Basal cell carcinoma characteristics as predictors ofdepth of invasion

Michael Jude Welsch, MD,a,b Blake M. Troiani, BS,c Lauren Hale, BS,a Joe DelTondo, DO,a

Klaus F. Helm, MD,a,b and Loren E. Clarke, MDa,b

Hershey, Pennsylvania, and Augusta, Georgia

From

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Background: Pretreatment risk stratification of basal cell carcinoma (BCC) is largely based on histologicsubtype reported from biopsy specimens.

Objective:We sought to determine the degree of concordance between characteristics identified on biopsyspecimen and excision and to determine if histologic characteristics other than subtype correlated withdepth of invasion.

Methods: Histologic specimens of 100 BCC biopsy specimens and corresponding excisions werereviewed. Anatomic site, histologic subtype, maximum depth of extension, contour of the lobules at theleading edge, elastosis characteristics, presence of necrosis, calcification, and ulceration were recorded.Concordance between biopsy specimens and their excisions with relation to depth of tumor lobules wasanalyzed.

Results: The concordance between the subtype of biopsy specimen and excision was 62%. Micronodulartumors had the greatest mean depth, followed by infiltrative, nodular, and superficial subtypes. Subtypereported from biopsy specimen (P = .0002) and excision (P\ .0001) correlated to depth and was superiorto age, contours of excision specimens, the presence of necrosis, and the extent of excisional solarelastosis. Gender, anatomic site, contours of biopsy specimens, elastosis color, elastosis type, the presenceof ulceration, and calcification did not correlate with depth.

Limitations: Selection bias is present as only standard excisions were included; BCCs treated by othermethods were not examined.

Conclusions: BCC subtype identified on biopsy specimen may not correlate with subtype identified onexcision. Morphologic subtype has the highest correlation with depth and reporting should reflect thehighest risk growth pattern if a biopsy specimen contains more than one pattern. Consideration should begiven to reporting necrosis and degree of solar elastosis. ( J Am Acad Dermatol 2012;67:47-53.)

Key words: basal cell carcinoma; biopsy; histologic features; invasion; solar elastosis; subtype.

Basal cell carcinoma (BCC) is the most com-mon malignancy among Caucasians. Thebiologic behavior varies, but many are locally

aggressive. BCCs have been stratified as low riskor high risk according to their propensity forrecurrence.1 Pretreatment assessment is important

the Departments of Pathologya and Dermatology,b Penn

ate Milton S. Hershey Medical Center, Hershey; and Medical

ollege of Georgia.c

orted by the Penn State Hershey Department of Pathology

search Initiation Grant Program.

licts of interest: None declared.

pted for publication February 18, 2011.

int requests: Michael Jude Welsch, MD, Department of

thology, H179, Penn State Milton S. Hershey Medical

because multiple treatment modalities are available.Risk factors considered include histologic subtype,horizontal diameter, anatomic location, and patienthealth status. The superficial and nodular subtypesare generally considered to be of lower risk forrecurrence, whereas infiltrative and micronodular

Center, 500 University Dr, PO Box 850, Hershey, PA 17033.

E-mail: mwelsch@hmc.psu.edu.

Published online April 16, 2012.

0190-9622/$36.00

� 2011 by the American Academy of Dermatology, Inc.

doi:10.1016/j.jaad.2011.02.035

47

J AM ACAD DERMATOL

JULY 201248 Welsch et al

subtypes are regarded as high risk. Clinically, lesionsin anatomically sensitive areas, such as the face, acralextremities, and genitalia, or lesions with large sur-face dimensions ([2 cm) are classified as high risk.2

Histopathologic diagnosis of BCC is usuallystraightforward, but the subclassification of lesionsis somewhat subjective. Identifying clinically use-

CAPSULE SUMMARY

d Factors that guide treatment of basal cellcarcinoma include histologic subtype.

d Nodular basal cell carcinomas extend tosimilar depths as micronodular andinfiltrative subtypes.

d Small biopsy specimens that report asuperficial and/or nodular subtype willshow a micronodular or infiltrativepattern in 26% of excisions.

d Adequate depth of biopsy specimenshould provide sufficient material foridentification of nonsuperficial subtypes.

ful information based onhistopathologic characteris-tics in biopsy specimens re-mains a subject of debate.In this study, we character-ized biopsy specimens andthe corresponding excisionsof BCC by histologic type,site, maximum depth of in-vasion, contour of tumor lob-ules at the leading (deep)edge, elastosis characteristics(color, extent, and depth),and the presence of necrosis,calcification, and ulceration.We analyzed the concor-dance of tumor characteristicsbetween biopsy specimens

and excisions and correlated those features withmaximum depth.

METHODSThis study was approved by the institutional

review board at the Penn State Hershey MedicalCenter in Hershey, PA. Archival materials of standardelliptical excisions of BCCs treated at our institutionfrom 2008 were selected. Only excisions for whichprior biopsy specimens were available for reviewwere included. Biopsy specimens and excisionswere fixed in formalin, embedded in paraffin, sec-tioned, and stained with hematoxylin and eosin. Allbiopsy specimens and excisions were reviewed andevaluated by the authors (L. E. C., M. J. W., andB. M. T.).

Tumor site was recorded from the original biopsyreport, and classified by the following anatomicregions: head and neck, trunk, lower extremity,and upper extremity. All biopsy specimens andexcisions were typed as superficial, nodular, micro-nodular, or infiltrative based on the predominanthistologic subtype ([50%). A second subtype wasnoted if present. Depth of the BCC was assessed inmillimeters by measuring the distance from thegranular layer of the epidermis to the deepest extentof dermal involvement by the tumor (depth wasrecorded in both the biopsy specimen and theexcisions from each case, with the greater of thetwo values considered the maximum depth).

Necrosis, ulceration, calcification, and solar elastosiswere considered present if they occurred in eitherthe biopsy specimen or the excision. When present,elastosis was graded by color (light, medium, or darkgray), type (A, B, C), and extent (superficial orgeneralized). Type A elastosis was defined as strandsof elastotic collagen intermingled among normal

collagen bundles. Type Bwas defined as small clumpsof elastotic collagen, andtype C as large, confluentclumps (Fig 1). Elastosis wasconsidered superficial if itwas confined to the dermisabove the superficial vascu-lar plexus and generalizedif it was present above andbelow the plexus (Fig 2).Tumor contour was definedas smooth/regular if the lead-ing edge of most lobules wasround and smooth, and ir-regular if the lobules wereangulated, jagged, or spiky(Fig 3). Spacing of tumor

lobules in excisions was measured in millimetersby recording the average distance between adjacentlobules.

Univariate statistical analysis was used to examinethe relationship between the maximum depth ofinvasion and every individual predictor. Multivariateanalysis was not used because of the high correla-tions between some predictors. For binary predic-tors, such as sex, biopsy specimen contours, and thepresence of necrosis, Student t test was used tocompare the depth between the two levels. All testsare two-sided. Welch-Satterthwaite t test for unequalvariances was used if applicable. Predictors withmore than two levels, such as biopsy specimen typeand locations, were analyzed by one-way analysis ofvariance. Age was treated as a continuous predictorand its effect was examined by simple linear regres-sion model. All statistical analyses were performedusing software (SAS 9.2, SAS Inc, Cary, NC).

Amultivariate analysis of covariancemodel was fitto examine the joint relationship between the re-sponse (the maximum depth of invasion) and mul-tiple predictors (eg, age, biopsy specimen type,contours of excision specimens, presence of necro-sis, and extent of solar elastosis). However, thismultivariate model became problematic because ofmulticolinearity, which means many of the predic-tors are highly associated with each other. Forexample, age is associated with biopsy specimentype (P = .0005, t test) and extent of solar elastosis

Fig 2. Superficial (A) and generalized (B) solar elastosis.

Fig 1. Solar elastosis with strands of elastotic collagenintermingled among normal collagen bundles (A); smallclumps of elastotic collagen (B); and large, confluentclumps of elastotic material (C).

Fig 3. Nodular basal cell carcinoma with smooth (A) andirregular (B) contours.

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VOLUME 67, NUMBER 1Welsch et al 49

(P = .0049, t test), and biopsy specimen type and thecontours of excision specimens are also associated(P = .0045, x2 test).

RESULTSDemographics

See Table I. In all, 100 patient biopsy specimensand excisions were reviewed that included 48women and 52 men with an age range from 36 to95 years (mean age 69 years). The age of the patientsignificantly correlated with depth (P = .0359). Inmen, lesions tended to be deeper (mean 1.45 mm)compared with women (mean 1.14 mm), but thedifference was not statistically significant.

SubtypeOn the 100 biopsy specimens, 59 were classified

as nodular, 23 as superficial, 13 as micronodular, and5 as infiltrative. The concordance between the sub-type diagnosed on the biopsy specimen and that ofthe excision specimen was 62%. Micronodular tu-mors had the greatest mean depth (2.01 mm),followed by infiltrative (1.82 mm), nodular (1.68mm), and superficial (0.71mm) types. In all, 44 of thebiopsy specimens included a secondary subtype.Subtype of the BCC reported from biopsy specimen

(P = .0002) and excision (P\.0001) was significantlycorrelated to depth.

Of the 82 lesions classified as superficial or nod-ular on the initial biopsy specimen, 21 (26%) werereclassified as micronodular or infiltrative type onreview of the subsequent excision specimen. In 8 ofthose 21 (38%), however, a micronodular or infiltra-tive component was also evident on the originalbiopsy specimen. When compared with lesions ofthe same subtype, the lesions that were reclassifiedon excision or contained micronodular or infiltrativesecondary subtypes did not differ significantly intheir depth.

SiteSuperficial and nodular lesions were found in all

anatomic sites studied (head and neck, trunk, upperextremity, lower extremity). None of the lesions on

Table I. Characteristic features of studied samples

Predictor n Mean 6 SD

P

value Significance

Gender .1458 NSF 48 1.35 6 1.00M 52 1.65 6 1.08

Age, y 100 69.36 6 12.52 .0359 SBiopsy specimen

morphologicsubtype

.0002 S

Infiltrative 5 1.82 6 0.70Micronodular 13 2.01 6 1.56Nodular 59 1.68 6 0.97Superficial 23 0.71 6 0.42

Anatomic site .1062 NSHead and neck 57 1.58 6 0.93Lowerextremity

8 0.73 6 0.41

Trunk 18 1.76 6 1.51Upperextremity

17 1.34 6 0.93

Biopsy specimencontours

.9922 NS

Irregular 61 1.51 6 0.76Superficial 39 1.50 6 1.40

Excision contours .0003 SIrregular 62 1.78 6 1.11Superficial 38 1.06 6 0.76

Excisionmorphologicsubtype

\.0001 S

Infiltrative 10 1.82 6 0.91Micronodular 23 1.51 6 0.91Nodular 39 1.98 6 1.19Superficial 28 0.72 6 0.31

Ulceration .7399 NSNot present 54 1.54 6 1.17Present 46 1.47 6 0.90

Necrosis .0022 SNot present 61 1.22 6 0.73Present 39 1.95 6 1.30

Elastosis color .6771 NSLight 12 1.27 6 1.41Medium 33 1.58 6 1.07Dark 53 1.54 6 0.97

Elastosis type .5028 NSA 47 1.41 6 0.99B 34 1.56 6 1.24C 17 1.75 6 0.77

Elastosis location .0335 SGeneralized 60 1.68 6 1.21Superficial 38 1.27 6 0.68

F, Female; M, male; NS, not significant; S, significant.

J AM ACAD DERMATOL

JULY 201250 Welsch et al

the lower extremity were infiltrative or micronodu-lar. Overall, the majority of all tumor occurred on thehead and neck (57%), followed by the trunk (18%),upper extremity (17%), and lower extremity (8%).

Superficial lesions were distributed relatively equallyamong sites: 6 were on the head and neck, 7 were onthe lower extremity, 4 were on the trunk, and 6 wereon the upper extremity. Nodular lesions were foundprimarily on the head and neck (39/59, 66%), withone on the lower extremity, 11 on the trunk, and 8 onthe upper extremity. Micronodular lesions occurredmostly on the head and neck (9/13, 69%), followedby two on the trunk and on the upper extremity.Three of 5 infiltrative lesions were found on the headand neck, whereas one was found on the trunk andon the upper extremity. Lesions on the lower ex-tremity were less deep than lesions of any other site(mean 0.73 mm). Among nodular lesions, thosefound on the trunk (11/59, 19%, mean 2.19 mm)were deeper than those found on the upper extrem-ity (8/59, 14%, mean 1.53 mm) and the head andneck (39/59, 66%, mean 1.57 mm). Anatomic loca-tion in general and among nodular lesions was notsignificantly correlated to depth.

ContoursOn the biopsy specimens, 61 had irregular con-

tours and 39 had smooth contours. On excisions, 62lesions had irregular contours and 38 had smoothcontours. In all, 73% of lesions demonstrated thesame contour on biopsy specimen and excision,representing a greater concordance than tumor sub-type. Shape of lobule contour of the leading edge onbiopsy specimens did not correlate with depth(mean values: smooth 1.50 mm, irregular 1.51 mm);however, tumor contour on excision specimenscorrelated with depth significantly (mean values:smooth 1.06 mm, irregular 1.78 mm; P = .0003). Ofthe 39 tumors with smooth contours within thebiopsy specimen, 14 had irregular contours onexcision (36%). The depth of the lesions with con-tours identified as smooth on biopsy specimen andthen as irregular on subsequent excision was signif-icantly greater than the depth of lesions with smoothcontours identified also on excision (P = .0082). Fourof those 14 (29%) had a micronodular or infiltrativeprimary or secondary growth pattern. Seven of the 14(50%) had a superficial or nodular pattern on boththe biopsy specimen and excision. Three of the 14(21%) had a superficial or nodular phenotype onbiopsy specimen, whereas the excision revealed amicronodular or infiltrative growth pattern.

NecrosisNecrosis was observed in all 4 tumor subtypes.

Four of the 5 infiltrative (80%), 8 of 13 micronodular(62%), 34 of the 59 nodular (58%), and 18 of the 23superficial lesions (78%) exhibited necrosis. Tumorswithout necrosis were significantly deeper than

J AM ACAD DERMATOL

VOLUME 67, NUMBER 1Welsch et al 51

those containing necrosis (mean values 1.95 mm and1.22 mm, respectively; P = .0022).

Solar elastosisAll but two tumors were accompanied by solar

elastosis; both of these were of the superficial type.The severity of solar elastosis as defined by all criteriacorrelated with increasing age (color [mean values:light 62.42, medium 68.85, dark 71.87]; type [meanvalues: A-67.87, B-69.71, C-74.71]; location [meanvalues: superficial 65.55, generalized 72.32]). Solarelastosis color was not significantly predictive ofdepth (mean values: light 1.27 mm, medium 1.58mm, dark 1.54 mm), nor was type of solar elastosis(mean values: A-1.41, B-1.56, C-1.75). Extent of thesolar elastosis, however, did significantly correlatewith maximum tumor depth (mean values: superfi-cial 1.27 mm, generalized 1.68 mm; P = .0335).Generalized solar elastosis was seen in the majorityof all subtypes: superficial (57%), nodular (61%),micronodular (69%), and infiltrative (60%).

Calcification and ulcerationSeven lesions had identifiable calcification on

either the biopsy specimen or the excision specimen.The presence of calcification did not correlate withdepth. Ulcerated lesions had a mean depth of 1.47mm, which did not statistically differ from the meandepth of 1.54 mm for lesions without ulceration.

DISCUSSIONBCC is a common cutaneous malignancy seen

every day in clinical dermatology and dermatopa-thology services. Clinically, classic BCCs present aspink papules with rolled borders and telangiectases.Aggressive tumors tend to be larger, ulcerated,locally destructive, and/or scarlike. Many treatmentmodalities are available, including destructive, top-ical, noninvasive, intralesional, surgical excision, or acombination of methods.3,4 Selection among themyriad of treatment options depends on the assess-ment of tumor risk based on clinical and histopath-ologic features of the tumor; therefore, basing thatassessment on features that accurately predict riskremains essential.

The goals of treatment are the eradication of theneoplasm with a minimal destruction to the sur-rounding tissue and the preservation of function andappearance. Definitive therapeutic surgical marginsare 2 to 3 mm when clinical borders of BCC aredistinct and 5 mm otherwise in 92% of cases.5

Although the cure rates for destructive techniquescompare favorably with those of standard ellipticalexcisions, they may lead to inferior cosmetic out-comes.6 Tumors on the face and those with

multifocal and/or infiltrative microscopic featureshave been associated with significant rates of incom-plete excision.7 Micronodular BCCs have beenshown to require more micrographic surgical stagesand greater width and depth of excision to achievecomplete clearance when compared with nodularBCCs.8

Ideally, classification of tumors should correlatewith biologic behavior. Various methods for classify-ing BCC based on clinical appearance, histopatho-logic subtype, degree of differentiation, and anatomiclocation have been reported.9,10 Classification basedon histopathologic subtype is the most widely ac-ceptedmodel.11 In this model, growth pattern is usedto stratify tumors with regard to propensity forextension, local recurrence, or aggressive local inva-sion. Althoughmany types andmixed types exist, the4 growth patterns widely recognized as prognosti-cally significant are superficial, nodular, micronodu-lar, and infiltrative.12 Superficial andnodularBCCs areregarded as low-risk lesions, whereas micronodularand infiltrative types are considered high risk.13 Thisstudy followed thatparadigm.Ahistologic continuumfrom low to high risk based on diminishing hostresponse and gain of permissive tissue environmenthas been proposed.14

Determining histologic type from biopsy speci-mens can present a challenge to pathologists. Overtime, the size of biopsy specimens has decreased,15

and although the rate of diagnosis of BCC hasremained consistent, the concordance between thetype as determined from a biopsy specimen and anexcision is reported at 80%.16 In addition, it has beenreported that 75% of tumors contained areas dem-onstrating more than one histologic type.17 Ourstudy showed a concordance rate of only 62%between subtype identified on biopsy specimensand the subsequent excisions, with 44% of thosebiopsy specimens containing a secondary subtype(eg, nodular type with a secondary micronodularcomponent).

Histopathologic characteristics in excisions havebeen studied previously with conflicting results(Table II). In the study by Dixon et al,18 age, distanceto resection margins, contour of invading edge,shape of cell groups, growth pattern, degree ofperipheral palisading, and nuclear pleomorphismcorrelated with tumor recurrence, whereas depth ofinvasion, degree of inflammation, actinic change,tumor necrosis, nuclear hyperchromasia, nucleoli,mitoses, amount of melanin, amount of amyloid, andsize of cell groups did not. In a study of excisionalspecimens of nodular, infiltrative, morpheic, andmicronodular subtypes, Takenouchi et al19 reportedthat gender, horizontal diameter, and subtype were

Table

II.Histopathologiccharacteristicsofcurrentstudycomparedwithpreviousstudies

Study

Specim

ens

No.ofcases

Measu

reAge

Gender

Subtype

Anatomic

site

Contour

Ulceration

Stroma

Elastosis

Calcification

Jacobsetal13

Excisions

56

Invasiveness

NC

NC

CX

CX

NC

NC

XDixonetal18

Excisions

104

Recurrence

NC

XC

CC

XX

NC

XTakenouchietal19

Excisions

236

Depth

NC

CC

NC

XNC

XX

XSlodko

wskaetal20

Excisions

86

Calcification

NC

NC

CNC

XNC

XC

eCurrentstudy

Excisionsan

dbiopsy

specimens

100

Depth

CNC

CNC

CNC

XC

NC

C,Correlation;NC,nocorrelation;X,notstudied.

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JULY 201252 Welsch et al

predictive of maximum tumor depth, whereas age,anatomic location, duration, and ulceration werenot. The study by Slodkowska et al20 indicated thattumor calcification was more common in infiltrativethan nodular BCCs. Chin et al21 compared vascularpatterns in nodular and morpheaform BCCs, butfound no significant difference. Infiltrative BCCshave long been recognized for their indistinct clinicalborders, tendency for recurrence and loss of pali-sading, hyalinization of the stroma, and irregular‘‘spiky’’ appearance on microscopic examination.13

The amount of elastotic material has been shown byMoon and Oh22 to be quantitatively increased in skincancers compared with sun-exposed skin of healthycontrol subjects.

Immunohistochemical and advanced clinicaltechniques (optical coherence tomography23) maypredict BCC depth and invasiveness, but may not bepractical for everyday use. Gene expression patternsof the mitogen-activated protein kinase pathwaysmay account for phenotypic differences amongthe superficial, nodular, and morpheic types.24

Increased Ki-67 antigen expression was seen inBCCs that later recurred compared with nonrecur-rent tumors, whereas p53 protein expression re-mained similar.25 CD44 expression has been shownto be increased within narrow strands of tumorcells,26 and increased CD44v6 and loss of palisadingwas correlated with greater depth of invasion.27

Our study specifically addressed the relationshipof age, gender, growth pattern (subtype), anatomicsite, contours of the leading edge, solar elastosis,necrosis, calcification, and ulceration to the depth ofBCC. Although age was significantly correlated withdepth, gender was not. The majority of tumors (59%)were of the nodular type, whereas the infiltrativesubtype was least common, accounting for only 5%.In general, BCC subtype correlated significantly withdepth whether ascertained from biopsy or excisionspecimens. As expected, superficial type BCCs had alower maximum depth of invasion as compared withthe remaining 3 subtypes. In contrast to the widelyheld perception that micronodular BCCs are associ-ated with a more aggressive course, our data suggestthat the nodular pattern correlates with greaterdepth. When a secondary component of micronod-ular or infiltrative pattern was present with a super-ficial or nodular primary subtype, tumors were notsignificantly deeper than those similarly classifiedbut without a secondary component. Furthermore,tumors classified as superficial or nodular on biopsyspecimen that were then classified as micronodularor infiltrative on excision did not have significantlydifferent depths from superficial or nodular tumorswith concordant growth patterns on excision.

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VOLUME 67, NUMBER 1Welsch et al 53

Although BCCs located on the lower extremity wereless deep than those located anywhere else, ana-tomic site did not significantly correlate with depth.Although contour of the leading edge did not predictdepth when evaluated on biopsy specimens, it didcorrelate with greater depth when evaluated onexcisions. When lesions found to have smoothcontours on biopsy specimen were subsequentlyfound to have irregular contours on excision, theirdepth was significantly greater than lesions withsmooth contours on both biopsy specimen andexcisions. Lesions containing necrosis were foundto be significantly less deep than lesions withoutnecrosis. Although the color and type of solar elas-tosis was not predictive of depth, lesions with gen-eralized solar elastosis were significantly deeper thanlesions with superficial solar elastosis. Neither thepresence of calcification nor the presence of ulcer-ation was found to significantly predict BCC depth.

Although biopsy specimen subtype may notcorrelate with the subtype identified on excision,tumors classified as superficial or nodular on biopsyspecimen that were then classified as micronodularor infiltrative on excision did not have significantlydifferent depths from superficial or nodular tumorswith concordant growth patterns on excision.Micronodular tumors had the greatest mean depth(2.01 mm), followed by infiltrative (1.82 mm), nod-ular (1.68 mm), and superficial (0.71 mm) subtypes.Biopsy reporting of BCC should reflect the highestrisk growth pattern if a biopsy specimen containsmore than one pattern. Although age, elastosislocation, and necrosis may be clues to the depth oftumor infiltration, morphologic subtype has thehighest correlation with depth.

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