Barr Scc Final

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CUTANEOUS SQUAMOUSCUTANEOUS SQUAMOUSCELL CARCINOMA: ACELL CARCINOMA: A

COMPREHENSIVECOMPREHENSIVECLINICOPATHOLOGICCLINICOPATHOLOGICCLASSIFICATIONCLASSIFICATION

DISCLOSUREDISCLOSURE

NO CONFLICT OF INTERESTNO CONFLICT OF INTEREST

NO FINANCIAL OR OTHERNO FINANCIAL OR OTHERRELATIONSHIP WITH ANYRELATIONSHIP WITH ANYPHARMACEUTICAL OR MEDICALPHARMACEUTICAL OR MEDICALDEVICE COMPANYDEVICE COMPANY

ACKNOWLEDGMENTSACKNOWLEDGMENTS

DAVIDDAVIDCASSARINO,M.D.Ph.D,ASSISTANTCASSARINO,M.D.Ph.D,ASSISTANTPROFESSOR, PATHOLOGY ANDPROFESSOR, PATHOLOGY ANDDERMATOLOGY,UNIVERSITY OFDERMATOLOGY,UNIVERSITY OFCALIFORNIA LOS ANGELESCALIFORNIA LOS ANGELES

ACKNOWLEDGMENTACKNOWLEDGMENT

Cassarino,D.SCassarino,D.S.,., DeRienzo,D.PDeRienzo,D.P.,., andandBarr,R.J.:Barr,R.J.:

CutaneousCutaneous SquamousSquamous Cell Carcinoma: ACell Carcinoma: A

ComprehensiveComprehensive ClinicopathologicClinicopathologic ClassifiClassifi--

cationcation..J.Cutan.PatholJ.Cutan.Pathol. 2006, Part 1;33:191. 2006, Part 1;33:191--

206.Part 2;33:261206.Part 2;33:261--279.279.

I. INTRODUCTION

- Most clinicians and pathologists do notadequately subtype invasive SCC, despite varyingaggressiveness (akin to superficial vs. infiltrative

and miconod BCC)- Distinct histologic subtypes of SCC exist, mostare well-accepted, but their malignant potential isoften not well-recognized or controversial

- Other parameters clearly influence biologicalbehavior, including tumor size, depth ofinvasion, degree of differentiation, perineuralinvasion, and host immunological status

BACKGROUND:

- Previous classifications not comprehensive, andnot based on malignant potential, although mostauthors comment on variants with moreaggressive behavior

- Ackerman initially proposed categorizing allSCCs as one entity with many faces, where hedescribed SCC arising from solar keratoses andcarcinoma in situ, as well as keratotic,pseudoglandular (adenoid), pale-cell (clear cell),necrotizing, verrucous, spindle cell, andkeratoacanthoma (KA)-like variants of SCC

ot subdivided based on mali nant otential


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- We divide invasive SCC into categories of low,intermediate, and high risk based upon rates of

recurrence and metastasis

Risk of metastasis

II. SUBTYPES OF SCCII. SUBTYPES OF SCC

Low (10%)

SCC arising inAK, HPV-related SCC,TLC, spindlecell CA

AcantholyticSCC, LELCS,invasive IEE

Desmoplastic SCC,Invasive Bowens,AdenosquamousCA, de novo SCC,radx & scar-assoc

A. LOW RISK INVASIVESCCs

Most SCCs are relatively indolent, vast majorityarise within AKs in sun-damaged skin of elderly,other low grade variants include:

- Verrucous carcinoma, other HPV-relatedSCCs, spindle cell SCC (unassociated withradiation), and tricholemmal carcinoma(TLC)

1. SCC ARISING IN AKs

Accounts for the vast majority of invasive SCC

- up to 95% of invasive SCC assoc w/AKs

- rate of AKs leading to invasive SCC estimatedat 0.2 - 10% per year

These tumors are often superficially invasive,well-differentiated, and cured by excision

Invasive SCC arising in AK only rarelymetastasizes, estimated risk 1%

2. SCC ASSOCIATED WITH HPV2. SCC ASSOCIATED WITH HPVINFECTIONINFECTION

VERRUCOUS CARCINOMAClinical:

Indolent, slow-growing tumors with exophytic

appearanceSeveral variants described, including:

- Oral (oral florid papillomatosis), anogenital(Buschke- Lowenstein tumor) or plantar (epitheliomacuniculatum), Epidermodysplasia verruciformis

(EDV) genetic (AR), sporadic and HIV-related forms

HPV association:

- VC: HPV 6 & 11 mostly, some 16 & 18

Histology: Verrucous carcinoma (all variants): proliferation of

enlarged, bland eosinophilic keratinocytes withbulbous downgrowths and pushing invasion

EDV: epidermal acanthosis with enlarged, mildlyatypical, bluish-gray keratinocytes, some perinuclearhalos


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VERRUCOUS CARCINOMA

Prognosis:

Low-grade tumors with very rare metastases(less than 2%)

So-called warty carcinomas are different andmore aggressive

Radiation therapy not recommended, asreported to lead to dedifferentiation to high gradeSCC

- Virtually all metastatic cases had beenirradiated

3. SPINDLE CELL SQUAMOUSCELL CARCINOMA

Clinical:

- Uncommon variant of SCC, usually arising insun-damaged skin, head and neck; moreaggressive tumors a/w/radiation or scars (highrisk SCC)

Histology:

- Usually large, dermal-based tumors composedof proliferation of poorly-differentiated, oval toelongated spindle cells; may see overlyingepidermal atypia or connections to invasive


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IPOX:

HMWCK (CK5/6 or 34BE12) or p63 to

distinguish from AFX, spindle cell melanoma,

leiomyosarcomaPrognosis for spindle cell and sarcomatoid(metatypical) SCC:

Most cases are actinic related, superficial and

have low risk of metastasis (analogous toAFX).

However, some cases may be more aggressive,

especially arising in scars or post-radiation

4. TRICHOLEMMALCARCINOMA

Clinical:

- Only rare cases reported, usu. sun-exposed skinof elderly patients, usually rapidly growingkeratotic papule/nodule, may be ulcerated

- Clinical dx usu. BCC or SCC

- No assoc w/Cowdens syndrome

Prognosis:

- Excellent, rare recurrences, no clearlydocumented metastases (unlike clear cell SCC)

Histology:

- Multilobular, infiltrative proliferation ofatypical, pale keratinocytes with peripheralpallisading and hyalinized BM, keratohyalinegranules; shows a high mitotic rate

- Pagetoid spread may be present

- Diffnt dx: desmo tricholemmoma, clear cellSCC, clear cell BCC, less likely: clear cellhidradenoma and metastatic RCC


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B. INTERMEDIATE RISK SCCs

These are less common tumors, and theirmalignant potential is more controversial, may

reflect the lack of large studies and reporting bias:- Acantholytic SCC, lymphoepithelioma-likecarcinoma of the skin (LELCS), intraepidermalepithelioma (IEE)/Borst-Jadassohn tumor withinvasion

1. ACANTHOLYTIC1. ACANTHOLYTIC(ADENOID) SCC(ADENOID) SCC

Clinical:

- Sun-exposed skin of elderly, male > female- Nonspecific presentation, usually nodular,pink/red lesion, often clinical dx is BCC, SCC,

or KA

Prognosis:

- Tumor of reported intermediate risk based onmetastatic rate, wide range reported (3 19%),likely the lower end of range

2. LYMPHOEPITHELIOMA2. LYMPHOEPITHELIOMA--LIKELIKECARCINOMA (LELCS)CARCINOMA (LELCS)

Clinical:

- Rare tumor, usually elderly on head and neck,sun-damaged skin

- Not EBV-related (as are nasopharyngealLELC)

- Differential diagnosis: rare :LCNEC with LH

Prognosis:

- Initially thought to be aggressive, but so faronly 2 metastases and 1 documented death fromthis tumor out of 40 cases

Histology: large epithelioid cells intermixed withlymphocytes and plasma cells


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3. INTRAEPIDERMAL EPITHELIOMA3. INTRAEPIDERMAL EPITHELIOMA(IEE)/JADASSOHN TUMOR WITH(IEE)/JADASSOHN TUMOR WITH

INVASIONINVASION

Controversial whether IEE is a true entity or not,Controversial whether IEE is a true entity or not,many may represent clonal SKs,many may represent clonal SKs,hidroacanthoma simplex, or clonal Bowenhidroacanthoma simplex, or clonal Bowenss

However, invasive tumors arising in these lesionsHowever, invasive tumors arising in these lesionsappear to be SCC, and have been reported to beappear to be SCC, and have been reported to bemore aggressive lesions (6more aggressive lesions (6 10% mets)10% mets)

Clinical:Clinical:

Few series, but most described as plaques withFew series, but most described as plaques withflat or verrucoid featuresflat or verrucoid features

C. HIGH RISK SCCsC. HIGH RISK SCCs

Similar to intermediate group, many of these areSimilar to intermediate group, many of these arerare tumors with few large studies to determinerare tumors with few large studies to determinemalignant potential:malignant potential:

-- Invasive BowenInvasive Bowens disease, desmoplastic SCC,s disease, desmoplastic SCC,malignant proliferating pilar tumormalignant proliferating pilar tumor

(PPT)/cyst,(PPT)/cyst, de novo SCC, adenosquamousde novo SCC, adenosquamouscell carcinoma,cell carcinoma, and SCC arising in associationand SCC arising in associationwith radiation,with radiation, burn scars, chronic conditionsburn scars, chronic conditionsandand immunosuppressionimmunosuppression

1. BOWEN1. BOWENS DISEASE WITHS DISEASE WITHINVASIONINVASION

Clinical:Clinical:

-- Often not wellOften not well--recognized clinically due to nonrecognized clinically due to non--specific features, but usually rapidly growing,specific features, but usually rapidly growing,

ulcerated tumor occurring in a scaly orulcerated tumor occurring in a scaly orerythematous patcherythematous patch

Prognosis:Prognosis:

-- 55 -- 8% of Bowen8% of Bowens disease may become invasive,s disease may become invasive,and up to 13%and up to 13% -- 20% of those patients develop20% of those patients developmetastases (higher in blacks)metastases (higher in blacks)

-- Putative assoc w/internal malignanciesPutative assoc w/internal malignancies

Histology:Histology:

-- Classic BowenClassic Bowens disease overlying an invasives disease overlying an invasivetumor composed of islands of squamoid totumor composed of islands of squamoid tobasaloid cells, often with central areas ofbasaloid cells, often with central areas ofnecrosisnecrosis

-- May show adnexal differentiation (eccrine,May show adnexal differentiation (eccrine,apocrine, or sebaceous)apocrine, or sebaceous)


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2. DESMOPLASTIC SCC2. DESMOPLASTIC SCC

Clinical:Clinical:

-- Aggressive variant, often on sunAggressive variant, often on sun--damageddamaged

skin, ears, cheeks, and nose, of elderly malesskin, ears, cheeks, and nose, of elderly malesPrognosis:Prognosis:

-- High rates of recurrence and metastasis (22High rates of recurrence and metastasis (22 77%, later reported on lip)77%, later reported on lip)


-- Cords and trabeculae of oval to spindledCords and trabeculae of oval to spindledsquamoid cells infiltrating a dense,squamoid cells infiltrating a dense,desmoplastic stroma (> 30% stroma), frequentdesmoplastic stroma (> 30% stroma), frequentkeratinization and perineural invasionkeratinization and perineural invasion

..PROLIFERATING PILARPROLIFERATING PILAR

TUMOR (PPT)/CYST, or SCCTUMOR (PPT)/CYST, or SCCARISING IN PPTARISING IN PPT

Clinical:Clinical:

-- Rare, usually scalp tumors, older adults,Rare, usually scalp tumors, older adults,

present as multinodular cystic masses, maypresent as multinodular cystic masses, mayulcerateulcerate

Prognosis:Prognosis:

-- PPTsPPTs are benign tumors with recurrentare benign tumors with recurrentpotential; malignantpotential; malignant PPTsPPTs/SCC arising in PPT/SCC arising in PPTare highly aggressive, frequently metastaticare highly aggressive, frequently metastaticcarcinomas (up to 30% metastases)carcinomas (up to 30% metastases)


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-- PPT: wellPPT: well--circumscribed dermal tumorcircumscribed dermal tumor

consisting of multiple haphazard,consisting of multiple haphazard,

interconnecting cystic lobules lined by ainterconnecting cystic lobules lined by astratified squamous epithelium exhibitingstratified squamous epithelium exhibiting

tricholemmal keratinization, and cystic spacestricholemmal keratinization, and cystic spaces

filled with keratin and debrisfilled with keratin and debris

-- Malignant PPT/SCC arising in PPT: areas ofMalignant PPT/SCC arising in PPT: areas of

severe cytological atypia, abundant mitoses, andsevere cytological atypia, abundant mitoses, and

stromal invasion are required for diagnosisstromal invasion are required for diagnosis

4. DE NOVO SCC4. DE NOVO SCC

Clinical:

- Poorly recognized, uncommon variant,presents on either sun damaged or protectedskin as nodule or indurated, erythematous area

with crusting, ulceration

Prognosis:

- 8-14% incidence of regional or distantmetastases

Histology:

- Infiltrative, dermal-based tumor with noe idermal or adnexal connections

5. ADENOSQUAMOUS5. ADENOSQUAMOUSCARCINOMACARCINOMA

Clinical:Clinical:

-- Rare but highly aggressive tumors, elderlyRare but highly aggressive tumors, elderlypatients, head and neck and genitaliapatients, head and neck and genitalia

Prognosis:Prognosis:-- Frequent recurrences and metastases leading toFrequent recurrences and metastases leading totumortumor--related death (up to 50%)related death (up to 50%)


-- Nests and lobules of squamous cells withNests and lobules of squamous cells withkeratocyts, foci of glandular diffkeratocyts, foci of glandular diffnt lined bynt lined bycuboidal to columnar cells with secretionscuboidal to columnar cells with secretions(mucin & CEA+)(mucin & CEA+)


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CEA+CEA+

6. SCC 2 TO CHRONICCONDITIONS & RADIATIONSCC develops more frequently in chronicallySCC develops more frequently in chronicallyinjured or immunosuppressed skin, including:injured or immunosuppressed skin, including:

-- Long standing ulcers, burns, sinus tracts,Long standing ulcers, burns, sinus tracts,organorgan transplant patientstransplant patients

Also, skin affected by chronic inflammatoryAlso, skin affected by chronic inflammatorydisorders such as:disorders such as:

-- Discoid lupus (DLE), lichen sclerosis, lichenDiscoid lupus (DLE), lichen sclerosis, lichenplanus, dystrophic EB, and lupus vulgarisplanus, dystrophic EB, and lupus vulgaris

These are aggressive tumors, with higher rates ofThese are aggressive tumors, with higher rates ofinvasion, recurrence, and metastatic potentialinvasion, recurrence, and metastatic potential

1. Burn scar SCC (Marjolins ulcer):

- predominance (3:1), LEs, latency period 4mos (acute) to 35 yrs (chronic), high metastaticrate (36 - 52%)

2. SCC arising in lupus (DLE):

- rare, more common in African-Americans,high metastatic rate (31%)

3. Radiation-induced SCC:

- increases risk of SCC by 3X, earlier age leadsto greater risk, tumors are aggressive andfrequently metastatic

- any histologic subtype, but spindle cell

common4. Immunosuppression-related SCC:

- cancer, HIV+, transplant, increased risk forSCC on sun-exposed sites (> BCC), risk relatedto degree and duration of immunosuppression


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C. SCC OF INDETERMINATEC. SCC OF INDETERMINATEMALIGNANT POTENTIALMALIGNANT POTENTIAL

Rare tumors which have only been the subject of

very few studies with small number of cases,therefore, their malignant potential is unclear:

- Signet ring and clear cell SCC, pigmented

SCC, papillary SCC, follicular SCC, SCC

arising in adnexal cysts;

- keratoacanthoma??

III. ADDITIONAL PROGNOSTICFACTORS IN CUTANEOUS SCC

- Despite the generally good prognosis ofcutaneous SCC, the behavior of metastatic SCC isvery poor, with less than 35% of patients survivingfor 5 years- The metastatic potential of SCC is clearly relatedto depth of tumor invasion:

< 2 mm in thickness never metastasized2 - 6 mm metastasized at rate of 4.5%

> 6 mm metastasized at rate of 15%(Breuninger et al., Microstaging of squamous cell carcinoma, Am J

Grade of differentiation has also been shown tobe of prognostic significance:

- Rowe et al. showed that poorly differentiatedSCC (Broders grades III-IV) has a much higherrate of metastasis than well and moderately-differentiated (grades I-II) (33% versus 9%, res.)

Also, perineural invasion is clearly an adverseprognostic finding, which portends higher rates

of recurrence and metastasis (up to 47% and 35-80%, res.)

ADDITIONAL PROGNOSTICFACTORS

IV. CONCLUSIONSIV. CONCLUSIONS

- Cutaneous SCC includes multiple subtypes ofvarying malignant potential

- It is recommended that the following features be

reported in routine pathology reports:1. Histologic subtype

2. Degree of differentiation (well, mod, orpoorly)

3. Approximate depth of invasion

4. Perineural invasion

5. Hematolymphatic invasion

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