Basal Cell Carcinoma

Slide 1 · Basal Cell Carcinoma

Mechanisms · clinical morphology · histopathology

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Why basal cell carcinoma matters

The most common invasive human cancer; Extremely frequent in routine dermatopathology.

Usually slow growing and treatable by local excision when recognized early.

Biologically distinctive because its central oncogenic driver is Hedgehog pathway activation.

The principal threat is local destruction; Distant spread is exceptionally uncommon.

Slide 3 · Learning objectives

Explain exposure-related and inherited susceptibility to basal cell carcinoma.

Trace PTCH, SHH, SMO and GLI1 signaling in normal and neoplastic settings.

Distinguish nodular, superficial, pigmented and ulcerated clinical presentations.

Recognize basaloid nests, peripheral palisading and stromal clefts in tissue sections.

Connect molecular pathogenesis with the rationale for targeted treatment.

Slide 4 · The dual identity: Common yet locally aggressive

Common clinical course

Slow evolution in most patients

Early recognition allows local cure

Metastasis is rare

Uncommon advanced course

Progressive invasion can damage contiguous structures

Facial soft tissues, bone or sinuses may be involved

Distant disease occurs only exceptionally

Slide 5 · Natural history depends on detection

Small cutaneous lesion

Slow local enlargement

Potential ulceration

Destructive invasion

Many lesions are recognized while limited and resectable.

Prolonged neglect permits continued local extension rather than rapid dissemination.

The distinction between low metastatic potential and local invasion is crucial.

Slide 6 · Metastasis is not the dominant hazard

BCC rarely metastasizes, even though it is an invasive malignancy.

Local tissue invasion explains the potential for clinically important morbidity.

Risk is not captured by the metastasis rate alone: The affected anatomical site matters.

Source emphasis: Most cancers are cured locally; Only a small minority behave destructively.

Slide 7 · Who develops basal cell carcinoma?

Classically occurs on sun-exposed skin in older, lightly pigmented adults.

Longstanding cumulative ultraviolet exposure contributes to disease risk.

Inherited defective DNA repair increases susceptibility to skin carcinoma.

Immunosuppression is another recognized risk context.

Slide 8 · Ultraviolet exposure and tumor formation

UV exposure

DNA damage

Selected driver alteration

Tumor expansion

UV-induced DNA injury can create acquired driver mutations.

Loss of PTCH function removes a normal brake on growth signaling.

Not every exposed keratinocyte becomes malignant; Other biological constraints remain.

Slide 9 · Exposure and host vulnerability

Exposure component

Sun-exposed cutaneous sites

A UV mutational signature is found in many BCC drivers

Lifetime exposure is important

Host component

Reduced immune surveillance in immunosuppressed people

Defective DNA repair in xeroderma pigmentosum

Inherited PTCH defect in Gorlin syndrome

Slide 10 · Immunosuppression changes susceptibility

BCC incidence is increased in immunosuppressed individuals.

The association is shared with cutaneous squamous cell carcinoma.

Immunosuppression is a risk modifier, not the defining molecular driver of BCC.

Interpret a suspicious lesion using morphology rather than immunosuppressive status alone.

Slide 11 · Xeroderma pigmentosum: Defective repair

Xeroderma pigmentosum is a disorder of nucleotide excision DNA repair.

Defective handling of UV-induced DNA lesions predisposes to skin malignancies.

Its relevance to BCC is the broader link between DNA damage and acquired driver mutations.

This is a distinct genetic route from inherited PTCH dysfunction in Gorlin syndrome.

Slide 12 · BCC and cutaneous SCC: Shared context

Feature

Basal cell carcinoma

Cutaneous squamous cell carcinoma

Major exposure

Sun exposure

Sun exposure

Molecular emphasis

Hedgehog/PTCH–SMO–GLI

UV-associated multiple drivers, including TP53

Typical morphology

Basaloid nests with palisading

Atypical squamous cells with keratinization

Clinical pattern

Very rare spread; local invasion

Regional spread occurs in a minority

Slide 13 · Risk interpretation exercise

A longstanding sun-exposed facial lesion develops in an older patient receiving immunosuppressive therapy. Which factors are relevant?

Teaching interpretation

UV exposure and immunosuppression both contribute to risk.

Age, site and pigmentation provide clinical context but not a tissue diagnosis.

A biopsy or excision requires histologic pattern assessment for definitive classification.

Slide 14 · Gorlin syndrome identifies a driver

Nevoid basal cell carcinoma syndrome (NBCCS) is also called Gorlin syndrome.

It is an autosomal dominant inherited predisposition to multiple BCCs.

Tumors may appear before age 20 years, unlike the usual sporadic presentation.

Investigation of NBCCS clarified the PTCH tumor-suppressor role.

Slide 15 · Gorlin syndrome is multisystem

Multiple cutaneous basal cell carcinomas are a defining tumor manifestation.

Associated neoplasms include medulloblastomas and ovarian fibromas.

Odontogenic keratocysts and palmoplantar pits are important clues.

Certain skeletal or other developmental abnormalities may also be present.

Slide 16 · NBCCS: Classify the manifestations

Category

Manifestations in the Robbins discussion

Skin

Multiple basal cell carcinomas; palmoplantar pits

Jaw

Odontogenic keratocysts

Other tumors

Medulloblastoma; ovarian fibroma

Development

Selected skeletal and other developmental anomalies

Slide 17 · Autosomal dominant risk is not tumor certainty

An individual with NBCCS inherits one nonfunctional PTCH allele.

The remaining functional allele provides a normal suppressor copy initially.

Somatic inactivation of that allele enables tumor development in a clone.

Inherited susceptibility therefore differs from a fully transformed cell state.

Slide 18 · PTCH is a two-hit tumor suppressor

Inherited predisposition → acquired event → tumor

Inherited PTCH defect

Second PTCH allele lost

SMO derepression

GLI1 signaling

The germline change creates a predisposed tissue field.

Acquisition of the second hit produces local loss of tumor-suppressor activity.

This framework explains why separate tumors can arise in one predisposed person.

Slide 19 · Ultraviolet light can supply the second hit

PTCH +/− tissue

Acquired PTCH hit

PTCH loss

BCC clone

In NBCCS, the second PTCH allele can be inactivated by an acquired mutation.

UV exposure is specifically identified as a frequent mutagenic source.

The oncogenic consequence is constitutive Hedgehog signaling in affected cells.

Slide 20 · Why rare syndromes explain common tumors

Inherited syndromes amplify one lesion mechanism enough to make it discoverable.

Identification of PTCH in NBCCS provided a route to study sporadic BCC.

Loss of PTCH activity is not confined to inherited cases.

Disease mechanism—not simply pedigree—therefore guides therapeutic development.

Slide 21 · Hedgehog signaling has normal functions

The SHH–PTCH–SMO pathway regulates embryonic patterning and development.

Robbins specifically emphasizes polarity and central nervous system development.

The pathway also participates in hair follicle formation and growth.

Its normal developmental role explains why constitutive signaling can affect both neoplasia and patterning.

Slide 22 · Hedgehog signaling: Ligand absent

Mechanistic explanation

Without sonic hedgehog ligand, PTCH suppresses SMO activity.

GLI1-dependent transcription is not pathologically stimulated.

PTCH is therefore a negative regulator of the pathway.

SHH absent

PTCH restrains SMO

GLI1 not induced

Growth program not activated

Slide 23 · Hedgehog signaling: Ligand present

Mechanistic explanation

SHH binding to PTCH relieves inhibition of SMO.

SMO activates downstream signaling culminating in GLI1 activation.

GLI1 promotes transcriptional programs supporting growth and survival.

SHH binds PTCH

SMO signaling permitted

GLI1 activated

Growth/survival genes expressed

Slide 24 · Normal pathway: Off versus on

Regulatory element

SHH absent

SHH present

PTCH–SMO relationship

PTCH inhibits SMO

SHH binding relieves inhibition

SMO signal

Suppressed

Active

GLI1 output

Not induced by SHH

Activated

Biologic context

Regulated baseline state

Ligand-dependent developmental signaling

Slide 25 · Mutant PTCH removes the brake

Mechanistic explanation

PTCH loss of function prevents normal restraint of SMO.

SMO can signal without SHH ligand binding.

GLI1 is constitutively activated in the neoplastic clone.

The pathway becomes ligand independent.

PTCH loss of function

SMO active without SHH

GLI1 persistently active

Tumor-promoting gene expression

Slide 26 · SMO mutation offers another entry point

The Robbins figure describes oncogenic mutations in PTCH and, less often, SMO.

The common functional endpoint is inappropriate SMO activity.

Upstream genetic events may differ while downstream GLI signaling converges.

The distinction matters for identifying the regulatory site of pathway activation.

Slide 27 · GLI1 links signaling to tumor behavior

PTCH loss

SMO signal

GLI1 activation

Growth and survival

SMO activity engages downstream transcriptional regulation.

GLI1 increases expression of genes that support tumor-cell growth and survival.

Constitutive signaling can sustain the basal-cell carcinoma growth program.

Slide 28 · Physiologic versus oncogenic signaling

Physiologic Hedgehog signal

Depends on SHH binding

PTCH regulation remains intact

Supports controlled development and homeostasis

Oncogenic Hedgehog signal

May operate without ligand

PTCH dysfunction or activating SMO change

Persistent GLI-dependent expression

Slide 29 · Inherited and sporadic BCC converge

Aspect

Inherited NBCCS-associated BCC

Sporadic BCC

Starting state

Germline PTCH loss-of-function allele

No inherited PTCH defect required

Acquired changes

Second PTCH allele inactivated

Somatic Hedgehog-activating mutations

Shared biology

SMO–GLI1 activation

SMO–GLI1 activation

Clinical tendency

Often multiple, potentially early lesions

Usually occurs in older sun-exposed persons

Slide 30 · A UV signature exists in PTCH mutations

PTCH loss-of-function mutations occur commonly in sporadic BCC.

That about one-third are C→T transitions.

This substitution pattern is a classic signature of UV-associated DNA damage.

Mutation type supports etiologic inference but does not replace pathologic diagnosis.

Slide 31 · Genetic associations need correct interpretation

PTCH is a negative regulator and tumor suppressor—not an oncogene activated by overexpression.

Mutant PTCH can activate the pathway through loss of normal inhibition.

SMO is a positive signaling component; Activating changes can produce a similar endpoint.

GLI1 is a downstream transcriptional effector rather than the original germline lesion.

Slide 32 · The molecular therapeutic rationale

Hedgehog driver

Persistent growth signal

Pathway inhibition

Tumor response

The driver pathway is functionally activated at the level of SMO/GLI signaling.

Hedgehog pathway inhibitors were developed from this causal understanding.

Targeting a disease dependency is different from merely treating surface ulceration.

Slide 33 · Molecular logic predicts clinical relevance

Most BCCs remain suitable for local treatment; Systemic targeting is not the default.

Locally advanced or metastatic disease creates a need for nonlocal therapy.

The Robbins discussion identifies Hedgehog inhibitors and immune checkpoint inhibitors as options.

Treatment selection and eligibility require patient-specific clinical assessment beyond this pathology scope.

Slide 34 · The classic pearly papule

Clinical interpretation

Typical BCC may appear as a small pearly or translucent papule.

The appearance reflects a characteristic surface phenotype, not a definitive histologic finding.

Examination should note the lesion contour, vessels, pigmentation and ulceration.

Clinical morphology schematic

Slide 35 · Telangiectasia supports suspicion

Clinical interpretation

Prominent dilated superficial blood vessels may be visible over a papule.

These are described as subepidermal telangiectasias in the text.

Their presence supports clinical recognition in an appropriate lesion and setting.

Clinical morphology schematic

Slide 36 · Skin pigmentation alters clinical appearance

Pearly change and telangiectasia can be less apparent in more highly pigmented skin.

Failure to see the textbook appearance does not exclude BCC.

Clinical descriptions need to accommodate a range of skin pigmentation.

Histologic confirmation remains applicable regardless of surface appearance.

Slide 37 · Pigmented basal cell carcinoma

Clinical interpretation

Some BCC lesions contain melanin pigment.

Such lesions can resemble a melanocytic nevus or melanoma on inspection.

Pigmentation alone does not establish a melanocytic tumor diagnosis.

Recognize the need for histologic distinction.

Clinical morphology schematic

Slide 38 · Superficial BCC is often plaque-like

Clinical interpretation

Superficial BCC may appear as an erythematous plaque.

Some superficial lesions are pigmented.

A flat plaque can be mistaken for a different cutaneous lesion, including melanoma.

Its architecture is often multifocal and near the surface.

Clinical morphology schematic

Slide 39 · Nodular and superficial patterns

Feature

Nodular BCC

Superficial BCC

Clinical appearance

Pearly or translucent papule/nodule

Erythematous or pigmented plaque

Growth geometry

Islands and cords may extend deeply into dermis

Multifocal growth arising from epidermis

Key recognition

Surface vessels, possible ulceration

Potential resemblance to other plaques

Slide 40 · Ulceration in advanced disease

Clinical interpretation

Older, neglected lesions can ulcerate.

The traditional term “rodent ulcer” reflects the destructive local behavior.

Ulceration is a clue to disease progression but is not exclusive to BCC.

Assessment must address depth and contiguous tissue involvement.

Clinical morphology schematic

Slide 41 · Local extension can threaten anatomy

Skin lesion

Dermal extension

Deep tissue invasion

Bone/sinus risk

BCC spreads predominantly by direct local growth.

The source describes invasion into bone and facial sinuses after prolonged neglect.

This route explains severe morbidity without requiring distant metastasis.

Slide 42 · Clinical patterns: Useful distinctions

Pattern

Typical surface description

Potential clinical problem

Nodular

Pearly papule; telangiectasia

Progressive depth and ulceration

Pigmented

Darkly pigmented papule or plaque

May mimic a melanocytic lesion

Superficial

Erythematous ± pigmented plaque

May resemble non-BCC plaques

Neglected lesion

Ulcerated, locally destructive growth

Deep invasion of adjacent tissue

Slide 43 · Histologic origin: Skin, not mucosa

Histologic interpretation

Tumors arise from epidermis or follicular epithelium.

The proliferating cells resemble the epidermal basal cell population.

BCC is defined here as a cutaneous tumor and does not occur on mucosal surfaces.

Epidermis

Dermis

Schematic — not a tissue section

Slide 44 · Basaloid differentiation is central

Histologic interpretation

Neoplastic cells resemble those of the normal basal epidermal layer.

Tumor cells tend to be relatively uniform and basophilic.

Architectural arrangement and the tumor–stroma interface are important clues.

Epidermis

Dermis

Schematic — not a tissue section

Slide 45 · Multifocal superficial histologic growth

Histologic interpretation

Superficial BCC can arise as separate foci from the epidermis.

The involved surface may cover several square centimeters.

The key concept is lateral multifocality rather than a single deep nodule.

Epidermis

Dermis

Schematic — not a tissue section

Slide 46 · Nodular BCC invades the dermis

Histologic interpretation

Nodular tumors grow downward as cords or islands of basaloid cells.

The nests may extend to different depths within the dermis.

Their growth pattern contrasts with flat, multifocal superficial lesions.

Epidermis

Dermis

Schematic — not a tissue section

Slide 47 · Basophilia and nuclear appearance

Histologic interpretation

Tumor islands are variably basophilic on conventional histology.

Nuclei are described as hyperchromatic.

The overall basaloid cytomorphology is interpreted together with architecture.

Epidermis

Dermis

Radial peripheral alignment

Schematic — not a tissue section

Slide 48 · Peripheral palisading: The rim clue

Histologic interpretation

Cells at the edges of tumor nests may align radially.

Their long axes are arranged roughly parallel around the tumor perimeter.

This peripheral nuclear arrangement is termed palisading.

Epidermis

Dermis

Radial peripheral alignment

Schematic — not a tissue section

Slide 49 · The tumor has a stromal context

Histologic interpretation

The source describes tumor islands within a mucinous extracellular matrix.

Many fibroblasts and lymphocytes can surround the basaloid nests.

Tumor–stroma relationships contribute to recognizing BCC.

Epidermis

Dermis

Schematic — not a tissue section

Slide 50 · Retracted stroma creates clefts

Histologic interpretation

In tissue sections, a clear space often separates tumor nests from adjacent stroma.

This is a sectioning artifact rather than an anatomic cavity in vivo.

Stromal retraction is diagnostically helpful but should be interpreted in context.

Epidermis

Dermis

Sectioning cleft

Schematic — not a tissue section

Slide 51 · BCC versus trichoepithelioma

Question

BCC interpretation

Why comparison matters

Basaloid islands present?

Yes, commonly

Appendage tumors may also be basaloid

Tumor–stroma cleft?

Frequently conspicuous artifact

Helps favor BCC in the appropriate context

Can one feature decide?

No; integrate multiple features

Morphology requires contextual interpretation

Slide 52 · BCC versus SCC: Morphology

Histologic feature

Basal cell carcinoma

Squamous cell carcinoma

Cell type

Relatively uniform basaloid cells

Atypical squamous cells

Architecture

Dermal nests or superficial multifocal growth

Infiltrating squamous tongues/lobules

Peripheral palisading

Characteristic pattern

Not a defining feature

Keratinization/intercellular bridges

Intercellular bridges not evident

Squamous differentiation may be evident

Slide 53 · Clinical suspicion and tissue morphology

Lesion observed

Tissue evaluated

Pattern recognized

Diagnosis integrated

The clinical lesion establishes the need to evaluate a cutaneous neoplasm.

Tumor architecture, basaloid cytology and stromal interface support BCC classification.

A pigmented or superficial appearance requires attention to relevant mimics.

Slide 54 · Histology exercise: A clefted island

A skin section shows dermal nests of small basophilic cells, peripheral palisading, and separation from stroma. What is favored?

Teaching interpretation

The combination strongly favors basal cell carcinoma.

Palisading and retraction are complementary architectural clues.

If the tumor is basaloid, relevant follicular appendage tumors remain considerations.

Slide 55 · Clinical exercise: Pearly nasal nodule

A slowly enlarging, pearly sun-exposed facial nodule contains visible fine vessels. What is the leading diagnostic consideration?

Teaching interpretation

Basal cell carcinoma is strongly suggested by the clinical morphology.

The lesion still requires appropriate clinical-pathologic confirmation.

Recognition while limited is important because most lesions are cured locally.

Slide 56 · Clinical exercise: A pigmented plaque

A flat pigmented erythematous plaque is clinically suspicious for melanoma. Which BCC pattern can produce this presentation?

Teaching interpretation

Superficial or pigmented BCC is within the differential.

The clinical impression alone cannot distinguish epithelial from melanocytic tumors.

Histology clarifies the lineage and tumor architecture.

Slide 57 · Syndromic exercise: Multiple early BCCs

A young patient presents with multiple BCCs, jaw keratocysts and palmoplantar pits. Which genetic syndrome should be considered?

Teaching interpretation

Nevoid basal cell carcinoma syndrome (Gorlin syndrome).

Autosomal dominant PTCH-related predisposition explains the phenotype.

A second acquired PTCH hit can drive the individual tumors.

Slide 58 · Advanced case: Neglected facial tumor

A longstanding ulcerated facial lesion infiltrates adjacent deep structures. Why is the presentation dangerous even without distant metastasis?

Teaching interpretation

Local destruction is the dominant hazard of most advanced BCC.

The source documents possible invasion of facial sinuses or bone after prolonged neglect.

Advanced disease warrants assessment beyond simple surface morphology.

Slide 59 · Local treatment is usually curative

The great majority of BCCs are identified early.

Local excision cures most patients discussion.

Treatment decisions depend on the extent and clinical context of the tumor.

The source does not provide detailed surgical margin or risk-stratification rules.

Slide 60 · When the disease is locally advanced

A rare subset of BCC cannot be managed as a straightforward small cutaneous lesion.

Hedgehog pathway inhibitors may be effective in advanced disease.

Immune checkpoint inhibitors are another therapy.

These statements describe treatment classes, not an up-to-date clinical sequencing guideline.

Slide 61 · Connect mutation to therapy

PTCH loss

Constitutive SMO

GLI1 expression

Pathway inhibition

PTCH inactivation makes SMO–GLI signaling ligand independent.

Therapeutic Hedgehog inhibition targets this pathway dependency.

Mechanism-guided therapy illustrates how inherited cancer genetics can inform treatment.

Slide 62 · Four linked dimensions of BCC

Dimension

Core teaching point

Risk

Sun exposure, pigmentation, age, immunity, DNA repair, inherited susceptibility

Driver

PTCH/SMO aberration produces GLI1-dependent Hedgehog signaling

Recognition

Pearly/telangiectatic, pigmented or superficial plaque presentations

Microscopy

Basaloid islands, peripheral palisading, stromal retraction

Clinical outcome

Usually cured locally; rarely deeply destructive or metastatic

Slide 63 · Avoid four common interpretation errors

Rare metastasis does not mean that BCC cannot invade or cause severe damage.

A pigmented lesion is not necessarily melanocytic, and a superficial plaque need not be SCC.

An inherited PTCH mutation establishes predisposition—not immediate malignant transformation.

A histologic retraction cleft is a diagnostic artifact, not a true intratumoral lumen.

Slide 64 · Core conclusions for pathology practice

BCC is a locally invasive skin carcinoma commonly related to UV-associated damage.

The dominant molecular lesion creates constitutive Hedgehog signaling through SMO and GLI1.

Recognize the spectrum from classic pearly nodules to superficial and pigmented lesions.

Histology integrates basaloid cell islands, peripheral palisading and stromal clefting.

Early local treatment is typically successful; Advanced lesions can be profoundly destructive.

Slide 65 · Primary reading and figure references

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

The Skin: basal cell carcinoma section.

Conceptual reference: normal and oncogenic Hedgehog signaling.

Morphologic reference: clinical and histologic basal cell carcinoma patterns.