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Differentiating Squamous CellCarcinoma from KeratoacanthomaUsing Histopathological CriteriaIs It Possible? A Study of 296 Cases

Bernard Cribier Pierre-Henri Asch Edouard Grosshans

Laboratoire d’Histopathologie Cutanée, Clinique Dermatologique des Hôpitaux Universitaires de Strasbourg,France

B. CribierClinique Dermatologique1, place de l’HôpitalF–67091 Strasbourg Cedex (France)Fax +33 03 88 11 60 40

Key WordsKeratoacanthoma • Squamous cell carcinoma •

Histopathological criteria • Differential diagnosis

AbstractBackground: Squamous cell carcinoma (SCC) and kera-toacanthoma (KA) are sometimes difficult to distinguishby histopathological examination, since cytological fea-tures are similar in both tumors. Distinctive criteria –mainly architectural – have therefore been proposed asan aid in diagnosis. Objective: The purpose of this studywas to evaluate the reliability of some of the criteria usedto make a distinction between SCC and KA. Methods:296 fully excised tumors previously classified as SCCor KA were randomized and examined independentlyby two examiners. Fourteen criteria, mainly based onthe architecture of the tumors, were determined on the262 slides for which a consensual diagnosis was made.Results: No single criterion was sufficiently sensitiveand specific to allow a clear-cut differential diagnosis.The 5 most relevant criteria were epithelial lip, sharp out-line between tumor and stroma in favor of KA and ulcer-ation, numerous mitoses and marked pleomorphism/anaplasia in favor of SCC. Intraepithelial polymorphonu-clear abscesses, intraepithelial elastic fibers, parakerato-sis and dyskeratosis and extension more lateral than

downward were not distinctive criteria, although theyare considered as classic distinctive features. Conclu-sion: Many of the criteria commonly used for the dif-ferential diagnosis of SCC and KA are not reliable. Thecombination of the 5 most useful criteria does not signif-icantly increase the specificity or sensitivity of the histo-logical diagnosis in difficult cases. Atypical or difficultcases should therefore be considered and treated asSCC, since a clear-cut distinction is not possible evenwith the aid of the most relevant criteria.

The distinction between squamous cell carcinoma (SCC)and keratoacanthoma (KA) has been a matter of discussionsince the first descriptions of KA [1]. All textbooks of der-matopathology propose distinctive criteria that may allowthe differential diagnosis between these two closely relatedtumors [2–5]. Nevertheless, there are atypical KA that aredifficult to distinguish from SCC. Hodak et al. [6] suggestedthat KA is actually an SCC, since they have observed truemalignant KAs with metastases. This opinion is not gener-ally admitted, and many authors still believe that the twoentities must be distinguished; otherwise there will be manyfuture reports on ‘series of self-healing crateriform squa-mous cell carcinomas’ [7]. KA is considered to be a variantof SCC by certain authors [8] or to belong to a spectrum of

Clinical and Laboratory Investigations

Dermatology 1999;199:208–212 Received: May 20, 1999Accepted: July 2, 1999

neoplastic processes that comprise warts at one end andSCC at the other end [9]. Grant-Kels [10] stated that ‘kera-toacanthoma highlights the limitations of light microscopy’.Therefore, there have been many attempts to find newertechniques that may help to distinguish the behavior of theselesions [10]. Many works were published, comparing theexpression of various markers in small series of SCC andKA, i.e. expression of p53 [11–13], Ki67 [14], TGF-α [15]or lectin peanut receptors [16–18]. DNA image cytometry[19] or flow cytometry [20, 21] was also proposed to dif-ferentiate the two tumors. We have recently shown thatstromelysin 3 expression is more intense in SCC than in KAand could be a marker of the biological behavior, sincestaining was even stronger in those cases of SCC which ledto metastasis [22].

Until now, none of these techniques allowed a reliabledifferential diagnosis in 100% of cases. There were indeter-minate results in all studies, because of considerable overlapbetween the results obtained in KA and SCC. Standardhistopathological examination remains the gold standard forthe distinction of SCC and KA, since all samples included inthe latter studies were selected using histopathological fea-tures. It is interesting to note that the histological inclusioncriteria are often not mentioned in many of these studies.There are only a few works in which the validity of the cri-teria commonly used for differentiating SCC from KA wasevaluated [23, 24].

In the present study, we have analyzed a large series ofSCC and KA to determine the reliability of common histo-pathological criteria that have been proposed as distinctivemarkers of SCC or KA.

Material and Methods

We selected 400 slides from the Laboratory of Skin Histopathologyof Strasbourg, diagnosed as SCC (n = 200) or KA (n = 200). Thesesamples originated from patients living in Strasbourg, France and inthe surrounding area. The cutaneous samples were fixed in Bouin’ssolution, paraffin embedded and stained with hematoxylin, eosin andsafran. The slides were first examined by one of us (P.H.A.) who elim-inated small biopsies and incomplete excisions. At the end of the selec-tion, the stroma beneath and beside the tumor was fully visible in the296 remaining samples (originating from 296 different patients).

The slides were then randomized and examined independently bytwo of us (E.G. and B.C.), without any information on clinical diagno-sis, evolution of the tumor or first histopathological diagnosis. Whenthe same diagnosis of straightforward SCC or KA could be made inde-pendently by the two examiners, the slides were selected for the studyof criteria.

The following criteria were then determined in all samples(answer: presence/absence): rounded shape (arciform disposition) ofthe lower part of the tumor [25]; sharp outline between the stroma andthe proliferating epithelium; central crater filled with keratin [1, 26];presence of at least one epithelial ‘lip’ at the lateral part of the tumor[26[; clear-cut demarcation between normal epidermis and tumoralcells laterally [E. Grosshans, pers. commun.]; intraepithelial elasticfibers (visible with standard staining) [27–30]; intraepithelial poly-morphonuclear abscesses [5]; ulceration [5]; extension more lateralthan downward [24]; extension beyond sweat glands [4]; marked pleo-morphism or anaplasia [22]; parakeratosis; dyskeratosis [23]; morethan 2 mitoses per high-power field (×40) [23, 24, 30].

The sensitivity (100% – the rate of false-negative results) andspecificity (100% – the rate of false-positive results) of each criterionwere analyzed according to the final diagnosis.

We then tried to combine the most reliable criteria that could beused in practice for the distinction of KA and SCC.

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Table 1. Determination of simplehistopathological features in 262 tumorsreadily classified as KA and SCC

¤Criteria KA, % SCC, % χ2 value p value(n = 142) (n = 120)

Arciform disposition 69 20 63 <10–9

Sharp outline stroma/proliferation 64 13.3 69 <10–9

Epithelial lip 83.3 14.2 125 <10–9

Keratin-filled crater 93.7 40.8 84 <10–9

Clear-cut demarcation epidermis/proliferation 87.3 37.5 69 <10–9

Intraepithelial elastic fibers 16.2 2.5 18 <10–4

Intraepithelial polymorphonuclear abscesses 47.9 42.5 0.77 n.s.Ulceration 3.5 57.5 93 <10–9

Lateral growth predominant 84.5 86.6 0.29 n.s.Extension beyond sweat glands 12.7 48.3 39 <10–9

Marked pleomorphism or anaplasia 14.8 75.8 99 <10–9

Mitoses 7 68 121 <10–9

Parakeratosis 62.7 78.3 7.3 <10–2

Dyskeratosis 65.5 89.2 19 <10–3

Results

A large proportion of the slides (88.6%) could easily beclassified into the same group by the two examiners: out ofthe 296 slides, 142 were classified as KA and 120 as SCC.In 34 cases, discrepancies were noted (11.4%). The pres-ence of the criteria was determined in the 262 first slides andthe results are detailed in table 1. None of the criteria wasboth very specific and very sensitive. The best criterion infavor of KA was the presence of a lateral lip (sensitivity83.8%, specificity 85.8%; fig. 1), and the best criterion infavor of SCC was the presence of more than two mitoses perhigh-power field (sensitivity 68%, specificity 93%; fig. 2, 3).

An ulcerated tumor and the extension beyond the sweatglands were specific criteria of SCC (specificity 96.5 and87.3%, respectively) but were not very sensitive (57.5 and48.3%, respectively).

Elastic fibers were often difficult to see without specialstaining, and this criterion was probably underestimated.Although elastic fibers were more frequently observed inKA, this criterion was not reliable, since its sensitivity wasvery low.

The 5 more useful criteria (i.e. which had a relativelyhigh specificity and a good sensitivity) were: sharp out-line between stroma and proliferation (in favor of KA =‘positive’ criterion); lateral lip (in favor of KA = ‘positive’

210 Dermatology 1999;199:208–212 Cribier/Asch/Grosshans

Fig. 1. Typical epithelial lip in a case of KA. Hematoxylin, eosin,safran. ×40.

Fig. 2. Intraepithelial elastic fibers (arrows) and mitotic figures in acase of SCC. Hematoxylin, eosin, safran. ×200.Fig. 3. Intraepithelial polymorphonuclear abscesses and mitotic fig-ures + cell pleomorphism in an SCC. Hematoxylin, eosin, safran.×200.

2

3

criterion); ulceration (in favor of SCC = ‘negative’ crite-rion); pleomorphism or anaplasia (in favor of SCC = ‘neg-ative’ criterion); mitoses (in favor of SCC = ‘negative’ cri-terion).

The analysis of the clear-cut KA and SCC (n = 262)shows that 90.8% of KA had more positive than negativecriteria, whereas 85% of SCC had more negative than posi-tive criteria. There were 3.5% of KA having more negativethan positive criteria and 3.3% of SCC having more positivethan negative criteria. In the rest of the cases, an equal num-ber of positive and negative criteria was noted.

In the 34 cases in which a discrepant diagnosis wasmade, a positive combination of the 5 criteria was found, in9 cases a negative combination, and an equal number of cri-teria was found in 5 cases. The slides were then reviewed bythe two examiners together, and a consensual diagnosiscould be established in 31 of the 34 cases. This consensualdiagnosis was consistent with the combination of the 5 cri-teria in only 74% of the cases (23/31).

Discussion

In the present study we showed that a 100% clear-cutdistinction is impossible by histological analysis only andthat only 5 criteria are of a certain value in differentiatingSCC from KA.

Many authors have proposed criteria that could be usedin the differential diagnosis of SCC and KA [2–5, 23–31].Nevertheless, there were only few attempts to examine thevalue of these criteria. In their study, Fischer et al. [23] com-pared 108 KA and 14 SCC. Because of the very low numberof SCC, there was a significant risk of error in the statisticalanalysis. The most convincing study was published in 1980by Kern and McCray [24], who examined 100 SCC and 100KA. They analyzed 10 criteria previously considered asgood markers of SCC and KA.

Our analysis was made only on fully excised tumors,because the majority of our criteria concerned the architec-ture of the tumors. The diagnosis of SCC or KA was estab-lished independently by two examiners, based on thepersonal experience of the authors. This is of course an arbi-trary method, but there is no other gold standard. As a mat-ter of fact, all works in which the goal was to distinguishKA from SCC using new markers were also based on thesame method for classification. Most often, the diagnosis ofSCC or KA is accepted on the basis of a previous histologi-cal analysis. As stated by many authors, it is possible to dis-tinguish the two tumors readily [2, 24, 25]. A consensualdiagnosis could be established in 88% of our cases, which is

close to the 81 and 86% of ‘confirmed’ cases in the study ofKern and McCray [24].

The results of this study show that many criteria cannotbe used for the differential diagnosis: (1) intraepithelialmicroabscesses were found in equal proportions of SCCand KA; (2) extension more lateral than downward wasobserved in the majority of our tumors, irrespective of theirclassification; (3) parakeratosis and dyskeratosis were morefrequently noted in SCC than in KA, but this criterion had avery low specificity; (4) elastic fibers were more frequentlyobserved in KA, as suggested by a few studies [27–29], butthey are difficult to see using conventional staining, espe-cially when present in small numbers. The use of immu-nohistochemistry [29] or orcein staining could of courseincrease the value of this criterion, but our purpose was todefine the best criteria using routine staining. Moreover,Ellis [28] has shown that although intraepithelial elasticfibers are more frequent in KA, this criterion is not reliablefor differentiating between the two tumors. In fact, the pres-ence of elastic fibers is a poorly sensitive criterion.

The p value is of poor interest in the differential diagno-sis, since useful distinctive criteria should be extremely spe-cific. The best criteria were therefore epithelial lip in favorof KA, which is both sensitive and specific, and the pres-ence of numerous mitoses in favor of SCC. Nevertheless,those criteria are neither extremely sensitive nor extremelyspecific and do not allow to make a clear-cut diagnosis. Forexample, mitoses were occasionally observed in the deeperpart of typical KA, as previously noted by many authors[2, 24, 25]. In the case of KA, some criteria could varyaccording to the stage at which the tumor was excised [2].The sharp outline of the lower part of the tumor is observedin the majority of KA, but in very early tumors in the pro-gression stage, small islands of cells can be observed in thedermis [2, 5, 23]. Fischer et al. [23], have even founddetached islands of cells in 60% of their KA. This is also thecase with mitoses that are not uncommon in early KA. Thisexplains why no single criterion can be used to distinguishKA from SCC. We did not analyze our cases according tothe stage of maturation, because this would have created toomany subgroups.

Only 5 criteria are of some interest in the distinction ofthe two tumors: epithelial lip, sharp outline demarcation,ulceration, pleomorphism/anaplasia and mitoses. All othercriteria analyzed in this work are of poor help, because theyhave a very low sensitivity or specificity. As a matter ofinterest, the most relevant criteria in favor of KA are archi-tectural, whereas the most relevant criteria for the diagnosisof SCC are cytological. This clearly shows that those casesare difficult in which architectural criteria are suggestive of

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a benign tumor, whereas cytological features are in favor ofmalignancy. Our results highlight once more the limitationof a morphological analysis as a marker of the tumoral bio-logical behavior. Since KA can share common cytologicalfeatures with true malignant tumors (SCC which led tometastasis), there is no satisfying correlation between histo-logical criteria and biological behavior in a noticeable pro-portion of cases. Since we were not able to obtain a long-term follow-up of all patients included in this study, thecorrelation between morphology and prognosis was not pos-sible.

Moreover, the combination of criteria adds little to thesensitivity or specificity of each single criterion. If the com-bination of histological criteria is of poor help in some of

the straightforward cases, it can obviously not be used incontroversial cases. This was illustrated by the secondanalysis of the 34 discrepant cases, in which the 5 ‘best’ cri-teria were not always in accordance with our consensualdiagnosis.

Even though histopathology allows to distinguish KAfrom SCC in the majority of cases, approximately 10–20%of cases remain that are extremely difficult to classify,despite the use of the most relevant criteria. It remains toestablish whether molecular biology studies could be ofsome help in such controversial cases. Whether all KAshould be considered as SCC is a different question whichwas not addressed in the present study.

212 Dermatology 1999;199:208–212 Cribier/Asch/Grosshans

1 Rook A, Whimster I: Keratoacanthoma – Athirty-year retrospect. Br J Dermatol 1979;100:41–47.

2 Lever WF, Schaumburg-Lever G: Histopathol-ogy of the Skin, ed 7. Philadelphia, Lippincott,1990.

3 MacKee P: Pathology of the Skin. London,Mosby-Wolfe, 1996.

4 Mehregan AH: Pinkus’ Guide to Dermatohisto-pathology. Norwalk, Appleton-Century-Crofts,1986.

5 Ackerman AB, Mendonça AMN, Guo Y: Dif-ferential Diagnosis in Dermatopathology I.Philadelphia, Lea & Febiger, 1992.

6 Hodak E, Jones RE, Ackerman AB: Solitarykeratoacanthoma is a squamous cell carcinoma:Three examples with metastases. Am J Derma-topathol 1993;15:332–342.

7 From L: Response of L From. Am J Dermato-pathol 1993;15:346.

8 Patel A, Haliday GM, Cooke BE, BarnetsonRS: Evidence that regression of keratoacan-thoma is immunologically mediated: A com-parison with squamous cell carcinoma. Br JDermatol 1994;131:789–798.

9 Ledo E: Wart, keratoacanthoma and squamouscell carcinoma: A spectrum of the same neo-plastic process? Int J Dermatol 1992;31:777–778.

10 Grant-Kels JM: Response of JM Grant-Kels.Am J Dermatopathol 1993;15:343–345.

11 Borkowski A, Bennett WP, Jones RT, Bor-kowski P, Harris CC, Ferreira LR, Kao GF,Trump BF: Quantitative image analysis ofp53 protein accumulation in keratoacanthomas.Am J Dermatopathol 1995;17:335–338.

12 Cain CT, Niemann TH, Argenyi ZB: Kerato-acanthoma versus squamous cell carcinoma:An immunohistochemical reappraisal of p53protein and proliferating cell nuclear antigenexpression in keratoacanthoma-like tumors.Am J Dermatopathol 1995;17:324–331.

13 Kerschmann RL, McCalmont TH, LeBoit PE:p53 oncoprotein expression and proliferationindex in keratoacanthoma and squamous cellcarcinoma. Arch Dermatol 1994;130:181–186.

14 Skalova A, Michal M: Patterns of cell prolifer-ation in actinic keratoacanthomas and squa-mous cell carcinomas of the skin. Am J Der-matopathol 1995;17:332–334.

15 Ho T, Horn T, Finzi E: Transforming growthfactor alpha expression helps to distinguish ker-atoacanthomas from squamous cell carcino-mas. Arch Dermatol 1991;127:1167–1171.

16 Ariano MC, Wiley EL, Ariano L, Coon JS,Tetzlaff L: Peanut lectin receptor, and carcino-embryonic antigen distribution in keratoacan-thomas, squamous cell dysplasias and carcino-mas of skin. J Dermatol Surg Oncol 1985;11:1076–1083.

17 Kanon G, Park HK: Utility of peanut agglutinin(PNA) in the diagnosis of squamous cell carci-noma and keratoacanthoma. Am J Dermato-pathol 1990;12:31–36.

18 Ramirez-Bosca A, Reano A, Valcuende F,Thivolet J, Castells-Rodelas A: Lectin-bindingsites in squamous cell carcinomas and kerato-acanthomas. Acta Dermatol Venereol (Stockh)1988;68:480–485.

19 Herzberg AJ, Kerns BJ, Pollack V, Kinney RB:DNA image cytometry of keratoacanthoma andsquamous cell carcinoma. J Invest Dermatol1991;97:495–500.

20 Randall MB, Geisinger KR, Kute TE, Buss DH,Prichard RW: DNA content and proliferativeindex in cutaneous squamous cell carcinomaand keratoacanthoma. Am J Clin Pathol 1990;93:259–262.

21 Stephenson TJ, Cotton DWK: Flow cytometriccomparison of keratoacanthoma and squamouscell carcinoma. Br J Dermatol 1988;118:582–583.

22 Asch PH, Basset P, Roos M, Grosshans E,Belocq JP, Cribier B: Expression of stromelysin3 in keratoacanthoma and squamous cell carci-noma. Am J Dermatopathol 1999;21:146–150.

23 Fisher ER, McCoy MM, Wechsler HL: Analy-sis of histopathologic and electron microscopicdeterminants of keratoacanthoma and squa-mous cell carcinoma. Cancer 1972;29:1387–1397.

24 Kern WH, McCray MK: The histopathologicdifferentiation of keratoacanthoma and squa-mous cell carcinoma of the skin. J Cutan Pathol1980;7:318–325.

25 Civatte J: Histopathologie cutanée. Paris, Flam-marion Médecine Sciences, 1982.

26 Chalet MD, Connors RC, Ackerman AB: Squa-mous cell carcinoma vs. keratoacanthoma: Cri-teria for histologic differentiation. J DermatolSurg Oncol 1975;1:14–15.

27 King DF, Barr RJ: Intraepithelial elastic fibersand intracytoplasmic glycogen: Diagnostic aidsin differentiating keratoacanthoma from squa-mous cell carcinoma. J Cutan Pathol 1980;7:140–148.

28 Ellis GL: Differentiating keratoacanthoma fromsquamous cell carcinoma of the lower lip: Ananalysis of intraepithelial elastic fibers andintracytoplasmic glycogen. Oral Surg 1983;56:527–532.

29 Jordan RCK, Kahn HJ, From L, Jambrosic J:Immunohistochemical demonstration of actini-cally damaged elastic fibers in keratoacantho-mas: An aid in diagnosis. J Cutan Pathol 1991;18:81–86.

30 De Moragas JM, Montgomery H, McDonaldJR: Keratoacanthoma versus squamous cellcarcinoma. Arch Dermatol 1955;77:390–395.

31 Schwartz RA: Keratoacanthoma. J Am AcadDermatol 1994;30:1–19.

References