Squamous Cell Carcinoma (Lecture 3)

Slide 1 · Squamous Cell Carcinoma

Cutaneous epithelial malignancy: mechanisms, morphology and clinical relevance

A pathology teaching lecture

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Explain the UV–DNA damage axis and additional risks for cutaneous SCC.

Distinguish actinic keratosis, carcinoma in situ and dermal invasion.

Recognize the morphologic spectrum of invasive squamous differentiation.

Relate common presentation, metastatic potential and therapy to pathology.

Slide 3 · Conceptual framework

Keratinocyte malignancy in a sun-damaged epithelium

The central diagnostic distinction is atypia confined above the basement membrane versus invasive growth into the dermis.

Slide 4 · Where cutaneous SCC fits

A malignant epithelial tumor of squamous/keratinocytic differentiation.

Most often arises on chronically sun-exposed skin of older adults.

Actinic keratosis and SCC in situ occupy the precursor / preinvasive spectrum.

Invasive SCC crosses the dermoepidermal basement membrane.

Slide 5 · The epidermal boundary that defines invasion

Epidermis

Dermis

Schematic — not a histologic specimen

Observe

Epidermis lies above the dermoepidermal junction.

The basement membrane is the diagnostic boundary.

Dermal tumor nests establish invasive growth.

Slide 6 · Relative frequency among cutaneous cancers

SCC is second to basal cell carcinoma among tumors of sun-exposed skin.

This comparison refers to cutaneous tumors, not SCC across all organs.

Early recognition and local excision explain why most lesions remain controllable.

Slide 7 · Age, sex and environmental context

Classically seen in older adults with cumulative sun exposure.

Most sites show a higher incidence in males than females.

The lower legs are a stated exception to the usual sex pattern.

The risk profile reflects exposure, pigmentation and host surveillance.

Slide 8 · The importance of anatomic location

Face, arms and dorsal hands are frequent actinic-damage sites.

Scalp lesions may be nodular or ulcerated when invasive.

The lip can develop actinic cheilitis as a related precursor.

Consider the skin site before generalizing findings from SCC of the oral cavity or lung.

Slide 9 · Clinical spectrum: Flat plaque to nodule

In situ SCC: A sharply demarcated, red, scaling plaque.

Invasive SCC: Often nodular with variable surface keratin.

Ulceration can occur as invasive lesions progress.

Gross appearance suggests but does not establish tissue invasion.

Slide 10 · Most tumors are recognized at a local stage

Invasive SCC is commonly discovered while small and resectable.

Clinical visibility facilitates early recognition.

Local excision is usually effective for readily recognized lesions.

Metastatic disease nevertheless matters because SCC is common.

Slide 11 · Etiology and predisposition

UV light, repair failure and impaired immunity

The malignant phenotype results from acquired driver alterations in susceptible keratinocytes.

Slide 12 · Three intersecting etiologic domains

Genotoxic exposure

UV radiation is the dominant driver; Ionizing radiation, arsenicals and industrial agents also matter.

Host susceptibility

Light pigmentation, defective nucleotide excision repair and immunosuppression modify risk.

Local tissue milieu

Chronic ulcers, draining osteomyelitis and old burn scars are associated with SCC.

Slide 13 · Lifetime UV exposure is the dominant risk

UV radiation produces DNA damage in epidermal keratinocytes.

Tumor incidence rises with the degree of lifetime sun exposure.

Chronic exposure supplies repeated opportunities for driver mutations.

Lightly pigmented individuals are especially susceptible to actinic change.

Slide 14 · UV injury creates mutagenic DNA lesions

UV irradiation

Sunlight reaches exposed skin

Pyrimidine dimers

DNA damage accumulates

Mutation selection

Drivers may become fixed

Clonal neoplasia

Atypia and malignancy emerge

This is a conceptual causal sequence, not a measured rate or a uniquely deterministic pathway.

Slide 15 · Why pyrimidine dimers matter

UV exposure creates lesions involving adjacent pyrimidine bases.

A subset of TP53 mutations occurs at these damaged sites.

Their mutational context supports sunlight as an upstream cause.

Unrepaired lesions increase the opportunity for permanent mutations.

Slide 16 · P53 alteration can precede invasive cancer

Sun damage

Keratinocyte DNA lesions

TP53 mutation

Impaired p53 function

Actinic keratosis

Early atypical clonal change

Further drivers

Potential progression to SCC

Early p53 dysfunction is suggested by its high prevalence in actinic keratoses.

Slide 17 · How to interpret TP53 mutations

Frequent TP53 mutations have been documented in actinic keratosis.

Thus p53 dysfunction is an early molecular event, not proof of invasion.

A TP53 mutation alone does not define SCC morphology.

Tissue architecture remains decisive for in situ versus invasive classification.

Slide 18 · Nucleotide excision repair protects the genome

UV DNA lesion

Pyrimidine dimer is present

NER pathway

Accurate excision repair

Restored DNA

Damage removed before fixation

Failure of this pathway permits mutagenic repair and accumulation of alterations.

Slide 19 · Xeroderma pigmentosum is mechanistic evidence

An inherited disorder involving nucleotide excision repair genes.

Defective repair of UV-induced pyrimidine dimers increases mutations.

Error-prone pathways may substitute when accurate repair fails.

The resulting mutation burden explains pronounced SCC susceptibility.

Slide 20 · Multiple drivers cooperate in cutaneous SCC

TP53 dysfunction

Disrupts a major tumor-suppressive response to DNA injury.

Increased RAS signaling

A contributor that favors keratinocyte transformation.

Reduced Notch signaling

Another common contributor to transformation.

Slide 21 · A multistep, not a single-hit, neoplasm

Initiating exposure

UV-induced DNA injury

Early alterations

TP53 and precursor atypia

Additional drivers

RAS↑, Notch↓ among others

Malignant phenotype

In situ or invasive SCC

Sequence is a didactic simplification; Source does not define a fixed obligatory mutation order.

Slide 22 · UV exposure also affects local immunity

Sunlight may transiently impair innate immunity in skin.

The mechanism is not fully understood.

Reduced immune elimination may allow damaged keratinocytes to persist.

This is a possible cooperating mechanism, separate from direct DNA damage.

Slide 23 · Immunosuppression: An important association

Tumor risk is elevated with immunosuppressive states.

Organ transplantation and chemotherapy are highlighted examples.

Reduced host surveillance may permit survival of altered keratinocytes.

Virus susceptibility has been proposed as an additional explanation.

Slide 24 · Potential consequences of reduced surveillance

Immunosuppression

Host defense is reduced

Immune escape

Damaged cells may persist

Clonal expansion

More opportunity for malignancy

Proposed biologic contribution, not a validated patient-level prediction

Slide 25 · HPV: Suspected association versus demonstrated role

General cutaneous SCC

Some cutaneous HPV types have been considered possible contributors; Causality is not established for ordinary SCC in this source.

Epidermodysplasia verruciformis

HPV types 5 and 8 as clearly implicated in SCC arising in this rare inherited condition.

Slide 26 · Epidermodysplasia verruciformis

Rare autosomal recessive disorder.

Marked susceptibility to cutaneous SCC.

HPV 5 and HPV 8 are clearly implicated in SCC arising in this context.

Do not equate this setting with all cutaneous SCC or with mucosal HPV-driven SCC.

Slide 27 · Additional carcinogenic exposures

Industrial agents

Tars and oils are associated with cutaneous SCC.

Systemic/toxic agents

Ingested arsenicals are listed among risk factors.

Physical exposure

Ionizing radiation can contribute to keratinocytic malignancy.

Slide 28 · Persistent injury and scar-associated SCC

Chronic ulcers are recognized settings for SCC development.

Chronic draining osteomyelitis is another listed predisposition.

Old burn scars are implicated.

These contexts broaden the assessment beyond sun-exposed skin.

Slide 29 · Do not import oral-cavity etiologies into skin SCC

Tobacco and betel nut chewing specifically for oral SCC.

They should not be presented as dominant causes of cutaneous SCC.

Cutaneous and mucosal SCC share squamous differentiation but differ in exposure biology.

Organ-specific context matters when interpreting risk-factor lists.

Slide 30 · Preinvasive disease

From actinic keratosis to full-thickness atypia

Atypia can extend progressively through the epidermis before tumor cells cross its basement membrane.

Slide 31 · Actinic keratosis is a key precursor

Occurs predominantly in chronically sun-damaged skin.

Is particularly common in lightly pigmented individuals.

Shows excessive keratin and dysplastic squamous epithelium.

Some lesions progress toward cutaneous SCC.

Slide 32 · How actinic keratosis appears clinically

Usually small, often less than 1 cm across.

Can be tan-brown, red or skin-colored.

The surface often feels rough or sandpaper-like.

Marked excess keratin may create a cutaneous horn.

Slide 33 · The distribution of actinic keratoses

Face and exposed arms are frequent sites.

The dorsal hands are another characteristic location.

Related sun-damaged changes may occur on the lips.

A precursor lesion identifies an area that has sustained cumulative exposure.

Slide 34 · Actinic keratosis: Lower epidermal atypia

Epidermis

Dermis

Schematic — not a histologic specimen

Observe

Atypical cells mainly occupy basal/lower layers.

Surface keratinization may be pronounced.

Basement membrane remains intact.

Slide 35 · Dyskeratosis and intercellular bridges

Atypical keratinocytes may acquire eosinophilic/pink cytoplasm.

This altered keratinization is described as dyskeratosis.

Intercellular bridges are visible in squamous epithelium.

This contrasts with basal cell carcinoma, where bridges are not seen.

Slide 36 · Hyperkeratosis versus parakeratosis

Hyperkeratosis: Thickened surface cornified layer.

Parakeratosis: Nuclei persist in cells of the stratum corneum.

Both may accompany actinic keratosis.

Surface change should be read alongside the distribution of cellular atypia.

Slide 37 · Solar elastosis documents chronic damage

Superficial dermal elastic material becomes thickened and blue-gray.

This change as elastosis.

It is associated with abnormal elastic-fiber production after sun injury.

Elastosis supports sun damage; It does not independently establish invasion.

Slide 38 · Atypia may progress in epidermal extent

Initial dysplasia affects the lower epidermal layers.

Progressively severe lesions show greater epithelial thickness involved.

Full-thickness nuclear atypia signifies carcinoma in situ.

In situ carcinoma can retain superficial maturation in some lesions.

Slide 39 · Carcinoma in situ: Atypia throughout epidermis

Epidermis

Dermis

Schematic — not a histologic specimen

Observe

Atypical nuclei extend through all epidermal levels.

No tumor nest has crossed into the dermis.

The boundary remains continuous.

Slide 40 · Actinic keratosis versus SCC in situ

Actinic keratosis

Cytologic atypia chiefly in basal/lower epidermis; Marked cornification and sun-damage changes often coexist.

Squamous carcinoma in situ

Atypical enlarged, hyperchromatic nuclei involve the full thickness of the epidermis; Still no basement breach.

Slide 41 · Clinical presentation of SCC in situ

Typically a sharply defined red scaling plaque.

Microscopic full-thickness atypia determines the in-situ designation.

A flat plaque does not alone prove that a lesion is noninvasive.

Clinical and histopathologic assessments provide complementary information.

Slide 42 · Invasive squamous carcinoma

Crossing the basement membrane changes the diagnosis

The defining histologic event is tumor penetration beyond the dermoepidermal junction.

Slide 43 · Invasive SCC: Atypical nests within dermis

Epidermis

Dermis

Schematic — not a histologic specimen

Observe

Neoplastic cells cross the basement membrane.

Tumor forms invasive dermal tongues or nests.

Dermal location distinguishes invasive from in situ disease.

Slide 44 · Invasive lesions: Gross morphology

Invasive SCC often appears as a nodule.

Variable keratin production produces an irregular hyperkeratotic surface.

Tumors may ulcerate.

Gross appearance can suggest an invasive lesion but is not a substitute for histology.

Slide 45 · Invasion requires architectural evidence

Examine the relationship between atypical epithelium and dermis.

Tongues or nests of malignant squamous cells extend beneath the junction.

The pattern is different from simple full-thickness intraepidermal atypia.

The important distinction is basement-membrane transgression.

Slide 46 · Squamous differentiation spans a spectrum

Well differentiated

Organized squamous lobules

Less differentiated

Reduced squamous maturation

Poorly differentiated

Marked anaplasia; Little keratin

Differentiation describes morphology; It is not the same concept as anatomical stage.

Slide 47 · Well-differentiated invasive SCC

Polygonal malignant squamous cells grow in relatively orderly lobules.

Substantial areas of keratinization may be present.

Squamous maturation remains readily recognizable.

Invasion still defines malignancy even when cells keratinize abundantly.

Slide 48 · Keratinization within invasive tumor islands

Schematic — tumor keratinization

Conceptual pattern

In differentiated SCC, polygonal squamous cells may form coherent lobules with conspicuous central keratinization. This graphic does not substitute for an H&E photomicrograph.

Slide 49 · Poorly differentiated SCC

Neoplastic cells may be highly anaplastic.

Squamous maturation can be minimal or difficult to identify.

Keratin may be restricted to individual cells (dyskeratosis).

Recognition of epithelial lineage may then require ancillary stains.

Slide 50 · Cytologic hallmarks of invasive SCC

Enlarged tumor-cell nuclei.

Irregular or angulated nuclear contours.

Prominent nucleoli may be visible.

Interpret cytologic atypia together with infiltrative architecture.

Slide 51 · Why keratin immunostains may be needed

Poor differentiation can obscure overt squamous maturation.

Immunohistochemical detection of keratins may confirm epithelial identity.

Robbins does not specify a universal diagnostic keratin panel here.

IHC supports, rather than replaces, architectural and cytologic interpretation.

Slide 52 · Morphology: Three questions at the microscope

Where is atypia?

Basal layer, full epidermis or dermal nests?

Is there keratinization?

Extensive, limited or only isolated dyskeratotic cells?

How atypical are cells?

Assess nuclear enlargement, contour and nucleoli.

Slide 53 · Diagnostic comparison across the spectrum

Feature

Actinic keratosis

SCC in situ

Invasive SCC

Main atypia

Lower epidermis

Full epidermis

Dermal tumor nests

Basement membrane

Not transgressed

Not transgressed

Transgressed

Clinical pattern

Rough keratotic area

Red scaly plaque

Often nodule / ulcer

Keratinization

Hyperkeratosis; dyskeratosis

Variable

Variable; may be extensive

Slide 54 · SCC and basal cell carcinoma: A focused contrast

Dimension

Cutaneous SCC

Basal cell carcinoma

Frequency

Second most common on sun-exposed skin

Most common invasive cutaneous cancer

Characteristic biology

UV injury; TP53, RAS, Notch alterations

Hedgehog-pathway activation

Differentiation

Squamous; keratinization possible

Basaloid morphology

Metastases

Uncommon but important

Exceptionally uncommon

Slide 55 · Clinical findings do not determine invasion

A thick keratotic lesion may still be predominantly intraepidermal.

An in-situ carcinoma can look like an ordinary scaly plaque.

The key decision requires histologic assessment of the junction.

Do not infer dermal invasion merely from surface hyperkeratosis.

Slide 56 · Clinical behavior and management

Most tumors are local; A minority metastasize

The population burden remains consequential despite relatively infrequent nodal spread.

Slide 57 · Regional-node metastasis: Context matters

Fewer than 5% metastasize to regional lymph nodes.

That figure is a broad textbook estimate, not a patient-specific prognostic score.

Skin SCC has lower reported nodal metastatic frequency than some mucosal/visceral SCC.

Do not treat all squamous cancers as having equivalent metastatic behavior.

Slide 58 · Why a low proportion still matters

Cutaneous SCC is common in the population.

A small metastatic fraction can still yield a substantial disease burden.

Local disease and metastatic SCC differ greatly in clinical consequences.

Management decisions must distinguish these disease states.

Slide 59 · Local excision is effective for many lesions

Invasive tumors are often detected while small and resectable.

Recognizable skin lesions facilitate definitive local treatment.

Local excision as effective in typical early lesions.

This teaching point does not specify margins or current surgical protocols.

Slide 60 · Locoregional metastatic SCC and radiation

Metastatic cutaneous SCC as generally chemotherapy resistant.

It describes sensitivity to radiotherapy.

Radiotherapy is cited for localized metastatic disease.

Actual modality selection depends on contemporary individualized oncology practice.

Slide 61 · High mutation burden supports immunotherapy

Cutaneous SCC has a very high somatic mutational burden.

High mutation load is linked to immune checkpoint inhibitor responsiveness.

Checkpoint inhibitors are often first-line for metastatic disease.

Specific agents and regimen decisions are intentionally outside this source-limited lecture.

Slide 62 · Why checkpoint inhibition can be effective

UV-mutagenized tumor

Many genomic alterations

Potential immune recognition

Tumor antigens may be detected

Checkpoint blockade

Antitumor response may increase

Mechanism is schematic and not a guarantee of response in any patient.

Slide 63 · Application 1: Precursor versus invasion

A chronically sun-exposed area shows a rough, scaly lesion. Histology demonstrates atypical keratinocytes confined chiefly to basal epidermal layers.

What diagnosis best fits the distribution of atypia?

Interpretation: Actinic keratosis; No dermal invasion is described.

Slide 64 · Application 2: Recognizing in-situ disease

A sharply outlined red scaly plaque contains enlarged hyperchromatic keratinocytes at all epidermal levels. The basement membrane remains intact.

Which feature makes this carcinoma in situ?

Interpretation: Full-thickness epidermal atypia without basement-membrane transgression.

Slide 65 · Application 3: The decisive invasive feature

An epithelial lesion has dermal tongues of atypical polygonal cells beneath the dermoepidermal junction and conspicuous squamous keratinization.

Which architectural finding establishes invasive SCC?

Interpretation: Malignant squamous epithelium within the dermis.

Slide 66 · Application 4: Inherited repair defect

A person with a rare inherited defect of nucleotide excision repair develops numerous UV-associated skin cancers.

Which molecular failure explains SCC susceptibility?

Interpretation: Ineffective removal of UV-induced pyrimidine dimers.

Slide 67 · Application 5: Interpreting an HPV association

A lecture slide states that HPV types 5 and 8 are proven causal agents in all sporadic cutaneous SCC.

Is this statement justified by Robbins?

Interpretation: No. Clear implication is specified for epidermodysplasia verruciformis.

Slide 68 · Synthesis: Recognize three separable layers of evidence

Etiologic evidence

Sun exposure, immunosuppression, repair deficiency and other documented risks.

Pathogenetic evidence

TP53 alteration, RAS and Notch pathway changes, mutational accumulation.

Diagnostic evidence

Extent of epidermal atypia, basement transgression and squamous differentiation.

Slide 69 · Final diagnostic synthesis

First identify the spatial extent of atypical keratinocytes.

Next determine whether the basement membrane has been crossed.

Then characterize squamous keratinization and differentiation.

Use keratin immunostains when severe anaplasia obscures epithelial lineage.

Slide 70 · Final biologic and clinical synthesis

Cumulative UV DNA injury is the dominant initiating context.

Repair defects, immunosuppression and other exposures modify risk.

A subset of actinic lesions progresses to in situ or invasive SCC.

Most lesions are treatable locally; Advanced disease may merit radiotherapy or checkpoint inhibition.

Slide 71 · Primary reference and evidence limits

Robbins, Cotran & Kumar: Pathologic Basis of Disease, 11th edition (2026).

Chapter 25, The Skin: Actinic Keratosis and Squamous Cell Carcinoma.

Basal Cell Carcinoma is used only for focused comparative teaching.

All morphology diagrams are native editable schematics, not clinical images.