Malignant White/Red Lesions

Question 1

List the white/red oral malignancies

Answer 1

-Squamous Cell Carcinoma
-Verrucous Carcinoma

Question 2

Why does the term “oral cancer” generally denote SCC?

Answer 2

Because 90% of oral cancers arise from the surface epithelium

Question 3

List other primary oral cancers

Answer 3

-Salivary gland carcinomas
-Lymphomas
-Melanoma or sarcoma (rare)

Question 4

List the secondary cancers

Answer 4

A metastasis to the oral cavity from a distant site (e.g. carcinoma, sarcoma, lymphoma/leukemia etc.)

Question 5

Oral Cancer Epidemiology

Answer 5

• 2% of all cancers in US
  -Most common cancer in India (men)
  -Male:Female (2:1)
  -Highest risk for white men >65yrs and black men in middle age
  -Increasing incidence overall if oropharynx is included
  -No significant improvement has been made in early diagnosis

Question 6

Oral Squamous Cell Carcinoma (SCC) Demographics

Answer 6

> 90% of all oral cancers are SCC

Question 7

SCC Risk Factors

Answer 7

-Similar to premalignant oral lesions
- 80% associated with tobacco with or w/o alcohol
-(20-25%) no identifiable risk factor - lateral tongue young adults (especially women) or gingiva (older women)
-Heredity does not appear to play a major role

Question 8

SCC Clinical

Answer 8

-Irregular shape, mixture of red and white
-Often ulcerated center with “rolled” border
-Exophytic (growing out) or endophytic (growing in) growth pattern
-Often much firmer (indurated) than surrounding tissues
-Early lesions = asymptomatic; pain is usually a late feature
-Ragged radiolucency is characteristic of bone involvement

Question 9

List the high risk sites for oral SCC

Answer 9

-Lateroventral tongue
-Floor of mouth
-Soft palate/tonsillar pillar
-Lip vermilion

Question 10

SCC Lip

Answer 10

-One of the more common sites of involvement, not really intraoral
-Secondary to ultraviolet light exposure
-Arises in the setting of actinic cheilitis
- 90% lower lip
-Crusted, nontender, indurated ulceration, typically <1cm when discovered
-Slow-growing, usually well-differentiated lesions
-Relatively good prognosis

Question 11

SCC Tongue

Answer 11

-Lateroventral tongue - most common intraoral site:
1. majority of pts have history of cigarette smoking and alcohol abuse
2. When oral SCC is seen in younger pts (<40yrs), it almost always develops at this site
-Dorsal tongue - uncommon

Question 12

SCC Floor of Mouth

Answer 12

-Second most common site for oral SCC
-Most pts have history of cigarette smoking and alcohol abuse
-Most likely location to develop from preexisting white/red lesion
-Often associated with 2nd primary malignancy

Question 13

SCC Gingiva/Alveolar Mucosa

Answer 13

-Intermediate risk site (3rd most common) for oral SCC
-More common in women at this site (2:1) and those without identifiable risk factors
-Most likely site for misdiagnosis as it may mimic benign/reactive gingival lesions (e.g.pyogenic granuloma) or periodontal disease

Question 14

SCC Palate

Answer 14

-Hard palate SCC is rare (unless reverse smoking)
-May develop in the maxillary sinus and invade through the sinus floor
-Most SCCs affecting the palate arise on the lateral soft palate. They likely show a visible premalignant lesion
-Most oropharyngeal carcinomas arise from the tonsillar region w/o a visible precursor lesion:
1. symptoms –> dysphagia, persistent sore throat, dull/sharp pain may be referred to ear, odynophagia

Question 15

SCC Buccal Mucosa

Answer 15

-“low risk” (uncommon) site for oral SCC in the western world
-Very common in the setting of betel quid use

Question 16

Clinical differential diagnosis for oral SCC

Answer 16

-Non-specific ulcer (i.e. traumatic)
-Specific infections: tuberculosis, deep fungal, syphilis
-Immune-mediated conditions: granulomatosis with polyangiitis, crohn disease

Question 17

SCC Radiographic

Answer 17

-Direct tumor invasion of bone (usually a late phenomenon) causes a “moth-eaten” radiolucency with ragged/ill-defined borders
-Pathologic fracture is possible

Question 18

Histopathology of malignant lesions

Answer 18

-Invasive cords and nests of malignant squamous epithelial cells arising from dysplatic surface epithelium
-Tumor cells show an increased nuclear/cytoplasmic ratio, cellular and nuclear pleomorphism, and mitotic activity
-Varying degrees of keratin production (keratin pearls) and dyskeratosis
-Desmoplasia - tumor-induced fibrosis

Question 19

Grading of malignant lesions

Answer 19

-“Superficially invasive” or “microinvasive” - very early lesions
-Multiple classification schemes
-Somewhat subjective interpretation of histologic differentiation:
1. Well differentiated (grade I; low grade)
2. Moderately differentiated (grade II; intermediate grade)
3. Poorly differentiated (grade III; IV; high grade)

Question 20

T/F: Differentiation does influence staging

Answer 20

FALSE!

Differentiation does NOT influence staging

Question 21

Describe the microscopic features that do affect stage and prognosis:

Answer 21

1. Depth of invasion (>5mm) correlates with increased risk for nodal metastasis
2. Extracapsular spread outside a lymph node, “extranodal extension” (ENE), is associated with a worse prognosis

Question 22

HPV Detection

Answer 22

-All oropharyngeal SCCs REQUIRE high-risk HPV (HRHPV) testing b/c affects staging
-Don’t do HRHPV testing on oral cancers

Question 23

Which HPV test should be used?

Answer 23

-Presence of HPV E6, E7 indicates transcriptionally active HPV infection so gold standard is to test for this. More expensive
-p16 immunohistochemistry (inexpensive, sensitive surrogate marker for HRHPV) is the routine test used

Question 24

After biopsy proven oral SCC (or other H/N cancer), what next?

Answer 24

1. Complete head and neck exam
2. Dental exam: PANX - will need to treat any unresolved dental issues
3. Imaging to evaluate the primary tumor, any second primaries, and nodal disease (MRI or CT with contrast, chest CT)
4. Multidisciplinary consultations as needed

Question 25

SCC Treatment

Answer 25

1. Early-stage lesions (T1,T2) - wide surgical excision (1cm margin), or radiation if pt can’t have surgery
2. Moderately advanced tumors: surgery + adjuvant radiation (try to avoid mandible) or combined chemoradiation
3. Advanced disease (recurrent or mets) or inoperable cases: radiation and/or chemotherapy

Question 26

Surgical Aspects

Answer 26

-Radical neck dissection: removal of lymphatics of lateral triangle of neck and associated structures
-Modified radical neck dissection: just lymph nodes, preserves associated structures
-Selective neck dissection: only select groups of lymph nodes

Question 27

SCC Radiation

Answer 27

-Intensity-modulated radiation therapy (IMRT): targets the tumor site and minimizes damage to surrounding tissue
-Brachytherapy (placement of tiny radioactive seeds) used for small intraoral tumors or with IMRT to increase dosage

Question 28

SCC Chemotherapy

Answer 28

-Induction chemotherapy NOT really beneficial for oral cancer
-Post-operative concurrent chemoradiation therapy gives the best locoregional control and disease-free survival:
1. Conventional fractioned radiation + cisplatin
2. Other drugs used: carboplatin, 5-fluorouracil, taxanes
-Distan mets - single/multi-agent chemotx

Question 29

SCC Targeted Therapies

Answer 29

-EGFR monoclonal antibody (Cetuximab)
-Immunotherapy: antibodies used to block checkpoints and thereby allow the immune response to occur.
1. Good response in melanoma and lung cancer
2. Used for recurrent or metastatic head and neck SCC who have progressed on or following platinum-based chemotherapy
3. Approved drugs: nivolumab and pembrolizumab

Question 30

Oral SCC Follow-up

Answer 30

-Periodic follow-up examination of entire mouth is necessary for the life of the pt
-Most recurrences will occur within the first 2 yrs
-May require biopsy of multiple areas

Question 31

Describe Field Effect/Cancerization

Answer 31

-All mucosa exposed to carcinogen has the potential for cancer development (“condemned mucosa”)
-Multiple (synchronous) primary tumors
-Second (metachronous) primary tumors
-Up to 25% will develop new upper aerodigestive tract malignancies, particularly if carcinogenic habits are continued

Question 32

Prognosis

Answer 32

-Overall 5yr survival (oral and oropharyngeal) = 67%
-Prognostic indicators for oral SCC = stage (tumor size, extent of metastatic spread)
-Prognostic indicator for oropharyngeal SCC = HPV status

Question 33

Oropharyngeal CA - Prognosis

Answer 33

-Often poorly differentiated and nonkeratinizing
-While most are diagnosed at advanced stage, early-stage survival is similar b/c prognosis is based on HPV status
-HPV+ tumors respond better to chemo and/or rad tx (b/c they lack TP53 and field cancerization)

Question 34

Oral SCC Prognosis

Answer 34

-Prognosis is generally poor b/c about 2/3 of pts present with Stage III or IV disease
-It is one of the worst prognoses of any major cancer
-Even with tx, significant disfigurement, disability, pain

Question 35

Verrucous Carcinoma

Answer 35

-Less aggressive form of SCC; large lesions can develop regular SCC in them
-Proliferative verrucous leukoplakia may give rise to this variant or classic SCC
-White or mixed red and white; papillary/verrucous plaque or mass
-Alveolar mucosa, hard palate and buccal mucosa are most frequent sites
-Tends to grow laterally. Invades with a “pushing margin” but doesn’t infiltrate
-Microscopically “bland” (not atypical) appearance can cause misdiagnosis as “hyperplasia”

Question 36

Verrucous Carcinoma Treatment

Answer 36

-Surgical excision is recommended. Not as aggressive surgery is needed as for SCC
-Radiation can be used as adjunctive tx but is less effective than surgery