Squamous Cell Carcinoma

Incidence

• 2nd most common skin cancer– Behind BCC, accounting for 20% skin cancers

• Due to propensity to metastasise, makes them responsible for majority of NMSC deaths

Pathogenesis

• UV– Incidence doubles with 8-10 degrees decrease in

latitude– Induces formation of pyrimidine dimers resulting

in DNA point mutations– Causes mutations in p53 tumour suppressor gene

• Skin pigmentation• Age• Primary dermatoses –

xeroderma pigmentosa, oculocutaneous albinism

• Immunosuppression – due to immunosuppressive drugs, UVR, viral infection esp HPV– Reversed ratio of BCC:SCC, SCC being 3x more

common in transplant patients– Higher rates – cumulative risk of SCC/ BCC in heart

transplant recipient is 3% at one year, 21% at 5 years, 35% at 10 years

Histological subtypes

• Pleomorphic• Adenoid/Acantholytic• Simplex• Small cell• Verrucous• Keratoacanthoma• Actinic keratosis• Bowenoid/Erythoplasia of Queyrat

Simplex

• Majority of SCCs• Atypical keratinocytes

develop within epidermis and invade the dermis

• Tumour cells are enlarged, hyperchromatic, variably pleomorphic nuclei, prominent mitotic activity

• Keratin pearls

Actinic Keratosis• Also SCC in situ, micro

invasive SCC, as there is considerable overlap in the histology

• Atypical keratinocytes that have not breached the dermal barrier– SCCIS is typically full thickness

keratinocyte atypia

• Rate of malignant transformation is 0.1% per lesion per year– About 16% will

eventually transform– Can progress to other

skin cancers such as sebaceous carcinoma

Pleomorphic

• AKA spindle / sarcomatoid, RARE• Associated with previous trauma

or RTX• Most commonly found on face

or sun exposed areas of elderly• Commonly ulcerate, but may

present as an exophytic mass

• Microscopically whorls of atypical squamous cells co-mingle with collagen fibres

• Pleomorphic giant/spindle cells may be present

• Neoplastic keratinocytes have hyperchromatic eosinophilic cytoplasm, elongated, pleomorphic and veiscular nuclei with multiple nucleoli

Small cell• May resemble metastatic small

cell neuroendocrine carcinoma or Merkel cell carcinoma

• Invades in cohesive nests with adjacent intense inflammatory and desmoplastic host response

• Stains for cytokeratin, but may stain for neuron specific enolase (NSE), a neuroendocrine marker

Verrucous• Exophytic or endophytic masses

growing at sites of chronic irritation

• Slowly locally invasive, little or no propensity to metastasise

• Morphologically appear well differentiated with little atypia

• Thickened papillae composed with well differentiated squamous cells invading into dermis

Verrucous• 3 distinct clinicopathologic subtypes

– Oral• Associated with tobacco chewing, betel

nut chewing, HPV, poor oral hygiene• Typically wart like white/gray lesion• Well differentiated

– Plantar• Many crypt like openings• Slowly enlarging, fleshy pink exophytic

mass• Verrucous hyper/para keratotic

component, epithelial crypts with keratinaceous debris

– Buschke-Loewenstein• Anogenital type, described by B-L in 1925• Occur most commonly in uncircumcised

men under 50, associated with HPV 6 & 11• Present as caulflower like lesions most

commonly on glans penis• Extensive verrucous acanthosis with

dermal extension, keratinocyte atypia minimal, hypergranulosis and crypt/sinus formation

Keratoacanthoma

• Period of rapid growth lasts 4-8 weeks

• Potential for spontaneous involution usually within 4-6 months, sometimes with considerable scarring

• Clinically tend to be rapid growing smooth, firm nodule with central keratin plug

• Histologically difficult to distinguish between benign KA and SCC KA type, so being amalgamated by histopathologists

• Atypical squamous proliferation with intradermal invasion

• Typically crateriform architecture with keratin plug and well developed collarette

Adenoid / Acantholytic

• Form a pseudoglandular appearance

• Cells arranged in cords and nests with clefts produced by acantholysis of cells leaving spaces that superficially resemble glands

• Enlarged free floating dysplastic keratinocytes found in lumina

• Clinically appear as ulcer on head & neck of men in 5th to 6th decade

• High incidence of recurrence after radiation therapy

• Tend to be more locally aggressive but metastasise less

Bowenoid

• Considered to be SCC in situ

• Most common site is head and neck, followed by limbs and then trunk

• Well demarcated, slow growing, erythematous scaly patch, usually small in size

• Histologically shows hyperkeratosis, acanthosis, psoriasiform hyperplasia, full thickness atypia, loss of polarity reflecting cessation of maturation

• When neoplastic keratinocytes invade the dermis, this lesion is termed Bowenoid SCC

• Especially associated with HPV – HPV2 with extragenital lesions, HPV16 with genital lesions

Metastasis

• Overall risk is 2 – 6%, not 0.5%

• Recurrent SCC has metastatic rate of 30%, and metastatic cases had a survival rate of 1/3

• Metastases tend to be to regional lymph nodes

• Most mets (and local recurrences) are found within first 2 years, and 95% within first 5 years

Risk factors for metastasis and recurrence

• Recurrence rate doubled and tripled metastatic rate– Size > 2cm– Grade 3 & 4 vs. Grade 1 & 2 tumours• Well differentiated has recurrence 7%, mod well diff 23%, poor

diff 28%

• Tumour thickness– 3 year recurrence free survival is 98% for <3.5mm, 84%

for > 3.5mm (Breslow thickness)• Rapid growth rate

• Sun exposed areas tend to metastasise and recur less than mucosal SCC

• Scar SCC are very aggressive

• Lip and ear SCC have higher metastatic rate than other head and neck sites (16 & 10%)– Probably due to decreased subcutaneous fat– Nose and scalp, anogenital are intermediate risk– Periungal SCC has high recurrence rate but almost never metastasises

• Previous treatment – recurrent cancers have a metastatic rate of 25%– Location – ear 45%, lip 32% metastatic rate

• Histopathology

– Isolated strands, infiltrative pattern, haphazard growth vs. broad pushing borders

– Perineural invasion (occurs in 2-14% SCC, most commonly H&N in elderly men)• Has been quoted as local recurrence 47%, regional mets 35%,

distant nodes 15%; so post op RTX commonly offered

– NO good evidence that any subtype has greater risk recurrence or metastasis

Immunosuppression

– Biologically more aggressive, with higher rates of lymph node metastases and deaths secondary to skin cancer

Tumour size

Size (cm) Metastatic rate

5 yr disease free survival

T1

< 2 1.4% 95-99%

T2

2 – 4 9.2% 85-60%

T3

> 4 > 13% 75-60%

T4

Invading deep structures

< 40%

Tumour depth and metastatic rate

Depth Metastatic rate

< 2mm 0

2 – 6mm 4.5%

> 6mm 15%

Grades

Broder’s Grade Undifferentiated cells

Ratio of differentiated cells

I – Well differentiated

< 25% 3:1

II – Moderately well differentiated

25 – 50% 1:1

III – Poorly differentiated

50 – 75% 1:3

IV – Anaplastic or pleomorphic

> 75% Nil

Surgical Management• Tumours < 2cm diameter are

successfully excised 95% of the time with a margin of 4mm, 6mm for high risk cases (Brodland & Zitelli)

• Tumours > 2cm diameter require margin of 10mm for equivalent local control rates

• Moh’s surgery

Other modalities

• Dessication and curettage– Lesions less than 2cm diameter have cure rates of

97-98.8%• Cryosurgery– Well localised, superficial lesions on trunk or limbs

• 5FU & Imiquimod & Photodynamic therapy– Useful for actinic keratoses

Radiation Therapy

– < 2cm tumours have a cure rate of 95%

– Adjunctive RTX must be given within 8 weeks for greatest efficiency– (Late) changes include :– atrophy, fibrosis, hypopigmentation, telangiectasia, ulceration

– “As late results of RTX can be poor, it is not recommended for patients under 60 yo with uncomplicated primary SCC”

– May hasten natural history of KA