head & neck cancer –resident lecture 2015. head and neck cancers - tumors arising from the...
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Head &
Neck
cance
r –R
esi
dent
lect
ure
2015
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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
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Anato
my
of
the H
ead a
nd
Neck
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Epid
em
iolo
gy-
Head a
nd
Neck
Cance
r 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)
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HNC: The Statistics
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
Cancer Cases and Deaths of the Oral Cavity & Pharynx by Sex, United States, 2012 Estimates
American Cancer Society. Cancer Facts & Figures 2012.
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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.
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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.
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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
American Cancer Society. Cancer Facts & Figures 2012.
Five-year Relative Survival Rates by Stage at Diagnosis, 2001-2007*
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 2001-2007, followed through 2008.
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Piccirillo JF, et al. National Cancer Institute. SEER Survival Monograph. Chapter 2
Relative Survival Rate (%) by Primary HNC Site, 1988-2001
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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
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Smoking-Associated HNC
American Cancer Society. Cancer Statistics 2012.
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Tobacco Use and Related Cancers on the Decline
American Cancer Society. Cancer Statistics 2012.
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Pos
sibl
e O
ccup
atio
nal
Ris
ks
for
Hea
d an
d N
eck
Can
cer Woodworking Leather manufacturing
Nickel refining Textile industry Radium dial painting
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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
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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
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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
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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.
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HPV-related Oral Cancer
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Rising Incidence of HPV-Associated Oral Squamous Cell Cancers in U.S.
Smoking related
*P <0.05APC, annual percentage change.
HPV related
10.0
9.0
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0
Ag
e-A
dju
sted
Inci
den
ce/
100,
000
Per
son
-Yrs
1975 1980 1985 1990 1995 2000 2004
Year of Diagnosis
HPV-U, APC1: 0.82HPV-U, APC2: -1.85*
HPV-R, APC3: 5.22*
HPV-R, APC1: 2.06*
HPV-R, APC2: -0.05
Chaturvedi AK, et al. J Clin Oncol. 2008;26:612-619.
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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.
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HPV-Associated Oropharynx Cancer
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
American Cancer Society. Cancer Facts & Figures 2012.
Ra
tes
pe
r 1
00
,00
0
Incidence Rates* by Stage at Diagnosis
*Age adjusted to the 2000 US standard population.
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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
Narisawa-Saito M, et al. Cancer Sci. 2007;98:1505-1511.
Accumulation of mutations Inhibition of apoptosis
Transformation
Telomerase activation(TERT transcription)
Ubiquitination Degradation
Degradation26s
proteosomesubunit?
calpain
RB RB
E6 E6
p53
PDZ
E6AP
NFX1
E7E7
E6AP
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Warning Signs of Head and Neck Cancer
Hoarseness
Erythroplasia
Referred otalgia
Persistent sore throat
Epistaxis
Nasal obstruction
Serous otitis
media
Neck mass
Non-healing
ulcer
Dysphagia
Submucosal
mass
Not all cancers present with symptoms at early stages!
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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
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Eve
nts
- tr
ansf
orm
ati
on o
f
norm
al m
uco
sa t
o in
vasi
ve
squam
ous
cell
carc
inom
a
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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%
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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.
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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
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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
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What is the most frequent intraepithelial neoplastic lesion that predispose to oral cancer?
Leukoplakia
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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%
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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.
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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.
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Sta
gin
g
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
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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
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Match
betw
een site
and
lymphatic d
rain
ange
Oral cavity
Laryngeal
cancer
Nasophary
ngeal
cancer
Thyroid
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)
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TNM Staging for the Oral Cavity
Primary tumor (T)TX Primary tumor cannot be assessedT0 No evidence of primary tumorTis Carcinoma in situT1 Tumor ≤ 2 cm in greatest dimensionT2 Tumor > 2 cm but ≤ 4 cm in greatest dimensionT3 Tumor > 4 cm in greatest dimensionT4a 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.
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TNM Staging for the Oral Cavity (cont)
Regional lymph nodes (N)NX Regional nodes cannot
be assessedN0 No regional lymph
node metastasisN1 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 metastasisM1 Distant metastasis
NCCN Clinical Practice Guidelines in Oncology: Head and Neck Cancers. V 2. 2011.
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TNM Staging Classification for the Lip and Oral Cavity
Anatomic Stage/Prognostic Groups*
Stage 0 Tis N0 M0Stage I T1 N0 M0Stage II T2 N0 M0Stage III T3
T1T2T3
N0N1N1N1
M0M0M0M0
Stage IVA
T4aT4aT1T2T3T4a
N0N1N2N2N2N2
M0M0M0M0M0M0
Stage IVB
Any TT4b
N3Any N
M0M0
Stage IVC
Any T
Any N
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 2. 2011.
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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
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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
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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
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Managem
ent-
Head
and N
eck
Cance
r 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
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Managem
ent-
Recu
rrent/
Rela
pse
d
Head a
nd N
eck
Cance
r
Recurrent disease – If
salvage surgery feasible,
surgery OR if no prior radiation,
then radiation indicated +
chemo Median survival is 5-9
months.
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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.
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What are the 3 structures that are potentially jeopardized by the comprehensive neck dissection procedure?
The sternocleidomastoid muscleThe internal jugular vein
The spinal accessory nerve
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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
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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 = 0.003) with altered-fractionation approaches.
Increased acute toxicity and hence not recommended as yet by NCCN routinely.
IMRT is being used.
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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%
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So When possible surgery
is the first Unless we are trying to
save the organ We then try chemotherapy and radiation together.
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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.
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Targeted therapies:
Cetuximab studied in combination with RT and compared to RT alone.
Showed improved loco regional and OS rates.
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Naso
phary
ngeal
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
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Naso
phary
ngeal
Cance
r Stage I and IIa (No &
no parapharyngeal space involvement ):
Treatment is RT alone For everybody else :
Cis/RT followed by Cis/5FU
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“Genes load the gun.Lifestyle pulls the trigger”
Dr. Elliot Joslin
Lifestyle Factors