Squamous Cell Carcinoma

Slide 1 · Squamous Cell Carcinoma

Head and neck pathology

Oral cavity and HPV-associated oropharyngeal disease

Morphology • molecular biology • clinical implications

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Separate HPV-associated from conventional HPV-negative head and neck SCC.

Explain site-specific risk factors, precursor lesions, and molecular alterations.

Recognize the morphologic patterns of keratinizing and nonkeratinizing SCC.

Connect primary-site behavior, cervical nodal spread, and prognosis.

Slide 3 · What is included in this lecture?

Within scope

Oral cavity squamous cell carcinoma

HPV-associated oropharyngeal SCC

Head and neck SCC molecular biology and behavior

Outside this source unit

Cutaneous SCC

Esophageal or pulmonary SCC

Detailed surgical staging algorithms

Slide 4 · SCC dominates head and neck malignancy

~95%

Of head and neck cancers are squamous cell carcinomas in the Robbins text

Most arise from mucosa lined by stratified squamous epithelium.

The remaining head and neck cancers include many salivary gland tumors.

The same histologic name encompasses biologically distinct etiologies.

Slide 5 · Anatomic site changes disease biology

Oral cavity

Ventral tongue and floor of mouth are frequent classic sites.

Tobacco and alcohol remain major exposures.

Keratinizing histology is typical.

Oropharynx

Palatine tonsil and base of tongue are favored HPV-related sites.

Occult mucosal primary may be very small.

Nonkeratinizing histology is characteristic.

Slide 6 · Two major etiopathogenic routes

Repeated mucosal carcinogen exposure

Tobacco • alcohol • areca-related products

Somatic genomic alterations

Multiple independent driver events

Conventional HPV-negative SCC

Often keratinizing; Oral cavity favored

Oncogenic HPV infection

Frequently HPV-16 in oropharynx

Viral E6/E7 expression

Disruption of cellular growth control

HPV-associated SCC

Often nonkeratinizing; Tonsillar crypts

Two etiologic routes; Simplified teaching schematic

Slide 7 · Classic exposures: Tobacco and alcohol

The Robbins classic oral cavity SCC phenotype is linked to chronic smoked tobacco use and alcohol.

Long-term carcinogen contact involves broad regions of upper aerodigestive mucosa.

Multiple independent primaries are one clinical consequence of this exposure pattern.

Slide 8 · Betel quid and paan: Regional risk

Common regional exposure

India and parts of Asia

Betel / paan preparations

May contain areca nut, slaked lime, and tobacco

Carcinogenic mucosal injury

Predisposition to oral cavity SCC

Conceptual sequence — schematic

Slide 9 · Lower lip SCC: Distinctive exposures

Sunlight (actinic radiation) predisposes to lower-lip SCC.

Pipe smoking is also identified as an important lower-lip exposure.

The specific mucosal site therefore helps interpret etiologic context.

Slide 10 · Young adults with oral tongue SCC

An increase in oral tongue SCC among some patients younger than 40 years.

Some affected patients have no smoking history or established HPV association.

The pathogenesis in this group remains unexplained in the supplied source.

Slide 11 · High-risk HPV drives oropharyngeal SCC

HPV-16

Prominent high-risk HPV type associated with oropharyngeal SCC

Association is particularly strong for tonsillar and base-of-tongue primaries.

HPV-related SCC is uncommon in the oral cavity compared with the oropharynx.

Anatomic origin is essential when interpreting an HPV-associated tumor.

Slide 12 · Why tonsillar crypt origin matters

Origin deep in crypt epithelium

Palatine or lingual tonsillar tissue

Limited surface abnormality

Premalignant mucosal lesion often not apparent

Early nodal presentation

Cervical lymphadenopathy can dominate

Conceptual sequence — schematic

Slide 13 · The screening challenge in oropharynx

Tonsillar crypts and base of tongue are difficult to survey directly.

A readily identifiable dysplastic mucosal precursor often is not present.

The cervical screening analogy does not translate directly to this anatomy.

Slide 14 · HPV association depends on subsites

Oropharyngeal SCC

A large fraction is oncogenic HPV-associated.

Tonsillar crypt / base-of-tongue primaries predominate.

P16 may serve as a useful HPV-associated marker.

Oral cavity SCC

Most tumors are not HPV-driven in this source.

Exposure-related keratinizing tumors are typical.

Do not equate any oral SCC with HPV-associated disease.

Slide 15 · Precursor lesions of classic SCC

Clinically abnormal mucosa

Leukoplakia and/or erythroplakia

Microscopic dysplasia

Disordered epithelial maturation

Possible invasive SCC

Stromal invasion; Not inevitable

Conceptual sequence — schematic

Slide 16 · Leukoplakia: A clinical designation

A persistent white patch or plaque not removable by scraping may be termed leukoplakia after excluding other causes.

It describes appearance—not a specific histologic diagnosis.

Biopsy establishes whether dysplasia or carcinoma is present.

Slide 17 · Erythroplakia warrants concern

Erythroplakia is a red, velvety mucosal lesion, sometimes eroded or depressed.

Compared with leukoplakia, it more often contains severe dysplasia or carcinoma.

Its red appearance may reflect epithelial abnormalities plus subjacent vascular inflammation.

Slide 18 · White versus red mucosal lesions

Leukoplakia

Clinically white plaque

May range from hyperkeratosis to severe dysplasia

Histology cannot be inferred from color alone

Erythroplakia

Clinically red or velvety lesion

Frequently severe dysplasia or carcinoma

High-priority histologic evaluation

Slide 19 · Dysplasia is the premalignant substrate

Loss of orderly squamous maturation signifies epithelial dysplasia.

Cytologic abnormalities and abnormal mitotic activity support the diagnosis.

The basement membrane remains intact before invasion.

Intact basement membrane

Epithelium

Connective tissue / stroma

Schematic — not a tissue specimen

Slide 20 · Carcinoma in situ: Full-thickness atypia

Carcinoma in situ represents full-thickness epithelial dysplasia.

Atypical epithelium is still confined above the basement membrane.

It is not synonymous with stromal invasion.

Intact basement membrane

Epithelium

Connective tissue / stroma

Schematic — not a tissue specimen

Slide 21 · Invasion establishes carcinoma

Malignant squamous cells penetrate into subepithelial connective tissue.

Nests and islands extend beyond the surface epithelial compartment.

Local infiltrative capacity underlies destructive growth and later spread.

Disrupted basement membrane

Epithelium

Connective tissue / stroma

Schematic — not a tissue specimen

Slide 22 · In situ disease need not precede invasion

Classic head and neck SCC can invade without an observed full-thickness in situ phase.

Therefore an identified precursor lesion does not establish a fixed linear timetable.

This differs from the classic stepwise cervical SCC narrative.

Slide 23 · Predicting transformation remains difficult

Histologic dysplasia grading has meaningful interobserver variability.

No single morphologic feature reliably predicts malignant transformation.

Molecular criteria for more precise risk prediction remain a research need.

Slide 24 · Field cancerization: The concept

Years of regional exposure

Multiple mucosal sites encounter carcinogens

Independent altered clones

Separate neoplasms can emerge

Metachronous primary tumors

Risk persists after original cancer is treated

Conceptual sequence — schematic

Slide 25 · Field disease is not the same as spread

Independent second primary

Arises separately in an exposed epithelial field

May have a distinct origin and site

Reflects multifocal carcinogenesis

Metastatic spread

Arises from cells of an existing malignancy

Nodal or distant deposits derive from primary tumor

Reflects dissemination of one clone

Slide 26 · Molecular transformation is multistep

Somatic mutations and epigenetic alterations

Changes accumulate within epithelial clones

Oncogenes and tumor suppressors

Growth restraint and signaling are perturbed

Clonal selection and invasion

Biologically heterogeneous cancers emerge

Conceptual sequence — schematic

Slide 27 · Sequencing uncovered SCC heterogeneity

Large-scale exome studies, including TCGA, characterized head and neck SCC mutations.

TP53, CDKN2A, and PIK3CA emerged as recurrent altered genes.

Different tumors often harbor distinct driver combinations.

Slide 28 · TP53: Frequent molecular alteration

TP53

Tumor-suppressor pathway

Most frequently mutated gene described in the SCC sequencing summary.

Mutation burden and pathway alteration differ by HPV status.

Direct TP53 mutation is typically not the route used by HPV-driven tumors.

Slide 29 · CDKN2A and PIK3CA: Recurring drivers

CDKN2A

Cell-cycle regulatory locus

Recurrent somatic alteration in conventional SCC

Part of tumor-suppressor control of proliferation

PIK3CA

Encodes a PI3K signaling component

Recurrent alteration in head and neck SCC

Highlights growth-signaling dysregulation

Slide 30 · NOTCH1 and FAT1: Newly emphasized genes

NOTCH1

Loss-of-function mutations identified in SCC sequencing.

Downstream NOTCH pathway components can also be altered.

FAT1

Tumor suppressor within the cadherin family.

Loss-of-function events form part of the SCC landscape.

Slide 31 · Not one mutation defines all SCC

Beyond TP53, individual recurrent gene alterations occur at substantially variable frequencies.

The genotype of one tumor may not represent another tumor from the same anatomic region.

HPV status further separates mutational profiles.

Slide 32 · HPV-negative SCC has more somatic mutations

HPV-negative route

Greater burden of acquired somatic mutations

Common alteration of cellular tumor-suppressor genes

Often linked with environmental carcinogen exposure

HPV-associated route

Viral oncogenes contribute to cell-cycle dysregulation

TP53 and RB mutation commonly unnecessary

Lower somatic mutation burden in textbook comparison

Slide 33 · Viral E6 and E7 change the route to cancer

High-risk HPV infection

Especially HPV-16

E6 / E7 oncoprotein expression

Functional disruption of p53 / RB control

Malignant proliferation

SCC without typical TP53 / RB mutations

Conceptual sequence — schematic

Slide 34 · P16: Surrogate marker of HPV association

HPV-associated growth dysregulation

RB-pathway perturbation

Strong p16 immunoreactivity

Detected with immunohistochemistry

Supports HPV-related classification

Interpret in the correct anatomic context

Conceptual sequence — schematic

Slide 35 · HPV-specific confirmation is sometimes needed

P16 immunohistochemistry

Assesses cellular protein expression

Strong positivity correlates with HPV association

Practical screening / surrogate technique

HPV-directed testing

PCR detects viral nucleic acid

In situ hybridization localizes relevant viral sequences

May resolve selected diagnostically uncertain cases

Slide 36 · Do not confuse marker with mechanism

P16 is a host-cell protein, not the viral genome itself.

Positive p16 staining is supportive—not identical to direct HPV detection.

Interpretation depends on morphology, site, and the clinical diagnostic question.

Slide 37 · Early keratinizing SCC: Clinical appearance

May begin as a raised, firm, pearly mucosal plaque.

Other early lesions are rough, irregular, or verrucous thickenings.

Pre-existing leukoplakic or erythroplakic mucosa may be present.

Slide 38 · Progressive keratinizing SCC: Ulcerated mass

Plaque or rough thickening

Visible mucosal surface abnormality

Enlarging irregular lesion

Progressive local growth

Ulcerated indurated mass

Protrusion with irregular or rolled borders

Conceptual sequence — schematic

Slide 39 · Small oropharyngeal primary, large neck node

Primary lesion

Can be very small and deep in tonsillar crypts

Little obvious surface mucosal alteration

May evade early direct visualization

Regional disease

Cervical lymphadenopathy may be prominent

Metastatic disease can be presenting finding

Nodal burden alone does not imply the classic HPV-negative biology

Slide 40 · Keratinizing SCC: Invasive nests

Malignant keratinocytes form islands and nests in stroma.

The tumor may invade skeletal muscle beneath mucosa.

Concentric keratin whorls demonstrate squamous maturation.

Invasive tumor nests with schematic keratinization

Schematic — not a histologic specimen

Slide 41 · Keratin pearls indicate differentiation

Concentric eosinophilic keratin accumulates within invasive tumor nests.

Prominent keratinization supports a well-differentiated pattern.

Keratinization alone does not determine aggressive behavior.

Invasive tumor nests with schematic keratinization

Schematic — not a histologic specimen

Slide 42 · Differentiation varies widely

Well differentiated

Recognizable squamous maturation

Often conspicuous keratin formation

Tumor nests resemble squamous differentiation

Poorly differentiated / anaplastic

Marked loss of keratinizing maturation

More primitive-appearing malignant cells

Occasional sarcomatoid morphology

Slide 43 · Histologic keratinization is not prognosis

The Robbins account states that degree of keratinization does not reliably correlate with growth behavior.

Well-differentiated morphology must not be equated automatically with low clinical risk.

Anatomic extent and etiologic class are important prognostic contexts.

Slide 44 · HPV-associated SCC: Nonkeratinizing nests

Nests and lobules contain nonkeratinizing basaloid malignant cells.

Keratin whorls are usually not the dominant pattern.

Morphology reflects a distinct etiopathogenic class.

Basaloid nonkeratinizing tumor nests

Schematic — not a histologic specimen

Slide 45 · Lymphoid background in HPV-related SCC

Nonkeratinizing tumor nests may lie within sheets of lymphocytes.

This setting mirrors lymphoid-rich tonsillar tissue.

Anatomic origin plus morphology guides ancillary testing.

Tumor nests within a lymphocyte-rich field

Schematic — not a histologic specimen

Slide 46 · Gross-to-microscopic correlation

Conventional oral SCC

Mucosal plaque → ulcerated / indurated mass

Invasive keratinizing islands in connective tissue

Visible surface dysplasia is often relevant

HPV-associated oropharyngeal SCC

Occult / small crypt-associated primary

Nonkeratinizing basaloid nests in lymphoid tissue

Prominent cervical nodal disease is possible

Slide 47 · SCC first infiltrates locally

Invasive epithelial tumor

Breaches mucosal basement membrane

Local stromal infiltration

Can extend into underlying muscle

Regional dissemination

Typically to cervical lymph nodes

Conceptual sequence — schematic

Slide 48 · Regional lymph nodes are critical

Cervical nodes are frequent first sites of metastatic spread.

The route and pattern of extension depend on the primary anatomic site.

HPV-associated tumors may show substantial nodal involvement with favorable relative outcomes.

Slide 49 · Potential sites of distant spread

Mediastinal lymph nodes

Nodal dissemination beyond the neck

Lung

Distant metastatic site

Liver

Visceral metastatic site

Bone

Skeletal metastatic site

Slide 50 · Why stage at presentation matters

~80% → ~20%

Textbook-reported 5-year survival: Early to late classic smoking/alcohol-related SCC

These estimates describe the source text, not a current patient-specific prediction.

Delayed detection contributes to the poor outlook in conventional SCC.

Avoid substituting degree of keratinization for stage assessment.

Slide 51 · HPV-associated status changes prognosis

HPV-associated oropharyngeal SCC

Long-term outcomes are generally more favorable.

Cervical nodal metastases can nevertheless be frequent.

Low second-primary risk in the Robbins comparison.

Conventional HPV-negative SCC

Classic prognosis worsens substantially with stage.

Repeated carcinogen exposure increases field effects.

Second primary malignancies are an important hazard.

Slide 52 · The second-primary problem

3–7%/year

Textbook-reported annual rate of new primary tumors in classical head and neck SCC

Reflects persistent risk within a carcinogen-exposed mucosal field.

A second primary is biologically distinct from metastasis.

Surveillance must extend beyond the originally treated lesion.

Slide 53 · Late consequences of field cancerization

Successful treatment of first primary

Local disease may be controlled

Persistent altered mucosal field

Additional independent clones remain

New squamous malignancy

Long-term outcome may be compromised

Conceptual sequence — schematic

Slide 54 · HPV-associated versus conventional SCC

Dimension

HPV-associated

HPV-negative classic

Typical site

Oropharynx

Oral cavity

Usual phenotype

Nonkeratinizing

Keratinizing

Etiologic context

High-risk HPV

Tobacco and alcohol

Primary presentation

Small / occult primary

Often visible mucosal mass

Cervical nodes

May be bulky

Variable

Second primaries

Relatively low risk

Higher field-related risk

Overall prognosis

Generally better

Generally worse

Slide 55 · Diagnostic reasoning begins with site

Assign exact primary subsite

Oral cavity vs oropharynx

Evaluate histologic morphology

Keratinizing vs nonkeratinizing

Correlate clinical and ancillary evidence

Consider p16 / HPV-specific tests as indicated

Conceptual sequence — schematic

Slide 56 · Biopsy asks three distinct questions

Is it invasive?

Surface-confined atypia versus stromal infiltration

What morphology?

Keratinizing versus nonkeratinizing pattern

Which etiologic setting?

Site, exposure history, HPV-related evidence

Where has it spread?

Anatomic extent and cervical nodal disease

Slide 57 · Case 1 — an ulcerated tongue lesion

A longstanding smoker has a firm ulcer with rolled margins on the ventral tongue. Biopsy shows invasive nests of atypical keratinizing cells.

Which etiopathogenic route and precursor context are most likely?

Clues for discussion

Anatomic site: Ventral tongue

Surface ulceration and induration

Keratinizing invasive nests

Slide 58 · Case 1 — interpretation

This pattern favors conventional HPV-negative oral cavity SCC.

An exposure-related precursor field may include leukoplakia or erythroplakia.

Clinical assessment must address local extension and cervical nodes.

Slide 59 · Case 2 — a cervical neck mass

An adult presents with bulky cervical lymphadenopathy. A small palatine tonsillar lesion is found; The biopsy shows nonkeratinizing nests within lymphoid tissue and strong p16 staining.

Which SCC subgroup is supported, and why?

Clues for discussion

Small tonsillar primary

Nonkeratinizing, lymphoid-rich histology

P16 strongly positive

Slide 60 · Case 2 — interpretation

An HPV-associated oropharyngeal SCC is strongly supported.

Primary site, histology, and p16 are concordant.

HPV-specific confirmation may be indicated in selected diagnostic circumstances.

Slide 61 · Core diagnostic distinctions

Carcinoma in situ vs invasion

Full-thickness atypia does not itself establish invasion.

Malignant cells within stroma establish invasive SCC.

HPV marker vs direct HPV test

P16 is a correlated cellular surrogate.

PCR / ISH interrogate viral material more directly.

Slide 62 · Summary: Four teaching conclusions

Etiology

Two dominant routes: Carcinogens and high-risk HPV

Morphology

Keratinizing oral SCC versus nonkeratinizing oropharyngeal SCC

Molecular

HPV-dependent changes differ from somatic-driver profiles

Outcome

Stage, HPV association, and field cancerization shape risk

Slide 63 · Source and image interpretation notes

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. 2026. Chapter 16, pp. 667–670.

The primary source comprises extracted textbook text; original plate images were not supplied.

All tissue illustrations in this deck are original editable SCHEMATICS, not clinical or histologic specimens.

Textbook epidemiologic and survival estimates are identified as source-reported rather than current registry estimates.