1. Head & Neck cancer –Resident lecture 2015

2. Head and Neck Cancers - Tumors arising from the epithelial lining of the upper aerodigestive tract - Squamous cell cancer or a variant is the most common histologic type

3. Anatomy of the Head and Neck

4. Epidemiology- Head and Neck Cancer
Accounts for 3% of all new cases of cancer in U.S.
2% of cancer deaths
M:F is 2.5 to 1 but as high as 7:1 in CA-larynx
75% of H & N cancer is related to cigarette smoking and alcohol
Use of BOTH tobacco and alcohol > multiplicative risk
CA- nasopharynx and paranasal sinus are NOT related to tobacco and alcohol
Incidence of 2nd primary cancer in patients with H & N CA is 3-7% annually, particularly for other sites of H&N, lung and esophagus (mucosal field defect)
Epidemiology- Head and Neck Cancer

5. HNC: The Statistics Women Estimated New Cases=11,710
Cancer Cases and Deaths of the Oral Cavity & Pharynx by Sex, United States, 2012 Estimates
Men
Estimated New Cases=28,540
8th leading cause of cancer in men
Lifetime probability is 1 in 69
Estimated New Deaths=5,440
Women
Estimated New Cases=11,710
Estimated New Deaths=2,410
American Cancer Society. Cancer Facts & Figures 2012. 5

6. U.S. Incidence Rates for HNC
In 2012, >40,000 new cases are expected
Incidence more than twice as high in men as in women
From 2004 to 2008, incidence rates declined by 1.0% per year in women and were stable in men
Incidence is increasing for oropharynx cancers associated with human papillomavirus (HPV)
American Cancer Society. Cancer Facts & Figures 2012.
National Cancer Institute. A Snapshot of Head and Neck Cancer. October 2011. 6

7. U.S. Incidence Rates for HNC
In 2012, >40,000 new cases are expected
Incidence more than twice as high in men as in women
From 2004 to 2008, incidence rates declined by 1.0% per year in women and were stable in men
Incidence is increasing for oropharynx cancers associated with human papillomavirus (HPV)
American Cancer Society. Cancer Facts & Figures 2012.
National Cancer Institute. A Snapshot of Head and Neck Cancer. October 2011. 7

8. U.S. Survival Rates for HNC
For all stages of HNC combined, about
84% survive 1 year after diagnosis
61% survive 5 years after diagnosis, and
50% survive 10 years after diagnosis
Five-year Relative Survival Rates by Stage at Diagnosis, *
Oral cavity
& pharynx
All Stages
Local
Regional
Distant
61%
82%
56%
34%
*Rates are adjusted for normal life expectancy and are based on cases
diagnosed in the SEER 17 areas from , followed through 2008.
American Cancer Society. Cancer Facts & Figures 2012. 8

9. Relative Survival Rate (%) by Primary HNC Site, 1988-2001
Piccirillo JF, et al. National Cancer Institute. SEER Survival Monograph. Chapter 2 9

10. Risk Factors for Head and Neck Cancer
Tobacco Products:
Smoking Tobacco
Cigarettes
Cigars
Pipes
Chewing Tobacco
Snuff
Ethanol Products
Chemicals:
Asbestos
Chromium
Nickel
Arsenic
Formaldehyde
Other Factors:
Ionizing Radiation
Plummer-Vinson Syndrome
Epstein-Barr Virus
Human Papilloma Virus
As with lung cancer, many etiologic agents and risk factors have been associated with head and neck cancer. While evidence for some of them may not be very strong, the risk of developing an oral, pharyngeal or laryngeal cancer increases linearly with tobacco and alcohol consumption.
Numerous studies have concluded that tobacco, which contains carcinogens such as polonium 210, nitrosamines, and aromatic hydrocarbons, is directly linked to development of carcinomas.
More than 90 percent of oropharyngeal cancers are associated with smoking.
Alcohol has a strong association with head and neck cancer as well, especially when a user also smokes or chews tobacco. Although alcohol itself is not a carcinogen, it promotes the carcinogenicity of tobacco.
Various chemicals have been associated with head and neck cancer, including asbestos, chromium, nickel, arsenic and formaldehyde. Whether asbestos is a risk factor for head and neck cancer is controversial. While it is a strong risk factor for lung cancer, some studies have found no increased risk of head and neck cancers among asbestos workers.
Other factors in head and neck cancer include ionizing radiation, Plummer-Vinson Syndrome, Epstein-Barr Virus and Human Papilloma Virus. Plummer-Vinson Syndrome is rare, but these patients definitely have a high incidence of hypopharyngeal cancer. Though a cause-and-effect relationship has not been established, Human Papilloma Virus DNA has been isolated from head and neck cancer as well as from cancers of the uterine cervix in females.

11. Smoking-Associated HNC
American Cancer Society. Cancer Statistics 2012. 11

12. Tobacco Use and Related Cancers on the Decline
American Cancer Society. Cancer Statistics 2012. 12

13. Possible Occupational Risks for Head and Neck Cancer
Woodworking
Leather manufacturing
Nickel refining
Textile industry
Radium dial painting
Possible Occupational Risks for Head and Neck Cancer
Various studies have shown that some head and neck cancers are strongly associated with specific occupations. For example, woodworkers in the furniture-building industry are prone to carcinomas of the paranasal sinuses. Paranasal sinus cancer is rare, but an occupational exposure history is important in patients with recurrent epistaxis, nasal obstruction, or facial pain. Other occupations with exposures related to head and neck cancer risk include leather manufacturing, nickel refining, textile industry and, historically, radium dial painting.

14. Which of the following is FALSE
A) Smokeless tobacco is associated with oral cavity cancer
B) Betel quid is associated with cancers of the oral cavity
C) Cigars are associated with lower risk of H and N cancer than cigarettes
D) All of the above is true
E) All of the above is False

15. Which of the following is FALSE regarding Head and Neck cancer?
A) Vitamin A may be protective
B) The Plummer-Vinson syndrome increase the risk of hypopharyngeal cancer
C) Nickel exposure is a risk factor for sinonasal cancer
D) All of the above is true
E) All of the above is false

16. E6 and E7are HPV proteins that inactivate the
Explain the relationship between HPV, E6 and E7 proteins and p53 and pRB proteins in causing cancer
E6 and E7are HPV proteins that inactivate the
tumor suppressor proteins p53 and pRb,
which results in loss of cell cycle regulation,
cellular proliferation, and chromosomal instability

17. Carcinogens and viruses:
Smokeless tobacco and other oral chewed carcinogens — betel quid are associated with the development of cancers of the oral cavity.
The Plummer-Vinson syndrome, seen in women younger than 50, associated with iron-deficiency anemia, hypo pharyngeal webs, dysphasia, and a higher risk of cancers of the postcricoid and hypo pharynx.
Maxillary sinus: are associated with certain occupational exposures (e.g., nickel, radium, mustard gas, chromium, and byproducts of leather tanning and woodworking).
HPV is associated with oral cancers (oropharynx and tonsillar areas), most common types are 16 and 18.

18. HPV-related Oral Cancer

19. Rising Incidence of HPV-Associated Oral Squamous Cell Cancers in U.S.
10.0
9.0
8.0
7.0
Smoking related
6.0
HPV-U, APC1: 0.82
Age-Adjusted Incidence/ 100,000 Person-Yrs
HPV-U, APC2: -1.85*
5.0
4.0
3.0
2.0
HPV-R, APC3: 5.22*
HPV-R, APC2: -0.05
1.0
HPV-R, APC1: 2.06*
HPV related
1975
1980
1985
1990
1995
2000
2004
Year of Diagnosis
*P <0.05
APC, annual percentage change.
Chaturvedi AK, et al. J Clin Oncol. 2008;26: 19 19 19

20. Risk Factors: HPV-Associated Oropharynx Cancer
Younger age
Current oral HPV infection
High-risk sexual behaviors
First sexual experience at young age
Increasing number of vaginal- and oral-sex partners
D’Souza G, et al. N Engl J Med. 2007;356:

21. HPV-Associated Oropharynx Cancer
Incidence Rates* by Stage at Diagnosis
90% of HPV-related oropharyngeal cancers due to infection with HPV 16 subtype
Associated with a 9-fold increased risk of oropharyngeal cancer
Specifically linked to squamous cell carcinomas of the base of the tongue, tonsil, and epiglottis
Risk of oral HPV infection is increased for smokers
Rates per 100,000
*Age adjusted to the 2000 US standard population.
American Cancer Society. Cancer Facts & Figures 2012. 21

22. HPV-Associated Oropharyngeal Carcinogenesis
Persistent HPV infection of the oral cavity may lead to genetic damage and altered immune function, promoting progression to cancer
Apoptosis is a potent host defense against microbes
Viruses counteract this response
E6/E7 inactivate p53 and Rb
p16 expression increased
Postmitotic keratinocytes enter S phase and replicate viral genomes
Accumulation of mutations Inhibition of apoptosis
Transformation
Telomerase activation (TERT transcription)
Ubiquitination
Degradation
26s proteosome subunit?
calpain RB E6
p53
PDZ
E6AP
NFX1 E7
Narisawa-Saito M, et al. Cancer Sci. 2007;98: 22

23. Warning Signs of Head and Neck Cancer
Serous otitis media
Neck mass
Non-healing ulcer
Dysphagia
Submucosal mass
Hoarseness
Erythroplasia
Referred otalgia
Persistent sore throat
Epistaxis
Nasal obstruction
In some cases, head and neck cancer produce early warning signs that can lead to early diagnosis and a high probability of cure. For example, hoarseness frequently occurs in the very earliest laryngeal glottic cancers. Up to 80 percent of early oral cancers will demonstrate erythroplasia.
Referred otalgia may accompany a cancer of the larynx, pharynx or oral cavity. In addition, a persistent sore throat for longer than two weeks in a patient with a smoking history should arouse suspicion for a possible cancer in the larynx and/or pharynx.
Epistaxis, nasal obstruction, and serous otitis media can all herald a nasopharyngeal cancer. Early cancer in many sites, e.g., the epiglottis, pyriform sinus, nasopharynx and paranasal sinuses, are silent with few signs. Although not an early sign, a neck mass may be the first presenting symptom. Any high-risk patient with a neck mass should be thoroughly evaluated for a head and neck primary cancer. A non-healing ulcer, dysphagia or a submucosal mass may also serve as warning signs of potential carcinomas.
Not all cancers present with symptoms at early stages!

24. What is the most common genetic alteration that is involved in the transformation of normal mucosa to invasive squamous cell cancer?
A) The loss of chromosomal region 9p21
B) The loss of chromosomal region 9p22
C) The loss of chromosomal region 9p23
D) The loss of chromosomal region 9p24

25. Events- transformation of normal mucosa to invasive squamous cell carcinoma

26. What is the percentage of patients with laryngeal carcinoma who have distant mets at the time of diagnosis?
A) 10%
B) 20%
C) 30%
D) 40%

27. Clinical Presentation
Less than 10% have distant disease at time of presentation.
Many signs & symptoms are loco regional and referable to the primary site
Hypopharynx/larynx → sore throat, hoarseness, difficulty swallowing
Glottic larynx involvement detected earlier as change in voice obviously noted
Painless lump in the neck.

28. Match HPV EBV Oropharynx Nasopharynx
Associated histopath: Lymphoepithelioma
Associated histopath: Basaloid
Sexual transmission
Oral transmission
E6 and E7
LMP-1 and EBNA1
Cofactors Diet and genetics
Cofactors Tobacco & alcohol
Unknown primary
Distant metastases
Match

29. A 54 yo gentleman with 30 yp smoking history presenting with early glottic cancer. Staging workup showed no involved neck nodes, and a 3 cm lung nodule. What does the lung nodule most likely represent?
A) Metastatic disease
B) Primary lung cancer
C) Both possibilities are equal

30. What is the most frequent intraepithelial neoplastic lesion that predispose to oral cancer?
Leukoplakia

31. 90% Which of the following is FALSE?
A) Leukoplakia is a white, hyperkeratotic patch, distinguishable from thrush in that it does not scrape off
B) Approximately 80% are benign lesions that can be observed without treatment.
C) Erythroplakia appears as a red, velvety patch and is associated with a 10% incidence of severe dysplasia, carcinoma in situ, or invasive disease on microscopic examination
D) All of the above is TRUE
90%

32. Diagnosis/Staging
Comprehensive exam of head and neck – using mirrors, fiberoptic scopes.
Pay attention to involvement of neck nodes.
Examination under anesthesia for larynx and pharynx tumors.
Imaging of head and neck –CT with contrast or MRI
Chest xray- to r/o lung mets or second lung primary
Incidence of spread below clavicles at time of presentation is < 10% (except nasopharyngeal), so CT chest is not indicated unless pt has bulky neck disease.
PET/CT – only if CT is equivocal or primary site is unknown. This makes triple endoscopy controversial.
Histological proof of CA obtained from primary site or neck. Needle biopsy preferred to excisional to avoid theoretical risk of seeding along the track.

33. Nasopharyngeal cancer The eustachian tubes are frequently invaded by
Which head and neck cancer characteristically can present with otitis media?
Nasopharyngeal cancer
The eustachian tubes are frequently invaded by
Nasopharyngeal disease, leading to otitis media that,
in an adult, mandates careful
assessment of the nasopharynx.

34. Clinical staging used, not pathologic = physical + radiographic
TNM staging system used
T – site-specific, but in general:
T1-3 = increasing size of tumor
T4= invasion of muscle, cartilage or bone
T4a = surgically resectable disease
T4b= locally unresectable disease
N- nodal involvement is the same for all EXCEPT nasopharyngeal
Staging

35. Clinical Presentation/Diagnosis - pathologic LN in the neck may suggest primary site - oral cavity CA spread to level I - larynx CA- level II and III - disease in IV, V →suspect thyroid or primary below neck

36. Match between site and lymphatic drainange
upper part of the neck (levels II and III)
submental and submandibular areas (level I)
upper part of the neck and posterior triangle (levels II and V)
Supraclavicular (levels IV and V)
Oral cavity
Laryngeal cancer
Nasopharyn geal cancer
Thyroid
Match between site and lymphatic drainange

37. TNM Staging for the Oral Cavity
Primary tumor (T) TX
Primary tumor cannot be assessed T0
No evidence of primary tumor
Tis
Carcinoma in situ T1
Tumor ≤ 2 cm in greatest dimension T2
Tumor > 2 cm but ≤ 4 cm in greatest dimension T3
Tumor > 4 cm in greatest dimension
T4a
Moderately advanced local disease
Lip - Tumor invades through cortical bone, inferior alveolar nerve, floor of mouth, or skin of face
Oral cavity - Tumor invades adjacent structures (eg, through cortical bone or into deep extrinsic muscle of the tongue, maxillary sinus, or skin of face)
T4b
Very advanced local disease
Tumor invades masticator space, pterygoid plates, or skull base and/or encases internal carotid artery
NCCN Clinical Practice Guidelines in Oncology: Head and Neck Cancers. V 37

38. TNM Staging for the Oral Cavity (cont)
Regional lymph nodes (N) NX
Regional nodes cannot be assessed N0
No regional lymph node metastasis N1
Metastasis in a single ipsilateral lymph node ≤ 3 cm in greatest dimension N2
Metastasis in a single ipsilateral lymph node > 3 cm but ≤ 6 cm in greatest dimension; or in multiple ipsilateral lymph nodes, none > 6 cm in greatest dimension; or in bilateral or contralateral lymph nodes, none > 6 cm in greatest dimension
N2a
Metastasis in a single ipsilateral lymph node > 3 cm but ≤ 6 cm in greatest dimension
N2b
Metastasis in multiple ipsilateral lymph nodes, none > 6 cm in greatest dimension
N2c
Metastasis in bilateral or contralateral lymph nodes, none > 6 cm in greatest dimension N3
Metastasis in a lymph node > 6 cm in greatest dimension
Distant metastasis (M) M0
No distant metastasis M1
Distant metastasis
NCCN Clinical Practice Guidelines in Oncology: Head and Neck Cancers. V 38

39. TNM Staging Classification for the Lip and Oral Cavity
Anatomic Stage/Prognostic Groups*
Stage 0
Tis N0 M0
Stage I T1
Stage II T2
Stage III T3 N1
Stage IVA
T4a N2
Stage IVB
Any T
T4b N3
Any N
Stage IVC M1
*Nonepithelial tumors (eg, lymphoid tissue, soft tissue bone, and cartilage) are not included.
NCCN Clinical Practice Guidelines in Oncology: Head and Neck Cancers. V

40. B) Tumors with massive local invasion of adjacent structures are T4
Which of the following is FALSE regarding staging of head and neck cancer?
A) Primary tumors of the oral cavity and oropharynx that are 4 cm or larger are T3
B) Tumors with massive local invasion of adjacent structures are T4
C) Vocal cord paralysis in the setting of a primary tumor of the larynx or hypopharynx indicates a T stage no less than T2.
D) For all primary sites except the nasopharynx, the nodal classifications are the same
No less than T3

41. IVc: The presence of distant metastases
What does each of the following represent: Stage IVa, IVb, IVc?
IVc: The presence of distant metastases
IVa: resectable locally-advanced disease
IVb: unresectable locally-advanced disease

42. In the European Organization for Research and Treatment of Cancer (EORTC) trial for head and neck cancer prevention, patients were randomly assigned to receive vitamin A for 2 years, N-acetylcysteine for 2 years, both treatments, or no treatment. Which was the arm that showed benefit?
A) Vitamin A
B) N-acetylcysteine
C) Both treatment
D) There was no benefit in any arm

43. Management- Head and Neck Cancer
Previously Untreated stage I, II, Low-bulk stage III
Single-modality therapy with surgery or radiation
Cure rates are % depending on primary site
Which modality is chosen depends on local expertise, anticipated functional outcome, and patient preference
Previously Untreated Higher bulk stage III, IV (T3,T4,N2,N3)
If resectable - surgery followed by RT +/- chemo based on path (favored option for oral cavity) OR chemo and radiation, with surgery upon relapse
If unresectable - chemo and radiation together
Cure rates are 10-65% and often at the cost of cosmetic and functional disability
Management- Head and Neck Cancer

44. Management- Recurrent/Relapsed Head and Neck Cancer
Recurrent disease – If salvage surgery feasible, surgery
OR if no prior radiation, then radiation indicated + chemo
Median survival is 5-9 months.
Management- Recurrent/Relapsed Head and Neck Cancer

45. Principles of surgery:
Goal: Complete removal of the tumor with negative margins.
A comprehensive neck dissection involves the en bloc removal of all five lymph node levels. The sternocleidomastoid muscle, the internal jugular vein, and the spinal accessory nerve are jeopardized.
If not called radical neck dissection.
Done when cancerous lymph nodes are suspected or known to be present.
Selective neck dissections are used, whereby fewer than five lymph node levels are removed, done when there are no palpable lymph nodes.

46. The sternocleidomastoid muscle The internal jugular vein
What are the 3 structures that are potentially jeopardized by the comprehensive neck dissection procedure?
The sternocleidomastoid muscle
The internal jugular vein
The spinal accessory nerve

47. Which of the following is NOT considered a contraindication for resectability?
A) Base of skull involvement
B) Fixation to the prevertebral fascia
C) Carotid encasement
D) Involvement of the pterygoid musculature
E) All of the above are considered unresectable

48. Principles of RT:
Can be used as a single modality to treat early-stage disease.
Standard, once-daily fractionation consists of 2.0 Gy per day with a total dose of 70 Gy or greater to the primary site and gross adenopathy and 50 Gy or greater to uninvolved nodal stations at risk.
When given postoperatively, the total dose to the primary site and involved nodal stations is 60 Gy or greater, and the dose to uninvolved nodal stations at risk is 50 Gy or greater.
Postoperative radiation generally begins 4 to 6 weeks after surgery.
Hyperfractionation being studied: but no significant differences in overall survival were demonstrated, a recent metaanalysis indicated a significant improvement in absolute survival at 5 years (3.4%; p = ) with altered-fractionation approaches.
Increased acute toxicity and hence not recommended as yet by NCCN routinely.
IMRT is being used.

49. Principles of Chemotherapy
Chemotherapy as a single modality is not curative for patients with H&N cancer
In unresectable squamous cell CA of H&N, concurrent chemo RT has been shown to  survival as compared to RT alone
For pts with locally advanced CA hypopharynx/larynx- chemoRT with surgery reserved for salvage compared to upfront surgery offers a significant chance of preservation of the larynx without compromising survival
Drugs used:
Cisplatin and infusional 5-FU → response in 60-90% of previously untreated patients; clinical CR in 20-50%
Other agents: MTX, carboplatin, paclitaxel, docetaxel, ifosfamide, topotecan, irinotecan response rates are 13-31%

50. So When possible surgery is the first
Unless we are trying to save the organ
We then try chemotherapy and radiation together. So

51. Adjuvant chemo RT
Cisplatin + RT adjuvant cat 1 if positive margins and extra capsular extension in involved LN’s.
For everything else like positive LN, perineural involvement only adjuvant RT, cat 1.

52. Targeted therapies:
Cetuximab studied in combination with RT and compared to RT alone.
Showed improved loco regional and OS rates.

53. Nasopharyngeal Know that US has type I (SCC)
China has typeII or III (undifferentiated or lymphoepithelioma)
Type II & III are more sensitive to chemo or RT and more often associated with EBV
Nasopharyngeal

54. Nasopharyngeal Cancer
Stage I and IIa (No & no parapharyngeal space involvement ):
Treatment is RT alone
For everybody else : Cis/RT followed by Cis/5FU
Nasopharyngeal Cancer

56. “Genes load the gun. Lifestyle pulls the trigger”
Lifestyle Factors
“Genes load the gun. Lifestyle pulls the trigger”
Dr. Elliot Joslin
Lifestyle Factors In the first half of the last century people were too busy trying to survive to worry about health as much we do today, much less about how we might practice healthier habits in order to prevent disease. Progress that did occur was brought about through the organization of unions in the workplace, legislatures, and public health ordinances. Toward the end of the century, in 1990, the Healthy People 2000 report made a call to work toward a culture that actively promotes responsible behavior and the "adoption of life-styles that are maximally conducive to good health■ (USDHHS, 1990). Since that time, there is more and more concrete evidence indicating that practicing healthy habits can significantly decrease our chances of developing chronic disease. Therefore, of all the health determinants that we have discussed, lifestyle factors are among the most controllable and influential factors influencing our health.
Author: Diane Wilson, USA
From “Lifestyle Factors and the Prevention Movement”