Basal Cell Carcinoma • Discus the Differential Diagnosis Jason Stratton MD Pathology Laboratory Associates/ Regional Medical Laboratory, Tulsa Oklahoma

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Objectives

• Introduce BCC Histology • Discuss Histologic Types and Importance. Basal Cell Carcinoma • Discus the Differential Diagnosis Jason Stratton MD Pathology Laboratory Associates/ Regional Medical Laboratory, Tulsa Oklahoma.

12 Duplicate BASAL CELL CARCINOMA Basal Cell Carcinoma (BCC) • first described by Jacob in 1827 • most common human cancer (Lacour, 2002). • Pathologyor • by 1998 roughly one million new cases annually in the • Various growth patterns USA (Miller and Weinstock, 1994) • Often mixed • 4th decade of life and beyond • All proliferation of basaloid cells • Exception with specific genodermatoses or in patients with w/ peripheral palisade immune compromise • All surrounded by fibromucinous • UV light the major etiology : light skin phenotypes stroma • Amyloid deposits – from release particularly predisposed keratin into stroma • Other risk factors: arsenic, coal tar derivatives, • Mitotic figures & apoptotic cells irradiation, scars, draining sinuses, ulcers, burn sites [all • Clefting artifact (retraction) foci of chronic inflammation] between tumor and stroma • Lack of hemidesmosomes

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BASAL CELL CARCINOMA BASAL CELL CARCINOMA histopathology Distributehistopathology of “undifferentiated” BCC • Indolent- or aggressive-growth types • Originally, BCC was classified into solid/undifferentiated vs • Indolent-growth variants (IGBCC) include those with specific differentiation • superficial – Eccrine • nodular basal cell carcinoma – Sebaceous • Nodulocystic – Keratotic/Pilar • Infundibulocystic – FollicularNot (pilomatricoma like) • Aggressive growth (AGBCC) variants • We now know that the only important histologic • infiltrative basal cell carcinoma prognosticator of biologic behavior is the architectural • micronodular growth pattern. • basosquamous (metatypical) carcinoma Do • morpheiform or sclerosing basal cell carcinoma 56

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BASAL CELL CARCINOMA histopathology of “undifferentiated” BCC BCC subtype and sun exposure

• In a retrospective series of 1039 consecutive neoplasms: • BCC in sun-protected skin usually of superficial type • 21% were nodular; 6.4%+ve margin (63.2%) vs only 21% nodular and 15.8% infiltrative • 17.4% were superficial; 3.6% +ve margin subtypes • 14.5% were micronodular ; 18.6% +ve margin • BCC in sun-exposed skin infrequently of superficial • 7.4% were infiltrative; 26.5% +ve margin type (14.3%), while 42.9% were nodular type, 33.3% • 1.1% were morpheiform; 33.3% +ve margin were infiltrative, and 3% each were of morpheaform • One-third of all tumors showed mixed patterns and metatypical subtypes (p=0.028) (Crowson et al, Sexton et al, J Am Acad Dermatol,1990 1996)

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Superficial Basal Cell Carcinoma

• Epidemiology or • Earlier age • Location • More frequent on trunk • Clinical features • More subtle • Often multiple • Erythematous patch BCC, superficial • Resemble dermatitis, but has pearly border / central superficial erosion w/ h/o of bleeding easily

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Superficial Basal CellDistribute Carcinoma

• Histopathology • Superficial lobules of basaloid cells • Usually confined to papillary dermis • Projecting from epidermis or adnexa • Multifocal Not• Usually connected by stroma & in 3D BCC, superficial Do 11 12

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Nodular Basal Cell Carcinoma

• Epidemiology • Later age; most common pattern (60-80%) • Location • More frequent on head Superficial basal cell carcinoma : atypical basaloid cells form an axis parallel to the • Clinical features epidermal surface; mitoses and apoptotic cells rare • Elevated pearly nodules • Assoc. w/ telangiectasia

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Nodular Basal Cell Carcinoma

• Histopathologyor • Large lobules of basaloid cells • Project into reticular dermis / deeper • May have adenoid (cribiform) or organoid pattern • Secondary features • Mucinous degeneration w/ cysts

Nodular BCC : courtesy Dr. G. Monks, Tulsa OK

15 16 Distribute Not

BCC, Nodular BCC, Nodular Do BCC, Nodular 17 18

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Micronodular Basal Cell Carcinoma

• Location • Most common site is back • Clinical features • Not specific

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Micronodular Basal Cell Carcinoma

• Histopathology or • Small lobules of basaloid cells • Project into reticular dermis / deeper • Fibrotic stroma

• Prognosis & predictive factors • Worse • Possibly b/c surgical margins often underestimated

Micronodular BCC : Plaque like;, poorly demarcated; nests smaller with individual fibrotic stroma; widely dispersed into deep dermis and/or subcutis

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DistributeInfiltrating Basal Cell Carcinoma

• Location • Usually on upper back & face • Clinical features • Pale, indurated poorly defined plaque • Paraesthesia / loss of sensation Not • Due perineural extension

DoBCC, Micronodular 23 24

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Infiltrative basal cell carcinoma clinical correlates

• poorly circumscribed • may invade subcutis and adjacent structures • perineural infiltration a distinct risk for recurrence • depressed yellowish or fibrotic plaque lacking rolled border or elevated nodule unless a co- existant nodular component

Courtesy Dr. Michael Wilkerson, Galveston TX

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Infiltrating Basal Cell Carcinoma

• Histopathology or • Infiltrative strands, cords, or columns of basaloid cells • Project into reticular dermis / deeper • Peripheral palisade & retraction usually absent • Frequent perineural invasion • No fibrosis / sclerosis • As seen in sclerosing / morpheiform variant • Prognosis & predictive factors • Worse • Again possibly b/c surgical margins often underestimated

BCC, Infiltrative 27 28 Distribute Not

Irregular tongues of tumor and stromal fibroplasia in mixed nodular and infiltrative growth BCC mitotic activity and individual Do cell necrosis 29 30

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Fibroepithelial Basal Cell Carcinoma (Fibroepithelioma of Pinkus, Pinkus tumor)

• Location • Usually on back • Clinical features • Elevated flesh colored / erythematous nodule • DDx: SK, acrochordon

Mixed nodular and infiltrative growth BCC

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Fibroepithelial Basal Cell Carcinoma

• Histopathology or • Arborizing network of cords of basaloid cells

• Prognosis & predictive factors • Indolent

BCC, (Fibroepithelioma of Pinkus) 33 34

DistributeBasosquamous Carcinoma (Metatypical carcinoma, basosquamous cell carcinoma)

• Clinical features • No distinguishing clinical features • Histopathology • More abundant cytoplasm Not • More marked keratinization • Prognosis & predictive factors • More aggressive behavior

Fibroepithelioma of Pinkus: fleshy Do lesion above natal cleft 35 36

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Basosquamous/metatypical carcinoma : inter- cellular bridge formation, keratinization; admixed nodular or superficial component Basosquamous carcinoma:

• Defined as an infiltrative growth BCC with areas of keratinization and/or intercellular bridge formation and a prototypic stromal response • Published recurrence rates 12-50% after surgical excision vs 4% after Mohs surgery

Garcia, Poletti + Crowson. J Am Acad Dermatol 2009; 60:137

37 38 Duplicate “Differentiated” basal cell carcinomas Basosquamous (metatypical) carcinoma: differential diagnosis • Basal cell carcinomas show various lineage differentiation features that do not impact prognosis: • keratoticor BCC (de Faria, 1985), • Keratotic/pilar BCC, most often a nodular BCC • infundibulocystic BCC (Walsh and Ackerman, 1990) • follicular BCC (Aloi et al, 1988) [has collision features with with horn cyst formation (primitive attempt at pilomatricoma] hair differentiation) • pleomorphic BCC (Garcia et al, 1995) • mixed [basal cell and squamous cell] carcinoma, • BCC with eccrine differentiation (Kato and Ueno, 1993) • BCC with sebaceous differentiation a collision between two clonally distinctive, • fibroepithelioma of Pinkus (Pinkus, 1953) geographically separate neoplasms in the same • BCC with myoepithelial differentiation (Suster + Cajal, 1991) biopsy or excision • squamous cell carcinoma

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Keratotic Basal CellDistribute Carcinoma

• Clinical features • May be studded w/ small keratin cysts (milia)

• Histopathology • Nodular architecture • ProminentNot keratin formation (horn cysts) center of tumor nodules

follicular BCC : matrical Do differentiation 41 42

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Pleomorphic BCC Pleomorphic basal cell carcinoma infiltrative type (“BCC with monster cells” )

• giant nuclei scattered through tumor lobules or clustered suggesting a similar clone • All cases evaluated by static image analysis cytometry have proven to be aneuploid • mitoses present same frequency as in typical nodular BCC; rarely atypical (Elston et al, 1993; Garcia et al, 1995) • pleomorphic cells a form of senescent atypia; impart no prognostic significance

43 44 Duplicate Basal cell carcinoma with eccrine or apocrine differentiation Basal cell carcinoma • seen in roughly 1% of nodular BCC in our experience “rippled pattern” (Kato and Ueno, 1993) or • Characteristic interlobular • centrally disposed in basaloid tumor cell aggregates palisade of nuclei are tubules lined by cuboidal epithelium with an • Remainder of histologic internal eosinophilic cuticle characteristics are similar to nodular BCC • decorate with immunohistochemical stains for • Shares almost identical carcinoembryonic antigen (CEA) and epithelial histology to “rippled type membrane antigen (EMA) sebaceoma”

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DistributeClear Cell BCC (BCC with Trichilemmal Differentiation)

• Clear cell change in otherwise typical BCC of any pattern due to glycogen accumulation in cytosol • Differential diagnosis : • sebaceous carcinoma • clear cell squamous cell carcinoma Not • other clear cell carcinomas metastatic to skin (ie renal cell ca or thyroid carcinoma)

Do BCC with sebaceous differentiation 47 48

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PAS PAS D

49 50 Duplicate or

BCC, Morpheiform / Sclerosing

BCC, Pigmented 51 52

PathogenesisDistribute of BCC Nevoid Basal Cell Carcinoma Syndrome (Gorlin syndrome, Gorlin-Goltz syndrome, basal cell nevus syndrome)

• Syndromal • Epidemiology • Mutation of PTCH1 • 0.4% of all BCCs; prevalence 1/57,000 • Sporadic • Genetics • Autosomal dominant • Associated with Sonic hedgehog pathway mutations • Mutation of PTCH1 gene on 9q22.3-q31 • P53 associated mutations • PTCH1 encodes inhibitor of hedgehog signaling pathway • CDKN2A and RAS family mutations • Also found in sporadic BCC • Cases with multiple subclones Not • Clinical features • Multiple BCC at early age (2y/o) • Begin on nape neck; most involve face & upper chest • Other findings • Palmar > plantar pits • Odontogenic keratocysts: lower jaw; multiple • Cutaneous cysts: milia, epidermal cysts • Bony abnormalities Do • Neoplasms: medulloblastoma (4y/o), cardiac & ovarian fibromas (puberty) 53 54

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Nevoid Basal Cell Carcinoma Syndrome Diagnostic criteria Diagnosis = 2 major or 1 major + 2 minor

• Major • Minor • >2 BCCs or 1 if <20y/o • Macrocephaly adjusted for • Odontogenic keratocyst height • >3 palmar pits • Frontal bossing, cleft lip / • Bilamellar Ca++ of falx palate, hypertelorism cerebri • Sprengel deformity, pectus, • Bifid, fused, or splayed ribs syndactyly of digits • • 1st degree relative w/ Bridging of sella turcica, NBCCS hemivertebrae, flame- shaped radiolucencies • Ovarian fibroma • Medulloblastoma Expressed in childhood or young adulthood as multiple BCC and other anomalies [jaw cysts, rib anomalies etc]; Courtesy Dr David Adelson, Univ of Okalhoma

55 56 Duplicate BCC: Sporadic Pathogenesis SHH pathway • patched gene (PTCH) encodes membrane receptor for Hedgehog signaling protein family • binding of secretedor morphogen shh to ptch activates cell membrane signaling protein smoothened (smo) • smo activates via gli1 pathway • Gli1 activates cyclinB1-cdk to phosphorylate pRB, release cell cycle block to S-phase → cell proliferation • Gli1 : ↑ TGFβ; PDGFR; ptch (Dicker et al, 2002) • Sporatic mutation can be: • Inactivating PTCH • Activating of SMO • Elsewhere in the pathway

57 58 Distribute

Not Recurrent BCC

Recurrent BCC : induration, erythema, ulceration or bleeding; Do Courtesy Dr M Wilkerson 59 60

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Neurotropic Basal Cell Carcinoma • Not uncommonly seen in our dermatopathology practice Neurotropic BCC • Identified in 0.47% of 7852 Mohs surgery patients in one study (Osguthorpe et al. Arch Otolaryngol Head Neck Surg 1997;123:871) • 28 SCC, 9 BCC • 20 of 25 with extracranial disease were alive without recurrence at 20 months follow up • Only 1 of 9 with intracranial disease alive without recurrence at 21 months • The histologic clue at Mohs surgery may be confined to an obscuring lymphoid infitlrate (Crowson and Yob, 2009)

61 62 Duplicate Differential Diagnosis for Basal Cell Carcinoma Merkel Cell • Any small round blue cell with crush artifact Carcinoma • Collision tumors • Could be encounteredor in Mohs both due to collision • Merkel cell carcinomas tumors or misdiagnosis due • Squamous cell carcinomas to artifact or small biopsy size. • melanomas • Typically a nodule on the sun exposed skin of elderly • Partially excised adnexal tumors or in immunosuppressed. • Trichilemmomas • Trabecular architecture with Neuroendocrine • Desmoplastic trichoepitheliomas cytology. • Metastatic lesions • High N:C ratio with mitosies and apoptotic bodies. • Primary cutaneous lesions with histologic overlap • Highly rate of metastasis

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Squamous Cell DistributeMelanoma and Carcinoma Melanoma insitu

• Collision tumors and • Occasionally collision basaloid variants that are tumors can be encountered called Basosquamous in excision specimens. carcinoma may be • Both encountered in similar encountered in Mohs clinical situations and both • BerEP4 staining can be can appear pigmented. usefulNot in distinguishing 2 • Vastly differing treatment • Background SCCIS not recommendations uncommonly seen in the background of BCC Do 65 66

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Trichilemmoma Trichoepithelioma

Solitary or multiples flesh colored • Solitary or multiple nodules papule on face of older adult • asymptomatic, slowly growing nodule on the face or neck of Associated with PTEN young adults mutation(cowden’s disease) • Associated with Brooke spiegler, Lobular basaloid proliferation of Rombo and Multiple familial cells with glycogenation of trichoepithelioma syndromes cytoplasm and accentuation of • Often have continuity with basilar cells. epidermis, numerous horn cysts with lobules of basaloid cells with both conventional and peripheral palisade. desmoplastic varieties can be seen • Papilary mesanchemal bodies Desmoplastic varieties have often seen. increased incidence of concurrent • Both conventional and BCCs in some studes. desmoplastic varieties can been seen

67 68 Duplicate Adnexal Neoplasms Primary cutaneous lesions with histologic overlap and metastases. • Cylindroma /Eccrine spiradenoma or • Both benign basaloid tumors most often • Endocrine mucin-producing sweat associated with CYLD mutations and brooke- gland carcinoma/primary mucinous spiegler syndrome. carcinoma • Scalp of adults • Most often face of older women • Basaloid cells surrounded by thick BM • Papillary growth pattern with mucin • Poroma/ dermal duct tumor production and neuroendocrine features • Benign basaloid tumor of probable eccrine origin. • Adenoid cystic carcinoma • Polygonal cells with occasional ducts without • Both primary cutaneous and breast/salivary palisade or clefting • Locally aggressive with propensity for PNI • Benign but malignant lesions can occur. • Cribiform/ tubular morphology with mucin • Trichofolliculoma in cysts • Nodule with multiple fine hairs protruding • Metastatic lesions for elsewhere on • Hamartomatous lesion that recapitulates hair the skin or deep soft tissue follicle • Surrounding dermal fibrosis • Fibrous histiocytoma varients • Microcystic adnexal carcinoma • Sclerosing sweat gland carcinoma of head and neck that is very locally aggressive. • Often has PNI. 69 70

Site Specific NeoplasmsDistributeIn summation

• Canalicular Adenoma • BCC is best classified by architecture, not cytology or • One of the most common benign salivary gland tumors of the upper lip. differentiation patterns • Demonstrate 2 layers of ribboned columnar cells in a pseudopallasade without clefting • The architecture has a specific pathophysiologic basis and is reproducible Not • Management depends upon accurate subclassification • With the possibility of collision tumors and sampling errors, a Mohs surgeon should be able to distinguish BCC from its differential diagnosis. Do 71 72

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