Oral Cancer Spring 2010 Junior Class - Hirsch

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anaplasia

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loss of ability to differentiate (or reversion to a primitive form); common characteristic of cancer cells

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transformation

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the point at which a cell no longer responds to the normal controls for growth; the point of autonomy or self-sufficiency in growth signaling; a property SHARED BY ALL NEOPLASMS

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malignant transformation

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process by which cells acqure the properties of cancer

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proto-oncogene

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normal gene that can become an oncogene through mutation or over-expression; code for proteins that help to regulate cell growth and differentiation

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oncogene

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modified gene or set of nucleotides that code for a protein believed to cause cancer

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tumor suppressor genes

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code for anti-proliferation signals and proteins that suppress mitosis and cell growth; generally tumor suppressors and transcription factors that are activated by cellular stress to DNA damage; AKA - anti-oncogenes

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carcinogens

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- agents that cause genetic damage and induce neoplastic transformation
- 3 categories: 1) chemical 2) radiant energy 3)virus or other microbe
- several agents may act to concert or synergize the effects of others

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what accounts for greatest improvement in oral cancer treatment in last 40 years...

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early detection

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two-hit theory of carcinogenesis (Knudson hypothesis)

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- cancers only initiated when a cell contains two mutant alleles
- individual w/ one mutant allele must experience a second somatic mutation to initiate tumorigenesis
- individuals who inherit mutant genes frequently develop tumors in more than one site

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"caretaker" genes

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- genes that do not directly control tumor growth but affect genomic stability
- examples would be mismatch repair genes, apoptosis and other putative DNA repair genes

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carcinogenesis

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- initiation - carcinogen causes genetic change (DNA damage), making cell vulnerable to other genetic changes (process can end here and no cancer will form)
- promotion - initiated cell exposed to agent that enhances growth into a larger mass (clonal expansion)
- progression - when tumor cells begin to rob normal cells of oxygen and nutrients; malignant tumors grow uncontrollably and eventually interfere w/ organ fxn

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p53 gene and cancer

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-this gene encodes a DNA-binding transcription factor responsible for cell cycle checkpoints activated after exposure to DNA damaging agents
- in tumor cells, p53 gene is mutated and expressed at greatly elevated levels
- AKA tumor suppressor protein; suppresses tumor growth in conjuction w/ p21 protein and cdk2 protein
- if mutated, there is no stop signal for cell division, and tumor forms
- normallly, this gene is activated and cell either repairs or enters apoptosis (cell death); unknown how cell is decided to repair or die

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dysplasia

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- the best evidence for a pre-neoplatic condition
- microscopic characteristics of cells in dysplasia are similar to (or very often indistinguishable from) cytologic features of malignancy

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incidence of oral cancer

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- oral cancer is ~4% of all new cancers in USA (excluding skin cancer)
- 25% of Americans will/have developed cancer in their lifetime

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age, sex, and cancer

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- age is most important risk factor; >95% of cancers occur in 40+ y/o
- men more than women, but cases of women are increasing 2:1

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histologic types of oral cancers

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- carcinomas are ~96% of all oral cancers
- most are squamous cell carcinomas from oral surface, w/ the rest derived from salivary glands
- sarcomas account for ~4% of malignancies in oral region

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where are cancerw most likely to develop

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- tongue, oropharynx (retromolar trigone), and floor of mouth are most common
- of tongue: 53% anterior 2/3, and 47% on base of tongue
- pain is most common first complaint followed by a "lump"

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stage and survival of oral cancers (once diagnosed)

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- 53-56% survive 5 years or longer
- most are diagnosed at a later stage, which greatly reduces the 5 year survival rate

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race and genetics for oral cancer

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- rate of blacks is twice that for whites
- no inherited trait nor family aggregation has been shown for oral cancer

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multiple cancers - risks w/ oral cancer

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- having developed oral cancer, pts at risk of second synchronous primary estimated at 15%
- higher risk for people who smoke and/or drink

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pre-cancerous lesions in oral cavity

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- leukoplakia
- erythroplakia
- erythroleukoplakia
a benign, morphologically altered tissue that has a greater than normal risk of malignant transformation

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leukoplakia

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- white (thickened sruface keratin) patch or plaque that cannot be characterized clinically or pathologically as any other diasease (EXCLUSION)
- the MOST COMMON oral pre-cancer
- cancer is only found in 5-25% of biopsy samples of leukoplakia; overall lifetime risk of malignant transformation = 4%
- occurs mostly in smokers; other chemicals, micro-organisms, trauma have been implicated as well

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proliferative verrucous leukoplakia (PVL)

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- high risk form of leukoplakia; multiple keratotic plaques w/ rough surface projections (initially simple flat hyperkeratosis); spread slowly
- tranforms into SQUAMOUS CELL CARCINOMA in 8 years
- females, minimal association w/ tobacco usage

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histopathologic alteration of dysplastic epithelial cells

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- enlarged nuclei
- high mitotic activity
- dark staining
- bulbous or teardrop-shaped rete ridges
- loss of polarity (lack of progressive maturation toward the surface)
- keratin or epithelial pearls
- loss of typical epithelial cell cohesiveness

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erythroplakia

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- red patch that cannot be clinically or pathologically diagnosed as any other condition
- alomst all true erythroplakias demonstrate significant epithelial dysplasia, carcinoma in situ, or invasive squamous cell carcinoma (90%)
- far less common than leukoplakias, but much greater potential to be malignant at time of biopsy or to develop into malignancy later
- older males; floor of mouth, tongue, and soft palate; well-demarcated erythematous macules or plaques w/ soft velvety texture; asymptomatic (unfortunately)
- lack of keratinization + epithileal thinness allows microvasculature to show through --> red appearance

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erythroleukoplakia

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- lesions w/ both red and white component

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plummer-vinson syndrome
aka: paterson-kelly syndrome

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- iron-deficiency anemia w/ associated glossitis and dysphagia
- high frequency of association w/ oral and esophageal squamous cell carcinoma
- females, 30-50 y/o; scandinavian and northern european background; burning tongue/mouth; angular chelitis and smooth red tongue are often present; dysphagia or pain on swallowing (esophogeal abnormalities...)
- brittle and spoon shaped finger-nails, and other signs of anemia (fatigue, short breath, weakness)

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oral submucous fibrosis

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- chronic, progressive, scarring, high-risk precancerous condition seen most frequently in India and Southeast Asia
- areas of opacification w/ loss of elasticity; fibrous bands may occur; anywhere in oral cavity
- may result from hypersensitivity reaction to dietary constituents (betel nut, capsaicin)
- a high risk precancerous condition; fibrous lesions are non-reversible --> restriciting many oral movements

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name 4 primary oral malignancies

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- squamous cell carcinoma (90-95% of cases)
- salivary gland malignancies
- melanoma
- sarcomas

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squamous cell carcinoma and oral cancer

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- 90-95% of oral cancers; most on lateral or ventral tongue, front of mouth (FOM), or retromolar trigon

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salivary gland malgnancies

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- 4-8% of oral malignancies
- major glands (80%) -- 90% of which are in parotid (mucoepidermoid carinoma, adenoid cystic carcinoma and adenocarcinoma ex mixed tumor)
- minor glands (20%) -- most in hard palatal mucosa (mucoepdermoid carcinoma, polymorphous low-grade carcinoma, adenoid cystic carcinoma, and adenocarcinoma ex mixed tumor)

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melanoma and oral cancer

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- <1% of oral cancers
- most on hard palatal mucosa or anterior maxillary gingiva

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sarcomas and oral cancer

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- <2% of oral cancers
- osteosarcoma - mostly in mandilble
- kaposi's sarcoma (HIV) - mostly on hard palatal mucosa or max gingiva
- lymphoma - most on ginigiva or in jawbones

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secondary oral cancers
(metastases from elsewhere in body)

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- <1% of oral cancers
- most in hard tissues - mandible; if in soft tissues gingiva or tongue
- most originate from common sites like lung, kidney, skin (melanoma), prostate (men) and breast (women)

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local invasion of oral cancer

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- invasion and destruction of surrounding tissue leaving them poorly demarcated
- aside from metastases, this is the most reliable feature that differentiates malignant from benign

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metastasis

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- tumor implants that are discontinuous from primary tumor
- hallmark feature of malignancy (benign do not metastasize)
- verrucous and basal cell carcinomas rarely metastasize

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spread of oral squamous cell carcinoma

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- mostly by local invasion and through lymphatics
- hematogenous spread is rare, but important in development of distant mets

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local extension of oral cancer

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- anatomic location and adjacent tissues is most important to local invasion
- muscle is easily invaded while periosteum offers a good barrier to invasion

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lymphatic spread of oral cancer

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- MOST IMPORTANT AND FREQUENT PATHWAY FOR SPREAD OF ORAL SQUAMOUS CELL CARCINOMA
- usually oral squamous cell carcinoma spreads to ipsilateral cervical lymph nodes
- lymph nodes are freely movable at first, but become fixed as tumor breaks through the capsule (fixed nodes do not always indicate mets)
- the more poorly differentiated a tumor is, the greater the risk of lymph node involvement
- the more posterior the tumor, the greater risk of lymph involvement
- the larger the primary tumor and greater depth, the more likely there will be lymph node involvement

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order and logic of lymphatic spread from oral cavity

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- first in uppermost, then middle, and finally lower cervical lymmph nodes
- most commonly involved node (in case of oral and pharyngeal cancer) is SUB-DIGASTRIC (jugulo-digastric)

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most common site of distant mets (from oral cancer to elsewhere)

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- lungs, liver and bones (however, any part of body may be affected)

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microscopically vs. clinically detectable nodes

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- nodes may be microscopically involved w/ tumor when they are not clinically detectable
- 20-35% of floor lesions
- 38-52% of tongue lesions
- 17% of gingival lesions
- 22% of hard palate
- 16% of buccal mucosa
- these are % of which cancers had eventual positive lymph node involvement after treating oral cancer and not the neck

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positive lymph node w/ unknown primary site

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- occasionally, lymph nodes show presence of metastasis, but primary site of tumor is undetectable
- primary site is eventually discovered in about 1/3 of these cases (60% of which are located in head and neck region)

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hematogenous spread of oral cancers

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- always a fear that biopsy/palpation might lead to hematogenous spread -- studies have been equivocal as to the effect on prognosis of this
- hematogenous spread gives rise to distant mets (below the clavicles)
- tumor size and extent of metastatic spread are the best indicators of pts prognosis (STAGING)

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metastasis to the oral soft tissues from primary site elsewhere

- uncommon, but significant

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- site predilection for this is gingiva, followed by the tongue
- nodular masses resembling hyperplastic or reactive growths; sometimes, ulceration and adjacent teeth may become mobile; mostly older males
- in males, most common site of primary tumor is lungs, kidney and skin (melanoma) -- prostate cancer has affinity for bone vs. soft tissue
- in females, most common site of primary is breast, genital organs, lung, bone, and kidney
- microscopic appearance of tumor should resemble primary tumor; prognosis is poor

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metastatic tumor to jaw (from primary site elsewhere)

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- breast (66%), prostate (50%) and lung (33%) are very likely to met to bone before pt dies
- vertabrae, ribs, pelvis, and skull are the most common sites of met to bone
- JAWS ARE UNCOMMON SITE FOR MET, but they ay be involved more frequently than reported
- mandible is most common site (80%); occur via hematogenous route
- most pts do not survive more than 1 year

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oral cytology - exfoliative cytology

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- used as simple, reliable and acceptable technique to support clinical judgement in helping differentiate benign and malignant lesions (not a substitute for biopsy, but adjunct too)

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cytological criteria for malignant cells

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- enlarged nuclei
- variation in nuclear size and shape (pleomorphism)
- prominent and irregular nuclear border
- increased nuclear-cytoplasmic ratio (decreased cytoplam)
- multiple prominent and irregular nucleoli
- hyperchromatism (increased nucleoproteins, DNA)
- abnormal chromatin pattern and distribution
- discrepancy in maturation (extreme variations)

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use of cytological reports

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- if clinical suspension remains in face of negative or atypical report, further smear or biopsy should be performed
- suspcious report indicates biopsy be performed immediately
- if smear contains malignant cells, biopsy is mandatory to confirm diagnosis

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biopsy

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- no tumor should be treated w/out confirmation of diagnosis by histological exam of tissue
- no good evidence from human studies that a properly performed biopsy will encourage spread of tumor locally, by lymphatics, or blood vessels
- however the specimen is obtained (incisional vs. excisional), it should be placed in an appropriate fixative immediately

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biopsy fixation

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- 10% buffered neutral formalin is considered best -- preserves widest range of structures; short fixation time; can be used for long-term storage; penetrates rapidly and evenly w/out overhardening
- speciment should be completely submerged in 5-10 times its volume of fixative

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fine needle biopsy

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- good technique for lymph node lesions, also useful for salivary gland lesions
- 22-guage and a special holder for a 10-20 ml syringe
- anesthesia is usually not required; just stick the lesion and suck stuff out

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toluidine blue

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- dye used to stain nuclear material (DNA)
- pre-malignant and malignant lesions maintain the blue color on staining and acid-bath

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Oral CDx study group findings

this is a brush biopsy manufacturer, what were the results of the study of their product

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- all Oral CDx "atypical" and "positive" results should be referred for SCALPEL BIOPSY AND HISTOLOGY to completely characterize the lesion
- their brush biopsy technique is more than 95% effective in identifying positive and atypical specimens

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who discovered x-rays

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- Wilhelm Conrad Roentgen - cathode ray tube w/ high voltage applied, he was able to ligth up paper covered w/ barium mixture from 3 feet away

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first therapeutic use of x-rays

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- 1897, Wilhelm Freud demonstrated disappearance of a hairy mole following x-ray treatment

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ionizing radiation

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- only high energy: UV-rays, x-rays and gamma-rays
ionizing = enough energy to break chemical bonds

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radiobiology

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- study of action of ionizing radiation on living things
- radiation has little to no effect on cytoplasm; however, only 1-2 alpha particles delivered to nucleus can be lethal

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which part of cell cycle is most sensitive to radiation

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during G1 of cell cyle (when chromosomes are dividing)

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repopulation - during radiation therapy

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- growth of tumor cells betwen fractions of radiation
- accelerated repopulation occurs around day 28 of therapy in H&N cancers
- on day 28 we typically begin accerlerated fractionation w/ concommitant boost
- decreased treatment time improves local control

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H&N cancer stats

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- 40,000 US cases per year
- only 1/3 of pts present w/ localized H&N cancer that is highly curable w/ surger and/or radiation therapy
- 1/2 of pts present w/ advanced or unresectable w/ cure rates at or below 50%

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dental evaluation: pre-radiation

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- extract non-restorable teeth (do not remove all teeth)
- make a fluoride carrier, customized mouth pieces or shielding
- radiation therapy should be delayed ~10-14 days to allow gingiva to heal