9. Oral Cancer and Precancer Flashcards
Oral squamous cell carcinoma (OSCC) and Oropharyngeal SCC
• 51,540 new cases in 2018
- 3.0 % of all new cancers
• 10,030 deaths in 2018
- >____ death per hour every day
• Incidence rates >2x higher in ____ than women
• 1.2% of population will be diagnosed in lifetime
• 5-year survival rates (2008-2014) – Overall – Early diagnosis (Stages \_\_\_\_) – Late diagnosis (Stages \_\_\_\_) • Late diagnosis accounts for over \_\_\_\_% of all diagnoses – African-American 33% – Caucasian \_\_\_\_%
• The biggest hurdle in improving 5-year survival rates is ____ and ____!
• Posterior boundary of oral cavity > PG folds ○ From the \_\_\_\_ to the \_\_\_\_ folds • Anterior boundary of oropharynx > PP folds ○ \_\_\_\_(tonsils) are located within the oropharyngeal region • No sex predilection, but more prevalent in \_\_\_\_ • Talking about cancer - 5 yr survival rates - "what are my chances?" ○ The rates guide \_\_\_\_ and \_\_\_\_ over many patients ○ 5 years from time of finishing diagnosis - whether the cancer recurs, whether they get new cancer, or whether the patient dies/lives • 65% - in the realm of OK survival rates • Most carcinomas use the TMN staging system ○ Subcategorize into I-IV stages ○ IV - the worse the prognosis • Ethnic variations - \_\_\_\_ have worse survival rate than Caucasians • Early diagnosis and prevention is critical
1 men I & II III & IV 60 55
awareness
early diagnosis
lips
PG
adenoids
males
treatment
prognosis
AA
Age of onset Median age = ____
Age of death Median age = ____
____% - Localized to primary site
____% - Spread to regional lymph nodes
____% - Cancer has metastasized
4% - Unknown
• Oropharyngeal cancer ○ After the age of 55 - primarily an older person's disease ○ From 20-54 - 25% of patients will get cancer [???] ○ Ones who get cancer at a younger age have a better \_\_\_\_ (only 15% of the 25% will die of the disease under 55) § This applies to all cancer types • At time of diagnosis: ○ 30% cancer localized to one area (I or II) § Implies that \_\_\_\_% of all cancers will have already spread to other sites/lymph nodes ○ Most oropharyngeal cancers are diagnosed \_\_\_\_ - which is what contributes to these numbers • Oropharynx spread - not a metastasis - considered to be \_\_\_\_ primary cancer if it's a different site
63 67 30 47 19
prognosis
70
late
secondary
Epidemiology of OSCC
• >90% occur in patients >____ yrs
• Increasing incidence in ____ patients (<40 yrs) without risk factors
• Ethnic and racial variation in survival not ____
– May reflect access to healthcare, level of education, and late diagnosis
• OSCC - implying we're talking about only oral cancer ○ Very different from oropharyngeal cancer • First number - both OSCC and oropharyngeal; the second number is for \_\_\_\_ only • We assumed increasing incidence was due to \_\_\_\_ for OSCC, but it's not; IT DOES NOT CAUSE THIS TYPE OF CANCER ○ For oropharyngeal it is because of \_\_\_\_
50
younger
prevalence
OSCC
HPV
HPV
The facts • Litigation against dentists is frequently related to oral cancer – Failure to \_\_\_\_ – Misdiagnosis – Inappropriate \_\_\_\_ dentistry • Oral cancer awareness is increasing
• Ultimate goal of cancer treatment is \_\_\_\_ • Need for appropriate – \_\_\_\_ – Detection – \_\_\_\_ – Diagnosis
• Post-therapeutic needs: rampant \_\_\_\_, xerostomia - it's the dentist's responsibility to treat these manifestations, not the oncologist
diagnose post-therapeutic prevention education recognition caries
OSCC is a multifactorial disease
Extrinsic factors \_\_\_\_ / smoking / smokeless tobacco \_\_\_\_ Ultraviolet light \_\_\_\_ nut Sanguinaria Psychoactive plants
Intrinsic factors
____ / epigenetics Genomic instability Chronic immunosuppression
Previous history of OSCC
• Multifactorial - both extrinsic and intrinsic factors Extrinsic factors • Smoking and chronic alcohol usage are the most common factors for \_\_\_\_-development and involved with oropharyngeal (but the biggest factor is \_\_\_\_) ○ Smokeless tobacco to replace cigarette smoking - some forms of it may increase risk of cancer, however ○ Can suggest usage - the risk is \_\_\_\_ but not absent entirely • UV light a risk factor for the \_\_\_\_ lip • Betel nut - naturally occurring substance > addictive, reddish coloration, contains a carcinogen > increases risk of OSCC • Sanguinaria and psychoactive plants - addictive and carcinogenic
Intrinsic factors
• These apply for all ____
• Long ____ - less of a cancer risk
• ____ (chronic immunosuppression) - secondary risk for OSCC
tobacco alcohol betel genetics OSCC HPV lower lower cancers telomeres cyclosporine
≥ 80% of all OSCC caused by tobacco / alcohol
• Smoking
– Active and passive
– ____x risk
• Alcohol
– Increases risk ____x
• Synergism
– >5 drinks/day + >20 cigs/day =
>____x increased risk than either alone
– >____x risk over non-smokers and drinkers
• Field cancerization
• Do not memorize any numbers - just the trends (stages) • Smoking has the highest risk of any factors for OSCC-development ○ No evidence that second hand smoke causes OSCC, but it may for \_\_\_\_ and certainly lung cancer • \_\_\_\_ drinking can be a risk for some patients • Previous smokers can have a lower risk than a current smoker, but still have higher risk than a never smoker ○ Smoking causes damage to DNA > propagated during cell division to yield new cells that contain the same damage > eventually, so much damage in DNA in one cell > allows the cell to proliferate uncontrollably ○ Field cancerization [???] - one cell exposed is all cells exposed in organ sites - i.e. bronchioles down to your lungs will be exposed to carcinogens § All \_\_\_\_ are affected somewhat equally § Patient with cancer on buccal mucosa is equally likely to occur at another area
8-20
6
13
50
oropharyngeal
social
areas
• Sun damaged skin - ____
○ Blue stain - ____ fibers
○ Can occur in any area - field cancerization effect
solar elastosis
elastic
Ethnic customs
• Betel nut (Areca nut)
– Commonly used in South and East ____
• Bidi
– Rudimentary, hand-rolled ____
• Yerba mate
– Ilex ____
• Toombak
– ____ snuff
• Khat / Qat
– ____ plant
- Shisha / Hooka (Water pipe)
- Yerba mate - ____ cancer is common (South America)
asia cigarette paraguayensis sudanese catha edulis esophageal
Intrinsic factors
• Not everyone who smokes or drinks develops OSCC
• Young age of onset almost always associated with inherent ____
• Increased risk by 2-4 fold if positive family history
– 1 or more ____ degree relatives affected
• Intrinsic factors further modify the risk of any given patient • OSCC is not a \_\_\_\_ inherited cancer ○ There is a risk if you have a first degree relative with cancer
predisposition
first
genetically
Intrinsic factors
• Genetic \_\_\_\_ • Short \_\_\_\_ • Chronic immunosuppression – \_\_\_\_ patients on medications – Severe \_\_\_\_ deficiency
• Telomeres are inheritable
polymorphisms
telomeres
transplant
iron
Genetic diseases associated with OSCC development • Fanconi anemia • Dyskeratosis congenita • Li-Fraumeni syndrome • Ataxia telangiectasia • Bloom syndrome • Xeroderma pigmentosum • Epidermolysis bullosa
• The risk for cancer is transferrable • XP (middle patient) > has \_\_\_\_ cancer but has a risk for OSCC • EB (BR patient) ○ \_\_\_\_ why it causes OSCC • What unifies all the other diseases (1-6) - characterized by mutations in proteins that regulate response to repair \_\_\_\_ > DNA becomes genomically unstable
skin
unknown
DNA damage
Possible risk factors?? More research is needed
• Lichen planus
– WHO-recognized ____ lesion
– No definitive well-controlled studies that indicate risk
• ____
– Increasing number of studies suggest elevated risk
• Systemic sclerosis
– Increased risk for ____ cancer
• ____
– Some studies suggest possible risk
• LP - if left untreated can result in cancer
precancerous
diabetes mellitus
tongue
marijuana
What does OSCC look like? \_\_\_\_ Leukoplakia Erythroplakia \_\_\_\_
* Important slide * OSCC can look like \_\_\_\_
non-healing ulcer
mass
anything
• Leukoplakia
– White lesion that does not ____ off and cannot be characterized as other pathology
• Erythroplakia
– ____ lesion that cannot be attributed to other pathology
• Erythroplakia - not \_\_\_\_ in origin and not \_\_\_\_
rub
red
vascularized
inflamed
What does oral pre-cancer look like?
____
____
* You also treat at this \_\_\_\_ * Patients with erythroplakia - more likely to be \_\_\_\_ than leukoplakias
leukoplakia
erythroplakia
stage
cancerous
• Bottom left - mass - it’s not precancerous (or dysplastic); it is either ____, reactive or ____
benign
cancer
Pre-cancerous & cancerous lesions have NO distinctive
____ features
clinical
Treatment Options
• Complete ____
• ____ red/white lesions in high risk areas should be excised
• Long-term ____
* \_\_\_\_ tongue - higher risk - more likely to not be seen quickly * \_\_\_\_ of the mouth - higher risk * [???] * If not cancerous in high risk area > still requires \_\_\_\_
removal all follow up posterior floor excision
Definitions • Hyperplasia – Increased \_\_\_\_ of cells • Hyperkeratosis – Increased \_\_\_\_ • Dysplasia – \_\_\_\_ stage – Only applies to \_\_\_\_ • Carcinoma – Cancer of \_\_\_\_ cells
• Hyperplasia and hyperkeratosis are not \_\_\_\_ diagnoses ○ However, if in high risk area - warrants excision • Dysplasia used only in context of \_\_\_\_ (squamous, glandular, etc.)
number keratin pre-cancerous epithelium epithelial pre-cancerous epithelium
Carcinogenesis arises from accumulation of ____ resulting in stepwise progression of normal mucosa to invasive SCC
• Changes at the \_\_\_\_ level ○ Mutations, amplifications of oncogenes, loss of TSGs, loss of cell cycle control and inability to regulate survival (via apoptosis) • [NOTES]
genetic changes
molecular
Molecular changes
• Mutations in proto-oncogenes / tumor suppressors
– ____, p53
– DNA damage ____
• Genomic amplification
– ____ receptor
– ____
• Epigenetic changes
– ____ DNA modifications
– ____ DNA and RNA including microRNAs
- ____ activation
- Genomic instability is a hallmark of cancer - regardless of the cancer type
p16
regulators
epidermal growth factor
cyclin D1
post-translational
non-coding
telomerase
Only five genetic alterations needed to induce epithelial transformation
- Overexpression of ____
- Inactivation of ____
- Overexpression of ____
- Overexpression of ____
- ____ activation• In vitro - induce artificial changes to induce transformation
cyclin D1 p53 EGFR c-MYC telomerase
Cytologic features of dysplasia • Hyperchromatic nuclei • Pleomorphism • Increase nuclear : cytoplasmic ratio • Dyskeratosis • Mitoses
• Dysplasia - precancer/premalignancy ○ Varying degrees - mild, moderate, severe and carcinoma in situ; to SSC • All dysplasias have the same cytological features (the same changes to the actual dysplastic cells): ○ Dark nuclei (hyperchromatic nuclei) § Picking up more \_\_\_\_ - implying there's more active DNA ○ Different size/shaped nuclei (pleomorphism) § Naturally, epithelial cells increase in size, nucleus increases and the nucleus becomes flatters as they differentiate - within each layer! § In slide, all nuclei look much darker, and are different in shape ○ Increased nuc:cyto ratio § A normal cell has a \_\_\_\_ ratio (cyto is synonymous with cell size) § In dysplasia, the ratio increases to \_\_\_\_ ○ Dyskeratosis § Expressing more \_\_\_\_ expression within the cell □ IF proteins that maintain architecture of the cell □ So the cells look more pink \_\_\_\_ than normal cells ○ Mitoses § Normally seen only in the \_\_\_\_ layer in epithelium § In dysplasia, you see mitoses above the basal layer □ Cell cycle has been perturbed, apoptosis has been perturbed
HA 1:3 1:1 cytokeratin cytoplasmically basal
Architectural features of dysplasia • Elongated rete pegs • Up to 1/3 = \_\_\_\_ • Up to 2/3 = \_\_\_\_ • Above 2/3 = \_\_\_\_ • Full thickness = \_\_\_\_
• Mild, moderate, severe, vs carcinoma - architectural distinction ○ Look at rete pegs, and division to 3 sections: lower, mid and upper third • Rete pegs are \_\_\_\_ in dysplasia - more cells within the epithelium • Look to see where the cytological changes are found • Carcinoma in situ does not imply cancer, but rather a \_\_\_\_ ○ Not all severe dysplasia are carcinoma in situs, but all carcinoma in situs are \_\_\_\_ ○ Treated the exact same way - a \_\_\_\_ distinction
mild moderate severe carcinoma in situ longer dysplasia severe dysplasia semantic
Epithelial hyperplasia and hyperkeratosis
• Small leukoplakia on lateral tongue • Biopsy reveals hyperplasia, with parakeratosis or orthokeratosis ○ Keratin pattern is \_\_\_\_ ○ This is not cancer, but can progress to cancer if untreated (especially with risk factors) § Rubbing off broken cusp - won't \_\_\_\_; but if \_\_\_\_ - it may
irrelevant
progress
smoking/drinking
Epithelial Dysplasia, Mild
• Leukoplakia
• Mild dysplasia
○ The changes induce longer rete pegs - take on a test tube shape architecturally
○ Pleomorphy, mitoses, etc. above the basal layer
§ Confined to the lower third
§ Above lower third - all nuclei look the same
□ As the cells mature, they regain the ability to ____ themselves
□ Haven’t lost all ability to ____ themselves
control
regulate
Epithelial Dysplasia, Moderate
* If lose ability to \_\_\_\_ > moderate dysplasia * Dark nuclei adjacent to cells with normal architecture in the middle 2/3
self-regulate
Epithelial Dysplasia, Severe / Carcinoma in situ
• \_\_\_\_ is still intact - the changes are all confined to within the epithelium - this is why it's still \_\_\_\_ ○ May have taken 1-1000 mutations to reach this stage, but didn't develop in a mutation to allow cells to progress past the BM
basement membrane
pre-cancerous
• Once invasion past BM - ____
○ Non-healing ulceration, small leukoplakia, large mass
○ Only applies to carcinomas (sarcomas don’t have ____!)
○ Can skip dysplastic stages, straight to carcinoma
○ It can also ____ backwards as well
squamous cell carcinoma
BM
regress
Squamous cell carcinoma
• Severe dysplasia - unlikely for it to regress back to anything but ____; more likely to progress to ____
• Presence of tumor islands invading into the ____ tissue
○ Can go anywhere it wants - can go into BV/LV resulting in metastasis, or bone, salivary glands, mucosa, etc
§ Organs heavily vascularized (____, brain, ____) is most likely where it will metastasize to
moderate SCC connective bone liver
Cytologic features of carcinoma • Hyperchromatic nuclei • Pleomorphism • Increase nuclear : cytoplasmic ratio • Dyskeratosis • Mitoses • \_\_\_\_
Architectural features of carcinoma • Invasion beyond the \_\_\_\_ • \_\_\_\_ • Invasion into adjacent \_\_\_\_ • \_\_\_\_
• All defining features of dysplasia is what we use to define carcinomas ○ Both the cell and nuclei are pleomorphic • In addition, anaplasia is applied to carcinoma ○ Poorly \_\_\_\_ cell § Dysplastic cells aren't anaplastic § Can look at cell, and cannot predict the cell's \_\_\_\_ ○ Not all cancers are \_\_\_\_! • All carcinomas exhibit the architectural features ○ Invasion beyond the BM ○ Keratin pearls § Cancers that look like the cell of \_\_\_\_ - well differentiated SCC - produce \_\_\_\_ produce within tumor islands § Not common to all carcinomas - only \_\_\_\_ SCC □ Because \_\_\_\_ cells produce keratin, other cell types do not develop (not in prostrate, breast, or colon cancers) ○ All carcinomas invade adjacent tissues and all have the propensity to metastasize \_\_\_\_, colon, \_\_\_\_, melanomas have high chances to metastasize
anaplasia BM keratin tissues metastasis
differentiated
origin
anaplastic
origin keratin well-differentiated squamous prostate breast
• Well-differentiated OSCC
○ ____ invading deep in connective tissue
○ Pink, globular structures - ____; and the presence of squamous cells
• Poorly-differentiated SCC ○ Cannot tell they're \_\_\_\_ ○ Do additional tests to figure it out § \_\_\_\_ - stain tissue with antibodies to proteins the cells express: □ \_\_\_\_ - if they don't express, can be a leukemia, \_\_\_\_, etc. ○ Highly pleomorphic, and anaplastic (very poorly differentiated) • Moderately-differentiated SCC ○ Look like \_\_\_\_ in origin, but the cells don't produce \_\_\_\_
tumor islands
keratin pearls
squamous
immunohistochemistry
cytokeratins
lymphoma
squamous
keratin
Histopathologic grade
• Has no bearing on ____
• Grading is strictly a \_\_\_\_ parameter - not a clinical parameter ○ Has no bearing on prognosis § A patient who has a poorly differentiated tumor may respond better than a patient with a well differentiated tumor; and vice-versa
prognosis
microscopic
linical Staging
• TNM classification
– Tumor size and invasion into adjacent anatomic structures
– Presence / absence of locoregional positive lymph nodes
– Presence / absence of distant metastasis
• Modalities used: – \_\_\_\_ exam – \_\_\_\_ or PET/CT scan – \_\_\_\_ – \_\_\_\_
• Clinical staging - guides how to approach therapy and our own ability to predict prognosis • For SCC - use the TNM classification (T = tumor size, N = presence/absence of lymph nodes, M = distant metastasis) ○ Each letter has subcategories (0-4) § T0 - nothing, not a tumor; not used clinically § T1 - used clinically; implies that a tumor is
clinical CT surgery histopathology 2 multidisciplinary
• Work-up is to yield parameters - TNM - to help guide approach to treatment
• T
○ T0 - not used
○ T1 - ____ cm
○ T4 - irrespective of size, has invaded locally into adjacent structure, or regionally distant
• The higher the number, the worse the prognosis
○ If N and M is 0, but T1 or T2 - stage 1 or stage 2
§ Good prognosis
○ And so on, increase T and prognosis gets worse
• N
○ N0 - no lymph nodes positive for cancer
○ As soon as have one lymph - N1 - stage ____
○ N2, N3 - stage ____
• M
○ M0 - no distant sites affected
○ M1 - there are distant sites affected - stage ____
• Lymph nodes are assessed by radiology - and they’re found within five areas in the H+N
○ As soon as one lymph node is suspicious for cancer - ____, and remove soft tissue and lymph nodes
• Presence of lymph nodes are assesed by ____ exam
○ ____ enlargements - could indicate lymph nodes that are positive for cancer
2
2-4
4
3
4
4
neck dissection
clinical
fixed
• More ____, use of CAT scans/radiographs
○ A certain size of lymph nodes
§ ____cm in diameter; anything more than that the lymph node needs to be assessed surgically and microscopically
diagnostically
1.5
Positron Emission Tomography (PET) / Computerized Tomography (CT)
• Very \_\_\_\_ technique ○ Inject a radioactive isotope conjugated to glucose § \_\_\_\_ ○ Taken up by all cells in body - most ends up in \_\_\_\_, but any cancer in order to survive needs energy and glucose § Cancer cells need more \_\_\_\_ to sustain survival § Lateral neck indicates a positive lymph node • Used to highlight tumor and to highlight the lymph nodes that may be positive
sensitive
18-F-deoxyglucose
brain
glucose
• Take out lymph nodes in five levels
○ [NOTES]
• Look for important landmarks: ____ carotid, ____, VII and ____
○ Remove all the ____ that’s between all the structures
○ Indicate with sutures to orient where the resection was in the patient’s body
○ Squish the tissue against table, and feel for bumps/nodules > lymph nodes
○ Fix and process them for microscopy
jugular
XI
SCM
fat tissue
Presence of lymph node metastasis?
Always at least Stage ____ cancer
• Lymph nodes with no tumor - N0 • If any lymph nodes has a tumor - N1 at least, and if more than one and then on opposite side can be N2 or N3 ○ This slide shows cancer within a lymph node • Any N status is stage \_\_\_\_; it is stage \_\_\_\_ if more than N1
III
3
4
Presence of distant metastasis?
Always Stage ____ cancer
* Full body scan for other sites * If found > M1 > stage 4 cancer
IV
Oropharyngeal SCC is a multifactorial disease
Extrinsic factors \_\_\_\_ / smoking / smokeless tobacco Alcohol \_\_\_\_ nut \_\_\_\_**
Intrinsic factors
Genetics / epigenetics Genomic instability Chronic immunosuppression
Previous history of OPSCC
* \_\_\_\_ is one of most important risk factors for oropharyngeal, not oral cancer * The same \_\_\_\_ factors play the same role in all cancers
tobacco betel human papillomavirus HPV intrinsic
OPSCC
• 70% of all OPSCC associated with HPV – Mostly HPV____
• Incidence rate of HPV-OPSCC, particularly ____ cancer is ____
• Typically ____, white, < ____ years, no or little ____ exposure, higher
____ status
• Strong association between ____ contact and OPSCC
• Tobacco related cancers are decreasing, but oropharyngeal cancers are increasing ○ Tonsillar cancer falls into category of oropharyngeal cancer - cells have limited resistance to HPV • Unlike oral cancer: ○ \_\_\_\_ patients ○ Limited tobacco users/alcohol users • More HPV subtypes than just 16 (18 is also common cancer causing virus)
16 tonsillar increasing male 60 tobacco socioeconomic oro-genital
younger
HPV-OPSCC: Diagnosis
• ____ immunohistochemistry – Reliable surrogate for ____
• DNA in situ hybridization
• Immunohistochemistry ○ Antibody to p16 (cell cycle protein) § A reliable surrogate of HPV infection § \_\_\_\_% reliable § Helps to guide therapy
p16
HPV
98
• HPV has two proteins that are protooncogenes
○ E6
§ Inhibits ____
○ E7
§ Inhibits ____
○ ____ regulates RB; so if Rb is inactivated by virus, then p16 levels will increase dramatically
p53
Rb
p16
Cancer therapeutics • \_\_\_\_ – 1st line therapy – < \_\_\_\_% survival for non-resectable tumors • Radiation therapy • Chemotherapy
• If cannot excise cancer in entirety > significant risk for occurrence > poor survival rate • Radiation therapy ○ Mandatory for \_\_\_\_, may even occur before a surgery and they response very well ○ May be \_\_\_\_ line, in addition to surgery • Chemotherapy used for patients with high stage cancers with \_\_\_\_ ○ Rarely a \_\_\_\_ line therapy for cancer
surgery 25 HPV first metastasizes first
THE FUTURE IS NOW
• Current cancer diagnosis and therapy is based on a ____ approach
• Gene signatures distinguish ____ tumors (lymphomas, brain cancer,
breast cancer) from less aggressive ones
– Chemotherapies are ____-tailored based on these signatures
• Personalize treatments depending on the patient ○ Based on actual sequencing of molecules expressed by cancers • [NOTES]
molecular
aggressive
patient
THE FUTURE IS NOW
• New technology has made it possible to identify a set of molecular changes and genomic signatures in the DNA of tumor cells that are distinct for tumor ____, that are not readily elucidated on the ____ level—and that can reveal a genetic blueprint of the patient’s tumor as discrete and singular as a fingerprint.
• Of all the tumor patients tested to date, approximately ____% of them have received genomic testing results that altered prognosis or empowered the treating oncologists to alter the patients’ treatment therapy or both.
subtypes
microscopic
75
• Can’t use ____ cancer yet as a means to personalize therapy
○ Caused by a variety of molecular changes, some may/may not be prognostic
oral
