Basal Cell Carcinoma

• Most common skin cancer in humans; men have higher rates than women (1.5–2:1).
• Over last 30–40 years, incidence risen 20%–80%; disproportionate increase in young US women.
• Worldwide: incidence doubled in Finland and Switzerland; increased 50% in Wales.
• Median age at diagnosis: 68 years.
• Australia 2002: BCC incidence 884 per 100,000/year; cSCC occurs at half the BCC rate in men, one-third the rate in women.
• Mortality from BCC rare, primarily in immunocompromised and BCNS patients.
• Metastatic BCC more likely from aggressive histopathologic patterns (morpheaform, infiltrating, metatypical, basosquamous).
• Perineural growth/invasion may indicate aggressive disease.
• Metastases often involve regional lymph nodes, lungs, bone, and skin.
• Age-adjusted mortality rate for BCC: 0.12 per 100,000.
• Mortality risk related to increasing age, lighter skin phototypes, male sex (>2× vs women).

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Clinical Features

• Usually arises in sun-damaged skin, but may develop in sites with minimal sun exposure (inner canthus, retroauricular); rarely on palms, soles, mucous membranes.
• No universally accepted classification scheme, though standardization of terminology has recently been proposed.
• Four major distinctive clinicopathologic types: nodular, superficial, morpheaform, fibroepithelial (fibroepithelioma of Pinkus).
• Combinations of latter three types with nodular BCC can occur.
• All types may ulcerate; ulceration more common in nodular type.
• Variable melanin may be present (most BCCs amelanotic); pigmented BCCs more common with darker skin phototypes.
• Confounding factor: many histopathologic patterns entwined with clinical subtypes — examples: cystic, mucinous, micronodular, basosquamous BCCs — seen more frequently in nodular type.

Nodular BCC

• Most common subtype (~50% of all BCCs).
• Shiny, pearly papule/nodule with smooth surface and arborizing telangiectasias.
• Can enlarge and ulcerate (rodent ulcer, phagedenic ulcer), but elevated rolled border usually persists — clinical clue.
• Variable pigmentation may be seen.
• Sites of predilection: face (cheeks, nose, nasolabial folds, forehead, eyelids); may arise in any hair-bearing skin area.
• Rarely occurs in non-hair-bearing sites (oral/genital mucosa, palms, soles).
• Clinical DDx (non-ulcerated): adnexal neoplasms, fibrous papules, intradermal melanocytic nevi, lichen keratoses, amelanotic melanomas; (ulcerated): see Table 45.3, Fig. 105.1.

Superficial BCC

• Well-circumscribed, erythematous macule/patch or thin papule/plaque; diameter few mm to several cm.
• Additional findings: focal crusts/scale, thin rolled border, variable melanin; larger lesions may show spontaneous regression (atrophy, hypopigmentation).
• Mean age at diagnosis: mid-50s — younger than other BCC types; most common subtype in younger age groups.
• Favors trunk and extremities; less often head/neck region. Multiple lesions may be present.
• Growth pattern primarily horizontal, but can become deeply invasive with induration, ulceration, nodule formation.
• Subclinical lateral spread accounts for significant recurrence rate after routine surgical treatment.
• Clinical DDx: solitary lichenoid keratosis, Bowen disease (more scale), inflammatory diseases (psoriasis, dermatitis, cutaneous lupus erythematosus).

Morpheaform BCC

• Less common subtype; slightly elevated to depressed area of induration, usually light pink to white, ill-defined borders; may resemble scar or morphea plaque.
• Surface typically smooth; crusts with underlying erosions/ulcerations or superimposed papules may occur.
• Elevated pearly border typically absent; telangiectasias may be present.
• Biologic behavior usually more aggressive, with extensive local destruction.

Fibroepithelial BCC (fibroepithelioma of Pinkus)

• Rare variant; skin-colored or pink, sessile plaque or pedunculated papulonodule with smooth surface.
• Favors trunk, especially lower back.
• Often occurs in individuals with multiple superficial BCCs.
• Clinical DDx: intradermal melanocytic nevus, large fibroepithelial polyp (skin tag).
• Some experts believe fibroepithelioma of Pinkus is a variant of trichoblastoma (not BCC).

In Vivo Imaging Methods

Dermoscopy

• Demonstrated benefit in diagnosis of pigmented and non-pigmented BCCs.
• Dermoscopic hallmark: well-focused arborizing vessels with foci of microulceration.
• Additional high-specificity findings: large blue-gray ovoid nests, multiple blue-gray globules, leaf-like structures, spoke-wheel areas; pigment network absent.
• Also: short, fine superficial telangiectasias, concentric structures, multiple "in-focus" blue-gray dots.

Reflectance confocal microscopy (RCM) — all BCC subtypes

1. Variable architectural disarray of epidermis.
2. Streaming pattern of elongated monomorphic nuclei polarized along same axis.
3. Tightly packed cells in papillary dermis with nodular/cord-like growth pattern.
4. Palisading of tumor cell nuclei.
5. Peritumoral dark cleft-like spaces (peritumoral mucinous edema).
6. Bright dendritic cells and melanophages (pigmented BCC).

• RCM can also determine surgical margins prior to excision.

Pathology

• Common feature across all types: aggregations of basaloid keratinocytes within variably fibromyxoid stroma.
• Connection to epidermis usually observed, at least focally.
• Tumor cells: large, relatively uniform nuclei, scant cytoplasm; indistinct cellular borders, inapparent desmosomes.
• Apoptotic cells common.
• Fibromyxoid stroma intimately associated with tumor islands, often showing increased cellularity.
• Characteristic feature: retraction of stroma around tumor islands creating microscopically visible clefts — useful in differentiating BCCs from simulators (not always present).

By subtype

• Nodular BCC: large, round/oval basaloid aggregations extending from epidermis into dermis. Overlying ulceration with inflammatory response may occur. Peripheral palisading usually prominent; peritumoral clefts often conspicuous. Central nuclei lack organization, more randomly distributed. Larger islands may develop central necrosis → cystic spaces.
• True cystic/nodulocystic BCC: contains mucin pools within tumor islands.
• Micronodular BCC: tumor islands much smaller than nodular; cellular features similar.
• Superficial BCC: small, superficially located buds of basaloid cells no deeper than papillary dermis, with/without clefting. Skip areas along epidermis in 2D section — synonym "superficial multifocal BCC." Evidence suggests many multifocal buds connect in net-like pattern (most tumors not truly multifocal).
• Pigmented BCC: overall nodular architecture; aggregates of melanin (often irregularly distributed), sometimes increased intratumoral melanocytes; melanophages frequently dispersed in dermis.
• Morpheaform, sclerosing, infiltrative BCCs: share similar features — strands/cords of basaloid keratinocytes extending between collagen bundles; islands may have very few cells, may surround nerves. Peripheral palisading absent; stromal retraction/cleft formation frequently not evident.
• Fibroepithelial BCC: thin anastomosing strands/cords projecting downward from epidermis in fenestrated pattern, embedded in fibrovascular stroma. Peripheral palisading and peritumoral retraction less prominent. DDx: eccrine syringofibroadenoma, reticulated seborrheic keratosis.
• Infundibulocystic BCC: cords of follicular germs with small infundibular cysts, differentiation toward hair follicle structures. Difficult to differentiate from trichoepitheliomas/other follicular adnexal neoplasms — PHLDA1 IHC (epithelial follicular stem cell marker) stronger/more diffuse in trichoepitheliomas. Multiple hereditary infundibulocystic BCC syndrome associated with germline SUFU mutation.

Additional histopathologic subtypes

• Basosquamous carcinoma (metatypical BCC, keratotic BCC): features of both BCC and cSCC. May behave more like SCC — greater likelihood of recurrence and metastasis. Estimated 1% of all keratinocyte carcinomas. Metastases may resemble original tumor or a poorly differentiated SCC.
• Micronodular BCC (histopathologic term): smaller basaloid aggregations infiltrating dermis. Destructive behavior with subclinical spread and high recurrence rates. Clinically presents as infiltrated macules/papules/nodules/plaques — indistinguishable from nodular BCC.
• Recent consensus project: group infiltrating, sclerosing, and micronodular subtypes under umbrella term "infiltrating BCCs."

Histopathologic simulators of BCC

• *Genuine BCC may rarely develop within a dermatofibroma.
• Other basaloid-tumor simulators: adnexal neoplasms (esp. trichoblastoma — clefts within stroma, not adjacent to basaloid islands; follicular germs/papillae simulating rudimentary hair follicles). Basaloid induction within dermatofibromas and reactive folliculocentric basaloid proliferation may also simulate BCC.

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• Basal cell carcinoma (BCC) is the most common human malignancy.
• BCC and squamous cell carcinoma (SCC, Chapter 141) are both carcinomas sharing keratinocyte lineage — collectively termed keratinocyte carcinomas (KCs).
• KCs account for more than 97% of all skin cancers.
• Traditionally BCC accounts for approximately 80% of KCs (BCC:SCC ratio 4:1), but evidence shows increasing SCC incidence with a more recent ratio of 2.5:1.
• US Medicare population (age ≥65 years) study showed a ratio of 1:1 (BCC:SCC).

• BCCs are nearly as common as all other human cancers combined.
• Underreporting is common; there is at least a 10% per year rise in BCC incidence worldwide.
• Average number of lesions per individual: 1.87 (Australia) and 1.64 (USA).
• 40–50% of patients with a primary BCC will develop ≥1 more BCC within 5 years.
• US Medicare data: KC incidence >2.4 million affected individuals/year, >4 million lesions; ≥50% are BCC.
• USA: annual average KC treatment cost rose 126% from 2006–2011, reaching $8.1 billion; cost of all other cancers combined rose only 25%.
• Global Burden of Disease Study 2013: KCs = 12.9 disability-adjusted life years (DALY) per 100,000 persons (a 6.2% reduction from 2005) = 0.13 years lived with disability (YLD).
• KCs accounted for only 0.03% of overall global skin disease morbidity/mortality burden of 1.79%.

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• UK NCRAS cohort study (2013–2015): first BCC count per person/year increased from 145,817 to 166,448 (14% increase); 85% were in England.
• European age-adjusted incidence: 352/100,000 person-years (males), 219/100,000 (females).
• Estimated annual percentage change: 5% in England, 0.3% in Northern Ireland.
• Netherlands: BCC incidence quadrupled over 37 years (1973–2009); more marked increase 2002–2009: 6.8%/year (men), 7.9%/year (women).
• Germany: current incidence 200/100,000 person-years, steadily increasing.
• USA: incidence increasing 4–8% annually; 2006 age-adjusted rate 1488/100,000 (males), 1019/100,000 (females).
• Australia (2002 data): age-standardised rates increased 35–42% from 1985–2002; 1041/100,000 (males), 745/100,000 (females).
• UK regional variation: highest in southwest England (362/100,000 person-years), lowest in Dumfries and Galloway (39/100,000 person-years) — higher latitude associated with lower UV irradiance.
• 80% of cases occur in people ≥60 years; age is an independent risk factor; median age at diagnosis: 71 years.
• BCC incidence higher in men than women.
• 5-year cumulative risk of developing ≥1 subsequent BCC: 29.2%; risk is highest in the first 6 months after first diagnosis.
• Males have a 30% higher risk of developing multiple BCCs than females.
• Patients aged 65–79 years have >80% higher risk of subsequent BCC vs patients <50 years.
• Risk factors: fair skin colour, red hair, inability to tan (markers of UV susceptibility).
• >10 actinic keratoses confers a fivefold increase in BCC risk.
• Other weaker positive associations: solar elastosis, solar lentigines, telangiectasia.
• KC incidence in white populations is 5- to 7-fold higher in USA/Australia than Europe.
• Proximity to equator = strong predictor of KC risk; strong inverse association between latitude and BCC risk.
• UV radiation is the most important risk factor for KC pathogenesis overall, but sun exposure has a greater effect on SCC risk than BCC risk.
• Unlike SCC (strong dose–response with cumulative lifetime sun exposure), for BCC intermittent sun exposure and childhood exposure may be more important.

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• Primary risk factors: UV light exposure and genetic predisposition.
• Other risk factors: Fitzpatrick skin types I and II, immunosuppression, advancing age, male sex, previous BCCs, chronic arsenic exposure.

Risk factors for BCC:

• Intrinsic factors:
• Fitzpatrick skin type I, II
• Iatrogenic immunosuppression
• HIV/AIDS
• Chronic lymphocytic leukaemia, non-Hodgkin lymphoma
• Previous history of BCC
• Photosensitising drugs, azathioprine
• Extrinsic factors:
• High solar UV radiation
• Tanning bed/solarium use
• PUVA, narrow-band UVB phototherapy
• Ionising radiation
• Outdoor occupation
• Chronic arsenic exposure

• Tumour cells resemble basal epidermal layer/appendageal matrix cells — scanty cytoplasm, compact dark nuclei, indistinct cell margins.
• Adjacent cells connected by bridges (desmosomes and tonofibrils shown by EM), distinct from Malpighian "prickles."
• Interaction with dermis produces characteristic marginal palisade of tumour cells and organised stroma.
• Tumour dependence on stroma demonstrated by transplantation experiments.
• Little organisation/differentiation within palisade; mitoses may be frequent; slow growth rate speculated to result from high rate of apoptosis.
• Cells may become acantholytic in some tumours; amyloid may be identified.
• Early lesions: tumour buds arise from epidermis, become confluent; superficial BCC shows reticular growth along interpapillary ridges with larger discrete central masses.
• Growth may be accompanied by involution in nearby areas leaving atrophic epidermis.
• Difficult to prove purely adnexal origin, though some lesions behave as though this is the case.
• Growth pattern variability: rounded expansile islands throwing off buds → multilobular masses with fibrous septa; reticular/cystic pattern where growth encloses connective tissue.
• Invasive strands with excessive fibroblastic (vs lymphocytic) response; can spread long distances along nerve sheaths.
• True invasion (no rounded masses, no palisade/organised stroma, destroys structures) occurs in a small proportion of cases; almost always ulcerated.
• Round-cell inflammatory reaction common, increases with ulceration; mast cells and Langerhans cells present; infiltrate correlated with tumour aggressiveness.
• Melanocyte proliferation causes pigmentation; mucin common in stroma; cystic cavities form from central necrosis (not glandular differentiation).
• True sebaceous/sweat gland differentiation reported but exceptional.
• Fusiform cell strands may represent rudimentary hair follicle differentiation.
• In vitro culture of nodular BCC cells shows keratinisation evidence after 30 days, suggesting inhibition by a dermal factor.
• CD-10, Bcl-2, cytokeratin 20, cytokeratin 15 may help differentiate BCC from trichoepithelioma (Chapter 137) — progress in this area has stalled.

Includes superficial, nodular, infiltrative, micronodular, and pigmented types.

• Superficial BCC:
• Proliferating atypical basaloid cells parallel to epidermal surface.
• Palisading basal cells forming slit-like spaces with Alcian blue-positive stromal mucin (often only clefting seen, as mucin washes away).
• Rarely show mitoses/apoptotic cells; may extend to hair follicles, rarely eccrine adnexa.
• Band-like lymphoid infiltrate; regression with papillary dermal fibrosis/mild inflammation may occur — requires careful multi-level search for atypical basaloid foci.

• Nodular BCC:
• Larger nests/lobules of basaloid cells in papillary/reticular dermis.
• Nests separated from stroma by slit-like retraction artefact.
• Stroma shows myxoid change; focal calcification within nests.
• Coexistent with superficial BCC in a third of cases; mitoses/apoptosis uncommon.
• Processing may cause tumour nest "retraction artefact."

• Micronodular BCC:
• Tumour nests much smaller than nodular type, widely/asymmetrically dispersed in dermis/subcutis/deeper structures.
• Subtle stromal proliferation, collagen with rare fibroblasts.
• Retraction artefact not usually seen.
• Perineural invasion may be seen.

• Infiltrative BCC:
• Elongated tumour cell strands, 5–8 cells thick, irregularly sized/shaped, poorly circumscribed.
• May invade subcutis and adjacent muscular/other structures.
• Sharp angulation of peripheral contours (like morphoeaform), rare slit-like retraction.
• Variable mitotic activity/apoptosis; frequently fibrotic stroma.
• More often associated with perineural invasion.

• Morphoeaform (morphoeic/sclerosing/desmoplastic) BCC:
• Columns 1–2 cells thick of basaloid cells in dense collagenous stroma.
• Sharply angulated cords with marked cell necrosis and mitotic activity.
• Desmoplastic stroma (dense collagen).
• Invasion of deep dermis and subcutis; perineural invasion often seen.

• Basosquamous (metatypical) BCC:
• Very poorly delineated variant; paucity of meaningful literature defining the entity.
• Represents BCC with true areas of SCC; extremely rare.
• Keratotic BCC often classified under this rubric.
• Suggested to have more aggressive behaviour, but not substantiated by large series with long-term follow-up.

• Naevoid BCC syndrome (NBCCS/Gorlin syndrome): autosomal dominant, distinct clinical/systemic features, multiple BCCs from early age.
• Results from germline mutations in patched-1 (PTCH1), a segment polarity gene (9q22.3) with tumour suppressor function.
• PTCH1 originally identified in Drosophila melanogaster; critical in vertebrate development.
• PTCH1 encodes a 12-pass transmembrane protein, acting as receptor for sonic hedgehog (SHH).
• PTCH1 acts as tumour suppressor, repressing smoothened (Smo), a G-protein-coupled receptor.
• Loss-of-function PTCH1 mutations → reduced Smo suppression → activation of Gli family transcription factors → nuclear import → sustained target gene activation.
• Gli proteins bound by Sufu; loss of Sufu → constitutive Gli activation (SHH pathway).
• Sonic hedgehog (SHH) pathway steps:

1. Shh ligand binds to Ptch-1
2. Smo relocates to primary cilium
3. Uninhibited Smo promotes Gli
4. Unbound Gli enters nucleus
5. Gli activates transcription

• Atypical protein kinase C iota/lambda (aPKC-ι/λ): novel Gli regulator; co-localises at centrosome with polarity signalling partners; forms complex with missing-in-metastasis (MIM), a scaffolding protein that potentiates Hh signalling.
• Activated aPKC-ι/λ upregulated in Smo-inhibitor-resistant tumours; targeting aPKC-ι/λ suppresses signalling/growth of resistant BCC cell lines.
• Somatic PTCH1 mutations have high frequency in familial BCC.
• Sporadic BCC: loss of function of PTCH1 in 80–90%, Smo in 10–20% of cases.
• MC1R gene variants ASIP and TYR (associated with fair skin, red hair, melanoma risk) may also be independent BCC risk factors.
• p53 tumour suppressor gene: 50% of BCCs carry a p53 mutation.
• Cytochrome P450s (CYP) and glutathione S-transferases (GST) detoxify oxidative stress products.
• Polymorphisms in GST and CYP2D6 associated with BCC susceptibility; some CYP2D6 allelic variants associated with multiple-presentation BCC phenotype.
• Telomerase activity: significant levels observed in BCC (as in most immortal/tumour cells), with no net telomere loss during proliferation.
• β-catenin and MT1-MMP increased in high-risk BCC — may play a role in locally invasive/destructive growth.

• General population: BCCs are 2–4× more common than SCCs.
• This ratio reverses in immunosuppressed patients (e.g. solid-organ transplant recipients), where SCCs occur more frequently.
• White-skinned transplant recipients: 10–16-fold higher risk of BCC vs non-transplanted population.
• HIV-infected patients and chronic lymphocytic leukaemia (CLL) patients have more aggressive KC.
• CLL patients are 14 times more likely to suffer BCC recurrences following Mohs surgery.

• Chronic inorganic arsenic exposure (drinking water) associated with BCC.
• UVB phototherapy and ionising radiation.
• Besides NBCCS, multiple early-onset BCC may be seen in other syndromes.

• Daylight UVA or UVB but not UVC induces the characteristic solar UV signature mutation, occurring preferentially at methyl CpG sites.
• UVA/UVB induce indirect DNA damage via reactive oxygen species (ROS) formation ("photo-oxidative stress" mechanism), forming DNA adducts.
• Complex DNA repair systems needed to prevent deleterious adduct effects; UV damage usually results in repair or apoptosis, rarely tumourigenesis.
• Xeroderma pigmentosum (impaired DNA repair): up to 2000-fold increased risk of skin cancer.
• BCCs are the most mutated human cancers, majority UV signature mutations.
• BCCs from chronically UV-exposed anatomical regions have higher mutation rates than intermittently exposed regions.
• Greater mutational burden → increased antitumour immune response → less aggressive phenotype.

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• Naevoid BCC syndrome: AD, gene PTCH1; cutaneous: epidermoid cysts, milia, palmoplantar pits; extracutaneous: calcifications of falx cerebri, coarse face, jaw keratocysts, macrocephaly, spine/limb/oro-facial malformations; neoplasms: medulloblastomas, rhabdomyosarcomas; diagnostic criteria: yes; DNA testing: yes.
• Bazex–Dupré–Christol syndrome: XL, gene unknown; cutaneous: flexural hyperpigmentation, follicular atrophoderma, hypohidrosis, hypotrichosis, milia; neoplasms: trichoepitheliomas; criteria: no; test: no.
• Rombo syndrome: AD, gene unknown; cutaneous: atrophoderma vermiculatum, red lesions, hypotrichosis, milia, telangiectasias; neoplasms: trichoepitheliomas; criteria: no; test: no.
• Xeroderma pigmentosum (Ch. 76): AR, genes XPA-XPG, POLH; cutaneous: actinic keratosis/cheilitis, lentigines, atrophy, photosensitivity, telangiectasias, mottled hypo-/hyperpigmentation; extracutaneous: DD/MR, eye anomalies, movement disorder, peripheral neuropathy, photophobia; neoplasms: melanomas, SCC, brain/visceral neoplasms; criteria: no; test: yes.
• Generalised follicular basaloid hamartoma syndrome: AD, gene unknown; cutaneous: comedones, hypohidrosis, hypotrichosis, milia; no extracutaneous or neoplasm features; criteria/test: no.
• Happle–Tinschert syndrome (Ch. 73): Sporadic, gene unknown; cutaneous: lesions over Blaschko lines, atrophy, hyperpigmentation, teeth abnormalities; extracutaneous: body asymmetry, DD/MR, spine/limb malformations; neoplasms: brain tumours; criteria/test: no.

• Genomic instability syndromes:
• Bloom syndrome (Ch.77): AR, RECQL3; café-au-lait spots, photosensitivity, telangiectasias; diabetes, GORD, growth delay, myelodysplasia, recurrent infections; leukaemias, lymphomas, epithelial cancers; criteria: no; genomic testing: yes.
• Werner syndrome (Ch.70): AD (atypical, LMNA)/AR (RECQL2); atrophy, calcifications, painful callosities, premature greying, scleroderma; cataract, diabetes, hypogonadism, peripheral neuropathy, premature atherosclerosis/osteoporosis, typical face; melanomas, (osteo-)sarcomas; criteria: no; test: yes.
• Rothmund–Thomson syndrome (Ch.75): AR, RECQL4; hypotrichosis, nail dystrophy, palmoplantar keratoderma, photosensitivity, poikiloderma, teeth anomalies; cataract, growth delay, myelodysplasia, osteoporosis, patellar hypoplasia, radial ray defects; Bowen disease, osteosarcomas, SCC; criteria: yes; test: yes.
• Muir–Torre syndrome (Ch.141): AD, MSH2, MLH1; no cutaneous/extracutaneous distinguishing features listed; keratoacanthomas, GI/urinary/endometrial neoplasms; criteria: no; test: yes.
• Disorders of folliculo-sebaceous unit:
• CYLD-associated syndromes (Ch.137): AD, CYLD; no distinguishing cutaneous/extracutaneous features; cylindromas, trichoepitheliomas, spiroadenomas, salivary gland adenomas; criteria: no; test: yes.
• Schöpf–Schulz–Passarge syndrome (Ch.137): AR, WNT10A; eyelid cysts, hypohidrosis, hypotrichosis, nail dystrophy, milia, palmoplantar keratoderma, teeth anomalies, telangiectasias; apocrine cystoadenomas, eccrine syringofibroadenomas, eccrine poromas, SCC; criteria: no; test: yes.
• Cowden syndrome (Ch.137): AD, PTEN; acral pseudoverrucoid lesions, acrochordons, fibromas, lipomas, oral/lip papillomas, vascular malformations; breast fibrocystic disease, Lhermitte–Duclos disease, macrocephaly, thyroid dysfunction; breast/gastrointestinal/ovarian/thyroid/uterine cancer, trichilemmomas; criteria: yes; test: yes.
• Syndromes with immunodeficiency:
• Cartilage–hair hypoplasia (Chs.65,66,70): AR, RMRP; hypotrichosis/alopecia; disproportionately short stature, metaphyseal dysplasia, peripheral joint laxity, pudgy extremities; non-Hodgkin lymphomas; criteria: no; test: yes.
• Epidermodysplasia verruciformis (Ch.25): AR, EVER1, EVER2; polymorphic, red, wart-like/flat papules; Bowen disease, SCC; criteria: no; test: yes.
• Disorders of melanin biosynthesis:
• Oculocutaneous albinism (Chs.63,68) OCA 1/2: AR, MATP, TYR, TYRP1; hair/skin/iris hypopigmentation; photophobia, reduced colour vision, strabismus, visual loss; melanomas, SCC; criteria: no; test: yes.
• Hermansky–Pudlak syndrome (Ch.68): AR, HPS1-HPS8; hair/skin/iris hypopigmentation; bleeding diathesis, granulomatous colitis, photophobia, pulmonary fibrosis, reduced colour vision, strabismus, visual loss; melanomas, SCC; criteria: no; test: yes.

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• Unlike SCC, there is no recognised premalignant stage of BCC.
• Typical course: slow progressive peripheral extension, producing thread-like "pearly" border and a nodule ± central depression or expanding ulceration.
• May show spontaneous fluctuation in size, areas of scarring and regression.
• Rapid growth traditionally thought unusual, but a prospective periocular BCC study showed surprisingly rapid growth: mean increase 1.46 mm in length (area 22 mm²) every 30 days, one BCC enlarging by 10 mm length (area 168 mm²) in the same period.
• Only significant risk factors for rapid growth: recurrent tumours and greater size at first examination; no additional effect of aggressive pathological features.
• Approximately 80% of all BCCs occur on the head and neck.
• Early BCCs: small, translucent/pearly nodules, raised telangiectatic edges.
• Presentation may vary: lichenoid, keratotic, excoriated, or ulcerated small lesions.
• More advanced lesions: classic "rodent ulcer" — indurated edge, ulcerated centre.
• Pigment, when present, unevenly distributed throughout the tumour.
• BCC classified into high- and low-risk groups for aggressive behaviour, incomplete excision and recurrence, influencing management choice.

• Clinically distinctive variants: nodular, superficial, morphoeic, and ulcerative types.
• 10–40% of BCCs contain a mixed pattern of ≥2 subtypes — highlights need for clinicopathological diagnosis.
• Fibroepithelial BCC (fibroepithelioma of Pinkus/premalignant fibroepithelial tumour): status heavily disputed; emerging consensus regards it as a variant of trichoblastoma.
• Other described types (infiltrative, infundibulocystic, micronodular, basosquamous) are histologically distinctive but lack distinguishing clinical features.

Nodular Basal Cell Carcinoma

• Commonest subtype, predilection for head and neck.
• Surface contour becomes more irregular with growth; variable vascularity.
• Surface arborising telangiectasia is a characteristic feature over flesh-coloured, shiny nodule with rolled borders (or pink/red).
• Cystic centres may be present, adding to translucent appearance.
• May contain pigmentation, seen more deeply in cystic centre — may cause diagnostic confusion with melanoma.

Superficial Basal Cell Carcinoma

• Predominantly on trunk and limbs.
• Thin plaques/patches, well-circumscribed, slightly raised, thread-like margin, irregular outline, may be deficient at part of circumference.
• Central zone usually scaly, may show central clearing/atrophy.
• Combined with increased vascularity, resembles SCC in situ/Bowen disease and Paget disease of the nipple.
• May have thickened papular islands of growth within margin; crusted/eroded.
• Patients with truncal superficial BCC demonstrate the highest rate of increasing BCC numbers.
• Often pigmented; can be difficult to differentiate from psoriasis, discoid eczema, or Bowen disease.

Morphoeic Basal Cell Carcinoma

• Also known as morphoeaform, sclerodermiform, or desmoplastic — dense fibrosis of stroma produces a thickened plaque rather than tumour.
• Account for 5% of all BCCs; ill-defined borders; difficult to diagnose clinically; often presents late.
• Exact margin near impossible to define clinically; palpation reveals firm skin texture extending irregularly beyond visible changes.
• Surface smooth, may be slightly raised or depressed; colour yellowish.
• Ulceration uncommon and only very superficial when it occurs.
• Can be mistaken for scars.

Ulcerative Basal Cell Carcinoma

• Not entirely clear this is a specific clinical subtype, as any BCC may ulcerate over time.
• May start as a small macule/papule, with expansion of thread-like margins, ulcerating at an early stage.
• Edge usually indurated.
• If left, tumour/ulcer may spread deeply, causing great destruction especially around eye, nose, or ear.
• Advanced cases justify the title "ulcus terebrans" (penetrating ulcer).

• Perineural invasion (PNI) is a sign of increased aggressiveness.
• Large Mohs surgery cohort in Australia: 2.7% of patients demonstrated PNI (general population incidence likely lower).
• Microscopic PNI (asymptomatic) carries much better prognosis than clinical PNI (neurological symptoms and/or imaging evidence of perineural spread).
• Risk factors for advanced disease and metastasis: prolonged neglect (fear of treatment, psychosocial factors, lack of access to care), multiple recurrences, clinical PNI, large lesion size, aggressive histopathological subtypes.
• Advanced BCCs encountered at a rate of 1–2%.
• Mutilation of face/scalp with destruction of nose/eye and exposure of paranasal sinuses/skull/dura/brain may eventually result in death.
• Progression to metastatic form is extremely rare (0.0028–0.55% of BCC).
• Metastasis via bloodstream (viscera, spinal column) or lymphatics to regional lymph nodes before dissemination.
• Basosquamous (metatypical) BCC has increased metastasis risk vs other subtypes — up to 38.1% of primary BCCs that metastasise are this subtype, despite basosquamous representing <3% of all BCCs.

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• Nodular BCC vs melanocytic naevus (especially if pigmented) or sebaceous hyperplasia — difficult on clinical exam alone.
• Naevi: distinguished if hairs grow from surface.
• Sebaceous hyperplasia: central keratin-filled pit.
• Scaling/crusting BCC vs warts, keratoacanthoma, SCC — debris can usually be removed easily; friable, relatively avascular tissue beneath is characteristic.
• Pigmented BCC ± ulceration vs malignant melanoma:
• BCC margin usually rolled, telangiectatic, multinodular, no pigmented halo.
• Colour more definitely brown vs dusky greyish-brown of melanoma (not reliable indicator).
• Dermoscopy can be diagnostic; if uncertain, excise entirely or perform representative partial biopsy/deep shave.
• Superficial BCC vs eczema, psoriasis, Bowen disease — thread-like margin on stretching often reveals diagnosis; some cases require biopsy to distinguish from Bowen disease.
• Morphoeic BCC vs morphoea or scar — outline usually less sharp, evolution more gradual/relentless.
• Chondrodermatitis nodularis helicis (Chapter 106) — usually tender.
• Dermoscopy greatly enhances diagnostic accuracy: adding dermoscopy to naked-eye exam increases sensitivity from 66.9% to 85% (P = 0.0001) and specificity from 97.2% to 98.2% (P = 0.006), greatest benefit with pigmented BCC.

• Naevi: lack of rolled telangiectatic edge; may be hairy.
• Sebaceous hyperplasia: central depression, usually multiple, on sebaceous-quality skin.
• Keratoacanthoma: central keratin plug typical, history of rapid evolution followed by involution.
• Squamous cell carcinoma: shorter history, indurated base (better felt on palpation).
• Bowen disease: scaly edge, lack of thread-like margin.
• Psoriasis: silvery scales, response to topical antipsoriatic therapy.
• Eczema: history of eczema, response to topical eczema therapy.
• Melanoma: grey-black discoloration and pigment spill, shorter history.
• Chondrodermatitis nodularis helicis: usually tender.
• Viral warts: keratotic "warty" surface.

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• Diagnosis of BCC is primarily clinical; biopsy advisable in clinically challenging cases.
• Nodular BCC: shave biopsy easily undertaken.
• Punch biopsy or incisional biopsy: larger specimen, decreased sampling error, more appropriate for identifying aggressive subtypes (e.g. morphoeic lesions).
• Punch biopsy accuracy for identifying BCC subtypes in mixed tumours is poor — concordance between biopsy and subsequent excision only 60.9%.
• Upstaging in diagnosis from preoperative biopsy at time of Mohs surgery occurs in up to 31% of cases.

• Non-polarised or cross-polarised light dermoscopy is an indispensable clinical adjunct.
• Vascular structures: arborising vessels, short fine telangiectasia (arborising vessels are the most noteworthy structures).
• Pigment structures: maple-leaf-like areas, spoke-wheel areas, multiple blue-grey globules, in-focus dots, concentric structures.
• Other non-vascular/non-pigmented structures: ulceration, multiple small erosions, shiny white-red structureless areas, white streaks.
• Dermoscopic criteria described for each subtype; greatest utility is differentiating BCC from benign naevi, Bowen disease, SCC, and melanoma.

• High-frequency ultrasound, optical coherence tomography (infrared light), in vivo reflectance confocal microscopy.
• High-definition optical coherence tomography (HD-OCT): high-resolution, micrometre resolution transverse/axial, visualises individual cells up to a depth of ~570 μm.
• Features described for four different BCC subtypes in transverse/axial directions; subepidermal/intradermal cell island aggregations with less refractile border correspond to palisading/peritumoral mucin on histology.
• OCT and reflectance confocal microscopy may have potential in presurgical margin assessment/non-histological assessment, but limited by optical resolution, learning curves, and cost.
• Confocal microscopy: real-time cellular morphology, thin optical sections, mosaics for Mohs surgery.
• Contrast agents: acridine orange (fluorescence) and acetic acid (reflectance confocal) used in ex vivo imaging to enhance nuclear contrast.

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• Both tumour factors (clinical/histological subtype, size, site) and patient factors (immunosuppression, previous PUVA or radiotherapy) must be considered.
• Stratification into low/high risk of tumour recurrence guides treatment modality choice.
• Other factors: local experience, treatment availability, cost.
• Recommended approach illustrated in Tables 140.6, 140.7, 140.8.
• Evidence-based review: best results obtained with surgery; radiotherapy is alternative/adjunct in selected cases.
• Primary aim: complete removal/destruction of BCC; secondary goal: functional/acceptable cosmetic outcome.
• Low-risk BCC: superficial therapies (topical treatments, PDT) and cryosurgery can be considered — cosmetic outcome may be superior but cure rate is lower.
• High-risk BCC should NOT be treated with curettage/electrodessication, cryosurgery, or superficial therapies other than in exceptional circumstances — histological margin examination is essential.

• Clinical examination (lesion suspicious for KC) → Full history, full cutaneous exam, skin biopsy, imaging (CT/MRI if suspicion of deep/advanced disease) → Diagnosis:
• BCC Low risk → see Table 140.6
• BCC High risk → see Table 140.7
• BCC with deep soft tissue involvement, PNI, bony erosion, or metastasis → Advanced disease → see Table 140.8

• Area L: trunk and extremities excluding hands, nail units, pretibial, ankles, feet.
• Area M: cheeks, forehead, scalp, neck, pretibial.
• Area H: "mask" areas of central face, eyelids, eyebrows, periorbital, nose, lips (cutaneous and vermilion), chin, mandible, pre- and postauricular, temple, ear, genitalia, hands, feet.
• Adapted from NCCN Guidelines Version 1.2020.

Imiquimod

• Stimulates Toll-like receptors 7 and 8 on dendritic cells/monocytes → increased cytokine/chemokine production → promotes Th1 innate and adaptive cell-mediated immune responses crucial to tumour destruction.
• Topical 5% imiquimod cream, applied five times per week over 6 weeks.
• Clears 69–100% of superficial BCC and 42–76% of nodular BCC on trunk/limbs.
• Lower response rate in nodular BCC, thicker superficial BCC, and high-risk anatomical sites (e.g. face).
• Superficial BCC <0.4 mm Breslow thickness may be better suited to imiquimod.
• May be more effective than PDT in treating superficial BCC.
• Recommended for superficial BCC in immunocompetent adults, maximum tumour diameter 2.0 cm.
• Side effects: flu-like symptoms (fever, chills, body aches, lymphadenopathy — may warrant discontinuation), reddening of skin, pruritus, erosion, ulceration, dyspigmentation, crusting.

5-Fluorouracil (5-FU)

• Disrupts DNA/RNA synthesis by inhibiting thymidylate synthetase, preventing purine/pyrimidine incorporation into DNA during S-phase.
• 5% cream: similar efficacy and safety to imiquimod for superficial BCC.
• Not recommended for nodular and high-risk BCC.
• Side effects: local irritation, redness, swelling, desquamation, tenderness (similar to imiquimod).

Photodynamic Therapy (PDT)

• Application of photosensitising agent (5-aminolaevulinic acid, methyl aminolaevulinate) followed by irradiation with red or blue light → production of ROS → necrosis/apoptosis of tumour cells.
• Systematic review/meta-analysis of 1583 treated low-risk BCCs: 86.4% complete clearance rate, good-to-excellent cosmetic outcomes.
• Found inferior to both imiquimod and 5-FU other than for superficial BCC below the knee in elderly patients.
• Full discussion of PDT role in Chapter 22.

Intralesional Interferon α2b (IFN-α2b)

• Requires multiple sessions and high associated costs, limiting use.
• Otherwise high reported cure rates approaching 98% at 12 years with good cosmetic outcomes.

Cryosurgery

• Liquid nitrogen application requiring lesional temperatures of −50 to −60°C.
• Appropriate for some low-risk primary BCCs.
• Limited by low levels of evidence and anecdote.
• Double 30-second freeze–thaw cycle for superficial BCC: 95.3% cure rate.
• Systematic review of recurrence rates: cumulative risk of 4–17% with average 5-year follow-up.
• Similar recurrence rate to standard excision for low-risk primary BCC, but worse cosmetic outcome (hypopigmentation frequent).
• Quick, relatively tolerable, no local anaesthesia required, but can be associated with significant morbidity with prolonged freeze times.

Curettage and Electrodessication (C&C)

• Widely employed — fast, cost-effective, especially for multiple superficial BCCs on trunk/limbs.
• Effectiveness studies mostly old, low evidence base.
• Reported 5-year cure rates: 91–97% for selected primary BCCs; 73–81% for higher-risk BCCs selected.
• Low-risk superficial non-facial BCCs best suited; should not be used for high-risk BCC.
• Avoid hair-bearing areas (potential follicular involvement).
• Results highly operator dependent.
• Principal limitation: histological margins cannot be assessed and true histological subtype may be inaccurate.
• Technique: repeated scraping until firm dermis reached, followed by electrodessication/cautery; up to three repeated cycles usual.
• Modified curettage-alone technique can delineate tumour extent before standard excision/Mohs.
• Should not breach the dermis; if fat exposed, formally excise the site.
• Healing unpredictable/site dependent; anterior chest, upper back, shoulders prone to hypertrophic scars/keloid.
• Mild scarring with textural change and depigmentation usual; vigorous diathermy gives less satisfactory cosmesis.

Standard Surgical Excision

• 4 mm clinical margin with postoperative margin evaluation is most effective treatment for low-risk BCC.
• Reported 5-year recurrence rates: 0.7–5%.
• Randomised prospective trial, 10-year follow-up: primary facial BCCs excised with 3 mm margins had 18% incomplete excisions and 12.2% recurrence rate.
• Recurrent BCC treated with standard excision: 32% incomplete excision, 13.5% recurrence rate.
• Primary repair, flap, or graft reconstruction can give good cosmesis/function, but caution needed regarding margin clearance adequacy (especially flap surgery).
• Aggregated review: mean recurrence rate of 27% if positive margins left untreated.
• If feasible: wider re-excision, or ideally Mohs micrographic surgery or CCPDMA (complete circumferential peripheral and deep margin assessment).
• Wider margins (up to 15 mm) can be considered for high-risk BCC — current evidence insufficient to accurately specify margin due to wide range of tumour/patient factors.
• Meta-analysis of >16,000 lesions: 4 or 5 mm surgical margins result in negative margins on pathology in only 85% of cases; relative risk of recurrence 4.2 with a 4 mm margin.
• Conclusion: "Mohs micrographic surgery offers the smallest overall defect size with the lowest recurrence rate for BCC and is the standard against which other treatments are compared."
• Alternative when Mohs unavailable for high-risk BCC: wide resection with CCPDMA.

Mohs Micrographic Surgery

• Discussed in Chapter 20.

Laser Therapy (Chapter 23)

• Super-pulsed CO2 laser: tissue-heating properties ablate tumours; non-specific effects, usually combined with curettage to remove char/residual friable tumour.
• Repeated cycles until firm dermal tissue remains; further laser application causes tissue contraction rather than vaporisation.
• Single retrospective study: 100% histological clearance, no recurrences at 3-year follow-up.
• Lack of histological confirmation of clearance means use should be restricted to low-risk non-facial BCC.
• Recurrences following CO2 laser ablation more challenging to treat (dense scar, longer disease interval to diagnosis, more aggressive histological pattern vs primary BCC).
• Pulsed dye laser: randomised placebo-controlled trial showed histological clearance at 6 months in 78.6% of cases; high incomplete clearance rate precludes use.
• Pulsed neodymium laser: large retrospective study for facial BCC showed low recurrence rate of only 1.8% (follow-up 3 months–5 years); however lack of histological assessment and risk of late recurrence/delayed treatment preclude use.

Radiotherapy (Chapter 24)

• External beam radiotherapy (EBRT) types:
• Superficial X-rays (low-voltage): energy 40–200 kV, 50% depth dose (D50) 7–10 mm.
• Orthovoltage (deep X-ray): 150–400 kV, D50 50–80 mm.
• Megavoltage X-rays, electrons, protons: >1000 kV, D50 10–200 mm.
• Brachytherapy (BT): radionucleotide iridium-192 moulds, or electronic miniature X-ray source (50–100 kV) — option for smaller superficial low-risk BCCs and selected high-risk primary BCCs.
• EBRT effective for primary/surgically recurrent BCC or incompletely excised BCC where further excision would be complex/contraindicated.
• Important role as adjuvant postoperative treatment for high-risk features (e.g. PNI).
• Also considered for patients unwilling/unable to tolerate surgery (comorbidities, antithrombotic therapy).
• Meta-analysis BT vs EBRT for KC: better cosmesis with BT; doses ranged 50 Gy/15 fractions to 64 Gy/32 fractions; similar recurrence rates, median local recurrence 2% at 1 year, 14% at 5 years.
• May be used palliatively to improve quality of life in advanced/inoperable disease.
• Incomplete clearance/recurrence higher and cosmesis poorer vs surgical excision.
• Should NOT be used for recurrent BCC where primary treatment was radiotherapy, or in NBCCS patients (increased radiation sensitivity, tendency to develop multiple BCCs in irradiated field).
• Use cautiously in patients under age 65 (risk of latent tumours in treated sites).
• Use with caution or avoid on distal upper and lower limbs.
• Practical difficulty: multiple appointments over many weeks for full fractionated course.

Electrochemotherapy (ECT)

• Local treatment aimed at enhancing chemotherapy effects.
• Performed under general/local anaesthesia with sedation.
• Chemotherapeutic agents (e.g. bleomycin or cisplatin) given IV or directly into tumour, followed by brief intense electric pulses (surface plates or needle electrodes) to increase cell membrane permeability.
• UK NICE: ECT may be useful for inaccessible/difficult-to-treat primary BCCs in carefully selected patients, but not in widespread use — RCT data notably lacking.
• Role remains controversial given high cure rates of other modalities.

Sonic Hedgehog Pathway Inhibitors (SHHi)

• Most spontaneous BCCs have hedgehog pathway mutations promoting aberrant signalling.
• 85–90% of BCCs have inactivating PTCH1 mutations; remaining 10% have activating SMO mutations — confirmed by whole exome sequencing.
• Molecular therapies downregulating hedgehog signalling: Smo inhibitors and transcription factor-mediated (Gli) inhibitors (class = SHHis).
• Two oral SHHis: vismodegib and sonidegib (both Smo inhibitors) — used for metastatic and locally advanced BCC not suitable for surgery/radiotherapy.
• Itraconazole (azole antifungal): mild hedgehog signalling effect, limited data.
• Patidegib (also known as saridegib, IPI-926): new semi-synthetic hedgehog pathway inhibitor, undergoing phase II/III trials for advanced BCC.
• Meta-analysis: vismodegib favoured over sonidegib in clinical practice.
• Overall response rate (ORR) locally advanced BCC: vismodegib 68.8% vs sonidegib 56.6%.
• Complete response rate (CRR) locally advanced BCC: vismodegib 30.9% vs sonidegib 3.0%.
• ORR metastatic BCC: vismodegib 39.7% vs sonidegib 14.7%.
• Vismodegib has fewer gastrointestinal and muscle side effects.
• Resistance to both agents involves similar mechanisms.
• Remarkable responses seen in locally advanced/metastatic disease, avoiding premature death or mutilating surgery (e.g. orbital exenteration avoidance).
• Prolongation of therapy leads to better responses but may require breaks (weeks to months) to reduce side effects without compromising response.
• Localised recurrences at edges of regressed tumour can be treated with standard surgical excision in most cases.
• Side effects (mostly reversible, can be incapacitating): muscle spasms, dysgeusia, decreased appetite, alopecia, weight loss, fatigue, nausea, myalgia, increased creatinine kinase, skin SCC (~4%), diarrhoea, amenorrhoea.
• Up to 25% of patients discontinue therapy due to side effects.

• Invasive non-surgical treatment: curettage and electrodessication (avoid terminal hair-bearing areas: scalp, pubic, axillae, beard — if adipose exposed, proceed to surgical excision); CO2 laser ablation with curettage; cryosurgery.
• Superficial treatment: imiquimod cream, 5-fluorouracil cream, photodynamic therapy (PDT), intralesional interferon.
• Standard surgical excision: 4 mm clinical margin, postoperative margin assessment; second intention healing or primary linear repair, skin graft, or flap.
• Negative margins → clinical follow-up by referring doctor/family physician/GP or dermatologist.
• Positive margins → Mohs micrographic surgery, or excision with CCPDMA, or wide re-excision if feasible, or radiotherapy if surgery not possible (see Table 140.7 for positive margins pathway).
• Radiotherapy: for patients where surgery contraindicated due to medical comorbidities, unacceptable surgical risk, antithrombotic therapy, high risk of bleeding, advanced age, surgical refusal, or risk of unacceptable scarring.
• Adapted from NCCN Guidelines Version 1.2020.

• Mohs micrographic surgery or excision with CCPDMA:
• Negative margins → clinical follow-up by referring doctor/family physician/GP or dermatologist; if PNI involving nerves >0.1 mm diameter seen, consider postoperative radiotherapy and/or MDT review.
• Positive margins → consider MDT meeting; re-excision if feasible, or radiotherapy, or systemic therapy (SHHi).
• Wider standard excision with postoperative pathology margin assessment and delayed repair:
• Negative margins → clinical follow-up 6-monthly; if PNI seen, consider postoperative radiotherapy.
• Positive margins → Mohs micrographic surgery or excision with CCPDMA; consider MDT meeting; radiotherapy or systemic therapy (SHHi).
• Adapted from NCCN Guidelines Version 1.2020. SHHi = sonic hedgehog inhibitor.

• No clinical recurrence: clinical review (e.g. 6–12 monthly); patient education, sun protection, self-examination for new primary BCC.
• Locally recurrent BCC: see Table 140.7.
• Nodal or distant metastatic BCC: consider MDT meeting to discuss options, including surgical resection, or radiotherapy, or systemic therapy (SHHi), or clinical trial recruitment.
• Adapted from NCCN Guidelines Version 1.2020.

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• Rare autosomal dominant familial cancer syndrome predisposing to multiple BCCs at early age (typically around puberty), with a variable combination of other phenotypic abnormalities.
• Abnormalities: characteristic facies (large forehead/frontal bossing), bifid/misshapen ribs, vertebral and other skeletal anomalies, keratocystic odontogenic tumours, palmoplantar pits, dysgenesis of the corpus callosum, calcification of the falx cerebri (earlier age than unaffected individuals), macrocephaly.
• Also known as Gorlin syndrome or Gorlin–Goltz syndrome.

• Estimated prevalence: 1 in 57,000 to 1 in 164,000, no sex predilection.
• High new mutation rate and variable expressivity make full assessment difficult, particularly in mildly affected individuals without family history.
• Skin lesions (including BCC) may develop in infancy but more frequently develop between puberty and 35 years of age, average age of onset 25 years.

• Histopathological appearance of BCCs in NBCCS is indistinguishable from sporadic forms.
• Tumours may induce fibrous stroma (as with trichoepithelioma/nodular BCC); may become papular/pedunculated.
• Deeper penetration due to greater aggressiveness, ulceration, invasion; lymphocytic infiltration.
• Pigmentation may occur in/around tumour bulk.
• Calcification and general architecture can resemble trichoepithelioma.
• Palmoplantar pits: focal absence of stratum corneum with vacuolisation of spinous layer.
• Ultrastructurally: pits show premature desquamation, reduced desmosomes/tonofibrils, delayed maturation of epidermal basal cells.
• BCCs have developed within palmar pits.

• NBCCS gene mapped to chromosome 9q22.3-3.1; frequently deleted in both sporadic and familial BCCs.
• Gene identified in 1996 with PTCH1 mutations in NBCCS germline and sporadic BCC tumour samples.
• PTCH1 = human homologue of protein patched homologue, first identified as key regulator of SHH pathway in Drosophila embryonic segmentation/imaginal disc specification.
• First reported example of a link between normal developmental genes and cancer.
• Phenotypic abnormalities consistent with heterozygote PTCH1 knock-out mouse studies.
• PTCH1 mutation rate in NBCCS: 40–80% across published studies.
• Mutation types: nonsense mutations, in-frame deletion, frameshifts (deletions/insertions), splice-site mutations.
• Larger deletions detected by comparative genomic hybridisation in a small number of patients — associated with additional clinical features from co-deletion of other genes.

• Skin manifestations: BCCs, skin tags, palmoplantar pits, milia, epidermoid cysts, lesions resembling dermal naevi.
• Affected individuals may develop up to 500 BCCs in their lifetime, more common in fair-skinned population, especially high-UV areas.
• BCCs often smaller, most commonly on face and trunk, less on limbs.
• Usual sites: eyelids, nose, cheeks, forehead; neck, trunk, axillae quite frequently involved; scalp and limbs usually spared.
• Individual BCCs: smooth-surfaced, rounded, elevated papules, flesh-coloured or pigmented, 1–15 mm diameter.
• Lesions increase in size/number up to late adolescence.
• Fine telangiectasia and milium-like bodies just below surface possible.
• Lesions involving axillae, neck, eyelids tend to be pedunculated.
• Most lesions behave relatively benignly with barely discernible growth.
• Some patients develop more aggressive BCC, difficult to treat, may cause significant morbidity or (rarely) death from extensive invasion/recurrence.
• Proportion developing aggressive tumours and risk factors not established.
• Aggressive tumours occur more frequently on eyelids or nose, can cause gross destruction.
• In one study, 4 of 5 aggressive BCC cases (of 36 NBCCS patients) received radiotherapy as initial therapy — suggests radiotherapy may contribute to tumour aggressiveness in some NBCCS patients.
• Other manifestations: multiple epidermoid cysts, milia, palmoplantar pits.
• Pits: useful diagnostic feature, occur in about 65% of adults with NBCCS, relatively rare in children; small, roughly circular, reddish base, usually 1–2 mm deep.
• Discrete patches of unusually long pigmented hair identified in three NBCCS patients from two unrelated families with confirmed heterozygous PTCH mutations, related to hedgehog signalling role in hair follicle biology.
• In many cases skin lesions resemble melanocytic naevi, neurofibromatosis (von Recklinghausen), or skin tags — true nature suspected only via associated features/family history.
• Correlation between clinical/pathological features of skin lesion range in NBCCS is still poorly understood.
• Other diagnostically useful phenotypic abnormalities: keratocystic odontogenic tumours (KOT), characteristic facies (broad nasal root, hypertelorism, frontal bossing), bifid/misshapen ribs, vertebral/skeletal anomalies, dysgenesis of corpus callosum, calcification of falx cerebri (earlier than non-NBCCS individuals), macrocephaly.
• KOT: typically posterior mandible, usually unilocular, radiological lucency, associated with crown of unerupted tooth; histologically show basal cell palisading and hyperplasia.
• Skeletal abnormalities: spina bifida occulta, bifid/splayed ribs, scoliosis or kyphosis.
• Less common associated anomalies: syndactyly, shortened metacarpals, cleft lip and palate, bicornuate uterus, hypogonadism (males), lymphatic cysts of the mesentery, ocular abnormalities (dystopia canthorum, cataracts, congenital blindness), various neurological disorders.
• Increased susceptibility to other neoplasms: rhabdomyosarcoma, ovarian and cardiac fibromas, and particularly medulloblastoma.
• Approximately 3% of NBCCS patients develop medulloblastomas; approximately 3% of medulloblastoma patients have NBCCS.
• Atypical clinical features (brachydactyly, pulmonary valve stenosis, neurodevelopmental disability) should prompt consideration of a contiguous gene deletion syndrome.

• Consensus: need for either 2 major criteria, 1 major + 2 minor criteria, or 1 major with molecular confirmation.

Major criteria:

• BCC before 20 years of age, or excessive numbers of BCCs out of proportion to prior sun exposure and skin type
• Keratocystic odontogenic tumour before 20 years of age
• Palmar or plantar pitting
• Lamellar calcification of the falx cerebri
• Medulloblastoma (typically desmoplastic)
• First-degree relative with NBCCS

Minor criteria:

• Rib abnormalities
• Other specific skeletal malformations/radiological changes (vertebral anomalies, kyphoscoliosis, short fourth metacarpals, postaxial polydactyly)
• Macrocephaly
• Cleft lip or palate
• Ovarian or cardiac fibroma
• Lymphomesenteric cysts
• Ocular abnormalities (strabismus, hypertelorism, congenital cataracts, glaucoma, coloboma)

• Full clinical history and examination.
• Imaging: orthopantogram, spinal, chest and skull X-ray, cardiac and pelvic (female) ultrasound, baseline brain MRI.
• Molecular genetic testing for PTCH1 and SUFU heritable pathogenic variants: detection probability up to 60% of cases depending on clinical diagnostic criteria.
• Genetic testing does not alter care of those meeting clinical criteria, but helps identify/manage unaffected relatives and confirms diagnosis in those not meeting all clinical criteria.
• Frequent dermatological screening recommended; radiological screening for medulloblastoma in those under age 8 years; KOT screening usually annual.

• Complex multisystemic disease — multidisciplinary approach required (oral maxillofacial surgery, oncology, genetics, psychiatry, plus dermatology).
• Large number of BCCs means standard surgical excision of all lesions not always practicable.
• Low-risk BCC: non-invasive surgical procedures (curettage and electrodessication, cryosurgery) or superficial therapies to keep treatment simple.
• Surgery is mainstay of treatment; high-risk BCC requires Mohs surgery or CCPDMA, as with sporadic BCC.
• Significant psychosocial impact from relentless new BCC development and frequent surgical procedures from a young age — fear of pain/needles/surgery can lead to treatment refusal or long delays.
• Radiotherapy is contraindicated: accelerated development of new BCCs within irradiated field can occur; recurrences frequently more aggressive/difficult to manage than initial primary tumour.
• Systemic chemoprevention: value still unclear.
• Systemic retinoids: isotretinoin >4 mg/kg and etretinate 0.7–1 mg/kg may reduce rate of new BCC development.
• Clinical benefits appear small relative to those seen in patients with multiple cutaneous SCCs.
• Vismodegib in NBCCS: tested in randomised double-blind placebo-controlled trial.
• Primary endpoint: reduction in incidence of new BCCs eligible for surgical resection with vismodegib vs placebo after 3 months.
• Secondary endpoints: reduction in size of existing BCCs.
• After mean 8 months' treatment: BCCs eligible for surgical excision significantly reduced to 2 per patient (treatment group) vs 29 (placebo group); significant reduction in size of existing BCCs.
• No tumours progressed while on treatment.
• Adverse events: routinely grade 1 or 2 — loss of taste, muscle cramps, hair loss, weight loss.
• 54% of patients receiving vismodegib discontinued drug treatment owing to adverse events.
• Treatment resistance may arise with alterations in the inhibitor pocket of SMO, as seen with sporadic BCC.
• Further study needed: intermittent dosing schedules, other delivery modes (e.g. topical patidegib), second-generation inhibitors (sonidegib), other hedgehog-targeting drugs (itraconazole), multidrug regimens.

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• Rare genodermatosis predisposing to multiple BCCs, typically with onset in the second decade of life.
• Approximately 20 cases reported in the literature.
• Additional features: dysgenesis of hair follicles resulting in follicular atrophoderma and hypotrichosis, plus hypohidrosis.
• Also known as follicular atrophoderma and basal cell carcinoma (Bazex) syndrome.

• X-linked dominant inheritance.
• 1995: linkage of three families to a 23.3 Mb region on chromosome Xq24-27.
• Later confirmed, critical region further elucidated to an 11.4 Mb interval on chromosome Xq25-27.1.

• Only females affected; no skeletal abnormalities or other organ systems involved.
• Main presenting features: follicular atrophoderma, hypotrichosis, hypohidrosis.
• Follicular atrophoderma present at birth or in early childhood — appears as "ice-pick marks," enlarged follicular ostia on dorsa of hands, elbows, feet, and face.
• Follicular changes not caused by injury/inflammation, but facial eczema may occur soon after birth.
• Anhidrosis of face and head, hypotrichosis possible.
• Milia reported as an associated feature.
• BCCs appear predominantly on the face, typically in the second decade, and resemble naevi.
• Pigmented BCC may be seen as early as age 5 years.
• Presence of multiple BCCs at early age raises likelihood of NBCCS, but presence of cutaneous abnormalities without associated skeletal abnormality or other organ system tumours can be seen in various rare inherited disorders including BDCS.

• Does not require the intensive follow-up and imaging seen with NBCCS.
• Management of the BCCs themselves is the same as sporadic/other BCC management.

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• Basal Cell Carcinoma (BCC): Most common cancer in humans
• Accounts for ~75% of all nonmelanoma skin cancers (NMSC) and ~25% of all cancers diagnosed in the United States
• Overall incidence increasing worldwide by 3%–10% per year
• Caused predominantly by ultraviolet B (UVB) light exposure
• Key genetic pathogenetic driver: Aberrant upregulation of the Hedgehog (HH) signaling pathway
• Locally invasive and destructive; metastasis is exceedingly rare (0.0028%–0.55%)
• Primary treatment options: Mohs micrographic surgery (MMS), standard surgical excision, curettage and desiccation (C&D), cryosurgery, radiation, topical therapies (imiquimod, 5-FU), Hedgehog inhibitors

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• Over 1 million new cases per year in the US
• Most common in elderly individuals, but disproportionately increasing in patients <50 years of age (especially women <40)
• Slight male predominance overall (e.g., Switzerland: 75.1 vs 66.1 per 100,000; Germany: 63.6 vs 54.0 per 100,000; Croatia: 54.9 vs 53.9 per 100,000)
• Predominantly affects sun-exposed skin of head and neck (nose is most common site: ~21%)
• Race & Skin Type:
• Rare in dark skin due to melanin photoprotection (only ~1.8% of BCCs occur in blacks; 19x more common in whites)
• Rising incidence in Asians (Chinese in Singapore >60 years)
• Highest risk: Light hair/eyes, fair skin, Northern European ancestry, inability to tan (Fitzpatrick skin types I–II)

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• UVB spectrum (290–320 nm) induces DNA damage and immunosuppression
• Pattern of sun exposure: Intermittent, intense sun exposure and childhood/recreational sunburns pose higher risk for BCC than cumulative occupational exposure
• Latency period: 20–50 years between UV damage and clinical onset
• Truncal BCCs: Result from acute intense exposures causing sunburn on skin of trunk in individuals whose facial skin tans better

• Hedgehog (HH) Pathway: Pivotal abnormality in virtually ALL BCCs
• PTCH1 mutation: Identified in ~90% of sporadic BCCs (loss of function of patched 1 tumor suppressor)
• SMO mutation: Activating mutations in Smoothened protein in ~10% of BCCs
• Both PTCH1 and SMO mutations carry UVB-signature transition mutations
• p53 Tumor Suppressor: UV-signature mutations in p53 present in ~50% of BCCs
• Immune Evasion:
• UV-induced BCCs express Fas ligand (CD95L) → induces apoptosis in CD95-bearing cytotoxic T cells
• BCC tumor nests are surrounded by immunosuppressive Foxp3+ regulatory T cells (Tregs) in a Th2-dominant microenvironment

• Organ transplant recipients: 18-fold increase in SCC, but only slight increase in BCC (transplant recipients develop more BCCs on trunk and arms compared to immunocompetent controls)
• Chronic alcoholics: Increased incidence of infiltrative BCC variants

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• Translucency / pearly appearance, telangiectasias, central erosion/ulceration, elevated rolled border

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• Slow-growing tumor with doubling time of 6 months to 1 year
• Progressive invasion into subcutaneous tissue, muscle, cartilage, and bone if untreated
• Follows low-resistance paths along embryonic fusion planes (nasofacial sulcus, retroauricular fold, medial canthus, inner ear canal)
• Giant BCC: Defined as tumor >5 cm in diameter; associated with severe physical/mental neglect; carries higher metastatic risk

• Uncommon in BCC (0.2% to 3.8% of cases); higher in aggressive/recurrent tumors and periocular lesions (>50% of periocular cases with orbital invasion)
• Clinical symptoms: Localized pain, paresthesias, numbness, motor weakness, or paralysis (e.g., brow ptosis from facial nerve temporal branch invasion)
• Most common in preauricular, malar, and periocular regions

• Extremely rare: 0.0028% to 0.55%
• Primary metastatic sites: Regional lymph nodes (50%) and lungs (35%), followed by bone/bone marrow
• Risk factors for metastasis: Large tumor size (>2 cm), deep invasion, morpheaform/infiltrative histology, basosquamous features, PNI, recurrent status
• Prognosis: Poor (mean survival 8–10 months after metastasis diagnosis)

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• Nests/islands of atypical basaloid keratinocytes with large hyperchromatic nuclei and scant cytoplasm
• Peripheral palisading of cell nuclei at margin of tumor nests
• Stromal retraction (peritumoral lacunae): Slit-like retraction artifact separating tumor nests from surrounding mucinous stroma

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• Shave Biopsy: Preferred initial method for elevated or superficial lesions
• Punch Biopsy: Indicated for flat, indurated, morpheaform, or recurrent lesions in scars to obtain full dermal depth

• Nodular BCC: Dermal nevus, SCC, adnexal tumor (trichoepithelioma, desmoplastic trichoepithelioma), dermatofibroma, amelanotic melanoma
• Pigmented BCC: Nodular melanoma, superficial spreading melanoma, lentigo maligna melanoma, blue nevus, compound nevus
• Superficial BCC: Bowen disease, nummular eczema single patch, psoriasis plaque, Paget disease, superficial spreading melanoma
• Morpheaform BCC: Surgical scar, morphea, desmoplastic trichoepithelioma
• Fibroepithelioma of Pinkus: Acrochordon (skin tag), intradermal nevus, neurofibroma

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• Gold Standard for high-risk BCCs; provides 100% margin evaluation while preserving tissue
• Cure Rates:
• Primary BCC: 99% 5-year cure rate (recurrence rate 1% vs 10% for standard excision, 7.7% for C&D, 8.7% for XRT)
• Recurrent BCC: 94.4%–96% 5-year cure rate (recurrence rate 4%–5.6% vs 17.6% for standard excision)
• Indications:
• Morpheaform, infiltrative, micronodular, or basosquamous histology
• High-risk anatomic sites (H-zone of face: eyelids, nose, lips, ears, temples, embryonic fusion lines)
• Recurrent or incompletely excised tumors
• Tumors >2 cm or with ill-defined clinical borders
• Perineural or bone invasion
• Immunosuppressed patients

• Surgical margin recommendations:
• Well-circumscribed primary non-morpheaform BCC <2 cm: 4 mm clinical margin (achieves 95% cure rate)
• Tumors 1–2 cm: 8 mm margin
• Tumors >2 cm or aggressive/morpheaform histology: 5 mm to 10 mm margin (or Mohs)
• Disadvantage: Standard "bread-loaf" tissue sectioning evaluates <1% of total surgical margin

• Operator-dependent; indicated ONLY for small (<1 cm), primary, non-morpheaform, nodular or superficial BCCs on low-risk trunk and extremities
• Cure rate: 98.8% for <1 cm lesions, dropping to 84% for >2 cm lesions
• Contraindicated on high-risk facial sites (H-zone), terminal hair-bearing areas, morpheaform, or recurrent tumors

• Liquid nitrogen double freeze-thaw cycles to −50°C
• Cure rate 92%–99% in select primary low-risk lesions; disadvantages include lack of margin control, hypopigmentation, scarring, and recurrence under dense scar tissue

• Imiquimod 5% Cream:
• FDA-approved for small (<2 cm), primary, superficial BCCs on trunk/extremities
• Dosing: 5 times per week for 6 weeks; clearance rate ~73%–75%
• Contraindicated for nodular, morpheaform, or facial BCCs
• 5-Fluorouracil (5-FU) 5%:
• Used for superficial BCC; recurrence rate ~21% (reduced to 6% if preceded by curettage)

• Mechanism: Small-molecule inhibitors of Smoothened (SMO) protein, inhibiting downstream HH signal transcription
• Indications: Metastatic BCC or locally advanced BCC not amenable to surgery or radiation
• Agents: Vismodegib (GDC-0449), Sonidegib; natural plant alkaloid precursor = cyclopamine

• Topical photosensitizer (MAL or ALA) + red visible light
• 5-year clearance for superficial BCC ~75%; higher recurrence rates than surgery; useful for multiple superficial lesions or poor surgical candidates

• Local control rate 93%–97%; useful for nonsurgical candidates, elderly patients, or as adjuvant therapy for positive margins / gross perineural involvement
• Disadvantages: Worsening long-term radiodermatitis, cosmetic deterioration over time, radiation-induced secondary malignancies

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• Excellent prognosis for primary treated BCC (overall 5-year cure rate >95%)
• Risk of developing a 2nd primary BCC: 36%–50% within 5 years
• Patients with history of BCC have significantly increased risk for cutaneous melanoma
• Follow-up: Full-body skin exam every 6–12 months

• Most common cancer in US, Australia, New Zealand, other light-skinned/moderate-sun-exposure populations; Hawaii — 14x higher incidence in European (esp. Celtic) ancestry vs. Japanese, 34x higher vs. Filipinos; persons of color can develop BCC (esp. with significant occupational sun exposure or immunosuppression); organ transplant/immunosuppression = risk factor in all populations
• Risk factors: intermittent intense sun exposure (prior sunburns), radiation therapy, positive family history, immunosuppression, fair complexion (esp. red hair), easy sunburning (skin types I/II), childhood blistering sunburns; indoor tanning strong risk factor for early-onset BCC (esp. women)
• Actinic elastosis/wrinkling NOT risk factors for BCC (interestingly); BCC relatively rare on dorsal hand (high sun exposure) where AK/SCC abound instead — SCC 3x more common than BCC on dorsal hand; suggests UVR-BCC mechanism not solely related to total UVR dose
• Prevention via sunscreen harder to demonstrate for BCC vs. AK/SCC; BCC:SCC ratio decreases northern (~10) to southern (~2) US; after first BCC, 44% risk of subsequent BCC within 3 years
• Many clinical morphologies exist — clinical diagnosis requires awareness of forms; different clinical/histologic types may have different biologic behavior, influencing therapy choice

• 50-80% of all BCCs; one/few small waxy semitranslucent nodules around central depression (± ulceration/crusting/bleeding); larger lesions show characteristic "rolled" border; telangiectases course through lesion; bleeding from slight injury (e.g., shaving) common
• Progressive growth: crusting over central erosion/ulcer, bleeding when crust removed, chronic gradually-enlarging ulcer; asymptomatic aside from bleeding
• Most frequent on face (85-90% head/neck), especially nose (25-30%); also forehead, ears, periocular areas, cheeks; any body part possible

• Dome-shaped blue-gray cystic nodules, clinically similar to eccrine/apocrine hidrocystomas

• White sclerotic plaque, 95% on head/neck; ulceration, pearly rolled border, crusting usually absent; telangiectasia variably present — often missed/misdiagnosed for a time
• Differential: desmoplastic trichoepithelioma, scar, microcystic adnexal carcinoma, desmoplastic melanoma
• Unique histology: basal cell strands amid densely packed hypocellular connective tissue; constitute 2-6% of all BCCs; fluorouracil use may be a risk factor for morpheaform vs. non-morpheaform BCC

• Aggressive subtype — deep infiltration of spiky basaloid epithelium islands in fibroblast-rich stroma; lacks morpheaform's scarlike appearance clinically
• Histology: hypercellular stroma, jagged-outline islands, squamous differentiation common

• Not clinically distinctive; micronodular growth pattern makes it less amenable to curettage

• "Superficial multicentric BCC"; common, ≥15% of total; favors trunk (45%) or distal extremities (14%); only 40% occur on head/neck; multicentricity is a histologic illusion from sectioning plane passing through branches of a single multiply-branching lesion
• Presents as dry, psoriasiform, scaly lesion; superficial flat growth, often little invasion/ulceration tendency; enlarges very slowly, may be misdiagnosed as eczema/psoriasis; can grow 10-15cm; close edge examination shows threadlike raised border
• Erythematous plaques with telangiectasia, occasional atrophy/scarring; may develop deeper infiltrative component with dermal fibrosis + multifocal ulceration = "field of fire" large BCC; may heal in one area (white atrophic scar) while spreading actively elsewhere; can have several simultaneously/over time
• Most common BCC pattern in HIV-infected patients

• All features of nodular BCC + brown/black pigmentation; typical type in dark-complexioned persons (Latin American, Hispanic, Asian); 6% of all BCCs; if ionizing radiation therapy chosen, pigmentation remains at lesion site

• Neglected ulcerated BCC; pearly border may go unrecognized; on lower extremity may be misdiagnosed as vascular ulceration

• Elevated, skin-colored, sessile lesion, lower trunk/lumbosacral/groin/thigh, up to 7cm; superficial, resembles fibroma/papilloma
• Histology: interlacing basocellular sheets extend downward forming epithelial meshwork enclosing hyperplastic mesodermal stroma; pink epithelial strands with blue basaloid buds (like infundibulocystic BCC) but more prominent fibromucinous stroma, lacks horn cysts; often shows sweat ducts within pink epithelial strands; slight inflammatory infiltrate possible
• Treatment: simple excision or electrosurgery

• Exophytic nodules of head/neck

• Thick sebaceous central-face skin → BCC resembling enlarged pore/stellate pit; virtually always nose, melolabial fold, lower forehead; generally men, majority smokers; many years pass before diagnostic biopsy (considered inconsequential)

• Without apparent carcinogenic factor (arsenic, radiation, chronic ulceration), BCC can occur in odd sites: scrotum, vulva, perineum, nipple, axilla

• Typically embryonal-cleft region of face, often deeply invasive; complete surgical excision safer than curettage; documented cases in children/teenagers unassociated with NBCCS or nevus sebaceous

• Chronic course, slowly enlarging, increasingly ulcerative; tends to bleed asymptomatically/easily; some fibrose/scar as they extend; peripheral spreading → configurate serpiginous patches; ulceration may burrow into subcutaneous tissue, cartilage, bone — extensive destruction/mutilation
• At least half of BCC deaths result from direct extension into vital structures rather than metastases

• Extremely rare (0.0028-0.55% of BCCs) — tumor cells require supporting stroma to survive
• Diagnostic criteria for metastatic BCC: (1) primary arises in skin; (2) metastases distant from primary, not simple extension; (3) histologic similarity between primary and metastases; (4) metastases not mixed with SCC
• 2x more common in men; immunosuppression does NOT appear to increase metastasis risk; most metastasizing BCCs arise on head/neck, large tumors recurring despite multiple surgeries/radiation; perineural or intravascular BCC histology increases metastasis risk
• Most common metastatic site: regional lymph nodes, then lung, bone, skin, liver, pleura; spread equally hematogenous/lymphatic
• Average 9 years between primary diagnosis and metastasis (range <1 to 45 years); once metastasized, rapidly downhill course — <20% survive 1 year, <10% survive >5 years

• Frisch et al: 37,674 BCC patients over 14 years — 3663 new cancers vs. 3245 expected in general population; melanoma and lip cancers most frequent; internal malignancies also excessive: salivary glands, larynx, lung, breast, kidney, lymphatics (non-Hodgkin lymphoma particularly high)
• BCC diagnosis before age 60 → higher rate of breast cancer, testicular cancer, non-Hodgkin lymphoma

• Organ transplant immunosuppression → ~10-fold increased BCC risk; some increased risk in HIV-infected and other immunosuppressed patients; CLL patients also increased risk
• In immunosuppressed population, childhood blistering sunburn history = strong risk factor for post-immunosuppression BCC development

• BCCs arise from immature pluripotential cells associated with hair follicle; mutations activating hedgehog signaling pathway (controls cell growth) found in most BCCs — genes: Sonic hedgehog, Patched 1 (PTCH), Smoothened (SMO); PTCH1 inactivation most common; SMO mutations associated with 10-20% of sporadic BCCs

• Correlation between histologic subtype and biologic behavior; BCCs classified low-risk vs. high-risk based on probability of subclinical extension, incomplete removal, aggressive local invasion, recurrence — dermatopathology report should include subtype descriptor when possible (shave biopsies often insufficient for accurate typing; superficial indolent pattern doesn't exclude deeper aggressive pattern)
• Patterns: nodular, superficial, infiltrative, morpheic, micronodular, mixed; nodular = low-risk; infiltrative, morpheic, micronodular = high-risk (aggressive local invasion, recurrence tendency); superficial BCC prone to increased recurrence from inadequate removal — tumor stroma at margin should count as positive margin
• Early lesion: small dark-staining polyhedral cells resembling basal cell layer, large nuclei/small nucleoli; occurs as epidermal thickenings or downgrowths connected to epidermis; progression → regular compact columns filling dermal tissue spaces (epidermal connection may become undetectable)
• Peripheral palisading (fence-post arrangement) characteristic (absent with cord/small-nest arrangement); cysts may form; interlacing strands → lattice-like pattern
• Dermal stroma integral/important — loose, fibromyxoid, sparse lymphoid infiltrate often present; highlighted by metachromatic toluidine blue staining (useful during Mohs surgery)

• Small BCC vs. small SCC distinction largely academic (both sunlight-caused, unlikely to metastasize, both require removal); biopsy always indicated (may be at definitive procedure if diagnosis likely + patient consents)
• Waxy nodular rolled edge fairly characteristic of BCC; SCC = dome-shaped, elevated, hard, infiltrated; early BCC may resemble sebaceous hyperplasia (depressed center, yellowish nodules around) — but sebaceous hyperplasia never bleeds/crusts
• BD, Paget disease, amelanotic melanoma, actinic/seborrheic keratoses can simulate BCC; shin ulcerated BCC often misdiagnosed as stasis ulcer (biopsy needed); pigmented BCC often misdiagnosed as melanoma/pigmented nevus; superficial BCC easily mistaken for psoriasis/eczema; careful search for rolled peripheral-nodule edge is key differentiator

• Individual thorough lesion evaluation — age, sex, size, site, lesion type all matter; no single ideal treatment; physician experience influences choice; biopsy for all suspected BCC (histologic subtype confirmation)
• Aim = permanent cure with best cosmesis (face = most common location); recurrences from inadequate treatment, usually seen 4-12 months post-treatment; minimum 5-year follow-up recommended (second BCC common)
• Usually surgical (see Ch. 32); some forms amenable to medical treatment, PDT, or radiation; higher recurrence with aggressive histopathology (infiltrative, morpheaform, micronodular), perineural/perivascular invasion, or immunosuppression
• Recurrence more deleterious in central face/eyelids/nose/lips/mouth/ears (re-removal more challenging); Mohs surgery has higher cure rate (all margin evaluation), warranted for high recurrence-risk situations (see Ch. 32)
• Electrochemotherapy (bleomycin + short electric pulses) = palliative skin-directed therapy for multiple/large BCC when conventional treatment not viable

Topical Therapy:

• Most effective for superficial BCC; nodular BCC cure rate only 65% with topical (unacceptable given other options); superficial BCC cured 80% of time with topical treatment
• Topical 5-FU twice daily ≥6 weeks — acceptable in thin/properly-selected tumors, otherwise not very effective (high recurrence)
• Imiquimod 3x/week with occlusion, or 5x/week without occlusion = favored topical patient-applied treatment for superficial BCC; 6-week duration (extendable); excellent cosmetic results especially anterior chest/upper back (where surgery scars significantly)
• PDT also an option; RCT: imiquimod superior to PDT, 5-FU non-inferior to PDT for superficial BCC; surgical excision has higher cure rates than topical therapy overall

Systemic Therapy:

• Vismodegib and sonidegib — SMO inhibitors targeting Hedgehog pathway; antitumor activity, clinically meaningful response for locally advanced/metastatic BCC
• Original vismodegib trials: significant but incomplete response for metastatic BCC; 33% complete response rate for locally advanced BCC; sonidegib response rates also significantly lower for metastatic vs. locally advanced BCC
• Side effects: muscle spasms, hair loss, elevated creatine kinase and lipase

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• AD inherited disorder ("basal cell nevus syndrome")
• Major diagnostic criteria: (1) multiple BCCs (>5) or a BCC before age 30; (2) odontogenic keratocysts of jaws; (3) palmar/plantar pits (≥2); (4) lamellar falx calcification under age 20; (5) first-degree relative with NBCCS
• Minor criteria: (1) childhood medulloblastoma; (2) lymphomesenteric/pleural cysts; (3) macrocephaly (97th percentile); (4) cleft lip/palate; (5) vertebral/rib abnormalities; (6) pre/postaxial polydactyly; (7) ovarian/cardiac fibromas; (8) ocular abnormalities
• Diagnosis: 2 major + 1 minor, OR 1 major + 3 minor; genetic testing shows some mutation carriers don't meet diagnostic criteria
• New proposed criteria (increase pediatric sensitivity since features can be delayed, allowing earlier sun-protection counseling): 3 points each for odontogenic cysts, BCC, palmar pits, falx calcification, bifid/splayed/extra ribs, structural eye anomalies; 2 points for macrocephaly, skeletal anomaly, medulloblastoma; 1 point for tall stature, structural brain anomalies, GU abnormality, strabismus, hearing impairment, natal teeth, cleft lip/palate; >6 points → genetic testing
• Caused by PTCH (PTCH1) gene mutations (most common), rarely SUFU gene mutations (associated with medulloblastoma susceptibility); mutations throughout PTCH gene, no site-phenotype correlation; most cause premature termination/shortened product; PTCH loss also via chromosome 9q22 deletions (~6% of NBCCS patients)
• Clinical findings depend on skin tone + mutation type (point mutation vs. chromosome deletion); 105-patient series: 80% light skin tone, first tumor mean age 23 in White patients; skin of color patients: palmar/plantar pits, odontogenic keratocysts, skeletal abnormalities most common, BCCs appear much later
• 9q22 deletion patients: typical NBCCS stigmata + often severe mental deficits, hyperactivity, overfriendliness with strangers, short stature, less often neonatal hypotonia, epicanthic folds, short neck, pectus, scoliosis, epilepsy

• BCCs multiple, usually numerous, appear age 17-35 typically (early age or any time after); marked central facial tendency (eyelids, periorbital, nose, upper lip, cheeks); fair skin type I + prior excessive UV especially prone to many BCCs
• Lesions 1-10mm, hyperpigmented/skin-colored, dome-shaped papules — resemble compound/intradermal nevi or small skin tags
• Polypoid/acrochordon-like BCC: unusual variant in NBCCS children — preadolescents rarely get true fibroepithelial polyps, so numerous ones (esp. head/neck) should suggest NBCCS
• Some BCCs indolent, others more aggressive growth within same patient

• ~90% of patients; as early as age 5, rarely after 30; mandible AND maxilla may show cystic defects (mandibular 2x more common); painless swelling presentation; usually keratinized lining (keratocysts), uncommonly ameloblastoma

• Distinguishing feature, usually apparent 2nd decade; up to 87% of NBCCS patients have pits; histology shows basaloid proliferation but does NOT progress/behave as BCC

• Most patients have radiographically-detectable skeletal anomalies; macrocephaly = first observed feature (explains high cesarean delivery rate in affected neonates)
• Other defects: bifid/fused/missing/splayed ribs, scoliosis, kyphosis; radiographic multiple-lesion evidence highly suggestive (mostly congenital — useful for diagnosis in patients too young for other manifestations)
• Cleft lip/palate in 5%; falx lamellar calcification evident in 90% by age 20; polydactyly occurs; numerous ocular findings reported — ophthalmologic evaluation recommended if suspected/confirmed; spina bifida fortunately uncommon

• Identical to nonsyndromic BCC histology; solid and superficial types most common

• Linear unilateral BCC syndrome: linear close-set papules ± comedones at birth, likely postzygotic mutation; biopsy shows BCCs that do NOT increase in size with age
• Bazex syndrome (X-linked dominant, distinct from Bazex acrokeratosis paraneoplastica): follicular atrophoderma of extremities, localized/generalized hypohidrosis, hypotrichosis, multiple early-onset facial BCCs
• Multiple hereditary infundibulocystic BCCs (AD syndrome): distinguished from NBCCS by absence of palmar pits/jaw cysts in most cases; clinically resembles multiple trichoepitheliomas — numerous skin-colored pearly papules on central face, accentuated nasolabial folds
• Generalized basaloid follicular hamartoma (BFH) syndrome: basaloid follicular hamartomas instead of BCCs, tiny palmar pits present; histologically may be indistinguishable from infundibulocystic BCC (hard to separate syndromes); BFH can have segmental presentation
• Rombo syndrome (one large Swedish family): multiple BCCs + vermiculate atrophoderma + hypotrichosis
• Multiple BCCs + myotonic dystrophy reported — possible additional genodermatosis association

• Genetic counseling essential; strict sun avoidance/maximum sun protection (as for xeroderma pigmentosum); avoid ionizing radiation (NBCCS patients particularly radiation-sensitive — multiple BCCs may appear in radiation therapy distribution used for medulloblastoma/BCC/other cancers)
• Regular monitoring + biopsy of suspicious lesions; topical tazarotene, 5-FU, imiquimod may help prevent and treat superficial tumors
• Oral retinoid therapy may reduce new BCC frequency and slow existing small BCC growth — but lesions regrow once stopped; vismodegib/sonidegib reduce tumor burden and prevent new BCCs in NBCCS, but poor tolerability → ~50% discontinuation rate; topical smoothened inhibitor formulation appears effective and better tolerated, causing BCC regression
• Surgical treatment (curettage/desiccation or excision) for most lesions; multiple-tumor removal under general anesthesia in OR sometimes needed for large BCC burden; PDT particularly beneficial for areas with prior multiple BCCs

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• Prevalence: Most common skin cancer and most common human malignancy (75–80% of all non-melanoma skin cancers).
• Pathophysiology: Derived from basal layer cells of the epidermis and hair follicle outer root sheath. Driven by dysregulated Hedgehog Signaling Pathway (PTCH1 gene inactivating mutations).
• Gorlin Syndrome (Nevoid BCC Syndrome): Autosomal dominant PTCH1 mutation; multiple BCCs at an early age, odontogenic keratocysts of jaw, palmar/plantar pits, calcification of falx cerebri.

Clinical Subtypes of BCC

1. Nodular BCC: Most common subtype (60%); pearly translucent papule or nodule with rolled borders and overlying arborizing telangiectasias; central ulceration (Rodent Ulcer).
2. Superficial BCC: Erythematous, scaly, thin patch with a fine thread-like rolled border on the trunk; mimics eczema or tinea corporis.
3. Infiltrative / Morpheaform / Sclerosing BCC: Waxy, scar-like white/yellow plaque with ill-defined borders; highly aggressive with extensive subclinical microscopic spread.
4. Pigmented BCC: Contains brown/black melanin pigment; mimics melanoma.

Treatment Guidelines

• Mohs Micrographic Surgery: Gold standard treatment (highest 5-year cure rate >99%); indicated for high-risk anatomic sites (H-Zone of face: eyes, nose, ears, lips, temples), morpheaform/infiltrative histology, recurrent BCC, and ill-defined margins.
• Standard Surgical Excision: 4 mm clear margins for low-risk primary trunk/limb lesions.
• Electrodessication and Curettage (ED&C): Indicated for low-risk superficial/nodular BCC on trunk and limbs.
• Hedgehog Pathway Inhibitors: Oral Vismodegib (Erivedge) or Sonidegib (Odomzo) for locally advanced or metastatic BCC.

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