head & neck cancer –resident lecture 2015. head and neck cancers - tumors arising from the...

Head &

Neck

cance

r –R

esi

dent

lect

ure

2015

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

Anato

my

of

the H

ead a

nd

Neck

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)

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.

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.

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.

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.

Piccirillo JF, et al. National Cancer Institute. SEER Survival Monograph. Chapter 2

Relative Survival Rate (%) by Primary HNC Site, 1988-2001

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.

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

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 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.

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

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.

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

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!

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

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

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.

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

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

D) All of the above is TRUE

90%

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.

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

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

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)

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.

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.

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.

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

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

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

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.

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.

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

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.

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.

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%

So When possible surgery

is the first Unless we are trying to

save the organ We then try chemotherapy and radiation together.

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.

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

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

“Genes load the gun.Lifestyle pulls the trigger”

Dr. Elliot Joslin

Lifestyle Factors