INTRO TO ORAL MUCOSA ...................................................................................................................................................................................... 2

HISTOLOGY OF ORAL MUCOSA ............................................................................................................................................................................................. 2

COMMON SKIN CONDITIONS ................................................................................................................................................................................ 4

STRUCTURE ...................................................................................................................................................................................................................... 5

EPIDERMIS ....................................................................................................................................................................................................................... 5

CONDITIONS .................................................................................................................................................................................................................... 5

ASSESSING A LESION: CLINICALLY AND HISTOLOGICALLY .....................................................................................................................................10

CLINICAL ASSESSMENT...................................................................................................................................................................................................... 10

HISTOLOGICAL ASSESSMENT .............................................................................................................................................................................................. 11

ASSESSING AN ORAL LESION AT RISK ..................................................................................................................................................................................... 11

ORAL CANCER AND PRE-CANCER ..........................................................................................................................................................................12

ORAL CANCER ................................................................................................................................................................................................................ 12

ORAL PRE-CANCER: ......................................................................................................................................................................................................... 13

CASE STUDIES .......................................................................................................................................................................................................15

WEEK 1 ........................................................................................................................................................................................................................ 15

WEEK 2 ........................................................................................................................................................................................................................ 18

WEEK 3 ........................................................................................................................................................................................................................ 20

PBL 1 – MS LACEA PLAKIA .....................................................................................................................................................................................24

PBL 2 – MR. SCOTT PHILLIPS .................................................................................................................................................................................24

VISUALIZATION AIDS ........................................................................................................................................................................................................ 26

PBL 3 – POGUE MAHONE ......................................................................................................................................................................................27

ORAL LICHEN PLANUS ...................................................................................................................................................................................................... 27

OTHER STUFF ................................................................................................................................................................................................................. 28

MEDICATION ADHERENCE ................................................................................................................................................................................................. 28

CHRONIC WOUNDS AND DIABETES ...................................................................................................................................................................................... 28

PHARMACOLOGY OF INTEGUMENTARY SYSTEM ..................................................................................................................................................28

WOUNDS ...................................................................................................................................................................................................................... 29

GLUCOCORTICOIDS .......................................................................................................................................................................................................... 29

ANTIBIOTIC AGENTS ......................................................................................................................................................................................................... 31

ANTIFUNGAL AGENTS ....................................................................................................................................................................................................... 32

ANTIVIRAL AGENTS .......................................................................................................................................................................................................... 33

DRUG VEHICLES .............................................................................................................................................................................................................. 33

IMMUNOSUPPRESSANTS ................................................................................................................................................................................................... 34

CHEMOTHERAPY ............................................................................................................................................................................................................. 35

TREATMENT OF COMMON SKIN & MUCOSAL CONDITIONS ....................................................................................................................................................... 36

ADVANCES IN ORAL LESION DETECTION ...............................................................................................................................................................39

COMPLICATIONS OF CANCER TREATMENT ...........................................................................................................................................................40

ORAL MANIFESTATIONS OF SYSTEMIC DISEASES ..................................................................................................................................................................... 40

COMMON SKIN CONDITIONS (MURPHY) ..............................................................................................................................................................41

MACULES AND PATCHES ................................................................................................................................................................................................... 41

PAPULES AND PLAQUES .................................................................................................................................................................................................... 42

NODULES ...................................................................................................................................................................................................................... 43

PAPULOSQUAMOUS ......................................................................................................................................................................................................... 43

VESICLE/BULLAE/PUSTULES .............................................................................................................................................................................................. 44

ORAL ULCERATION .......................................................................................................................................................................................................... 45

CONNECTIVE TISSUE DISEASES ............................................................................................................................................................................................ 45

SKIN CANCER NODULES .................................................................................................................................................................................................... 46

RANDOM LESIONS AND DX ..................................................................................................................................................................................47

Intro to Oral Mucosa Histology is the underlying code, dictating how cells and tissues look and if that is within normal limits or not.

Oral Mucosa:

Mucous membrane = Moist lining of body cavities that communicate with the exterior

2 separate tissue components:

1. Covering Epithelium

2. Underlying (supportive) connective tissue

Functions:

Protection Separates deep tissues and organs from environment. Withstands mechanical forces of mastication and surface abrasion/insults

Sensation Receptors respond to temp, touch, pain, and taste

Secretion Saliva lubricates and aids in swallowing, digestion, microbial defence, acidic buffering, remineralization, taste mediation

Histology of Oral Mucosa

Oral Epithelium = Stratified squamous epithelium made mostly of keratinocytes (although not all oral mucosa surfaces are keratinized)

- Cells arranged tightly and in distinct layers. Superficial layers are shed and replaced as cells are pushed up from

basal to apical

4 layers of epithelium:

1. Stratum Basale

2. Stratum Spinosum (AKA Prickle cell layer)

- Prickly from desmosomes -> protrude as cell

shrinks during stain processing.

3. Stratum granulosum

4. Stratum Corneum

Keratinocytes:

Because Keratinized tissues have slower epithelial rate, recall exams are booked approx. 6-8 weeks (otherwise won’t see

much change). Non-keratinized tissues are faster, and recalls can be made 3 - 3.5 weeks.

Clinical Correlate:

- Chemotherapy targets rapidly dividing cells (mitotic activity). So cancerous AND rapidly dividing healthy cells are

affected.

o GI Epithelium, Oral epithelium, hematopoietic precursors in bone marrow (↓ immunity)

o Oral effects occur in 7-10 days, and non-keratinized mucosa is affected the most. ↓ protection, ↓

secretion, ↓ sensation.

o Once therapy is over it will take 3.5 weeks to recover

Keratinized Oral Epithelium (Orthokeratinized) Parakeratinized Non-Keratinized Oral Epithelium

- Masticatory Mucosa - Inflexible, tough, abrasion resistant - Tightly connected to underlying tissue

Histology: Basal Layer – Cuboidal/columnar Prickle Layer – Large cells + prominent desmosomes Granular Layer – Flatter cells, keratohyalin granules Keratinized layer – Flattened, dehydrated, packed with fibrillar material

- Transitional epithelium between keratinized and non-keratinized

- Nuclei are retained

- Lining Mucosa - Flexible, less abrasion resistant, less tightly bound

to underlying tissue Histology: Basal Layer – Cuboidal/columnar Prickle Layer – Large cells + prominent desmosomes Intermediate Layer – cells start to flatten Superficial Layer – Flattened cells, nuclei persist but ↓ organelles

Non-Keratinocyte Epithelial Cells Cells Description Histology

Melanocytes - Produce Melanin - Neural Crest Ectoderm derived - 11 Weeks Gestation: Migrate to epithelial surface (reside at basal cells) - # is the same for everyone. Skin darkness depends on: # of melanosomes,

the size of melanosomes, the # of melanin within melanosomes and their rate of degradation.

Long dendritic processes extend to distribute melanosomes to surrounding area (pigment containing organelles) Appear clear (non-staining cytoplasm)

- 1 for every 10-20 keratinocytes

Langerhans Cells - Dendritic cells lacking desmosomes - Supra-basal within the epithelium - Migrate from bone marrow, move in and out of epithelium - Process Ag from environment to present to Tcells

Merkel Cells - Non-dendritic found within basal layer - May come from keratinocytes - Sensory cells responding to touch

Inflammatory Cells

- Associated with Langerhans cells - Modulated by Keratinocytes

- Produce IL-1 -> activates Tcells + ↑ MSH rec. on melanocytes

Basal Membrane + Connective Tissue

Connective Tissue papilla + epithelial rete pegs -> ↑ surface area of attachment to be stronger

against tensile and shear forces

Basement Membrane:

- Hemidesmosomes attach basal cells to basement membrane

- Lamina lucida layer contains integrins and laminin to bind to Type 4 and

7 collagens within the lamina densa

Lamina Propria (Connective Tissue)

- Loose tissue consisting of ground substance and few collagens (floor of mouth)

- Can also have an abundance of collagen depending on location (gingiva)

- Fibroblasts secrete collagen and ground substance.

o Contractile (helps wound contraction)

Inflammation Chronic inflammation can last months -years -> results in proliferation of blood vessels, fibrosis and tissue necrosis

- Tissue destruction = hallmark of chronic inflammation

Oral Mucosa Organization Mucosa Example Description

Lining Mucosa

Floor of Mouth, Ventral tongue, Buccal mucosa, Soft Palate, Alveolar Mucosa, Labial Mucosa

- No masticatory function - Soft, Pliable, Nonkeratinized - Red b/c underlying vasculature (can be yellow if adipose is underneath) - Gapes when incised, allows room for LA fluid

• When we see a white lesion in an area typically non-keratinized we are worried -> could be altered maturation = pre-cancerous

Masticatory Mucosa

Gingiva, Hard Palate - Keratinized - ↑ opaque, so see less vascularization (pink colour) - ↑ keratinization = ↑ whiteness - No gape when incised, no room for LA

Specialized Mucosa

Lips Dorsal Tongue

Lips: - Labial mucosa = non-keratinized stratified squamous - Vermillion border = transition into keratinized - Few glands = susceptible to dehydration Dorsal Tongue: - Keratinized - Papilla + taste buds

Common Skin Conditions Function Description

Protection Barrier btwn body and environment Radiation shield from UV Protects from mechanical, chem, thermal insults Selectively permeable to water -> prevents dehydration Protects against microbes

Sensation Receptors for touch, pressure, pain, temperature

Thermoregulation Insulates against heat loss (hair, fat)

Dissipates heat via sweat, blood dilations

Metabolic Subcutaneous fat energy storage Vitamin D

Structure Layer Description

Epidermis Stratified Squamous Epithelium - Keratinized

Dermis

Fibrous and fibro-adipose tissue to support epidermis - Contains blood vessels, nerves, and sensory receptors

2 Layers: Papillary dermis (superficial) – immediately beneath epidermis. Thinner collagen and elastic fibres Reticular dermis (deep) – Thick bundles of type I collagen and thick elastic fibers

Hypodermis - Not in oral mucosa

Adipose tissue w/supporting fibrous bands (septa) and blood vessels

Adnexal Structures - Not in oral mucosa

Nails, Hair follicles, sebaceous glands (secretes waxy sebum to waterproof), apocrine glands - Occupy dermis layer mostly

Arrector pili muscle -> goosebumps when cold.

Epidermis - Tough abrasion resistant, water resistant UV blocker

- Avascular (vascularization not until basement membrane)

4 Layers:

Stratum Basale

1 layer cuboidal cells on basement membrane - Stem cells, very mitotically active - Pickup pigment from adjacent melanocytes

Hemidesmosomes attach to basement membrane

Stratum Spinosum

Large polyhedral “Prickles” between cells = prominent desmosomes from processing technique

Stratum Granulosum

1-3 layers thick - Contains keratohyalin granules (produces keratin)

Stratum Corneum

Many layers of fused and flattened keratinized cells (missing nuclei and organelles)

- Diffusion barrier - Lipid-rich Lysosomal vesicles secrete “cement” to hold

cells together

Skin Colour and what it is from

Conditions

Brown Epidermal Melanin

Red Dermal Oxygenated hemoglobin

Blue Dermal Reduced hemoglobin

Yellow Epidermal carotenoids

Conditions Description Image

Sebaceous Hyperplasia

Benign disorder of sebaceous gland - 50-60 year olds -> Equal Male:Female Prevalence

Cause: ↓ androgen associated with aging Signs/Symptoms: Asymptomatic, soft, pale, yellow, shiny, umbilicated bumps. Resembles cauliflower 1-4mm diameter

- Can become red, irritated, and bleed with shaving or scratching - Only cosmetic issue, no clinical significance

Histology: Enlarged mature lobules of sebocytes around duct

Acne Chronic inflammatory condition - Eruption of comedo (clogged pore/follicle)

Risk Factors:

- ↑ sebum production (regulated by androgens) - Hyperkeratinization of follicle (keratin plugs pore) - Propionibacterium acnes infection - Inflammation

Treatment:

- Topical Retinoids – regulate epithelial cell growth. - Benzoyl Peroxide - ↓ risk of bacterial resistance - Salicylic Acid – Less potent than retinoids - Estrogen-containing oral contraceptives - Minocycline (100-200mg/day)

- Can cause hyperpigmentation of oral mucosa and bone

Rosacea = Prominent facial flushing/erythema. Starts as ↑ blush in 20’s, but fixed in 30+ - Vascular hyperreactivity and ↓ innate immunity - 3:1 Female : Male ratio - Pilobaceous unit (= hair, hair follicle, arrector pili muscles, and sebaceous gland) involved. But

1° issue is vascular (not follicular) Clinically: Erythema, telangiectasia, coarse skin, inflammatory rxn resembling acne

- Associated with hot drinks, emotion, heat, rapid body temp changes Treatment:

- Sunscreen, and laser treatment Chronic:

- Can lead to rhinophyma (hypertrophy of sebaceous glands on nose)

Sebhorrheic Keratosis

Most common benign epithelial tumor in older patients - Forehead, neck and hands - Hereditary (autosomal dominant), occurring after 30

Clinically: - Well-circumscribed, yellow-brown, raised lesions, feel greasy, plugged follicles

Histology: - Exophytic proliferation basilar epidermal cells (vary degrees of keratinization, acanthosis &

papillomatosis). Melanin pigmentation Differential DX:

- Melanoma, Verruca Vulgaris Treatment:

- Not usually treated unless there are cosmetic issues. - Electrodesiccation, laser ablation, curettage, cryosurgery, or shave excision

Actinic Keratosis Thick scaly growth (keratosis) caused by sun (actinic) Clinically:

- Flat or elevated w/ erythematous base. 3-10mm diameter can grow - Precursor to cutaneous squamous cell carcinoma -> malignant potential - ↑ risk for fair skinned with ↑ sun exposure.

Histology: - Aggregates of basal keratinocytes (extending upwards involving granular and cornified layers).

Acanthosis, parakeratosis and dyskeratosis. - Cells vary in size and shape - UV induced mutations present (TP53, p16 tumor suppressor deletion) - ↑ risk to get this if immunosuppressed after organ transplant

Treatment: - Effudex (topical chemotherapy) - Aldara (imiquimod) – Up reg. cytokines to induces immune system

Squamous Cell Carcinoma

Cutaneous SCC = 2nd most common skin cancer - Not fatal but can cause disfigurement - UV exposure = most significant risk factor - >90% have loss of TP53 gene

Markers for ↑ Risk: - Fair skin, repeated sunburns, blue or hazel eyes, blonde or red hair, albinism

Clinically: - Shallow ulcer w/ elevated margin, covered with plaque. - Scaling, deep ulceration, crusting and cutaneous horn. - May follow nerves and vessels - 5% metastasize -> 3x more likely if >2cm

Basal Cell Carcinoma Most common skin cancer -> from sun exposure - Non melanocytic (not typically brown) slow growing - Incapable of metastasis -> b/c needs surrounding stroma support to grow - Can be umbilicated

Clinically: - Pearly pink/white, domed papule with prominent telangiectatic vessels - Definitive diagnosis needs biopsy

Treatment: - Surgical excision, curettage/electrodessication, micrographic surg.

Nevoid Basal Cell Carcinoma Syndrome (NBCCS)

- Gorlin Goltz syndrome - Auto. Dominant -> early onset BCC in teens and 20’s - Palmar/plantar pitting - KCOT? - Frontal Bossing - Calcification of Falx cerebri - Bifid ribs

Solar Lentigo (age spots)

Associated with Aging (90% in whites >60 yrs) Clinically:

- Light yellow-brown, round/oval, discrete and scattered Treatment:

- Cryosurgery/lasers

Psoriasis Often associated with arthritis (and sometimes geographic tongue) - Immune-mediated with genetic predisposition - Arthritis 12 years after lesions (6-42% of patients) - Approx 1/3 of patients have 1st degree relative with psoriasis also- Genetic!

Clinically: - Well-defined round/oval plaques that coalesce & cover with silvery white scales - 80-90% develop nail disease (abnormal growth, pitting, subungual hyperkeratosis) - Wax and Wave with flares associated with stress and infection

Therapies: - Target cytokines, dendritic cells and T-cells within lesions - PUVA (Psoralen, photoactivator with UVA)

Cutaneous Lichen Planus

Often between 30-60 yrs. Acute onset on wrists, forearms and legs 6P’s:

- Planar (flat) - Pruritic - Purple - Papules - Polygonal - Plaques

Covered with lacy, reticular white lines (Wickham Striae) - Common to see hyper-pigmentations as lesion clears - Can resolve spontaneously within 1-2 years

Therapy: - Topical corticosteroids

Nevi Cells have tyrosinase

(converts melanin within

melanosomes)

Nevomelanocytic Nevi - Can be congenital (@birth) but most appear in childhood (acquired melanocytic nevi) Dropping Off/Abtrofung Effect:

1. Initially, flat macular lesion w/ nests of nevus cells clustered at basement membrane. 2. Lesion elevates as cells extend (drop off) into underlying submucosa. 3. Eventually lesion will only consist of submucosal cells. By adulthood most nevi are intradermal (submucosal)

- ↑ #’s of melanocytic nevi (>50) = risk factor for malignant melanoma Cutaneous Junctional Nevus

- Well-circumscribed brown-black macule. Appears during childhood/adolescence - Discrete nests of nevus at dermo-epidermal junction on rete pegs

Cutaneous Compound Nevi

- Most common in children and adolescents. ↑ with age - Can be minimally elevated to dome-shaped or polypoid - Tan-dark brown

Intradermal Nevi

- Most common melanocytic nevi - Usually dome-shaped, nodular, polyploid lesions. Flesh coloured - May have coarse hairs

Blue Nevi

- Benign pigmented lesion (blue macule). - Pigment cells (spindled dendritic cells confined to connective tissues-Deep)

- Most common on hard palate

Melanoma 3-5% of all skin cancers. -> 75% of all deaths from skin cancers Predisposing Factors: ↑ sun exposure, fair skin 2 distinct phases of growth:

1. Radial (horizontal) growth: Malignant cells spread lateral along dermoepidermal junction 2. Vertical Growth: Penetrate into dermis and subcutaneous by malignant cells

Prognosis: - Thin = better prog. - Not extending into papillary dermis is better for prog. - BANS (Back, Arm, Neck, Scalp) = high risk areas - Ulceration = ↑ mitotic activity = ↑ prog.

Melanotic Macules - Asymptomatic - Discrete - Tan, brown, or black - Flat - Usually less than 1 cm - Even pigmentation Common Sites: - Gingiva, lower lip, palate, buccal mucosa, alveolar ridge Treatment: - Generally no treatment required, “wait and watch” approach - No known malignant transformations

Assessing a Lesion: Clinically and Histologically

Clinical Assessment 1. Type of Lesion

Primary Descriptors Secondary Lesions

Flat Macule - <1cm Patch - >1cm

Scale Epidermal cells from abnormal keratinisation which died and shed

Raised Epidermis (surface) only: Papule - <1cm Plaque - > 1cm Subepithelial w/ or w/o epithelial: Nodule - < 1cm Mass - >1cm

Crust Dried serum and cellular exudates

Fluid Containing

Clear Fluid: Vesicle - <0.5cm Bulla - >0.5cm Fluid & Pus: Pustule - < 0.5cm Abscess - > 0.5cm Blood: Hematoma (Fresh) vs Bruise (Old) Petechiae - <2mm Purpura - 2mm – 1cm Ecchymosis - > 1cm

Erosion Discontinuation of epithelial lining Limited to epidermis

Ulcer Discontinuation of epithelial lining extending into epidermis/dermis

Atrophy Thinning of epidermis/dermis leading to depression in skin

Fissure Linear discontinuation of epithelial lining with sharply demarcated margin (can extend to dermis)

2) Colour

Red/Purple Erythematous - ↑ blood flow to vessels (dilation) in area Purple/Violaceous – Extravasation of blood into skin from vessel

Brown Melanin – Pigment in skin to give brown discolouration Haemosiderin –Brown breakdown product of haemoglobin, typically occurs after purpura.

Yellow Lipid Deposition – Lipoma, Xanthelasma (cholesterol deposits) Bilirubin – Jaundice (bilirubin >35umol)

3) Surface Features

Normal Lesion is below skin surface

Abnormal Change in stratum corneum (outermost layer): Hyperkeratosis - ↑ stratum corneum thickness b/c ↑ keratin deposition within cells Scales – Cells have died and been shed Break in Epithelial Surface: Exudate Crust Erosion Ulcer Fissure Change in size of epidermis/dermis: Atrophy

4) Shape of Lesion 5) Consistency 6) Others

Histological Assessment 1) Surface Epithelium from top most – bottom

Superficial keratinous layer: Keratinized -> Nucleus or not? (Para vs orthokeratinized Non-Keratinized Intermediate Spinous Layer: Normal width Expanded Atrophic Cellular Atypical change Epithelium – Connective Tissues Junction: Basement Membrane Yes/No? Rete Ridges Yes/No? Subtending Connective Tissue Abnormal? ↑ # cells?

Assessing an oral lesion at risk 1. History of Present Illness

- LOPQRSTAAA for pain

- Onset, Location, Intensity, Frequency Duration

- Aggravating and/or relieving factors

- Changing over time (better, unchanged or worse?)

2. Medical History

- Medications

- Allergies

- Systems review (Skin, GI, Joints

- Medical conditions (hospitalizations, chronic conditions)

- Risk Factors (smoking, alcohol, betel nut, illicit drugs)

- Family History

3. Examination

- Extraoral

o Visual and palpation: swelling, asymmetry or

mass

- Intraoral

o Difficult areas: Lingual to retromolar, Tonsillar,

Vestibules

4. Differential Diagnosis

- Inherited or Congenital

o White Spongy Nevus

- Infection (Bacterial, viral, fungal)

o HPV, Squamous papilloma, Heck’s Disease,

Candidiasis

- Inflammatory

o Lichen Planus, Host vs Graft, Contact lichenoid

mucositis, Pemphigus

- Iatrogenic

o Amalgam Tattoo, Frictional hyperkeratosis

- Idiopathic

o Leukoplakia, Erythroplakia

Round Oval

Irregular

Spherical Domed

Pedunculated Sessile

Flat-topped Pointed

Finger-protrusions

Borders Diffuse – Hard to tell where lesion begins/ends Discrete – Obvious border of lesions

Colour Homogenous – 1 consistent colour Non-Homogenous - >1 colour

Firm/ Elastic firm

Soft/Fluctuant

Bony/Bony hard

Bleeding on palpation

Blanched on palpation

Pain on palpation

Clinical correlation: White

lesions in the ventral

tongue/floor of mouth are of

great concern because it is not

an area of frequent trauma

and it is where saliva

(containing dissolves irritants)

pools chronically.

Oral Cancer and Pre-Cancer

Oral Cancer - Malignancy in the oral cavity

= 6th most common cancer in the world, <50% 5-year survival rate

- ↓ prognosis b/c: High Incidence, Poor prognosis, High morbidity, Late diagnosis

- Survivors have severe cosmetic and functional compromise

Common types:

- Squamous cell carcinoma - Verrucous carcinoma - Salivary gland tumor - Melanoma - Metastatic malignancy

Etiological Factors

Tobacco - Smoke and smokeless

Alcohol - Independent, but w/ smoking 15x ↑ risk

Sunlight (UV) - Lower lip high risk zone

Genetics Microorganisms

- HPV - Chronic candidiasis - Syphilis

Nutrition - Iron Deficiency (Plummer Vinson syndrome)

Chronic irritation Gender Location

Major Factors impacting prognosis:

TNM Staging

T – Size of 1° tumour - T1: <2cm - T2: 2-4cm - T3: >4cm - T4: Invading adjacent structures (cortical bone, deep muscles of tongue,

maxillary sinus)

N – lymph node involvement - N0: No nodal involvement - N1: Single ipsilateral node, <3cm - N2a: Single ipsilateral node, >3cm - <6cm - N2b: Multiple ipsilateral nodes, <6cm - N2c: Bilateral nodes, <6cm - N3: Node >6cm

M – Metastases

- M0: No distant metastases - M1: Distant Metastasis (Lung, Liver, Bone)

Staging:

- Stage 1: T1N0 - Stage 2: T2N0 - Stage 3: T1-3 N1 - Stage 4a: T1-3 N2 / T4 N0-2 - Stage 4b: Tx N3 / Tx M1

Histological Grading

Well Differentiated Moderately well-differentiated Poorly Differentiated

Location Tongue (Worst Prognosis) Gingiva/Palate Floor of mouth Buccal Mucosa Lip (Best Prognosis)

Nodal Zones

- Zone 1: Submand. Triangle (metastasis from ant. 2/3 of tongue, FOM, Gums, Buccal mucosa)

- Zone 2: Upper Jugular chain (Metastasis from nasopharynx)

- Zone 3: Midjugular chain (Metastasis from oral cavity, pharynx, or larynx)

- Zone 4: Lower Jugular chain (metastasis from thryroid, pyriform sinus, upper esophagus)

- Zone 5: Posterior Triangle (Metastasis from nasopharynx, posterior scalp, ear, temporal bone)

Oral Pre-Cancer: Pre-malignancy = morphologically altered tissue where cancer is more likely to occur than normal

- Most still don’t become cancer 😊

WHO Pre-Malignant Oral Lesions:

1. Oral Dysplasia

2. Oral Submucosa Fibrosis (from chewing betel nuts)

3. Verrucous Leukoplakia (no dysplasia)

4. Actinic Keratosis

5. Oral Lichen Planus

6. Discoid Lupus

7. Dyskeratosis Congenita

8. Epidermolysis Bullosa

Gold Standard for Risk Assessment

If a lesion is suspected as being risky -> Biopsy taken and sent to pathologist -> Pathologist makes diagnosis and

determines the presence and degree of dysplasia

Dysplasia

Criteria for Dysplasia a. Irregular stratification/Loss of polarity of cells in epithelium b. ↑ mitosis c. Nuclear hyperchromatism d. ↑ nuclear/cytoplasmic ratio e. Polymorphism of cells f. Abnormal Keratinization

Categorization Mild Dysplasia - Changes limited to basal 1/3 (basal and parabasal cells only)

Moderate Dysplasia - Lower ½ of epithelial cells affected

Severe Dysplasia - Lower 2/3 of epithelial cells affected

Carcinoma in situ (CIS) - Every layer of epithelial cells affected - Basement membrane still intact

Invasive Squamous Cell Carcinoma - Basement membrane disrupted invasion into surrounding tissues and circulation

Presentations of premalignancies

Leukoplakia = White patch/plaque that doesn’t rub off and is not diagnosed as any specific disease

Erythroplakia = Fiery red patch that cannot be characterized either clinically or pathologically as any other definable lesion

Erythroleukoplakia Red and white patch that is not characterized clinically or pathologically as any definable disease

Problems in Clinical Diagnosis (Late diagnoses):

1. Reactive vs OPL

- Medical Hx, Smoking Hx, Drug Hx, General Health

- Be familiar with presentations of common oral conditions

(Lichen Planus, Canker sore etc)

- Culture the lesion (fungal swab, Viral culture)

- Assess possible etiological factors (sharp tooth or

restoration causing white spot)

2. High Risk vs Low Risk Areas and Factors

a. Site of Lesion

- Ventrolateral tongue

- Floor of Mouth

- Soft Palate region

b. Appearance of Lesion

- (Worse) Red >> Red and White >> White (Better)

- (Worse) Diffuse >> Discrete (Better)

- (Worse) Non-Homogenous >> Homogenous (Better)

c. Size and change over time

- ↑ Size = ↑ Risk

- ↑ # of lesions = ↑ Risk

- ↑ Speed of progression = ↑ Risk

Case Studies

Week 1 Case 1 Case 2

70F, Hx of cutaneous melanoma on upper back. Remote Hx of smoking (quit 40yrs ago) 32F, asymptomatic pigmented lesion

- Non-smoker, exposed to 2nd hand smoke since young - Lesion present for 12 yrs, no clinical change

Lesion Description Lesion Description

A – Asymmetrical B – Irregular Diffuse borders C- Brown, Homogenous colour D - ~ 10mm x 3mm E – Unknown if evolving L – Left side of soft palate

Colour: Blueish, Homogenous Borders: Distinct Shape: Oval Raised?: No, flat macule. Dimensions: 1cmx0.5cm Location: Hard Palate (palatal to 26)

Differential Diagnosis Differential Diagnosis

Melanotic Macule - Flat, discolored areas of skin (typically <1cm wide), generally distinct

Minocycline Hyperpigmentation - Occurs if patient is on acne medication

Melanotic Nevus - Regular Borders, Symmetric, Nevus cells (variant of melanocytes from neural crest, tend to

cluster), slightly raised - Rare in the oral cavity - Cannot be differentiated from melanoma so should be completely excised.

Amalgam Tattoo - Caused from Amalgam particles penetrating mucosa. Grey colour

Melanoma - Non-homogenous, Brown, Diffuse Borders

Smokers Melanosis - Diffuse, patchy, irregular pigmentation on anterior facial mand. And max gingiva

Blue Nevi - Type of melanocytic Nevus, most commonly on hard palate - Blue colour by having the nevus cells accumulate close to the rete pegs but deep in the surface

epithelium. B/c deeper in tissue reflect light different, so looks blue instead of brown Amalgam Tattoo - Caused from Amalgam particles penetrating mucosa Hematoma - Ruptured blood vessel

Vascular Malformation - Structural anomaly of blood vessel (like a varicose vein)

Drug Induced Pigmentation (Malaria, or Acne medication) - Chloroquine and Minocycline can cause blue-black discoloration especially on hard palate

Histology Histology

- Pigmentation in CT -> Melanotic Macule characterized by ↑ pigmentation in Basal-layer, lamina propria or both

- Not likely a nevus -> no islands of melanin - Not likely melanoma -> no Dysplasia

- Brown pigments are Melanin. Melanocytes (spindled dendritic cells) produce melanin and distribute them to surrounding cells in melanosomes.

- Islands of melanin within CT but not in basal membrane is indicative of blue nevus. Nevus cells haven’t reached the intradermal layer yet.

Supporting Info Supporting Info

- Recurrence of melanoma can be concerning - Smoking ↑ exposure to carcinogens and risk of cancer - Biopsy should be performed to rule out melanoma

- With nevus cells so deep, longer wavelength light is absorbed by the cells superficial to melanin, blue is reflected back (so looks blue)

- Not likely related to smoking Hx. Smokers melanosis usually occurs in attached anterior mandibular gingiva and papillae, not on hard palate. It is also usually more generalized

- Slight possibility that polycyclic amines (nicotine etc) enters circulation and indirectly stimulate melanocytes to deposit melanin. However would disappear after 3 years of smoking cessation

Case 3 Case 4

28M Asia, Healthy, Non-smoker, Asymptomatic 32M, Multiple medications, but on drug holiday

Lesion Description Lesion Description

A – Asymmetrical B – Well defined border C – Brown/Black, non-homogenized D – Variable (>6mm), flat E – Unknown Location: Keratinized tissue of Maxilla

- Purple/Red non homogenous, Irregular and Raised on the hard palate with white exudate on the left side of palate, 3cm x 2cm Diffuse lateral border

- Red/Purple, asymmetrical, flat, Buccal Vestibule, Diffuse borders, Atrophic epithelium

Differential Dx Differential Dx

Amalgam Tattoo - No alamgam resto’s

Smoker’s Melanosis - Non-smoker

Kaposi Sarcoma - Not shown histologically (Large nodules + Purple)

Racial Pigmentation - Not widespread on both arches

Trauma - Asymptomatic, and would expect more localized

Melanotic Macule - Not usually widespread

Melanoma - Most commonly on palate and gingiva - Melanosis usually appears before developing into melanoma

Haemangiona - Usually a focal point, not widespread over entire palate

Hematoma - Multiple varied raised lesions or trauma make this unlikely

Nicotinic Stomatitis - Unknown Smoking Hx, Description doesn’t match nicotinic stomatitis

Drug Induced Hyperpigmentation - This would be flat and diffuse, without purulent exudate - Pt is on a drug holiday (no drugs)

Squamous Cell Carcinoma - Submucosal changes occurred, so not likely

Kaposi’s Sarcoma - Purple lesions and histological presentation - Caused by Human Herpes Virus (HHV) 8

Histology Histology

- Hyperkeratosis - Pigmented malignant melanocytes (brown spindle cells) diffusely infiltrated in the subepithelial CT

and submucosal area - Loss of rete pegs - Indistinct basal cell layer

- Blue Cells -> Infiltration of spindle-shaped endothelial cells and some inflammatory cells - Red cells -> RBC extravasated from ill formed vascular channels

Supporting Info Supporting Info

2 Subtypes: - Invasive Melanoma (vertical growth into CT, no significant lateral spread) - In situ Melanoma (Horizontal growth along basement membrane for months-yrs before

vertical growth

- Less common than cutaneous melanoma - Immunohistochemistry used to differentiate from other poorly differentiated neoplasms: 3 specific

antibodies released from melanoma are screened/stained. This can also show occult locations of the lesion

3 Phases: - Patch (spindle cells present rather than spores); - Plaque (Dermal proliferation of spidle-like endothelial cells, forms sinuous vascular space); - Nodule (Visible hyaline globules)

- Likely has comorbidities (HIV, AIDS, or Iatrogenic), possible they stopped taking anti-retroviral drugs,

allowing disease to take hold and progress lesion

Case 5 Case 6:

56F, Hx multiple recurrent pigmented lesions since young, enlarging over time

27F, Pregnant for 6 months (2nd baby), Braces on lower jaw removed 3 months ago

Lesion Description Lesion Description

Asymmetrical, nodular; Blue/Purple colour; 1-3cm diameter; Evolving over time; Soft, smooth, Sessile; Located on lips, ear, tongue.

Location: Buccal Gingival of 43 to mucogingival junction ; Size: 1cm x 0.5cm Elevated/Flat: Elevated, Sessile Nodule; Border: Defined ; Ulcerated: Yes ; Colour: Hyperkeratotic, pink + 2 erythematous ulcerations, Homogenous (except ulcerations), Texture: Smooth, Bulbous.

Differential Dx - Hemangioma Differential Dx – Pyogenic Granuloma

Pyogenic Granuloma - Caused by trauma and ↑ Estrogen, but doesn’t often affected multiple sites - Patient is menopausal (↓ Estrogen) though and no trauma reported,

Congenital hemangioma - Occurs in segmental patters (Frontotemporal, Maxillary, Mandibular, Frontonasal) - Symptom of Sturge Weber Syndrome

Hemangioma – Sturge-Webber Syndrome - Abnormally dilated blood vessels causing pooling, Develops after 40yrs - Port Wine Stain appears from over-abundance of capillaries near surface - Colour change from bleeding under the skin

Pyogenic Granuloma - Relatively common, Exuberant tissue response to irritation or trauma - Presents as hyperplastic granulation tissue, no pus unless ulcerated - Can be caused by hormonal changes (pregnancy) or drugs - Found predominantly in the gingiva, tongue, lower lip, buccal mucosa - Localized reactive lesion, not cancerous

Peripheral giant cell granuloma: - Not related to hormones or drugs - Hyperplastic fibroblasts with multinucleated giant cells (not seen), does not show granulomatous

inflammation Peripheral Odontogenic Fibroma - Tend to be lighter in colour, likely not the dx

Trauma - Must test by checking occlusion and for sharp teeth or restorations

Neoplasm - Would need biopsy to confirm

Histology Histology

- Small channels are blood vessels bundled up and are surrounded by discontinuous layer of pericytes and reticular fibres

- Proliferation of endothelial cells and capillaries in a lobular pattern + Acute and chronic inflammation - Empty holes of non-uniform diameters = proliferating vascular channels - Thick purple border = Hyperplastic parakeratinized epithelium

Supporting Info Supporting Info

- Likely Sturge-Webber syndrome: A neurological disorder marked by a distinctive port-wine stain on the forehead, scalp, or around the eye. This stain is a birthmark caused by an overabundance of capillaries near the surface of the skin

- Involves skin innervated by 1+ branches of trigeminal nerve - Vascular defect can extend intraorally (as seen in this patient)

- Composed primarily of hyperplastic granulation tissues with ↑ capillaries-> appears as red mass - Prequently caused by calculus or foreign materia within gingival creviice - Develops in 5% of pregnancies b/c of hormonal imbalance and ↑ response to irritation - Estrogen ↑ Vascular endothelial growth factor from macrophages

Week 2

Case 8 Case 9

49F, sore gums for >1yr, Especially painful when brushes teeth, bleeding often

Lesion Description Lesion Description

- 1cm x 2 cm, Red Homogenous, flat patch - Atrophic, Non-ulcerative lesion in the midline of the tongue. - Defined borders

Asymmetric, flat erythematous patch, well circumscribed generalized across the gingiva (lingual and palatal) on both arches with diffuse borders and irregular shape

Differential Dx Differential Dx

Trauma Carcinoma/oral cancer Erythroplakia Pseudomembranous Candidiasis

- Creamy White lesion, can be removed by scraping to reveal erythematous surface and occasional bleeding

Hyperplastic Candidiasis (Median Rhomoid Glossitis) - Smooth homogenous/nodular white lesions, CANNOT be removed with scraping - Atrophic red “rhomboid shape” lesion along midline of tongue with no apparent papilla - Well circumscribed, can be slightly elevated - Histologically can see hyphae perpendicular to surface (makes it hard to scrape off) and chronic

inflammatory cell infiltrates at lamina propria - Usually asymptomatic

Gingivitis/ Periodontitis - Would not see separation of basement membrane

Acute herpetic gingivostomatitis Pemphigus vulgaris,

- Idiopathic autoimmune disease against desmosomes connecting epithelial cell:Epithelial Cell - Painful ulcers preceded by flaccid and short-lived vesicles and bullae -> rupture leaving red,

painful ulcerated base with friable epithelial border - May show Nikolsky sign

Pemphigoid Lichen Planus Trauma Cancer Erythema Multiforme Impetigo

Histology Histology

- Hyphae infiltrating the epithelium. Perpendicular to surface is indicative of a chronic hypertrophic candidiasis because they won’t easily wipe off.

- Epithelial hyperplasia with bulbous rete ridges - Hyperkeratinisation

Intraepithelial clefting with keratinocyte acantholysis - Spinous layer cells in epithelium fall off from basal layer, desmosomes lose connection. - Basal Layer remains connected to Basement membrane

Under direct immunofluorescence staining: - Intercellular deposits of IgG antibodies on the surface of

keratinocytes in and around the lesions through out epidermis.

- IgG Ab attached onto desmogleins (transmembrane glycoproteins of desmosomes giving cell-cell adhesion

- Fish-net pattern: Fluorescence staining desmogleins surrounding the cells

Supporting Info Supporting Info

Fungus: Candida Albicans (over 150 species of candida, albicans is most common (50%) Patient may suffer from other Issues: Local:

- ↓ Salivary gland function (↓ immune mediators in saliva) - Drugs (inhaled steroids) that ↓ immune system - Dentures predispose to candida infection - High carbohydrate diet

Systemic: - Stress, ↓ immunity - Broad spectrum antibiotics altering local flora - Smoking, Diabetes, Cushing’s syndrome, HIV, Vitamin B deficiency

Would the patient have skin lesions? - Oral manifestations occur before skin lesions (early sign of pemphigus vulgaris) so they may

not yet have skin lesions. Oral signs are the initial sign of disease in 60% - Can present as ulcers, vesicles, bullae and pustular lesions as well as mucosal erosions

What is the impact if the diagnosis is delayed? - Open sores are highly susceptible to infection -> risk of endocarditis - Pemphigus is systemic disease, so longer we wait the more wide spread it can become

Complications: - Skin Infection, or spreading into bloodstream (Sepsis) - Periodontal disease if have large blisters in mouth - Medication side effects

What are the subtypes

1. Pseudomembranous -> Wipes off, classic presentation 2. Erythematous -> Red, erythematous patches on palate, buccal mucosa or dorsal tongue (Acute

Atrophic, Chronic Atrophic, , Angular Cheilitis) 3. Hyperplastic -> Nodular or speckled, less common, possible association with malignant

transformation -> can lead to Median Rhomboid glossitis

Pemphigus vs. Pemphigoid

Pemphigus Pemphigoid

Target Desmogleins (part of desmosome) in cell to cell connection

Laminin proteins (part of hemidesmosomes)

Histology Spinous Layer separates from basal layer (Basal still attached to basement membrane)

Subepithelial acantholytic appearance (Full separation of the basement membrane)

DIF Fishnet appearance (fully surrounding cells)

Wavy appearance (follows basement membrane along rete ridges)

Referral Dermatologist Opthalomogist

Case 10 Case 11

Stressful job, Ulcers for 3-4 months, very painful especially on tongue. 5mg Prednisone didn’t help. Is taking 0.5mg Xanax to help anxiety, and quick smoking 4 months ago

“Ulcers” change every day

Lesion Description Lesion Description

Slightly Raised papule, White center with erythematous circle. Non-homogenous - 0.5cm x 1 cm, Oval shaped and sessile with well defined border

Asymmetry: Yes Border: Diffuse: Colour: Red Diameter: >6mm Evolving: Yes, daily Non-homogenous Erosive Patch (non-elevated, >1cm) Hyperkeratosis at borders of lesion

Differential Diagnosis Differential Diagnosis

Traumatic ulcerative granuloma with stromal eosinophilia - Hx of trauma in 50% of cases - Surrounding tissue indurated, develops quickly, and heals slowly -> often confused with

malignancy - Deeply penetrating inflammation with chronic inflammatory cells infiltrating - Granuloma = cluster of immune cells when immune system walling off foreign invasion - Eosinophilia = ↑ # eosinophils recruited to specific site in body - Stromal = Connective tissue, blood vessels, nerves, ducts etc - Largely Self healing ulceration - Instigating factors appear to be mucosal trauma

Recurrent aphthous ulcer - Superficial inflammation

Trauma Ulcerative lichen planus Lichenoid reaction

Candidiasis -> White lesion that can be scraped off Reiter Syndrome -> Inflammatory arthritis developing in response to infection elsewhere Lichen Planus -> Lacy White Lesion Leukoplakia -> White Lesion Systemic Lupus Erythematosus -> Autoimmune disease with erythroplastic patches (skin lesion looks unrelated though) Herpes Simplex Virus -> Patients lesions change everyday so unlikely Drug Reaction -> Daily changes make this unlikely Geographic Tongue (Benign migratory glossitis)

- Variation of normal, doesn’t require a biopsy - Often asymptomatic, but can develop fear of oral cancer - Chronic, migratory, macroscopic lesion on tongue epithelium (changes in colour, size and

location) - Lesions form from loss of filiform papillae (islands of ulceration). Usually sensitive but painless

Histology Histology

Nuclei are same size and cells are similar Disrupted stratification Big pink cells = muscle cells, Small pink cells = eosinophils LOSS of rete ridges

- Not provided

Supporting Information Supporting Information

- Eosinophils appear to be reactive tissue response to unknown antigen entering after mucosal trauma

- Delayed healthing attributed to ↓ synthesis of transforming growth factor. - Eosinophils release cytokines (tumor necrosis factor) which induces further tissue damage

- Comorbidities: Nutritional deficiencies, psoriasis, allergy, hormonal disturbances etc - Incurable but may spontaneously resolve

Week 3 Case 12 Case 13

Recurrent white lesions bilaterally on tongue and buccal mucosa. 10 pack year smoking Hx. Quit for 5 yrs

45 M - Hx of taking medication for more than 5 years for acne treatment (stopped about 5 weeks ago)

Lesion Description Lesion Description

Lacy Patch, bilateral on buccal mucosa and lateral tongue. 2-3cm, diffuse borders, pseudomembranous, white, irregular and slightly raised

4cmx4cm flat patch, localised to the hard palate. Bilateral symmetry, homogenous grey/blue colour. Marked erosion or hypoplastic enamel also

Differential Diagnosis Differential Diagnosis

Chronic Hyperplastic Candidiasis - Occurs on buccal mucosa and lateral tongue - Speckled/homogenous white lesion - Associated with Smoking, stops when smoking stops - Can progress to severe dysplasia or malignancy - Parakeratosis and intraepithelial inflammation with fungal hyphae deeper into mucosa

Plaque-like Lichen Planus - Slightly raise/flat white area on oral mucosa - Cannot be rubbed off - Indistinguishable from other focal leukoplakias - Most common on tongue - Autoimmine lesion -> destruction of basal cell membrane and intense lymphocytic infiltrate in

lamina propria Leukoplakia

- No hyphae in staining Lichenoid Reaction / Oral Lichen Planus

- Usually drug induced lichenoid unilateral and associated with new drug - Not contact induced lichenoid ( no amalgam or allergenic restos) - Not OLP because no intense subepithelial band of leukocytes

Squamous Cell Carcinoma - No Hyphae in histology

Pseudomembranous Candidiasis - White soft plaques, that can coalesce - Present on tongue, palate, and buccal mucosa - Can rub off

Drug Induced Pigmentation - Possibly from minocycline acne treatment - Found on hard palate because epithelium is thinner there vs. soft palate and alveolar ridges

(easier to see pigmented dermis and bone) Physiologic (racial) Pigmentation

- Commonly on attached gingiva of darker skinner people (this patient is not dark skinned, and the lesion location is not consistent with this dx

Melanoma - Commonly on hard palate, but there is no loss of rete pegs, distinct basal cells, and no hx of

smoking Nicotinic Stomatitis

- No Hx of smoking, no hyperkeratosis, no inflamed minor salivary glands Smokers Melanosis

- No Hx of smoking Amalgam tattoo

- Uncharacteristically large Karposi’s Sarcoma

- Not elevated plaque or mass, no spindle cell proliferation or abnormal blood vessels/extravated RBC

Blue Nevus - Usually smaller that 6mm

Histology Histology

- Find fungal hyphae parallel to surface of epithelium (makes easy to wipe off) - Associated with immunosuppression - Smoking can instigate by ↓ immune response in area - Xerostomia can induce candida over growth by ↓ immune mediators in saliva - Broad Spectrum drugs can also ↑ candida growth by disturbing the normal flora of the mouth

- Basement membrane intact - Melanin is sequestered in macrophages (as shown in the macrophage stain)

Supporting Info Supporting Info

- Plaques composed of fungal microbes, keratotic debris, inflammatory cells, bacteria, desquamated epithelial cells

- Wiping off leaves painful erythematous, eroded ulcerated surface

- Treatment is not needed. Pigmentation fades away after drug is stopped. - If cosmetics is a big issue can use a laser to remove pigmentation

- -

Case 14 Case 15

59F, single pigmented lesion on left floor of the mouth. Noticed 3 years ago, no symptoms

50M with lesions on right buccal mucosa and lower labial mucosa

Lesion Description Lesion Description

Flat Grey patch (1cmx1cm) diffuse borders located on the floor of the mouth adjacent to an amalgam filling on the 36.

Buccal: Raised, spherical pedunculated. Smooth with discrete borders, mucosal coloured and homogenous. About 0.5-1cm nodule.

Differential Dx Differential Dx

Amalgam Tattoo - Nearby amalgam resto - Amalgam present In histology (black irregular dots with structureless pattern)

Ecchymosis - Would clear ager a few weeks, not for 3 years

Melanotic Macule - Usually brown (not grey) - Would be able to see melanin deposits histologically

Blue Nevus - Blue-black smooth surfaced macule - Often on palate - Would show proliferation of melanocytes

Melanocanthoma - Brown-black macule, solitary and well circumscribed - Very rare - Would be able to see acanthosis of the superficial epithelium

Drug induced pigmentation - NSAIDs, Antimalarials, amiodarone, tetracycline, acne medication, heavy metals - Expect to see more wise spread lesion here

Mucosal Melanoma - No change in 3 years - Very rare - Would see polymorphous patter with large, blue-grey plaques asymmetrical and non-

homogenous, irregular borders, irregular shape with associated swelling, ulceration, bleeding and pain.

Squamous Cell Carcinoma - No concerning features though (its smooth, defined and not evolving) - Not high risk site (FOM or ventro-lateral tongue) - Lacks nests of squamous epithelial cells extending into dermis

Fibroepithelial polyp secondary to trauma - Firm, painless swelling mainly found on inside of cheeks, lips and tongue - Reactive localized scarring from trauma or chronic irritation - Frequent cheek biting - ↓ rete ridges from hyperplasia of CT

Salivary gland tumor - Uncommon - Not painful - Nit high risk site

Histology Histology

- Silver amalgam stains collagen and elastic fibers giving black colour - Found in connective tissue and sometimes within walls of blood vessels

- Firovascular cores covered with squamous epithelium - Blood vessels with surrounding immune cells - Central core = loose collagen with ↑ vascularization - Possible to have ischemic necrosis from torsion of lesion - Hyperparakeratosis

Supporting Info Supporting Info

- Implantation of amalgam particles by friction or preparing amalgam resto’s - Most common pigmentation of oral mucosa, palate and tongue - Inflammation not often seen, unless particles are large (well tolerated material) - No treatment necessary

- AKA Focal Fibrous hyperplasia - Collagen overproduction. Fibroblasts are mature and scattered throughout the dense collagen

matrix

Case 16 Case 17

40M with bump on the gums

57M, History of trauma on right tongue

Lesion Description Lesion Description

Exophytic, pink nodule, homogenous pink colour, well circumscribed with discrete borders. Asymmetrical but unilateral on the gingival papilla between 31 and 32. 0.5 x 1cm

Raised mass (>3cm), Red with white/yellow center, oval domed sessile shape, non-homogenous colour

Differential Dx Differential Dx

Strawberry Gingivitis - Typically more widespread and red

Fibroepithelial Polyp - Often from chronic trauma/inflammation (possibly from sharp edges, calculus, overhanging

restos Central Ossifying fibroma

- Well demarcated/rarely encapsulated neoplasms - Consists of fibrous tissues with varying amounts of mineralization resembling bone

Peripheral Ossyfying fibroma - Hyperplastic growth of gingiva - Can be large enough to separate the teeth - Typical to find interdentally

Pyogenic Granuloma - Vascularized so would expect to be more red

Gingival Hyperplasia - Would be more generalized, and no Ca blocker noted

Squamous cell carcinoma - Unlikely b/c of size of lesion and location at only 1 tooth

Fibroepithelial Polyp - Clinically have different appearances (Polyp is uniform in colour)

Peripheral Ossifying Fibroma - Only gingival tissue affected (this is a tongue yo)

Granular Cell Tumour - Rare, but should still be considered especially when on tongue and yellow colour involved - Nodular appearance with yellowish colour with hard consistency

Squamous Cell Carcinoma - Red, White or mixed lesion with a change in surface texture producing smooth granular or

rough crusted leasion - Often found ventrolateral of tongue or FOM

Fibroma - Difference in colour and histology

Histology Histology

- Pink parts are calcifications of bone - ↑ fibroblasts in calcified areas - Hypercellular fibroblastic stroma (↑ height of CT)

- Epidermal layer invaginates into subepithelium to form nests - Parakeratinized stratified squamous epithelium - Pseudoepitheliomatous hyperplasia (your guess is as good as mine…) - Dropped down rete ridges - Keratin pearls in CT - Granular cell proliferation - NOT encapsulated

Supporting Info Supporting Info

- Triggered by trauma, infection, plaque, restorations - Hyperplastic growth of the gingiva - Contain mineralized tissues - Can be pedunculated or sessile - Islands of woven (immature) bone and osteoid are seen - Chronic inflammatory cells seen around periphery, and surface can become ulcerated.

- Derived from Schwann cells - <2% malignant - Should always be considered in Differential for nodular lesions of tongue with yellow colour

Case 17 Bonus Case

65F Lesion present for >1yr, tried nystatin tx, hx of smoking (25yrs ago) and no skin lesions

Blue Asymptomatic lesion on lip

Lesion Description Lesion Description

White with red plaque (non-homogenous), diffuse atrophic border, 2cm x 1.5cm on left lateral anterior tongue. Raised white texture with atrophic red periphery

Slightly raised papule (0.5cm x 0.5cm), purple/blue homogenous, domed sessile

Differential Dx Differential Dx

Granular Cell Tumor - Granular cytoplasm (accumulation of lysosomes) - Hyperplasia of overlying epithelium (often mistaken for SCC) - Not seen in our histology

Squamous Cell Carcinoma - Basement membrane intact

Carcinoma in situ - Intact basement membrane - Dysplastic changes throughout full thickness of epithelium - Smoking Hg

Trauma - Lesion has lasted for 1 yr (would have expected healing by now) - Wouldn’t find dysplastic changes in histology

Lichen Planus - Histology would show degeneration of basal layer of epidermis and band of lymphocytic

infiltrate at dermal-epidermal junction Lichenoid Rxn

- Would see similar histology to lichen planus, which we don’t see….problem solved Pemphigus Vulgaris

- Presents as painful blisters (first presentation is in mouth), but we don’t see blisters here Pemphigoid

- Autoimmune presenting with skin rashes and blistering. No other skin lesions around body though so we rule it out

Candidiasis - Didn’t improve with nystatin - Wouldn’t be unilateral and would spread to more areas of oral cavity

Varix - ↑ chance we get varix with age - Common site to have varix (lower lip, exposed to sun)

Hematoma - Could be hematoma if it doesn’t blanch when palpated. Cant tell from a photo - Would typically be flat though

Amalgam tattoo - Not raised typically, and usually located closer to the posterior of the oral cavity

Drug induced pigmentation - More commonly found on gingiva and palate and not raised

Histology Histology

- Stratification is preserved - Enlarged spinous layer - Intact basement membrane - ↑ nuclear-cytoplasmic ratio - ↑ mitotic figures and nucleoli - Mild-Moderate dysplasia

- Tortuous and dialated venules - Thrombus has formed in concentric layer of platelets and erythrocytes. - RBC seen around periphery

Supporting Info Supporting Info

- see metastasis, but would still refer to Oral Surgeon to have it removed before it progresses to Invasive SCC

- Focal dilation of a single vein - Represent vessel wall weakness caused by chronic sun exposure and subsequent dilation - Thrombis may occur (although insignificant) and cause lesion to become firm

PBL 1 – Ms Lacea Plakia

Leukoplakia Erythroplakia

= White patch that cannot be clinically diagnosed as any other disease and have ↑ risk of cancer

- Does not have association with any causative agent, EXCEPT tobacco - Diagnosis must be made by exclusion of other diseases and a need

for hisopathology via biopsy - Often not leukoplakia, but reactive hyperplasia)

= Red patch that cannot be clinically diagnosed as any other disease and has ↑ risk of cancer

- Not associated with anything EXCEPT tobacco

Premalignancy

- Morpjologically altered tissue in which cancer is more likely to occur than normal - Majority DO NOT become cancer

Cancer Risk Elevators:

1. Hx of oral cancer 2. Appearance of lesion (Non-homogenous, white lesion) 3. Site of lesion (Floor of Mouth, Ventrolateral tongue, soft palate) 4. Size of lesion (>6mm) 5. Female 6. Non-smoker with lesion

Where to Biopsy:

- Worst appearance if only single lesion - If multiple lesions, highest risk site, or worst part of every lesion - DON”T biopsy the center of an ulcer (only dead cells in there) - Must include normal margin if biopsy is of verrucous lesion

PBL 2 – Mr. Scott Phillips Hyperplasia Mild Dysplasia Moderate Dysplasia Severe Dysplasia / Carcinoma in Situ Invasive Squamous Cell Carcinoma

↑ Cell # Abnormal shape in lower 1/3rd of epidermis

Abnormal shape in lower 2/3rd of epidermis

Abnormal shape in > 2/3 of the epidermis, but not 100% CIS: 100% of epidermis is dysplastic, but no penetration into basement membrane

Dysplasia penetrates into basement membrane. - If invades neuron or vasculature =

Metastasis

Clinical Limitations in ID’ing high risk lesions:

- Need to recognize what the worst part of the lesion is for the biopsy

- Not all lesions are clinically visible (can use Toluidine Blue, or Veloscope)

Ulceration Erosion

= Open sore on external or internal surface caused by a break in the skin or mucous membrane failing to heal

- Disrupts full epithelial thickness

= Shallow/superficial ulceration - Disrupts partial thickness of

epithelkium

Visualization Aids

Advantages Disadvantages

Fluorescent Visualisation Determined by: Biochemical properties (natural production of fluorophores), and architecture (microscopic and clinical)

- Fluorescent changes occur before clinical changes -> aids in early detection of possible pre-cancerous lesions

- Very Sensitive to cellular changes. Indicates early on if something is wrong

- Because it shows problem sites before clinical observations, when excising a full lesion, use Veloscope to find the actual margin of the lesion (5% recurrence when use veloscope to find margin, vs 30-40% recurrence without)

- Not Specific. While it can show early cellular changes, it doesn’t show what those changes are. Could be cancer, or candidiasis, or hyperkeratinisation. Leads to high false positive rates.

- Can lead to bad psychological trauma on patient if rely on Veloscope too heavily for cancer diagnosis.

Cancer Screening Dyes - Toluidine Blue - Stains –‘ve charged DNA (↑

Mitotic rate and ↑ pore size in cancer means dark blue stain)

- High specificity. If stained dark blue, higher chance that it is pre-cancerous / cancerous lesion

- Canc show individual areas of further progression (worst sites of lesion) -> darker blue

- Not very sensitive. Needs ↑ cellular changes (DNA production) to show a change with the dye.

PBL 3 – Pogue Mahone

Oral Lichen Planus = Acute or chronic inflammatory dermatosis affecting skin or mucous membranes

- Oral Lichen Planus (OLP) os more common than cutaneous LP (CLP) - Onset 30-60, Females > Males - Characteristic white lines (Wickham Striae) - May contain both red and white elements, and have different textures and present with multiple types at the same time (tricky to dx)

Pathogenesis - Inflammatory response to an Ag (self or exogenous) - CD8 cytotoxic T lymphocytes trigger basal keratinocyte apoptosis - Basement membrane disrupted by mast cell proteases, keratinocyte apoptosis and matrix

metalloproteinases (MMP) associated with collagen cleavage

Diagnosis Presentation is variable, but it should be bilateral (if not ↓ chance its OLP) - Lichenoid reactions and OLP are indistinguishable clinically

Differential

- Lichenoid mucositis - Oral Pemphigoid - Discoid Lupus Erythematous (DLE) - Pemphigus Vulgaris - Systemic Lupus erythematous (SLE) - Plasma cell gingivitis - Graft vs Host disease (GVHD) - Squamous Cell Carcinoma - Candidiasis (Hyperplastic + Papular)

Treatment 2-4 weeks until noticeable

symptom ↓

↑ Oral Hygiene Remove areas causing mechanical Trauma (Broken restos, sharp cusps etc) Topical corticosteroids (4x/ day on tried tissue, after meals and before bed) Antifungals if concurrent fungal infection is suspected Tacrolimus or Cyclosporine creams (Calcineurin inhibitors)

Clinical Types Image Descriptions

Reticular OLP

- Most common - Frequently on buccal mucosa - Painless - Bilateral

Presentation - Lacy appearance, multiple and bilateral on buccal mucosa and/or

gingiva

Erosive/Ulcerative OLP

Hyperplastic/Plaque Like Irregular white raised flat topped plaques - Can be clinically indistinguishable from leukoplakia - Commonly presents as multiple lesions on dorsum of the tongue

Bullous

- Rare - Painful bullae on buccal mucosa (typically between 1st and 2nd

molars) - Burst to form ulcerations

Papular Dense covers of papules

Other stuff Protopic Ointment Tacrolimus topical ointment

- Immunosuppressant (Calcineurin inhibitor) - Used if immune system is NOT compromised and for short durations

Tantum Mouthrinse Benzydamine oral rinse + Locally acting NSAID - Local anaesthetic + analgesic

Used as anti-inflammatory tx in the mouth/throat

Oral Side Effects of Antihypertensive Meds

Medication Oral Side Effects

Hydrochlorothiazide (Diuretic) Xerostomia Lichenoid drug reactions

Metoprolol (β-blocker) Lichenoid Dug Reactions

Nifedipine (Calcium channel blocker) Diltiazem (CCB)

Gingival hyperplasia

Ramipril (ACE Inhibitor) Cough Dysgeusia Lichenoid reactions

Prolonged Aspirin Gingival bleeding Petechiae Ecchymoses Prolong bleeding time

Simvastatin (HMG-CoA reductase inhibitor) Xerostomia

Medication Adherence 3 factors that affect compliance with Rx

Patient Related ↓ health literacy (Anti-vaccinators) ↓ Involvement in tx decision making process Inability to pay for it

Physician Related Complex drug Rx’s Communication barriers (Socioeconomic, and language) Ineffective communication about adverse effects Provision of care by multiple physicians (↓ continuity)

Health Care System Related

Office visit time limitations (5 mins usually) Limited access to care ↓ Health information technology

Chronic Wounds and Diabetes - ↓ wound healing is major complication with diabetic patients -> Inflammatory response is ↑ and more intense

o Cytokines become more destructive and promote apoptosis

o Fibroblasts cannot make enough ECM or keratinocytes to heal wound

- Peripheral vascular disease means ↓ oxygenated blood to tissues and ↑ ischemia

Pharmacology of Integumentary System Function of Skin = Barrier from mechanical damage, dehydration, microbial invasion and temp variation

- Also involved in thermoregulation (via capillary beds in skin), Vitamin D synthesis, and sensory

Wounds Promoting Factors Inhibiting Factors

Wound Healing - Moist (but not wet) environment - Warmth - Oxygen - Nutrients - Contamination free (microbes, foreign bodies etc)

- ↓ Blood Perfusion - Old Age (related to ↓ Nutrition) - Concurrent disease (Diabetes, cancer, anaemia) - Drugs (Steroids, bisphosphonates in extractions) - Smoking - Immobility

Clinical Correlate: - There is ↓ perfusion of the mandible -> ↑ change of getting a dry socket complication

post extraction.

Wound Type Characteristics Image

Epithelializing / Granulating

Clean red/pink, usually shallow w/minimal exudastes

Sloughy Yellow slough covering part/all of wound. Can be dry/wet. Visible bone/tendon appears yellow

Necrotic Dead tissues creates black, dry, leathery eschar

Infected Yellow/Green color, possible surrounding cellulitis or unbroken skin. May smell bad

Exuding All features above (except necrotic) can produce pus

Cavity May be deep or a shallow cavity; sinuses are narrow cavities which can extend to depth including tracking to bone or btwn wounds

Malodorous Fungating tumors and infected and necrotic wounds giving offensive smell

Glucocorticoids *Systemic corticosteroids will produce systemic effects, and side effects -> Consult physician or specialists before using*

Mechanism of Action 1. Diffuses through cell membrane, binds to cytoplasmic glucocorticoid receptor

2. Receptor activates and enters nucleus -> binds steroid response elements on target DNA 3. Gene transcription is affected (↑/↓)

Effects Across the Body

Metabolic Effects Stimulate gluconeogenesis and glycogen synthesis when fasting ↑ Serum glucose

- Stimulate Insulin release, ↓ glucose uptake by muscles, stimulated lipolysis, stimulate amino acid release from muscle catabolism

Catabolic / Anti-anabolic effects Occurs in lymph, connective tissues, muscle, peripheral fat and skin - In bone: Osteoporosis in Cushing’s syndrome (issue w/ long term glucocorticoid tx)

Anti-Inflammatory/Immunosuppressive

Effects

- Affects concentration, distribution, and function of peripheral leukocytes - Suppress inflammatory cytokines/Chemokines - ↓ egress of neutrophils from vasculature and activation of immune cells - ↓ T-cell proliferation and activation - ↓ Fibroblast function (collagen + GAGs production) -> ↓ wound healing

CNS Effects - Adrenal insufficiency associated with depression - ↑ glucocorticoids can cause behavioural disturbances (insomnia, euphoria followed by

depression)

GI effects - Peptic ulcers from ↓ immunity to H. pylori - ↑ Peptic acid and pepsin release

Renal Effects - Inhibits vasopressin (ADH) secretion -> ↑ H2O loss. But also mineralocorticoid -> ↓ H2O loss = neutral H2O effects

- Cortisol deficiency causes impaired renal function, augmented vasopressin

Chronic Use - If previously treated with glucocorticoids for long time assume they have adrenal suppression (3-12 months after cessation of glucocorticoid therapy)

What to do: - Single dope of steroid pre-op - 6 – 10mg dexamethasone

OR - ↑ pre-op dose (1-3x) Orally, or IM/IV. Taper back over several days to baseline

Dental Implications - ↓ resistance to infection - ↓ wound healing - ↓ pituitary adrenal function if chronic = need med consult for invasive procedures to ensure

they don’t need prophylactic corticosteroid supplementation.

Therapeutic Use:

- Oral Ulceration (lichen planus, erythema multiforme, pemphigus vulgaris, pemphigoid, angular cheilitis)

- TMJ disorders - Allergy - Postoperative sequelae (inject dexamethasone before surgery to ↓ swelling and bleeding. ↑

patient comfort

Rx Sample Oral Autoimmune disease (Topical) - Dexamethasone Elixir, 0.5ml/5ml, Disp: 250ml, Sig: Rinse with 5ml for 2 minutes 4 times/day

and spit Oral Autoimmune Disease (Systemic)

- Prednisone 30-60mg PO daily for 1 week followed by 1 week dose taper - Prednisone 5mg tablets, Disp: 40tabs, take 4 tabs in AM and 4 tabs at noon for 5 days - USE EXTREME CAUTION WITH SYSTEMIC MEDS AND CONSULT WITH PHYSICIAN

Topical Antibiotics Topicals for Acne

- Bacitracin - Mupirocin - Retapamulin - Polymyxin B Sulfate - Neomycin and Gentamycin

- Clindamycin - Erythromycin - Metronidazole - Sodium Sulfacetamide - Dapsone

Antibiotic Agents MOA Supplemental Info

Penicillin β-Lactams

Inactivates transpeptidase enzyme responsible for crosslinking peptidoglycan in cell wall

- Cell lysis

Pharmacokinetics: Oral absorption varies within penicillin family

- Stability in acid and with food - Widely distribute, but lipid insoluble, crosses BBB if meninges

inflamed. Elimination: Rapid via renal route Adverse Effects:

- Hypersensitivity

Cephalosporin β-Lactams

Same as penicillin but more stable against bacterial β-Lactamases (broader spectrum)

Limitations: - ↓ against enterococci, MRSA, and anaerobic gram-negative

bacilli - Except ceftaroline which is used for skin and soft

tissue infections of MRSA, Enterococci, and anaerobic gram -neg. bacilli

Adverse Effects: - If patients is allergic to Penicillin there is a possibility they are

allergic to this too - Because so broad spectrum we are affected their normal

flora pretty significantly (Can come down with C. diffcile infection)

Bacitracin Cyclic Peptide

Inhibits cell wall formation by interfering w/ dephosphorylation of lipid carrier transferring peptidoglycan to walls

Clinical Correlate:

If patients state they have been “allergic their whole life” or last

reaction was 30 years ago recommend they get tested. Penicillins

are really useful for us and alternatives have big issues.

Mupirocin Protein Synth inhibitor

Bind isoleucyl transfer-RNA synthetase to stop protein synthesis

Effective against gram + aerobic bacteria (including MRSA)

Retapamulin Protein synth inhibitor

Bings to 50S ribosomal subunit (at P-site)

Gentamicin Protein synth inhibitor

Binds 30S ribosomal subunit resulting in defective cell membrane

Dapsone Related to sulfonamides

Inhibits folate synthesis by being competitive antagonist of PABA (preventing normal use of PABA to synthesize folic acid)

Antifungal Agents Antifungal Agents Mechanism of Action Examples

Topical Imidazoles

Broad Spectrum (very widely used topically) - Inhibit ergosterol synthesis = no cell wall

Clotrimazole Ketoconazole

- ↑ risk of severe drug reactions. Check with pharmacist or Lexicomp for interactions

- Used for Candida if not contra-indicated Fluconazole

- Metabolized in liver and excreted via kidneys.

- High concentration in breast milk

Polyene Antifungal

Binds ergosterol in fungal cell membrane -> forms pores and intracellular contents leak out = death

Nystatin Amphotericin B Topical and Oral forms of nystatin are NOT absorbed on ingestion. -> Can swallow it and you will just poop it out.

- Vehicle typically have 50% sucrose = High caries risk. Ask for sugar free

Pyrimidine Analog Interferes with DNA and RNA synthesis selectively in fungi

Rarely used Echinocandins Block β-glucan synthesis to prevent cell wall synth.

Allyamine (terbinafine) ↓ ergosterol to prevent synthesis of fungal cell membrane

Sample Rx

Oral Candidiasis Rx: Nystatin oral suspension 100,000 units/mL; Disp: 300mL; Sig: Rinse and hold in mouth with 5mL solution for 2 mins. 4 times/day for 14 days Rx: Nystatin ointment/cream 100,000 units/g; disk 15g (or 30g tube); sig apply to affected area 4 times/day for 2 weeks, do not eat or drink for 30 mins after use Rx: Ketoconazole 200mg tabs, Disp: 14 tabs, Sig: Take 1 tab per day Rx: Flucaonazole 100mg caps, Disp 16 caps, Sig: Take 2 caps the 1st day and 1 cap/day until resolved.

Antiviral Agents Antiviral Agents Mechanism of Action Supplemental Info

Anti-Herpes Virus -ovir’s

- Acyclovir - Valacyclovir - Famciclovir - Penciclovir

Inhibit viral DNA polymerase and DNA synthesis

Pharmacokinetics: - Renal: Excreted via kidneys, ↓ dose in renal dysfunction and

repeat after dialysis - Liver: No mods needed with liver disease

Resistance: - Short term use only to prevent resistance

Adverse Effects: - Nausea, Vomit, Diarrhea

Management: - 1st attack:

Lidocaine 2% viscous (numbs mucosa so kids can eat and drink without pain) Valacyclovir within 3 days of onset

- 2nd attack Valacyclovir at 1st indication of attack (tingling) Topical acyclovir ointment or penciclovir

Antiviral Rx:

HSV Infection Initial Episode: Rx: Valcyclovir 2g STAT followed by 2g 12hours later Acyclovir 200mg caps, Disp: 50 caps, SIG: Take 2 Caps 5 times per day for 7 days Recurrent episodes: Rx: Acyclovir 200mg capsules, Disp: 50 Caps, Sig: Take 1-2 caps 5 times per day for 5 days Minor cold sores: Rx: Acyclovir ointment 5% Disp: 15g tube; Sig: Apply thin layer to lesion 6 times per day for 7 days Rx: Penciclovir cream 1%, Disk: 5 g, Sig: Apply every 2 hours during waking hours for 4 days.

Drug Vehicles Factors of vehicles:

1. Solubility of the drug within the vehicle

2. Rate of release of the agent from the vehicle

3. Ability of the vehicle to hydrate (and penetrate

stratum corneum)

4. Stability of therapeutic agent in the vehicle

Type Description Lotion An oil in water emulsion with High H2O content

- Liquidy consistency Small amount of alcohol added to help solubilization of active ingredient and ↑ evaporation of solvent from skin

- Acne lotions (non-sticky, fast drying) Easy to apply in large areas, hairy areas, and skin prone to folliculitis/acne

Cream Oil in water creams (vanishing creams): - Spread easily - Don’t leave skin greasy

Water in Oil creams (cold cream): - More greasy and more emollient

Creams contain emulsifiers and preservatives = allergy potential

Ointment Semi-solid prep of hydrocarbons (petrolatum, mineral oil, paraffins etc) Strong emollient -> useful in dry skin

- Provides protective film on skin - Greasy, sticky, retains sweat -> not good for skin prone to acne, or hairy

Contains very little water and has no preservatives

Paste Powder + Ointment - Powder ↑ porosity (breathability) -> good for rashes where protection + breathability is needed - ↑ consistency so it is harder to rub off

Gel Transparent, contains cellulose ethers in water or water-alcohol mix - Liquify on contact with skin, dry and leave thin film of active meds - Useful in hairy areas

Immunosuppressants - Overall goal of these meds is to ↓ production/action of communicative cytokines and chemokines (IL-1, IL-2,

TNFα etc)

Drugs MOA Adverse Reactions / Dental Considerations

Glucocorticoids - Prednisone

Crosses membrane and binds cytoplasmic receptor - Receptor complex enters nucleus and ↓ Tc

of cytokines

↓ resistance to infection ↓ wound healing ↓ pituitary adrenal function if chronic

Calcineurin Inhibitor - Cyclosporine

- Tacrolimus

Form complex that binds & inhibits calcineurin -> ↓ IL-2 = ↓ proliferation of T-cells

- Gingival Hyperplasia - ↓ wound healing - Consult with physician before any

invasive procedure

Antiproliferatives - Azathioprine

- Mycophenolate mofetil

Aza: Metabolized to mercaptopurine -> inhibits DNA synthesis Converted to mycophenolic acid -> inhibits purine synthesis -> ↓ T and B cell proliferation

Bone marrow suppression GI disturbances Bone Marrow Suppression

Monoclonal Ab - Basiliximab

- Binds the a-subunit of IL-2 receptor on activated T-cells -> IL-2 antagonist to prevent T-cell proliferation

Anti-cytokines - Infliximab

- Adalimumab

Bind TNFα and inhibit proinflammatory effects

Susceptible to infection and reactivation of TB Nausea Hypersensitivity

Blood disorders

Chemotherapy 3 Main approaches to cancer treatment:

1. Surgical excision

2. Irradiation

3. Drug therapy

a. Kills constant fraction of tumour independent of size (90% 95% etc)

b. After single dose, still many cells viable, so a drug holiday is taken for body to recover and another dose

is taken to shrink tumor further (usually until its small enough to surgically remove)

Three compartment model of cancer cells:

Compartment A Dividing Cells - Only these cells susceptible to chemo drugs because they are the only dividing cells

Compartment B A) Resting phase (G0), not dividing but have capacity to

Compartment C A) No longer able to divide -> volume of tumour

Toxic Effects of Chemo Drugs:

- Bone Marrow toxicity

- Impaired wound Healing

- Immunosuppression

- Hair loss

- Oral and GI mucosal damage

- ↓ growing in children

- Sterility

- Teratogenicity

- Carcinogenicity

Agent Drugs MOA

Alkylating Agents Cyclophosphamide Mechlorethamine Carmustine Cisplatin Nitrogen mustard (best used on hotdogs or pretzels)

Cross links the DNA double helix, preventing unwinding -> prevent replication

- Used to treat cutaneous T-cell Lymphoma

Anti-metabolites Methotrexate -> psoriasis, folate antagonist Azathioprine -> Autoimmune and inflammatory dermatosis Fluorouracil -> Actinic keratosis, Actinic cheilitis, Superficial Basal Cell Carcinoma Hydroxyurea Mercaptopurine (also immunosuppressant)

Block the pathways involved with DNA synth - Methotrexate -> inhibits dihydrofolate reductase - Fluorauracil -> inhibits thymidylate synthetase - Mercaptopurine -> inhibits purine synth

Cytotoxic antibiotics Doxorubicin Dactinocycin

Microbial products with effects of DNA/RNA to inhibit mammalian cell division

- Isolated from Streptomyces

Plant Derivatives Affect microtubules & ↓ mitotic spindle formation = No mitosis

Hormones Tamoxifen Prednisone Androgens

Glucocorticoids ↓ DNA synthesis - Physiological agonists, antagonists or hormone

inhibitors to disrupt tumour growth

Protein kinase inhibitors

Inhibit growth factor kinases to ↓ GF signal transduction

Monoclonal antibodies

Rituximab ↓ cancer cell growth with many mechanisms. - Super specific so they are less toxic to the body in

general

Dental Considerations: -> This shit is important yo

Drug Interaction

Cisplatin (Alkylating Agent)

↑ Potential nephrotoxicity and ototoxicity of NSAIDs and aminoglycosides

Methotrexate (Anti-metabolite)

NSAIDs -> Potential methotrexate toxicity with low doses to NSAIDs Salicylates -> Can cause toxic plasma concentration or methotrexate

Tamoxifen (Hormone)

Hepatotoxic Drugs -> ↑ toxicity of tamoxifen

Cyclophosphamide (Alkylating Agent)

Barbituates / Liver metabolic Enzyme stimulants -> ↑ Cyclophosphamide conversion/breakdown

Fluorouracil (Anti-metabolite)

Diazepam -> incompatible

Integument Condition Chemotherapeutic Agent

Psoriasis Methotrexate (anti-metabolite)

Autoimmune and Inflammatory Dermatosis Azathioprine (Anti metabolite)

Actinic Keratosis Fluorouracil (Anti metabolite)

Actinic Cheilitis

Superficial Basal Cell Carcinoma

T-Cell Lymphoma Cyclophosphamide (Alkylating Agents) Mechlorethamine Carmustine

Treatment of Common Skin & Mucosal Conditions

Bacterial Infections Primary Infection -> Single species and involved areas of healthy skin

Secondary Infection -> Polymicrobic and in areas of previously damaged skin (physical barrier lost). Often normal flora

Condition Agent Info Treatment

Erysipelas Β-hemolytic streptococci Often on lower extremities IM procaine, penicillin G or VK

Impetigo Strep. Pyogens +/- S. aureus Common in kids, highly contagious Penicillinase-resistant penicillins (dicloxacillin) Cephalosporin (cephalexin) Clindamycin if penicillin allergy

Cellulitis S. Pyogenes, S. Aureus Acute spreading infection affecting epidermis and dermis and spreads throughout superficial fascia

- Edema and erythema - Painful lesion w/ poor margin

Antibiotic therapy + incision and drainage of pus (antibiotic wont clear it all without drainage)

Bites Polymicrobe usually - Pasteurella from dogs and cats - Oral flora from humans

Aggressive irrigation, topical dressing. Antimicrobials are not necessary, but can consider tetanus.

Acne Vulgaris

- Most commonly occurs during puberty and usually self limiting - Small cysts (comedones) form within hair follicles (blockage from keratinous material + sebum) - Propionibacterium acne releases free fatty acids within comedone -> Inflammatory response

Therapy Family Drugs MOA

Exfoliants Resorcinol Salicylic Acid Sulfur

- Mild drying and peeling of skin by irritation, damaging superficial skin layers and inciting inflammation

Topical Retinoids Tretinoin Adapalene Tazarotene

- First line treatment, ↓ obstruction within follicle

Topical Antibiotics Benzoyl peroxide - ↓ sebum production and ↓ free fatty acids - Side effects: dryness, irritation

Erythromycin and Clindamycin - Adjunct therapy, less effective lately due to resistance

Azelaic Acid (Azelex) - Antibacterial, anti-inflammatory and comedolytic

Dapsone - 5% topical gel (Aczone) anti-inflammatory and anti-bacterial

Oral Antibiotics (Tetracyclines)

Minocycline Doxycycline

Minocycline: Associated with pigmented lesions, autoimmune hepatitis, SLE-like syndrome

- Doxycycline is photosensitizer

Anti-Sebum agents Isotretinoin - ↓ Sebum production and inhibits P.acnes growth, ↓ inflammation

Oral Contraceptives Spironolactone

- Anti-androgenic compound Cyproterone acetate

- Anti-androgenic

Oral Corticosteroids - High Doses, short duration

FUNgal infections Condition Clinical Features Treatment

Candidiasis (Candida albicans)

Inflammatory papules and plaques Very common in HIV individuals Found on tongue, buccal mucosa as white patches

- Can be associated with poorly fitted dentures

-Remove predisposing factors (antibiotics, chronic wetness) -Topical Antifungals: Nystatin, or azoles (clomitrazole etc) -Add glucocorticoid lotion for associated inflammation

Viral Infections Condition Clinical Features Treatment

Herpes Simplex -Vesicular eruptions of skin and mucosa - During 1st infection, not many have clinical signs and symptoms, but can have gingivostomatitis - Viral lays dormant in trigeminal ganglion until reactivated (Cold, stress, immunosuppression) -> lesion on lip, palate, gingiva Incubation: several days – 2 weeks

Topical acyclovir 5% ointment Topical penciclovir 1% cream Palliative:

- Lidocaine 2% viscous rinse - Hydration and fluid diet

Herpes Zoster (HHV-3)

-Lays dormant in posterior dorsal root ganglion Symptoms: Pain along infected dermatome, 2-3 days later vesicular eruption

Antivirals and possibly corticosteroids within 72hrs of skin lesions Famciclovir 500mg pot id for 7days & Valacyclovir 1g pot id for 7 days Acyclovir 800mg 5 times/day for 7-10days

Hand-Food-Mouth Disease

Coxsackie Virus Symptoms: Sore throat, mouth pain (difficulty eating), fever, Vesicles over buccal mucosa and tongue, hands and feet

Self-limited: recovery in 2 weeks - Treat symptoms (pain)

Immunological/Inflammatory Condition Clinical Features Treatment

Pemphigus Vulgaris

Widepsread vesicles and bullae -> ulceration Pathogenesis: Rxn to desmosome proteins in keratinocytes Dx: Biopsy with DIF

Corticosteroids (oral or IV) Occasionally immunosuppressants (methotrexate, cyclophosphamide, azathioprine)

Aphthous Ulcers Focal immune dysfunction of T-cells - Etiology unknown (triggers = trauma, stress, malnourishment,

allergy etc)

No tx - If severe: corticosteroids or tetracycline

suspensions - Fluconinonide ointment (0.05%) - Dexamethasone elixir (0.5mg/5mL) - Trimcinolone paste (0.1%)

Erythema multiforme

Etiology: Infection, drug rxn, malignancy, vaccination, autoimmine etc etc Self limiting, keep mouth clean - Topical corticosteroids may help - Acyclovir to prevent recurrence of HSV

Mucous Membrane

Pemphigoid

Painful ulcers with vesicles and bullae - Autoimmune antibodies against basement membrane

Corticosteroids Immunosuppressants

Lichen Planus May affect skin, scalp, nails, mucous membranes - Prritic polygonal flat-topped violaceous papules - Network of white lines (wickham’s striae)

Topical and systemic corticosteroids Immunosuppressants

Burns

Types Thermal, Radiation, Chemical, Electrical

Complications Hypovolemia Infection Hypothermia Ileus (digestive backup)

Treatment IV Fluids Wound cleaning dressing Antibiotic treatment: First 5 days should target Staphylococci and Streptococci

The Lips Condition Clinical Features Treatment

Actinic Keratoses Epithelial changes (scaly shedding) from prolong UV exposure - Potential to turn into SCC

Oval plaques <1cm typically on lower lip, forehead, cheeks, temples, ears

Cryotherapy Topical Fluorouracil

Angioedema Swelling of the lips - IgE allergic reaction precipitated by drugs or food - Can be hereditary (rare autosomal-dominant

Identify causative agents Antihistamines Corticosteroids

Advances in Oral Lesion Detection Methods of detection

Phenotype a) Clinical level – White light, fluorescent visualization, Toluidine Blue b) Pathology – Staining with immunohistochemistry/fluorescence

Genotype a) Genetic – Oncogene, Tumor suppressor gene, DNA repair gene b) Epigenetic – Methylation (DNA and Histone), miRNA

Step 1: Fluorescence Visualization (Phenotype) Step 2: Quantitative Cytology (Phenotype) Step 3: Molecular test using LOH (Genotype)

Visual Aids

Digital Imaging - Photos allow you to monitor the evolution more accurately than just memory - Allow you to refer back to the case for further analysis without the distractions of the other areas

of the mouth. More focused. - Good for insurance and legal records. Will start taking photos of cavities even for when insurance

companies call.

Toluidine Blue Dye

- Metachromatic, acidiphilic stain with ↑ affinity to nucleic acids - In English: Binds to Acidic DNA

In Cancer: - ↑ Mitotic activity = ↑ DNA = ↑ staining with dye - ↓ intercellular barrier = ↑ Pore size = ↑ dye penetration

*Very specific for cancer, but not very sensitive* Darker blue = more dysplastic

VELscope (Fluorescence Visualization)

- NOT UV, or fluorescent light. Simply white light with a filter to only let blue wavelengths through - Autofluorescence comes primarily from collagen -> Hyperkeratosis appears bright b/c ↑ collagen

**Not specific to cancer, any irregularity will appear black (lichen planus looks the same as cancer), but is sensitive to small changes**

- Use to demarcate early dysplastic changes in cancer for excisional biopsies to ensure ALL is removed.

Cytometry

High Resolution Microscopy Imaging Cytometry (cNPS)

o Captures changes in: DNA Content (ploidy) and Nuclear morphology features

When used in Combination with FV get ↑ Sensitivity and Specificity (super exciting actually, feeeelll it)

Molecular Testing

- Testing for Loss of Heterogenicity (LOH)

o Look for Short Tandem Repeats (STR)/Microsatellites that are indicative of known alleles

o When 1 chromosome loses an wild type allele, the functional gene backup is lost. If the last remaining

allele is mutated or deleted = cancer -> This is called the 2 hit hypothesis

- Can predict likelihood of cancer developing based on the number of alleles/backups present

- Problems though! -> Expensive, time consuming, uses radioisotopes and the scoring is subjective. So it’s a nice

idea, but clinically probably will never translate effectively

New Coolness

- Topical Photodynamic Therapy

o Apply a photosensitizer to the lesion to make it more susceptible to damage by light

o Shine a light on the lesion -> Kills cells!

o Still needs some more research, but it’s a pretty cool innovation.

Complications of Cancer Treatment Treatments Acute Complications

(at start until 3 months after) Chronic Complications

(3 months later)

Surgery Radiation Chemotherapy Combination Therapy Immunotherapy Personalized Genomic Programs Bone Marrow Transplants

Pain Hemorrhage (Radiation mostly) Xerostomia Trismus (Surgery and Radiation) Mucositis Infection Nausea and Vomiting Taste Disturbance

Pain Trismus and scarring Xerostomia Infection (fungal and viral) Osteonecrosis Graft vs Host Disease Consequences of medications

Oral Manifestations of Systemic Diseases Hereditary Conditions

MEN IIb (Multiple Endocrine Neoplasia IIb) Medullary Thyroid carcinoma Cowden syndrome

Autoimmune Conditions

Vascular Conditions Vesiculobullous

Pemphigus Vulgaris Systemic Lupus Desquamative Gingivitis

Strawberry Gingivitis Wegener’s granulomatosis

GI Inflammatory Conditions

Crohn’s Disease Ulcerative Collitis Celiac Disease GERD/Bullimia (Oral granulomatosis) (Pyostomatitis Vegitans) (Geographic Tongue) (Erosion of teeth and mucosa)

Hematopoietic Malignancy HIV

Leukemia/pancytopenia Acute Myelocytic Leukemia Candidiasis Karposi’s Sarcoma

Drug Induced

Malignant Melanoma Non-healing extraction Site

Common Skin Conditions (Murphy) Macules Flat, non-palpable, <1cm Vesicle Fluid filled <0.5cm

Patch Flat, non-palpable, >1cm Bulla Fluid filled >0.5cm

Papule Raised bump <1cm Pustule Pus filled 0.1cm-0.2cm

Plaque Broad raised, >1cm Erosion Superficial open wound, loss of epidermis only

Nodule Elevated circumscribed <1cm predominant in dermis

Ulcer Deep open wound, loss of epidermis and deep into dermis

Wheal Papule/plaque from vascular fluid leakage

Fissure Shallow crack in skin

Papulosquamous Papules with scaling

Macules and Patches Vitiligo Autoimmune

- Loss of melanocytes and pigment from affected areas - Spontaneous regimentation can happen, but pretty

rare - Michael Jackson

Port Wine Stain Birthmark -> swollen blood vessels/capillaries making skin look purple

- 3/1000 people - Gets darker colour as age

Solar Lentigo - Benign, irregular shaped hyperpigmented macule - Larger and darker than ephelides (freckle) - Associated with UV exposure and aging -> More

abundant in caucasian

Telangiectasias

Small dilated vessels near surface of skin or mucous membrane - “Red threads in different patterns”

Occur in many conditions: - Sun damage - SLE - Hereditary

Hemorrhagic Telangiectasias - Post-radiation - Rosacea - Cirrhosis - Pregnancy

Epstein-Barr Virus (EBV) - Human Herpes Virus 4 -> Most common virus in humans

- Causes infectious mononucleosis (Mono) but can affect nervous and hematological systems

Symptoms: - Fatigue - Swollen lymph nodes -

Rash - Fever - Swollen liver - Inflamed throat - Enlarged spleen

Oral Petechiae, Purpura, Ecchymosis

Petechiae – 1-2mm Purpura <1cm (but larger than petechiae Ecchymosis >1cm

Papules and Plaques Lesion Image Description

Acrochordon

- AKA skin tag or fibroepithelial polyp - Found in areas with skin creases (neck, armpit, groin, eyelids)

Fibrous Papules

- Dome, firm, flesh coloured papule -> broad base - Occasionally pedunculated

Neurofibroma

Solitary lesions have unknown etiology - If multiple = neurofibromatosis and autosomal dominant

Develop anywhere in the nervous system Not painful

Xanthelasma

Lipid deposit in skin (often upper eyelid) - Yellow papules and plaques or macules - Associated often with hyperlipidemia - Ask about cholesterol

Milia

Small (1-2mm) white cysts of the base of follicle or sweat gland - Keratin entrapped beneath the epidermis

Seborrheic Keratosis

Most common benign epithelial tumor in elderly - Hereditary - Light brown – black with sharp delineated margins

Stuck on appearance DDx: Melanoma, Verruca Vulgaris (warts)

Venous Lakes (type of varix)

Soft, compressible, blue 0.2-1cm papules, fluctuant - Common on vermillion border, face, eart

Sun damage to walls of superficial veins -> dilation - Slow growing and asymptomatic

DDx: Melanoma, Pigmented basal cell carcinoma

Nodules Lesion Image Description

Keratoacanthoma

- Puff pastry with an indurated center filled with crushed hazelnuts

- Central core fo keratine surrounded by collar of raised skin - Often mistaken for SCC (histology even is similar)

Verruca Vulgaris

Common wart, caused by Human Papillomavirus (HPV) - Appears as firm, circumscribed papules or nodules

Aquired Angioedema

Facial swelling -> IgE mediated allergic reaction (often to food or drug)

Papulosquamous Papules with scaling

Lesion Image Description

Actinic Keratosis (AK)

Thickened scaly growths (caused by excess sunlight) -> UV damage - Multiple discrete, flat or elevated keratotic lesions

Most common pre-cancerous lesion - #1 precursor to cutaneous SCC

3 outcomes: - Regress - Persist unchanged - Invasive SCC (0.1%-10%)

Psoriasis

Immune mediated with genetic predisposition - Wax and wane related to stress, infection, drugs - Defect in keratinocyte proliferation (8x ↑ turnover)

Well defined erythematous plaques covered with silvery scales

Pityriasis Rosea

Rash the disappears after 6-8 weeks - Initial mother patch followed by spreading of daughter patches - Difficult to Dx until daughter patches appear

Exfoliative Cheilitis

(Chapped Lips)

Exfoliative cheilitis: Rare condition -> continuous peeling of lips Factitial cheilitis: presents as exfoliative, but caused by attention seeking behaviour or OCD to pick/chap lips

Vesicle/Bullae/Pustules Lesion Image Description

Herpes Zoster (HHV-3) Predominantly older and immunocompromised patients - Sensory nerves of trunk, head, neck affected - Involved Trigeminal Nerve

Unilateral maculopapular rash -> becomes vesicular, pustular and then -> ulcerative

- Remission in several weeks Complications

- Secondary infection of ulcers - Post-hepatic neuralgia - Motor paralysis - Ocular inflammation

Contact Dermatitis Eczematous dermatitis, reaction to environment - Irritant CD or allergic CD (type IV delayed hypersensitivity)

Allergic CD: - Poison Ivy, Nickel, Rubber, Latex, Cosmetic preservatives

Impetigo Acute superficial bacterial infection (Streptococci and/or S. aureus) - Common in children, highly contagious

Small vesicles on face extending periorally and base of nose - Crust and pus as vesicles rupture

Oral Ulceration Differential Dx:

Lesion Image Description

Recurrent Aphthous Stomatitis

Affects 25% of population - Unclear etiology (Stress + Systemic issues +

Immunocompromised) Tx: Symptoms and topical corticosteroids Common in:

- Women - Non-smokers - <40 - High socioeconomic status (↑ Stress) - Caucasians

Connective Tissue Diseases Lesion Image Description

Scleroderma

Chronic autoimmune CT disease -> Hardening of skin / mucosa - Systemic sclerosis - Overproduction of collagen - Associated with Sjogren’s syndrome

On Head and Neck: - ↓ oral opening - Microvascular changes - Widening PDL - Bony resorption - Xerostomia

Skin Cancer Nodules Lesion Image Description

Basal Cell Carcinoma Most common skin cancer - Found with long term sun-exposed skin

Markers for vulnerability - Fair skin, Hazel or blue eyes, Blonde or Red hair

Presentations: - Indurated pearly pink/white papule or nodule - Telangiectatic vessels on surface - Center becomes ulcerated and crusted over time

Slow Growing (20-50 years) - Incapable of metastasizing via blood or lymphatics

Squamous Cell Carcinoma Second most common skin cancer - Keratinocytes that are damaged from sunlight - Significant potential to metastasize (3x more likely if >2cm)

Course is slow but destructive - Not often fatal but can cause disfigurement

Affected areas: - Lower lip - Tip of ear - Forehead - Nasal Bridge

Presentation: - Firm shallow ulcer with elevation, indurated margins - Occasionally can be verrucous papules or plaques - Induration reflects tumor infiltration of adjacent tissues

Melanoma Develops from Melanocytes - ↑ incidence - 75% of all deaths from skin cancers

Predisposing factors: - Family Hx - Extensive sun exposure - Fair Complexion - Precursor lesions (multiple nevi and dysplastic nevi

2 Phases of growth: 1. Horizontal Growth -> spread laterally along dermoepidermal

interface 2. Vertical growth -> Penetration of dermis and subcutaneous

tissue. High Risk Sites (BANS)

- Back - Arm - Neck - Scalp

Random Lesions and Dx Image Dx Image Dx

Frictional Keratosis

Hyperplastic Candidiasis

Lichen Planus

Drug Induced Lichenoid Reaction

Regular ass

Aphthous Ulcers

Traumatic ulcer with stroma eosinophilia

(TUGSE

Oral Cancer

Geographic tongue

Erosive Lichen Planus

Benign Mucous Membrane Pemphigoid

Pemphigus Erythema Multiforme

Herpetic Ulcer

Herpetic Gingivostomatitis