. High Suspicion
    1. Oral cavity lesions that do not heal or that bleed easily
    2. Chronic hoarseness, cough, stridor or change in voice - laryngeal Ca
    3. Nasal obstruction and/or recurrent epistaxis - nasopharyngeal Ca or sinus Ca
    4. Tongue pain and/or mass - tongue Ca
    5. Odynophagia, dysphagia, sore throat - hypopharyngeal or esophageal lesions
    6. Eustachian tube dysfunction - nasopharyngeal Ca
    7. Persistent lymphadenopathy or neck mass
    8. Any chronic persistent head and neck pain and/or mass should be investigated
    9. These patients are at life-long risk for a second primary tumor at another site
  2. Complete Head and Neck Exam Essential
    1. Careful examination of mucous membranes: examination and palpation
    2. Indirect and fiberoptic (direct) Laryngoscopy
    3. Look for serous otitis media in nasopharyngeal Ca (osbstructed Eustachian tube)
    4. Look for multiple primary lesions
    5. Fine needle aspiration for neck nodes or masses has >90% accuracy
  3. Standard Radiography
    1. Computerized Tomographic (CT) with contrast or Magnetic Resonance Imaging (MRI)
    2. Positron Emission Tomography (PET) scans with 2-deoxyglucose are increasingly done
    3. Imaging of head and neck with contrast
    4. Assess for local invasion
    5. Assess lymph node (LN) involvement
  4. Staging by TNM and Clinical (Stage 0-IV) Systems
    1. ~30% of patients present with confined T1 (<2cm) or T2 (<4cm) lesions
    2. Prognosis depends both on LN involvement and tumor size as well as tumor resectability
    3. Molecular staging is being refined and will likely be more accurate than anatomic stages
    4. Staging is done, but therapeutic decisions usually grouped as local, locally advanced (operable or inoperable), and metastatic
  5. Soluble Interleukin-2 (IL2) Receptors [12]
    1. sIL2-R alpha chain produced from cleavage of membrane bound IL2-R
    2. Patients with <70 pmol/L sIL-R at diagnosis at reduced risk for relapse over 3 years
    3. These findings were independent of stage or tumor grade
    4. sIL2-R is an independent prognostic marker in head and neck cancer patients

E. Staging Nasopharyngeal Carcinoma [7]navigator

  1. Standard TNM staging system
  2. Tumor (T) in Nasopharynx
    1. T1 - tumor confined to nasopharynx
    2. T2 - tumor extends to soft tissues of orophynx and/or nasal fossa
    3. T2a - without parapharyngeal extension
    4. T2b - with parapharyngeal extension
    5. T3 - invades bony structures and/or paranasal sinuses
    6. T4 - intracranial extension and/or involving cranial nerves, infratemporal fossa, hypopharynx, or orbit
  3. Lymph Nodes (N)
    1. NX - not assessable
    2. N0 - no regional LN involvement
    3. N1 - unilateral metastasis to LN, <6cm, above supraclavicular fossa
    4. N2 - bilateral metastasis to LN, <6cm, above supraclavicular fossa
    5. N3 - metastasis in LN; N3a >6cm dimension; N3b extension to supraclavicular fossa
  4. Metastasis (M)
    1. M0 - no metastasis
    2. M1 - metastasis present
  5. Stage Grouping
    1. Stage 0: T1s, N0, M0
    2. Stage I: T1, N0, M0
    3. Stage IIA: T2a, N0, M0
    4. Stage IIB: T1/2, N1, M0 or T2b, N0, M0
    5. Stage III: T1/2/3, N2, M0 or T3, N0/1/2, M0
    6. Stage IVA: T4, N0/1/2, M0
    7. Stage IVB: Any T, N3, M0
    8. Stage IVC: Any T, Any N, M1

F. Treatmentnavigator

  1. Multiple modality therapy is standard of care in all but most localized disease
  2. Surgery
    1. Mainstay of therapy for all stages of disease
    2. Goal is conservation of organ function with removal of tumor
    3. Improved cosmetic results have been obtained
    4. Induction (neoadjuvant) chemotherapy prior to surgery can reduce surgical extent and improve chances of cure
    5. Induction chemotherapy with paclitaxel, a cisplatin, and fluorouracil (5-FU) prior to surgery improved overall survival versus surgery alone [1]
    6. Side effects are possible cosmetic deformity, loss of function (speech, swallowing)
    7. Overall, most cancers require dysfiguring surgeries
    8. Positivity of surgical margins following resection is major prognostic factor
  3. Local Disease
    1. Surgery - may be curative for local disease; debulking often required in advanced disease
    2. Radiation therapy
    3. The benefits of adjuvant chemotherapy in nonmetastic head and neck cancer are small (~10% benefit) and even questionable [8]
    4. Routine use of adjuvant chemotherapy in early disease is discouraged
    5. In advanced laryngeal cancer, pre-surgical chemotherapy can allow larynx sparing [3]
  4. Radiation Therapy
    1. Can be curative for locoregional disease, particularly glottic, base of tongue, tonsillar cancers
    2. Combination with chemotherapy for locally advanced and metastatic disease
    3. Shortening treatment time by increasing from 5 to 6 radiation fractions weekly is beneficial (66% versus 73% disease specific overall survival) but increases morbidity [14]
    4. Hyperfractionated radiotherapy superior to accelerated or standard for stage III-IV [16]
    5. Post-operative radiotherapy combined with cisplatin is superior to radiotherapy alone in high risk / locally advanced squamous head and neck cancer [19,20]
    6. Cetuximab (an EGF-R blocker) in combination with high-dose radiotherapy improved progression free and overall survival in locoregionally advanced head and neck SCC [25,26]
    7. Substantial side effects with mucositis, xerostomia
    8. Risk of xerostomia doubles with adding cisplatin (which is usually done)
    9. Amifostine IV given daily concurrently with postoperative radiotherapy reduces xerostomia
    10. Pilocarpine, a cholinergic agonist, reduces sensation of dry mouth
    11. Erythropoietin improved anemia but not cancer control in radiation therapy patients [15]
  5. LN Involvement
    1. Radical Neck Dissection
    2. Radiation for occult involvement or low tumor volumes
    3. Combination chemotherapy + hyperfractionated irradiation improves survival, relapse free survival, and locoregional control of disease
    4. Patients with poor therapeutic responses usually die of complications of local disease
    5. Neoadjuvant chemotherapy followed by radiation therapy may be curative [3]
  6. Anti-EGF-R MAb (cetuximab, Erbitux®) [13,24,25]
    1. IgG1 MAb against ligand binding domain of epidermal growth factor (EGF) receptor (EGF-R)
    2. Enhances cytotoxic effects of radiation in squamous cell type of HNC (SC-HNC)
    3. In combination with high-dose radiotherapy, improved disease control and survival in locoregionally advanced SC-HNC [25]
    4. Acne-like skin rash in up to 88% of patients, severe in 12%
    5. Loading dose of cetuximab 400mg/m2 IV over hours, then 250mg/m2 over 1 hour weekly
    6. Initially approved in relapsed colon cancer
  7. Inoperable Stage III/IV SC-HNC
    1. Radiation with concurrent chemotherapy is standard of care
    2. Initial induction chemotherapy with cisplatin + 5-fluorouracil (5FU) improves survival
    3. Standard of care now induction chemotherapy with cisplatin + 5FU (PF) followed by chemoradiotherapy (carboplatin weekly with radiotherapy 5 days per week)
    4. Three-year survival with PF 48% versus 62% for docetaxel (Taxotere®) added to PF [27]
    5. Docetaxel+PF superior locoregional control, but increased neutropenia, veruss PF [27]
  8. Stage IV HNC
    1. Combination chemotherapy combined with radiation and/or surgery is standard
    2. 5-fluorouracil (FU) + cisplatin based regimens are mainstay of treatment
    3. Taxanes (paclitaxel, docetaxel) are also very active and may be combined with platinums
    4. In locally advanced laryngeal Ca, cisplatin with current radiotherapy is superior to induction chemotherapy given before radiotherapy or radiotherapy alone [4]
    5. Disease free survival highest with concurrent cisplatin/radiotherapy but rates of mucosal toxicity were also highest with this regimen [4]
  9. Patients who continue to smoke during radiation therapy have reduced response rates
  10. Chemoprevention with Retinoids
    1. Isotretinoin (vitamin A derivative), low dose, is active against leukoplakia
    2. Controversial role in preventing second primary lesion occurrance

References navigator

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  22. Ford CN. 2005. JAMA. 294(12):1534 abstract
  23. Sudba J, Lee JJ, Lippman SM, et al. 2005. Lancet. 366(9494):1359 abstract
  24. Cetuximab and Bevacizumab. 2004. Med Let. 46(1184):46
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