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




Accounts for 3% of all new cases of cancer in U.S.


Use of BOTH tobacco and alcohol > multiplicative risk

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)
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
CA- nasopharynx and paranasal sinus are NOT related
to tobacco and alcohol
HNC: The Statistics
Cancer Cases and Deaths of the Oral Cavity & Pharynx
by Sex, United States, 2012 Estimates
Men
 Estimated New
Cases=28,540

8th

Lifetime
probability is 1
in 69
leading cause
of cancer in men
Women
 Estimated New
Cases=11,710
 Estimated New
Deaths=2,410
 Estimated New
Deaths=5,440
American Cancer Society. Cancer Facts & Figures 2012.
U.S. Incidence Rates for HNC


In 2012, >40,000 new
 Incidence more than
twice as high in men as
women
 From 2004 to 2008,
incidence rates declined
1.0% per year in
were stable
cases are expected
in
by
women and
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.
U.S. Incidence Rates for HNC


In 2012, >40,000 new
 Incidence more than
twice as high in men as
women
 From 2004 to 2008,
incidence rates declined
1.0% per year in
were stable
cases are expected
in
by
women and
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.
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, 2001-2007*
Oral
cavity
&
pharynx
All
Stages
61%
Local
82%
Regiona Distant
l
56%
34%
*Rates are adjusted for normal life expectancy and are based on cases
diagnosed in the SEER 17 areas from 2001-2007, followed through 2008.
American Cancer Society. Cancer Facts & Figures 2012.
Relative Survival Rate (%) by
Primary HNC Site, 1988-2001
Piccirillo JF, et al. National Cancer Institute. SEER Survival Monograph. Chapter 2
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
Smoking-Associated HNC
American Cancer Society. Cancer Statistics 2012.
Tobacco Use and Related Cancers
on the Decline
American Cancer Society. Cancer Statistics 2012.
 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
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
 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
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.
HPV-related Oral Cancer
Rising Incidence of HPVAssociated Oral Squamous Cell
Cancers in U.S.
10.0
Age-Adjusted Incidence/
100,000 Person-Yrs
9.0
8.0
7.0
6.0
Smoking related
HPV-U, APC1: 0.82
5.0
HPV-U, APC2: -1.85*
4.0
3.0
2.0
1.0
HPV-R, APC2: -0.05
HPV-R, APC1: 2.06*
HPV-R, APC3: 5.22*
HPV related
0
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;26:612-619.
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;356:1944-1956.
HPV-Associated Oropharynx
Cancer
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
 90% of HPV-related
Incidence Rates* by Stage at Diagnosis
*Age adjusted to the 2000 US standard
population.
American Cancer Society. Cancer Facts & Figures 2012.
HPV-Associated Oropharyngeal
Carcinogenesis

Persistent HPV infection of the oral cavity may lead to genetic
damage and altered immune function, promoting progression to
cancer
Accumulation

Apoptosis is a potent host
defense against microbes

Viruses counteract this
response



PDZ
E6
E6
E6AP
Transformation
E6AP
E6/E7 inactivate p53
and Rb
Telomerase
activation
(TERT transcription)
NFX1
p16 expression increased
Postmitotic keratinocytes
enter S phase and replicate
viral genomes
of mutations
Inhibition of
apoptosis
p53
Ubiquitination
Degradation
calpain
E7
RB
RB
E7
26s
proteosome
subunit?
Degradation
Narisawa-Saito M, et al. Cancer Sci. 2007;98:1505-1511.
Warning Signs of Head and Neck Cancer

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



Hoarseness
Erythroplasia
Referred otalgia
Persistent sore throat
Epistaxis
Nasal obstruction
Not all cancers present with symptoms
at early stages!
 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
 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%
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.

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
 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
 What is the most frequent intraepithelial
neoplastic lesion that predispose to oral
cancer?
Leukoplakia
 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
90%
D) All of the above is TRUE
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.
 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.
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 2. 2011.
TNM
Staging
for
the
Regional lymph nodes (N)
NX
Regional nodes
cannot
Oral
Cavity
(cont)
be assessed
N0
N1
N2
N2a
No regional lymph
node metastasis
Metastasis in a single
ipsilateral lymph node
≤ 3 cm in greatest
dimension
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
NCCN ClinicalMetastasis
Practice Guidelines
in Oncology: Head and Neck Cancers. V 2. 2011.
in a single
TNM Staging Classification for the
Lip and Oral Cavity
Stage 0 Tis
N0
M0
Anatomic Stage/Prognostic
Groups*
Stage I
T1
N0
M0
Stage II
T2
N0
M0
Stage III
T3
T1
T2
T3
N0
N1
N1
N1
M0
M0
M0
M0
Stage
IVA
T4a
T4a
T1
T2
T3
T4a
N0
N1
N2
N2
N2
N2
M0
M0
M0
M0
M0
M0
Stage
IVB
Any
T
T4b
N3
Any
N
M0
M0
Stage
Any Any
M1
*Nonepithelial tumors (eg, lymphoid tissue, soft
IVC
T
N
tissue bone, and cartilage) are not included.
NCCN Clinical Practice Guidelines in Oncology: Head and Neck Cancers. V 2. 2011.
 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.
No less than T3
D) For all primary sites except the
nasopharynx, the nodal classifications are the
same
 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
 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

Previously Untreated stage I, II, Low-bulk stage III




Single-modality therapy with surgery or radiation
Cure rates are 52-100% 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
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.

Selective neck dissections are used, whereby fewer than
five lymph node levels are removed, done when there
are no palpable lymph nodes.
Done when cancerous lymph nodes are suspected or
known to be present.
 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
 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
Principles of RT:


Can be used as a single modality to treat early-stage disease.

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.

Increased acute toxicity and hence not recommended as yet by NCCN
routinely.

IMRT is being used.
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.
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 =
0.003) with altered-fractionation approaches.
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%
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.
Targeted therapies:

Cetuximab studied in combination with RT and
compared to RT alone.

Showed improved loco regional and OS rates.
Lifestyle Factors
“Genes load the gun.
Lifestyle pulls the trigger”
Dr. Elliot Joslin