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Subdirección de Educación Continua de la Facultad de Medicina, UANL Biblioteca Central planta baja,

Av. Francisco I. Madero y Dr. Eduardo Aguirre Pequeño Col. Mitras Centro Monterrey, N.L. México C.P. 64460

Tels.: 8329-4193, 8347-5867, [email protected]

MEDICINA DÍAAL

Número 1 Volúmen 1

Revista ElectrónicaSubdirección de Educación ContinuaFacultad de Medicina, UANL

CIRUGÍAMEDICINA INTERNAPEDIATRÍAPSIQUIATRÍAQUÍMICA CLÍNICA

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Discrepancies Between Fluorescein Angiography andOptical Coherence Tomography in Macular

Edema in Uveitis

JEANNETTE OSSEWAARDE-VAN NOREL, LAURENS P. CAMFFERMAN, AND ANIKI ROTHOVA

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● PURPOSE: To assess the frequency and characteristicsof discrepant findings between fluorescein angiography(FA) and optical coherence tomography (OCT) in uve-itic macular edema (ME).● DESIGN: Retrospective cross-sectional study of 112yes of 78 patients with uveitic ME on FA, OCT, oroth.

● METHODS: ME was graded on OCT and FA of uveitisatients attending the University Medical Centertrecht. The frequency and severity of discrepant find-

ngs were analyzed, and the clinical findings at the time ofmaging were assessed. The imaging studies were com-ared with the clinical characteristics.

● RESULTS: Positive results of both imaging methodsFA�/OCT�) were observed in 61 (54%) of 112 eyes,hereas discrepant results occurred in 51 (46%) of 112

yes. The FA�/OCT� discrepancy occurred in 3430%) of 112 eyes, and the FA�/OCT� discrepancyccurred in 17 (15%) of 112 eyes. No correlationsetween the discrepant imaging results and age, gender,uration of uveitis or ME, visual acuity, or cause ofveitis were identified. FA�/OCT� and FA�/OCT�iscrepancies comprised typically mild degrees of ME.he FA�/OCT� discrepancy occurred in 50% of eyesith birdshot chorioretinopathy (7/14), and the FA�/CT� discrepancy occurred more often in intermediateveitis than in other anatomic locations. Although theA�/OCT� consistency was noted frequently in activeveitis, the FA�/OCT� discrepancy was common inyes with inactive uveitis (8/18; 44% of inactive eyes).

● CONCLUSIONS: Our results emphasize that FA andOCT are complementary investigations, each revealingdifferent aspects of the pathophysiology of uveitic ME.(Am J Ophthalmol 2012;154:233–239. © 2012 byElsevier Inc. All rights reserved.)

Accepted for publication Feb 3, 2012.From the Department of Ophthalmology, University Medical Center

Utrecht, Utrecht, The Netherlands (J.O.-v.N., A.R.); and the Depart-ment of Ophthalmology, Erasmus Medical Center, Rotterdam, TheNetherlands (L.P.C., A.R.).

Inquiries to Jeannette Ossewaarde-van Norel, Department of Ophthal-mology, University Medical Center Utrecht, P. O. Box 85500, NL-3508GA Utrecht, The Netherlands; e-mail: a.ossewaarde-vannorel@
umcutrecht.nl
© 2012 BY ELSEVIER INC. A0002-9394/$36.00doi:10.1016/j.ajo.2012.02.003

M ACULAR EDEMA (ME) IS A CONDITION CHARAC-

terized by intraretinal accumulation of fluid in themacula, which is a major cause of decreased visual

acuity in multiple ocular disorders, including uveitis.1–3 Clin-cal signs may manifest first when severe macular involve-ent has already developed. In contrast, therapeutic

nterventions are effective mostly in the early stages of ME.ntil the introduction of the optical coherence tomography

OCT), fluorescein angiography (FA) was the most widelysed method to evaluate the retinal vascular perfusion andhe integrity of the inner blood-retinal barrier. OCT hasecome increasingly important in the assessment of ME byevealing quantitative data about retinal thickness and infor-ation on anatomic abnormalities of the retinal layers.Although both FA and OCT are able to verify the

resence of ME, discrepancies occasionally have been re-orted.4–11 Contradictory results from these examinationsomplicate clinical decision making. In this study, we inves-igated the incidence and nature of discrepancies between FAn OCT in a large group of patients with uveitis andttempted to clarify the factors causing these discrepancies.

METHODS

IN THIS STUDY, WE RETROSPECTIVELY INCLUDED ALL 78

patients (112 eyes) with uveitis and ME who underwentboth FA and OCT within an interval of 2 weeks at theUniversity Medical Center Utrecht during a 21-monthperiod from January 2007 through September 2008 andwho did not undergo any therapeutic interventions be-tween the FA and the OCT.

Excluded from study were 4 patients in whom poor-quality or misaligned OCT scans were obtained. Criterionwas whether the software program could make a good fit onthe inner and outer border of the retina. Medical charts ofpatients were reviewed for sex, age, duration of uveitis andof ME at the time of the imaging studies, anatomicclassification, cause of uveitis, and best-corrected visualacuity. Our uveitis population included 22 patients withassociated systemic diseases and 40 patients with anunknown cause of uveitis (Table 1). Fluorescein angio-grams and OCT scans were assessed in a masked fashion for
characteristics of ME by 2 observers (J.O.-v.N., L.P.C.).
LL RIGHTS RESERVED. 233

mailto:[email protected]


ratstcs

All FA photographs were recorded using a Zeissdigital fundus camera (Zeiss FF 450 plus fundus camera;Carl Zeiss AG, Oberkochen, Germany). Fluoresceinangiograms were graded according to a modified gradingsystem (Table 2), that is, a combination of the criteriareported by Yannuzzi and the proposed grading system of

TABLE 1. Discrepancies According to the Cof the

FA�/OCT�

(n � 43)

Cause

Associated systemic

diseases 14

Sarcoidosis 12

HLA-B27 0

Multiple sclerosis 0

Other 2

Intraocular infections 1

Established clinical

entitiesa 6

Undeterminedb 22

Mean agec (range), y 55 (13 to 83)

Median duration uveitisc

(range), y 2.8 (0 to 24.9) 2

Median duration MEc

(range), y 1.0 (0 to 16.1) 0

Median Snellen VAc

(range) 0.5d (0.01 to 1.2) 0.

FA � fluorescein angiography; ME � macula

VA � visual acuity.aIncludes birdshot chorioretinopathy, periphebThis group also includes all patients with pacOnly the left eye is included, unless the uveidNot significant (Kruskal-Wallis test).

TABLE 2. Modified Fluorescein Angiographic GradingSystem for Macular Edema

Grade Characteristics

0 No perifoveal hyperfluorescence

1 Faint perifoveal hyperfluorescence: specific

localization of hyperfluorescence too difficult

because of very minimal leakage

2 Evident perifoveal hyperfluorescence in an area

centered on the fovea of less than 1 optic

disc diameter


centrad on the fovea of between 1 and 1.5

optic disc diameter(s)


centrad on the fovea of more than 1.5 optic

disc diameters

the Angiography Scoring for Uveitis Working m

AMERICAN JOURNAL OF234

Group.12,13 In addition, we registered the number ofaffected clock hours separately. ME was assessed onimages obtained at least 5 minutes after intravenousinjection of 5 mL 20% sodium fluorescein. In this study,only the cases in which there was obvious leakage in thecenter (grades 2 through 4) were classified and analyzedas ME.

OCT was performed with the StratusOCT (StratusOCT 3000, software version 4.0.1; Carl Zeiss Meditec, Inc,Dublin, California, USA). Mean central retinal thickness(CRT; inner, 1000 �m;) was recorded, and 6 radial lineimages were reviewed on screen for the presence of ME,intraretinal cysts, associated central serous retinal detach-ment (CSRD), epiretinal membranes, vitreoretinal attach-ment with or without traction (vitreoretinal traction vs�adhesion), or a combination thereof. Poor quality ormisaligned OCT scans were excluded from the analysis(n � 12). The following characteristics of ME wereegistered: diffuse macular edema, cystoid macular edema,nd CSRD. Diffuse ME presented as diffuse thickening ofhe retina, disturbance of the orderly layered retinaltructure, spongelike low reflective areas, or a combinationhereof. Cystoid macular edema was characterized bylearly defined intraretinal cystoid spaces. In a CSRD, aeparation between neurosensory retina and retinal pig-

of Uveitis and the Baseline Characteristicsients

�/OCT–

� 26)

FA–/OCT�

(n � 9)

Total

(n � 78)

7 1 22

4 1 17

1 0 1

0 0 0

2 0 4

1 1 3

14 3 13

14 4 40

8 to 77) 49 (26 to 73) 53 (13 to 83)

.03 to 31.9) 1.6 (0.01 to 6.2) 2.8 (0 to 31.9)

to 9.9) 0.6 (0 to 6.0) 0.7 (0 to 16.1)

.1 to 1.2) 0.6 (0.01 to 1.2) 0.6 (0.01 to 1.2)

ma; OCT � optical coherence tomography;

ltifocal chorioretinitis, M. Eales.

nitis.

s unilateral in the right eye.

ausePat

FA

(n

52 (1

.0 (0

.5 (0

65 (0

r ede

ral mu

rs pla

tis wa

ent epithelium was present in addition to ME.14

OPHTHALMOLOGY AUGUST 2012

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a
Based on a meta-analysis of 3 large studies investigatingretinal thickness in northern and northwestern Europeansusing the StratusOCT,15–17 we chose an upper limit valuef 249 �m for CRT, which is 2 standard deviations abovehe mean central retinal thickness (pooled mean of 205.5 �ooled standard deviation of 21.7 �m). ME on OCT wasonsidered in cases with CRT higher than 249 �m orhen evident cystoid spaces could be observed on radial
ines (n � 5).The activity of the uveitis was classified as active or

nactive, based on the presence or absence of aqueous or

TABLE 3. Distribution of Eyes with Discrepaof the Macular Edema on Optical Coherence

the Presence or Absenc

FA�/OCT�

(n � 61)

Location

Anterior 1 (50%)

Intermediate 6 (37.5%)

Posterior 22 (61%)

Pan 32 (55%)

OCT

Median CRT (range), �m 318 (188 to 615) 2

FA grade

0 or 1d

2 43e

3 9

4 9

FA

Median clock hours, n

(range) 12f (1 to 12)

OCT

Epiretinal membrane 31g

Uveitis

Active 56h

Inactive 5

CRT � central retinal thickness; FA � fluores

phy.

The grade of leakage, the number of clock

membrane did correlate between the 2 eyes (r �

and P � .001, respectively). The analyses aft

conclusions as described above, except for the

more prevalent in the FA�/OCT– group than in

P � .03).aRelatively more eyes with intermediate uveiti

on OCT) compared with the other uveitis locatibBiased by selection criterion of CRT � 249cThe CRT is significantly lower for the FA–/OC

with the (nondiscrepant) FA�/OCT� group (P �dGrade 1 of macular edema was not includeeFA�/OCT� vs FA�/OCT– (P � .076).fFA�/OCT� vs FA�/OCT– (P � .01).gComparing all 3 groups: P � .02.hComparing all 3 groups: P � .002.

itreous cells, or both, signs of activity on fluorescein

OCT VS FLUORESCEIN ANGIOGRAPHVOL. 154, NO. 2

ngiography13 (such as vasculitis, optic disc leakage, andcapillary leakage outside the perifoveal area), or a combi-nation thereof.

An analysis of variance was used to test for differences inmean age, duration of uveitis, duration of ME, visual acuity,and CRT between eyes with ME on both examinations, MEsolely on FA, and ME solely on OCT. The Dunnett post hoctest was applied to determine any differences between sepa-rate groups. A chi-square equation was used to calculatedifferences between groups for frequencies of cause, locationof uveitis, FA grade, presence of CSRD, presence of epiretinal

s to the Location of the Uveitis, the Severityography and Fluorescein Angiography, and

an Epiretinal Membrane

�/OCT–

n � 34)

FA–/OCT�

(n � 17)

Total

(n � 112)

50%) 0 2 (100%)

25%) 6 (37.5%)a 16 (100%)

25%) 5 (14%) 36 (100%)

34%) 6 (10%) 58 (100%)

187 to 248) 274c (160 to 464) 270 (160 to 615)

17 17

31 74

2 11

1 10

1 to 12) 0 (0 to 7) 10 (0 to 12)

8 5 44

29 9 94

5 8 18

angiogram; OCT � optical coherence tomogra-

rs involved, and the presence of an epiretinal

and P � .02, r � 0.31 and P � .07, and r � 0.55

luding 1 eye per patient resulted in the same

r (grade 2) leakage, which also was significantly

A�/OCT� group (25/26 eyes vs 30/43 eyes;

in the FA–/OCT� group (macular edema solely

� .016).

r FA�/OCT– group.

roup (macular edema solely on OCT) compared

7, Mann–Whitney U test).

is study (see Methods).

ncieTom

e of

FA

(

1 (

4 (

9 (

20 (

15b (

10 (

cein

hou

0.39

er inc

milde

the F

s eyes

ons (P

�m fo

T� g

.00

d in th

membranes, and presence of vitreoretinal traction. All statis-

Y IN UVEITIC MACULAR EDEMA 235

aed6s

tical analyses were performed using SPSS for Windowsversion 15.0 (SPSS, Inc, Chicago, Illinois, USA). We in-cluded all eyes with ME in our analyses because, in bilateralcases, no correlation was found in the occurrence of discrep-ancies and CRT measurements between the left and the righteyes (P � .78).

RESULTS

ONE HUNDRED TWELVE EYES OF 78 PATIENTS (MEAN AGE, 53

years; range, 13 to 83 years) fulfilled the diagnostic criteriaof ME either on FA or on OCT. Our study cohortcomprised 21 eyes (19%) with severe ME that was FAleakage group 3 and 4 and 16 eyes (14%) with a CRT ofmore than 400 �m.

ME present in both imaging examinations (FA�/OCT� group) was present in 61 (54%) of 112 patients,nd discrepancies were documented in 51 (46%) of 112yes (Table 3). ME visible solely on FA (FA�/OCT�iscrepancy) was noted in 34 (30%) of 112 eyes (34/51;7% of those with discrepancies) and ME was identifiedolely on OCT (FA�/OCT� discrepancy) in 17 (15%) of

FIGURE 1. Images from a 13-year-old boy with an intermedi-ate uveitis and a discrepancy between fluorescein angiographyand optical coherence tomography results. (Top) No fluores-cein leakage is visible in the macular area, although on opticalcoherence tomography, the fovea is thickened (Top left, centralretinal thickness, 487 �m) with (Bottom) large intraretinalcysts. His left eye showed a similar discrepancy.

112 eyes (19/51; 37% of those with discrepancies). In t


Figures 1 and 2, 1 illustration is given of each type ofdiscrepancy. The CRT of the FA� group (FA�/OCT�and FA�/OCT�) did not differ from that of the FA�group (269 vs 274 �m; P � .98). A CSRD was present in15% of the eyes with ME and was not correlated with 1 ofthe 3 groups.

● CLINICAL CHARACTERISTICS: The FA�/OCT� groupand both groups with discrepancies (FA�/OCT� andFA�/OCT�) did not differ in gender, age, duration ofuveitis, duration of ME, and visual acuity (Table 1).Specifically, a longstanding uveitis (duration � 5 years)was not associated with a specific type of discrepancy. TheCRT did not differ between the patients with duration ofuveitis longer or shorter than 5 years (P � .2). There wasa high correlation between a cystoid appearance of the MEon FA and the appearance of cysts on OCT (R � 0.66,P � .000). Cystoid ME on OCT was found more often in

FIGURE 2. Images from a 49-year-old woman with idiopathicpanuveitis and a discrepancy between fluorescein angiographyand optical coherence tomography results. (Top) A grade 2macular leakage is visible on fluorescein angiography, but(Bottom) optical coherence tomography shows a retina ofaverage thickness (Top right, central retinal thickness, 195�m). (Bottom) All 6 radial lines showed the same appearanceof the retina without obvious retinal cysts. The leakage is a mildform of grade 2, but is still evident. The optic disc is hyper-fluorescent. Her right eye showed a more active uveitis, withobvious cystoid macular edema on fluorescein angiography andoptical coherence tomography.

he FA�/OCT� group compared with the FA�/OCT�


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group (34/61 eyes vs 4/17 eyes; P � .03). The FA�/OCT�roup was characterized by the most severe ME with theighest CRT (median, 318 �m; range, 188 to 615 �m)ompared with the FA�/OCT� group (median, 274 �m;ange, 160 to 464 �m; P � .007; Table 3) and a higherumber of affected clock hours compared with the FA�/CT� group (median, 12 vs 10; P � .01). Moreover, the

rades of FA leakage were higher in the FA�/OCT�roup: 9 (15%) of 61 eyes in the FA�/OCT� group hadrade 4 leakage compared with 1 (3%) of 34 eyes in theA�/OCT� group (Table 3); however, this was notignificant (P � .09).

The 112 eyes were subdivided according to the activityf the uveitis. The FA�/OCT� consistency was observedore frequently in active than in inactive uveitis (56/94 vs

/18; P � .019). Moreover, the FA�/OCT� discrepancyas the largest group in the inactive eyes (8/18 eyes; Table), and nearly half the eyes in the FA�/OCT� group hadnactive uveitis (8/17 eyes).

● ANATOMIC CLASSIFICATION: FA�/OCT� consis-ency was the most frequent finding for all anatomicntities of uveitis, with the exception of intermediateveitis. Intermediate uveitis exhibited a FA�/OCT�iscrepancy in 6 (38%) of 16 eyes, in contrast to othernatomic types of uveitis (P � .016; Table 3). The mean

age was lower in the group of intermediate uveitis com-pared with the other groups: 37 versus 56 years (P � .000).

● CAUSE: No associations were observed between thespecific causes of uveitis and FA/OCT discrepancies (Table1). The FA�/OCT� discrepancy was observed in 7 (50%)of 14 eyes in patients with birdshot chorioretinopathy(BSCR) compared with 5 (19%) of 27 eyes with sarcoid-osis and 22 (30%) of 74 eyes with other diagnoses.Compared with the entire group of eyes with diagnosesother than BSCR, this difference was not statisticallysignificant (P � .09). In addition, the CRT was lower inBSCR patients compared with the other uveitis groups, butdid not reach the level of significance (14 eyes; median,240 �m; range, 187 to 396 �m vs median, 274 �m; range,160 to 615 �m; P � .07).

● ADDITIONAL FEATURES ON OPTICAL COHERENCE

TOMOGRAPHY: The presence of an epiretinal membraneon OCT in the 3 groups is shown in Table 3. The ME eyeswith associated epiretinal membranes on OCT (n � 44)exhibited a higher CRT than the ME eyes withoutepiretinal membranes (median, 342 vs 273 �m; P � .000).

urprisingly, the eyes with ME and associated epiretinalembranes had a smaller incidence of the FA/OCT

iscrepancies than the eyes with ME but without epiretinalembranes (13/44 [30%] vs 38/68 [56%]; P � .007). The

frequency of severe (grade 4) FA leakage was higher in thegroup with an epiretinal membrane (7/44 vs 3/65; P �
.047). Vitreomacular traction was seen on the OCT in i

3.5% (4/112) of all ME eyes, and vitreomacular adhesionwas visible in an additional 2.7% (3/112).

DISCUSSION

DISCREPANT RESULTS OF FA AND OCT IN EYES WITH IN-

flammatory ME were identified in 46% of eyes (51/112)and were present predominantly in mild degrees of ME.The FA�/OCT� discrepancy was the most frequent typeof discrepancy and occurred in 50% of patients withBSCR. The FA�/OCT� discrepancy occurred more oftenin young patients with intermediate uveitis.

The results suggest that the FA�/OCT� group mayconcern atrophic retinas, in which macular edema remainsunnoted if there are no cysts. Because the increased CRTwas a selection criterion, we could not test our hypothesisof atrophic retinas with ME and negative OCT results inthe present study. The occurrence of retinal cysts on OCTscans in retinas with normal thickness (� 252�m) re-cently was reported in eyes with various causes of ME.18

The frequency of discrepant results in our study is higherthan previously reported. Earlier studies on uveitic macularedema reported an incidence of discrepant results in 11% to13%9–11; however, these studies used other inclusion criteria,ifferent methods for the assessment of ME on FA and OCTeg, not recording the CRT), their design was not aimed atetecting all FA/OCT discrepancies, or a combinationhereof. Moreover, in the study of Antcliff and associates, FAhotographs were graded as early as 3 minutes after fluores-ein injection and an OCT device with poorer axial resolu-ion (OCT 2000 scanner; Humphrey Instruments, Saneandro, California, USA) was used.11 In a recent study of

Brar and associates, eyes with ME on FA (with variouscauses) were analyzed for their findings on spectral-domain(SD) OCT.4 Four (3.7%) of 107 eyes did not show OCTabnormalities, but in 17 eyes (15.9%), microcysts on SDOCT were found, which likely would have been missed withthe Stratus OCT. Their lower percentage of FA�/OCT�discrepancies also may be the result of the bias that theexaminers did know that the FA showed ME, and thereforewere more prone to detect subtle changes in the OCT scan,which would have been unnoted otherwise. Recently, morestudies on the correlation between FA and SD OCT in MEwere published, however, with no or a very limited number ofuveitis patients5–8 or only consideration of cystoid changesn OCT and FA.6

The occurrence of discrepancies between FA and OCTcould be explained by the following hypotheses. First, insuf-ficient resolution of the time-domain OCT apparatus, com-pared with the SD OCT, may explain the missing ofmicrocysts. The lower prevalences of FA�/OCT� in thetudies using the SD OCT confirm this hypothesis. However,n this study, the criterion of an increased retinal thickness isot influenced negatively by using a time-domain OCT

nstead of an SD OCT. Second, the media opacities fre-


quently present in uveitic patients negatively influence thesignal-to-noise ratio and may result in false-negative results.19

Third, some of the discrepancies may be explained by thearbitrary ceiling value of CRT, which may not represent theclinical significance and could lead to overestimation orunderestimation of ME on OCT.

Several hypotheses explaining the occurrence of thetrue discrepancies were put forward. Patients with retinalatrophy may exhibit FA leakage, whereas the atrophicretina may not exceed the boundary of 249 �m, whichcould explain FA�/OCT� discrepancy. Our study in-cluded many patients with a long duration of uveitis andME, and it is possible that in these patients, thinning ofthe retina associated with lower CRT values developedgradually. In these patients, the longstanding vascularleakage still may be present and may clarify the FA�/OCT� discrepancy. This phenomenon is supported by thefinding of frequent FA�/OCT� discrepancies in patientswith BSCR who also exhibited lower CRT values com-pared with the other uveitis entities (median, 240 �m;range, 187 to 396 �m vs median, 274 �m; range, 160 to615 �m; P � .07). The averaging of the central retinalthickness on OCT may be a second cause of a lessersensitivity for ME in some cases, especially in patients witha slight focal leakage in only a few clock hours.

The FA�/OCT� discrepancy may be explained by theinitial accumulation of fluid in the intracellular spaces orin the subretinal space, leading to retinal thickening but(as yet) no evident leakage.20–22 In patients with previousuveitis, the leakage across the vascular wall may be absent,whereas (the remainder of) accumulated fluid still may bepresent. Our results support this hypothesis, because nearlyhalf of the eyes with an inactive uveitis exhibited thisdiscrepancy, in contrast to the active eyes (P � .002). In
addition, it was suggested that tractional membranes may
uveitis. Br J Ophthalmol 2004;88(9):1159 –1162.


lead to ME with minimal or absent fluorescein leakage;however, this phenomenon was not observed by us, prob-ably because of the low prevalence in our study.23

Inevitably, there are some shortcomings in our study.First, the definition of ME on FA and OCT differ. Thediameter of the optic disc for defining grade 2 ME on FAis larger than the area of the central 1 mm of the OCTscan. Second, the grading of macular leakage on FA isimprecise, but this is the case for all studies. It is notpossible to grade the severity of the ME on FA byregistration of the pixel gray value, because this value isdependent on several confounding factors (media opaci-ties, pigmentation level of the macula, etc.) and, more-over, is not linearly related to the concentration offluorescein because of quenching. Instead, we chose to usethe diameter of the ME area (as have other investigators)and the number of clock hours as 2 ways to grade theseverity of the ME. In addition, our study includes uveiticME in different stages of disease activity. Future studies ofFA and OCT in patients with sufficient numbers ofpatients in diverse stadia or types of ME may reveal theadditional characteristics of FA/OCT discrepancies andmay help to clarify the pathogenesis of ME in uveitis.

In conclusion, we report on discrepant FA and OCTfindings in 46% of uveitic eyes, predominantly occurring ineyes with mild ME. Although the FA�/OCT� discrep-ancy predominantly was present in eyes with BSCR, theFA�/OCT� discrepancy was associated with an interme-diate location of uveitis. Although the FA�/OCT� con-sistency was noted frequently in active uveitis, the FA�/OCT� discrepancy was common in eyes with inactiveuveitis. Our results show that FA and OCT are comple-mentary investigations, each revealing different aspects ofthe pathophysiologic features of uveitic ME, and this may
influence the therapeutic decisions.
ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST ANDnone were reported. Publication of this article was supported by the Dr. F. P. Fischer Foundation, Amersfoort, The Netherlands. The Fischer Foundation had no rolein the design or conduct of this research. Involved in Design of study (J.O.-v.N., A.R.); Conduct of study (J.O.-v.N., L.P.C., A.R.); Collection of data (J.O.-v.N., L.P.C.);Management of data (J.O.-v.N., L.P.C.); Analysis of data (J.O.-v.N., L.P.C., A.R.); Interpretation of data (J.O.-v.N., L.P.C., A.R.); Preparation of manuscript (J.O.-v.N.,L.P.C., A.R.); Review of manuscript (J.O.-v.N., L.P.C., A.R.); Approval of manuscript (J.O.-v.N., L.P.C., A.R.). The study design consisted of a retrospective reviewof data. Because no changes in standard patient care were involved, the Institutional Review Board of the University Medical Center Utrecht waived the need forapproval of this research retrospectively. The study adhered to the Declaration of Helsinki and applicable laws in The Netherlands.

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5. Wolf-Schnurrbusch UE, Ceklic L, Brinkmann CK, et al.Macular thickness measurements in healthy eyes using sixdifferent optical coherence tomography instruments. InvestOphthalmol Vis Sci 2009;50(7):3432–3437.

6. El-Ashry M, Hegde V, James P, Pagliarini S. Analysis ofmacular thickness in British population using optical coher-ence tomography (OCT): an emphasis on interocular sym-metry. Curr Eye Res 2008;33(8):693–699.

7. Eriksson U, Alm A. Repeatability in and interchangeabilitybetween the macular and the fast macular thickness mapprotocols: a study on normal eyes with Stratus opticalcoherence tomography. Acta Ophthalmol 2009;87(7):725–730.

8. Jun JJ, Duker JS, Baumal CR, et al. Cystoid macular edemawithout macular thickening: a retrospective optical coher-ence tomographic study. Retina 2010;30(6):917–923.

9. Gupta V, Gupta P, Singh R, Dogra MR, Gupta A. Spectral-domain Cirrus high-definition optical coherence tomographyis better than time-domain Stratus optical coherence tomog-raphy for evaluation of macular pathologic features in uveitis.Am J Ophthalmol 2008;145(6):1018–1022.

0. Wolter JR. The histopathology of cystoid macular edema.Albrecht Von Graefes Arch Klin Exp Ophthalmol 1981;216(2):85–101.

1. Freeman G, Matos K, Pavesio CE. Cystoid macular oedemain uveitis: an unsolved problem. Eye 2001;15(Pt 1):12–17.

2. Tranos PG, Wickremasinghe SS, Stangos NT, Topouzis F,Tsinopoulos I, Pavesio CE. Macular edema. Surv Ophthal-mol 2004;49(5):470–490.

3. Johnson MW. Tractional cystoid macular edema: a subtlevariant of the vitreomacular traction syndrome. Am J Oph-
thalmol 2005;140(2):184–192.

The Diagnosis of Endometrial Carcinomas With ClearCells by Gynecologic Pathologists: An Assessment

of Interobserver Variability and AssociatedMorphologic Features

Oluwole Fadare, MD,* Vinita Parkash, MD,w William D. Dupont, PhD,zGeza Acs, MD, PhD,y Kristen A. Atkins, MD,8 Julie A. Irving, MD,z

Edyta C. Pirog, MD,# Bradley J. Quade, MD, PhD,** M. Ruhul Quddus, MD,wwJoseph T. Rabban III, MD, MPH,zz Russell Vang, MD,yy and Jonathan L. Hecht, MD, PhD88

Abstract: The purposes of this study are to assess the level of

interobserver variability in the diagnosis of endometrial carci-

nomas with clear cells by gynecologic pathologists based purely

on their morphologic features and to comparatively describe the

cases of putative clear cell carcinoma (CCC) with and without

significant interobserver variability. A total of 35 endometrial

carcinomas (1 slide per case) were reviewed by 11 gynecologic

pathologists (median experience: 10 y) from 11 North American

institutions. The cases were selected from the files of 3 in-

stitutions on the basis of the presence of at least focal clear cells

and had previously been classified as a variety of histotypes at

these institutions. Diagnoses were rendered in a blinded manner

and without predetermined diagnostic criteria or categories. The

k values between any pair of observers ranged from 0.18 to 0.69

(combined 0.46), which was indicative of a “moderate” level of

interobserver agreement for the group. Subgroups of “confirmed

CCC” [cases diagnosed as such by at least 8 (73%) of the 11

observers, n=14] and “possible CCC” (cases diagnosed as CCC

by Z1 but <8 observers, n=13) were compared with regard to

a variety of semiquantified morphologic features. By combining

selected morphologic features that displayed statistically sig-

nificant differences between the 2 groups on univariate analyses,

the following approximate morphologic profile emerged for the

confirmed CCC group: papillae with hyalinized cores in Z33%

of the lesion, clear cells in Z33% of the lesion, hyperchromasia

in Z33% of the lesion, the absence of nuclear pseudo-

stratification in >3 cells on the papillae, the absence of nuclear

pseudostratification in glands in Z33% of the lesion, the absence

of diffuse grade 3 nuclei, the absence of long and slender papillae

in Z33% of the lesion, and glands and papillae lined by cuboidal

to flat, noncolumnar cells. In a backward stepwise logistic re-

gression analysis, features from the profile that predicted the

confirmed CCC group included: (1) absence or minimality of

diffuse sheets of grade 3 nuclei [P=0.025; 95% confidence in-

terval (CI), 0.0266-0.363]; (2) absence or minimality of nuclear

stratification in glands and papillae (P=0.040; 95% CI, �0.228

to �0.0054); and (3) glands and papillae lined by cuboidal to flat,

noncolumnar cells (P=0.008; 95% CI, 0.0911-0.566). The 2

groups displayed significant overlap regarding a wide variety of

features, and no single case displayed a full complement of po-

tentially diagnostic features. Morphologic patterns associated with

cases with very high levels of interobserver variability (defined as

cases with Z4 different diagnoses rendered for them, n=9) in-

cluded the near-exclusive or exclusively solid pattern of clear cells

(3/9) and glandular/papillary proliferations whose only CCC-like

feature was the presence of clear cells (2/9). In conclusion, the

diagnosis of endometrial carcinomas with clear cells by gyneco-

logic pathologists is associated with a moderate level of inter-

observer variability. However, there is a morphologic profile that

characterizes cases that gynecologic pathologists more uniformly

From the *Department of Pathology, Microbiology, and Immunology,Vanderbilt University School of Medicine; zDepartment of Bio-statistics, Vanderbilt University Medical Center, Nashville, TN;wDepartment of Pathology, Yale University School of Medicine, NewHaven, CT; yDepartment of Anatomic Pathology, Moffitt CancerCenter, Tampa, FL; 8Department of Pathology, University ofVirginia, Charlottesville, VA; #Department of Pathology and Labo-ratory Medicine, Weill Medical College of Cornell University and NewYork Presbyterian Hospital, New York, NY; **Department of Path-ology, Brigham and Women’s Hospital and Harvard Medical School;88Department of Pathology, Beth Israel Deaconess Medical Centerand Harvard Medical School, Boston, MA; wwDepartment of Patho-logy and Laboratory Medicine, Women and Infants Hospital andBrown University, Providence, RI; zzDepartment of Pathology, Uni-versity of California-San Francisco, San Francisco, CA; yyDepartmentof Pathology, Johns Hopkins Hospital, Baltimore, MD; andzDepartment of Laboratory Medicine, Pathology, and MedicalGenetics, Royal Jubilee Hospital, Victoria, BC, Canada.

Presented at the 101st Annual Meeting of United States and CanadianAcademy of Pathology, Vancouver, BC, Canada, March 19, 2012.

Conflicts of Interest and Source of Funding: The authors have disclosedthat they have no significant relationships with, or financial interestin, any commercial companies pertaining to this article.

Correspondence: Oluwole Fadare, MD, Department of Pathology,Microbiology, and Immunology, MCN C-2310D, VanderbiltUniversity Medical Center, 1161 21st Avenue S, Nashville, TN 37232(e-mail: [email protected]).

Supplemental Digital Content is available for this article. Direct URLcitations appear in the printed text and are provided in the HTMLand PDF versions of this article on the journal’s website,www.ajsp.com.

Copyright r 2012 by Lippincott Williams & Wilkins

ORIGINAL ARTICLE

Am J Surg Pathol � Volume 36, Number 8, August 2012 www.ajsp.com | 1107


http://www.ajsp.com

classify as CCC, and the presence of these features is supportive of

a CCC diagnosis in an endometrial carcinoma with clear cells.

Cases that display broad and significant qualitative deviations

from the aforementioned profile should prompt the consideration

of a diagnosis other than CCC.

Key Words: endometrial clear cell carcinoma, interobserver

variability, interobserver reproducibility

(Am J Surg Pathol 2012;36:1107–1118)

A lthough several decades have elapsed since its originaldescription as a distinct clinicopathologic entity, en-

dometrial clear cell carcinoma (CCC) continues to remaina singularly enigmatic histotype as compared with its se-rous and endometrioid counterparts. The historical evo-lution in the definition of the appellation—CCC—is inand of itself informative in this regard. The fact that asubset of endometrial carcinomas displays prominentglycogen-related cytoplasmic clarity has been recognizedsince at least 1911.1,2 However, the first report of a “clearcell carcinoma of the endometrium” in the English-lan-guage literature was a description of 2 cases by Kay in1957.3 In that report, the author noted that “secretorycarcinoma of the endometrium is a term that might well beused to characterize this entity, as there is evidence to showthat the tumor glands secrete glycogen,” and that he wasusing the term CCC to refer to “an exaggeration of thesecretory process noted in a number of endometrial tu-mors.”3 “Secretory carcinoma” thus evolved, albeit tem-porarily, as a histotype that was essentially synonymouswith CCC, and the first published series of “CCC” includedconventional CCC as well as tumors that would be classi-fied by contemporary criteria as the secretory variant ofendometrioid carcinoma.4 The notion that secretory carci-noma and CCC represent clinicopathologically distinctentities was initially advanced by Fechner in 1968,5 and thepoint was subsequently emphasized in a 1976 report byKurman and Scully.6 The diagnostic criteria for CCC in thelatter report, which were essentially extrapolated from thethen well-known features of ovarian CCC, emerged overthe subsequent 35 years as the diagnostic standard for thishistotype.7 However, the cases reported as CCC during thatperiod have also displayed a degree of clinicopathologicheterogeneity that is arguably beyond the expected. CCChas been reported to represent as high as 7% of endo-metrial carcinomas by some authors8 and as low as 1% byothers.7 The reported 5-year survival rate for patients withstage I CCC has varied widely from 44.2% to 85%.9–12

Overall survival for stage II patients has similarly rangedwidely from 27% to 72%.9,13 Very minimal advances havebeen made in deciphering the underlying molecularpathogenesis of CCC,14 at least as compared with endo-metrioid15 and serous carcinomas.16 In 1 noteworthyanalysis, 2 cases of mixed endometrial serous carcinomas(ESCs)/CCC displayed identical mutations in the TP53gene in the morphologically distinct components, and 1case of mixed CCC/endometrial endometrioid carcinoma

(EEC) displayed identical mutations in TP53 and PTEN, aswell as microsatellite instability, in both components.17 Theauthors concluded that a monoclonal origin for bothcomponents in each of these mixed carcinomas waslikely, and that CCC “represent(s) a heterogeneous groupof tumors that arise through different pathogeneticpathways.”17 At the morphologic level, diagnostic diffi-culties may arise due to the somewhat nebulous nature ofCCC’s diagnostic criteria, and the fact that some tradi-tionally CCC-associated morphologic features, includinghobnail cells, clear cells, and hyaline globules, amongothers, are not entirely histotype specific. In 1 recentanalysis of a single institution’s experience, a remarkablyhigh proportion—72.5%—of all CCCs were reportedlyseen in association with other histotypes of endometrialcarcinoma,18 as compared with 30.5% of ESCs at the sameinstitution.19

Given the totality of these reports, it is possible thatthe clinicopathologic heterogeneity that has been asso-ciated with CCC is related to variations in how patho-logists diagnose this histotype. Accordingly, the currentstudy was conducted to assess the level of interobservervariability in the morphologic diagnosis of endometrialcarcinomas with clear cells by gynecologic pathologists,and to comparatively describe the cases of putative CCCwith and without significant interobserver variability.

MATERIALS AND METHODS

Case SelectionThis study was approved by the institutional review

board at Vanderbilt University (Institutional ReviewBoard #110642) and was based on archived pathologicmaterial. The 35 study cases were retrieved from the filesof the Department of Pathology at Vanderbilt UniversityMedical Center (Nashville, TN), Beth Israel DeaconessMedical Center (Boston, MA), and Wilford Hall MedicalCenter (San Antonio, TX). Thirty of the 35 cases werefrom Vanderbilt University Medical Center and BethIsrael Deaconess Medical Center and were identifiedfrom their electronic databases by using the search terms“clear cell” in conjunction with “uterine” or “endometrialcarcinoma” or nonsubstantive variations thereof. Thecases generated from the search were then further selectedon the basis of (1) availability of slides, (2) the presence ofat least focal (Z10% of the tumor) cells with clear cyto-plasm within the tumor (clear cells), as assessed by 1author (O.F.), and (3) the fulfillment of a broad studygoal of having in the final study set some representationof the major histotypes of endometrial carcinoma. Caseswere thus added to meet preset numerical quotas for eachhistotype. The original diagnoses for these 35 cases in-cluded CCC, ESCs/uterine papillary serous carcinomas,EEC, undifferentiated carcinoma/unclassified carcin-omas (UC), mixed carcinomas comprising variouscombinations of the aforementioned histotypes, and car-cinomas that were interpreted as being predominantly of1 histotype displaying “focal” differentiation of another

Fadare et al Am J Surg Pathol � Volume 36, Number 8, August 2012

1108 | www.ajsp.com r 2012 Lippincott Williams & Wilkins

histotype. There was no specific attempt to enrich thedataset with diagnostically problematic cases. However,all 5 of the Wilford Hall Medical Center cases were eitherconsultation material (n=4) or from study sets (n=1)and had previously been segregated for being morpho-logically noteworthy. The final dataset included slidesfrom 28 hysterectomy specimens and 7 endometrial bi-opsies that were obtained from 35 different patients.

Observers and Case ReviewsBy design, the 11 observers in this study were spe-

cialized practitioners of gynecologic pathology thatwere at least at the associate professor level and/or hadbetween 6 and 20 years of posttraining experience. Theminimum and maximum experience parameters were setto eliminate the potentially confounding effects of verylow or very high levels of experience. The overall medianexperience of the group was 10 years (mean 10.5 y; range,7 to 16 y). The entire slide set, comprising 1 slide fromeach of the 35 study cases, was shipped sequentially to all11 observers during a 6-month period. A blank form thatwas to be completed with the diagnoses after each ob-server’s slide review was also circulated. There were nopredetermined diagnostic criteria or categories, and theaforementioned form only had the following instructions:“These 35 slides are from 35 different patients. Pleasereview each slide and fill in a diagnosis. Presume the slideis representative of the entire endometrial proliferation inthe corresponding uterine cavities. Patient 32 received acourse of progestins in the months before her hysterec-tomy. The other patients have no known relevant clinicalhistories.” The initial morphologic evaluation of all caseswas performed by 2 authors (O.F. and V.P.). All caseswere assessed for the presence and extent (0 to 3+ scale)of 44 morphologic features, including (Figs. 1–3): (1) tu-mor architecture [papillary, solid, tubulocystic, glandular;the nature of the papillae, if present: small and roundpapillae (ie, rounded or oval with stromal cores thattypically occupied >50% of the diameter of the papillae,and which were typically lined by no more than 25 epi-thelial cells), long and slender papillae (ie, >0.5mm inlength, several times as long as it was wide, and possessinga fibrovascular core), tufting or budding papillae, com-plex and branching papillae (ie, papillae displaying hier-archical branching, irrespective of the nature of itssubsidiary or terminal units), hyalinized papillae (ie,papillae with hyalinized stromal cores), inflammatorypapillae (ie, papillae with prominent fibrovascular corestromal inflammation), nuclear stratification on papillae];(2) cytologic features [clear and/or eosinophilic cyto-plasm, well-defined membranes, hobnail cells, columnar,flat, or cuboidal cell shapes, overt squamous differ-entiation with or without cytoplasmic clarity, prominentnucleoli, hyperchromasia, eccentrically placed nuclei inthe cell, nuclear pseudostratification (of >3 cell layers),and nuclear grade. Nuclear grade was graded on a3-tiered scale, with grade 1 nuclei showing general uni-formity in size and shape, grade 2 nuclei showing a 2-fold

variation in nuclear shape and/or size, and grade 3 nuclei(synonymous with the presence of severe pleomorphism)displaying a 3-fold or greater variation in nuclear shapeand/or size as compared with the background cells(Fig. 1E); the “predominant” nuclear grade was the nu-clear grade for at least half of the cells for the slide.Diffuse grade 3 nuclei were considered to be present whenat least a third of the tumoral areas displayed foci withconfluent sheets of tumor cells with grade 3 nuclei];(3) stroma in the nonpapillary areas (inflammatory,fibroblastic, hyalinized, myxoid): fibroblastic stroma isessentially a nonmyxoid, nonhyalinized, nonsignificantlyinflamed stroma; that is, it was the default description ofthe stroma when none of the other features were present;(4) size of the lesional area on the slide; (5) presence of atumor area on the slide that was devoid of clear cells and/or was otherwise cytoarchitecturally distinct from thebackground (non–clear cell area). A non–clear cell areawas defined as an area that occupied a substantial portion(Z10%) of the tumor on the slide, which was devoid ofclear cells and was cytoarchitecturally distinct from theclear cell areas. For cases with a non–clear cell area,morphologic features were evaluated in both regions; (6)psammoma bodies; (7) targetoid bodies; (8) open tumorrings; (9) necrosis; (10) lymphovascular space invasionevident on the evaluated slide; (11) myometrial invasionevident on the evaluated slide; (12) hyaline bodies, (13) adistinct intraepithelial growth pattern of the lesion in thebackground, otherwise non-neoplastic endometrium; and(14) mitotic figures (MF) per 10 high-power fields (HPF;assessed with an �40 objective—0.55mm in diameter—and counted in the most mitotically active area). Theevaluated features are based in part on the previouslyestablished morphologic profile of ovarian CCC.20 Mor-phologic features 1, 2, and 3 as outlined above werescored on a 0 to 3+ scale, with 0 being indicative of theabsence of the feature, and scores 1+ (minimal), 2+, and3+ being indicative of the presence of the feature in<33%, 33% to 66%, and >66% of the tumor, re-spectively. Morphologic features 5 to 13 were scored in abinary manner (present or absent).

Statistical AnalysisInterobserver variation between individual patho-

logists regarding their rendered diagnoses was assessedusing k statistics21 and the following benchmarks: 0 to 0.2(slight agreement), 0.21 to 0.4 (fair agreement), 0.41 to 0.6(moderate agreement), 0.61 to 0.8 (substantial agree-ment), and 0.81 to 1 (near-total to total agreement).Subgroups of cases (see below) were compared regardinga variety of morphologic features using the Fisher exactor Student t tests as appropriate. A backward stepwiselogistic regression analysis was also performed, in whichall candidate variables were initially considered, andvariables that did not significantly predict the confirmedCCC group were progressively eliminated. A 2-tailedP value of <0.05 was considered to be statisticallysignificant in all analyses.

Am J Surg Pathol � Volume 36, Number 8, August 2012 Diagnosis of Endometrial Carcinomas With Clear Cells

r 2012 Lippincott Williams & Wilkins www.ajsp.com | 1109

A B

C D

E F

FIGURE 1. Depictions of selected morphologic features (the images are not necessarily representative of the entire tumor thatwas evaluated). A, Cuboidal cells with clear cytoplasm and well-defined nuclear membranes; predominant nuclear grade 2; raregrade 3 nuclei (arrows) (from case 2; classified as CCC by 10 of 11 observers). B, Cells with clear to eosinophilic cytoplasm andwell-defined nuclear membranes; abundant hyaline globules (from case 27; classified as CCC by 10 of 11 observers). C, Glandslined by cuboidal and hobnail cells; significant nuclear pseudostratification is absent (from case 5; classified as CCC by 10 of 11observers). D, Glands and papillae, variably lined by pseudostratified and nonstratified nuclei (from case 13; classified as CCC andEEC by 4 and 3 of 11 observers, respectively). E, Foci of diffuse grade 3 tumor nuclei in the upper field). Foci of grade 1 tumornuclei in lower field (from case 24, classified as CCC by 11 of 11 observers). F, Tubulocystic pattern with cystic units that are linedby flat cells (from case 31; classified as CCC by 9 of 11 observers).



FIGURE 2. Depictions of selected morphologic features (the images are not necessarily representative of the entire tumor thatwas evaluated). A, Small rounded papillae with stromal hyalinization, and lined by hobnail, cuboidal, and flat cells withoutsignificant nuclear pseudostratification (from case 24; classified as CCC by 11 of 11 observers). B, “Inflammatory papillae” andlong and slender papillae lined by cuboidal cells with eosinophilic cytoplasm and grade 1 nuclei (from case 2; classified as CCC by10 of 11 observers). C, Long slender papillae lined by columnar cells with and without nuclear pseudostratification (from case 14;classified as EEC by 11 of 11 observers). D, Budding papillae, predominantly nuclear grade 2, scattered grade 3 nuclei; prominentnucleoli (from case 6; variable responses). E, Papillae with nuclear pseudostratification (from case 14; classified as EEC by 11 of 11observers). F, Distinct non–clear cell area in lower field (from case 26; classified as EEC by 5 observers, and classified as mixedcarcinoma containing at least EEC and CCC by 5 observers).



FIGURE 3. Depictions of selected morphologic features (the images are not necessarily representative of the entire tumor thatwas evaluated). A, Solid pattern in a case that was classified as CCC by all observers (from case 10). B–E, Solid patterns in somecases that received a variety of responses each [(A) case 3; (C) case 29; (D) case 16; (E) case 26]. Case 16 displayed rare foci ofkeratinization in an otherwise uniformly solid tumor. F, An example of a case with high interobserver variability (from case 13;classified as CCC and EEC by 4 and 3 of 11 observers, respectively).



RESULTS

Interobserver VariabilityGiven the absence of preset diagnostic categories, a

wide variety of responses were received. For the purposesof statistical and subsequent analyses, the following as-sumptions were made: (1) cases diagnosed as “high-gradeadenocarcinoma with features of clear cell carcinoma”(n=7) were coded as CCC; (2) “high-grade adenocarci-noma with clear cells,” “high-grade adenocarcinoma, un-classified,” “adenocarcinoma, unclassified,” “anaplasticcarcinoma,” and “undifferentiated carcinoma” (total n=13)were all coded as UC; (3) adenosquamous carcinoma(n=4), “endometrioid (adeno)carcinoma with mucinousdifferentiation,” and “endometrioid (adeno) carcinomawith squamous differentiation” were all coded as EEC(Table 1). Thus coded, the general distribution of the385 (35�11) possible diagnoses was as follows: CCC(n=158), EEC (n=125), mixed carcinoma (n=38),ESC (n=32), UC (n=15), carcinosarcoma (n=4), di-agnosis deferred (ie, a definitive diagnosis was not renderedpending immunohistochemistry and/or other ancillary

studies, n=13). The k values between any pair of ob-servers ranged from 0.18 to 0.69 (combined: 0.46; SD 0.08),which is indicative of a “moderate” level of interobserveragreement (Table 2). If potential outliers are removed (ie,the observer with lowest k value, or the observers with thelowest and highest k values, or the observer with thehighest k value), the recalculated combined k value stillfalls in the “moderate” level of the interobserver agreementin each of the 3 parenthesized scenarios. The k values forEEC, CCC, ESC, mixed EEC/CCC, and mixed CCC/ESCwere 0.58, 0.62, 0.35, 0.36, and �0.02, respectively (com-bined k value for all histotypes: 0.46). The distributionof diagnoses and a description of the frequencies ofvarious morphologic features are outlined in Supple-mentary Tables 1 and 2 respectively. (Supplemental DigitalContent, http://links.lww.com/PAS/A134).

“Confirmed CCC” and “Possible CCC”:Morphologic Features

The 35 cases were classified into 2 subgroups: a group1 of “confirmed CCC” (n=14) that comprised cases di-agnosed as such by at least 8 (73%) of the 11 observers, and

TABLE 1. Diagnostic Frequencies for the Various Histotypes

No. Diagnoses (%, Approximated)

CCC Endometrioid Carcinoma Serous Carcinoma UC Carcinosarcoma Mixed Carcinoma Diagnosis Deferred

Case #1 0 (0) 11 (100) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)Case #2 10 (91) 0 (0) 0 (0) 0 (0) 0 (0) 1 (9) 0 (0)Case #3 4 (36) 4 (36) 0 (0) 1 (9) 0 (0) 1 (9) 1 (9)Case #4 0 (0) 10 (91) 0 (0) 0 (0) 0 (0) 1 (9) 0 (0)Case #5 10 (91) 0 (0) 0 (0) 0 (0) 0 (0) 1 (9) 0 (0)Case #6 2 (18) 1 (9) 2 (18) 1 (9) 0 (0) 4 (36) 1 (9)Case #7 9 (82) 2 (18) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)Case #8 0 (0) 10 (91) 0 (0) 0 (0) 1 (9) 0 (0) 0 (0)Case #9 2 (18) 4 (36) 2 (18) 1 (9) 0 (0) 2 (18) 0 (0)Case #10 11 (100) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)Case #11 0 (0) 4 (36) 0 (0) 0 (0) 0 (0) 7 (64) 0 (0)Case #12 0 (0) 11 (100) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)Case #13 4 (36) 3 (27) 2 (18) 1 (9) 0 (0) 1 (9) 0 (0)Case #14 0 (0) 11 (100) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)Case #15 0 (0) 7 (64) 0 (0) 0 (0) 0 (0) 3 (27) 1 (9)Case #16 1 (9) 4 (36) 0 (0) 1 (9) 2 (18) 0 (0) 3 (27)Case #17 0 (0) 0 (0) 9 (82) 0 (0) 0 (0) 0 (0) 2 (18)Case #18 0 (0) 11 (100) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)Case #19 11 (100) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)Case #20 8 (73) 0 (0) 2 (18) 0 (0) 0 (0) 0 (0) 1 (9)Case #21 2 (18) 1 (9) 6 (54) 1 (9) 0 (0) 0 (0) 1 (9)Case #22 0 (0) 11 (100) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)Case #23 9 (82) 1 (9) 0 (0) 1 (9) 0 (0) 0 (0) 0 (0)Case #24 11 (100) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)Case #25 1 (9) 4 (36) 0 (0) 0 (0) 0 (0) 6 (54) 0 (0)Case #26 1 (9) 5 (45) 0 (0) 0 (0) 0 (0) 5 (45) 0 (0)Case #27 10 (91) 0 (0) 0 (0) 1 (9) 0 (0) 0 (0) 0 (0)Case #28 8 (73) 0 (0) 2 (18) 0 (0) 0 (0) 1 (9) 0 (0)Case #29 3 (27) 1 (9) 0 (0) 6 (54) 0 (0) 0 (0) 1 (9)Case #30 1 (9) 1 (9) 4 (36) 1 (9) 0 (0) 3 (27) 1 (9)Case #31 9 (82) 1 (9) 0 (0) 0 (0) 0 (0) 0 (0) 1 (9)Case #32 1 (9) 6 (54) 3 (27) 0 (0) 1 (9) 0 (0) 0 (0)Case #33 11 (100) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)Case #34 10 (91) 0 (0) 0 (0) 0 (0) 0 (0) 1 (9) 0 (0)Case #35 9 (82) 1 (9) 0 (0) 0 (0) 0 (0) 1 (9) 0 (0)

Bold indicates diagnosis that was rendered with the highest frequency.



http://links.lww.com/PAS/A134

a group 2 of “possible CCC” (n=13) that comprised casesdiagnosed as CCC by Z1 but <8 observers. Given the 14cases in group 1 and the 11 observers, there were 154possible diagnoses, 136 of which were CCC. The dis-tribution of the remaining 18 diagnoses rendered was asfollows: EEC, n=5; ESC, n=4;, UC, n=2; mixed car-cinoma, n=5 (3 CCC/ESC, 2 CCC/EEC); diagnosis de-ferred, n=2. As such, there was no overwhelminglyprevalent non-CCC alternative diagnosis in group 1. Thecorresponding distribution for the 143 (13�11) possiblediagnoses in group 2 was as follows: CCC, n=38; EEC,n=34; ESC, n=23; UC, n=13; carcinosarcoma, n=3;mixed carcinoma, n=23 (10 EEC/CCC, 4 EEC/ESC,6 EEC/ESC/CCC, 3 CCC/ESC); diagnosis deferred, n=9.Groups 1 and 2 are compared with regard to a variety ofmorphologic features in Table 3. As expected, given that allcases in both groups were classified by at least 1 observer asCCC, there was some degree of morphologic overlap be-tween the 2 groups. Nevertheless, clear differences werediscernable. Morphologic features that were highly pre-valent (present in Z50% of cases) in group 1 includedpapillary growth pattern, solid architecture, nonspecificglands, small round papillae, cells with eosinophilic and/orclear cytoplasm, hobnail cells, prominent nucleoli, hyper-chromasia, necrosis, glands and papillae being lined bycuboidal or flat cells, and a fibroblastic, nonmyxoid stroma(Figs. 1, 2). Many of these features were also seen inZ50% of the group 2 cases, including: papillary, glandular,and solid growth patterns; cells with eosinophilic cyto-plasm, prominent nucleoli, and fibroblastic, nonmyxoidstroma; and necrosis. The following features were com-paratively more prevalent in group I in a statistically sig-nificant manner: papillae with hyalinized cores in Z33% ofthe lesion (P=0.016), clear cells in Z33% of the lesion(P=0.046), hyperchromasia in Z33% of the lesion(P=0.03), and glands and papillae lined by low cuboidalor flat cells (P=0.01). Two features that approached butdid not attain statistical significance (P=0.05 to 0.099) inthis regard for group 1 included hobnail cells in Z33% ofthe lesion (P=0.098) and the presence of any tubulocysticpattern (P=0.098). Morphologic features that were com-

paratively more prevalent in group 2 in a statistically sig-nificant manner included nuclear pseudostratificationin >3 cells on the papillae (P=0.004), nuclear pseudos-tratification in glands in Z33% of the lesion (P=0.016),glands and papillae lined by columnar cells (P=0.012),long and slender papillae (P=0.046), the presence ofdiffuse grade 3 nuclei (P=0.033), and the presence of adistinct non–clear cell area (P=0.014). Long and slenderpapillae in Z33% of the lesion (P=0.08) appeared to bemore prevalent in group 2 but did not attain a statisticallysignificant difference when compared with group 1. Thegroups did not significantly differ with regard to the le-sional size and most other features (Table 3). Although themitotic index of group 2 cases (mean 11MF/10HPF) washigher than that of the group 1 cases (mean 5.3MF/10HPF), this difference did not attain statistical sig-nificance (P=0.11). Most cases in group 1 had multifocalcells with grade 3 nuclei intermixed with cells with grade 2nuclei; however, in only 1 group 1 case was there confluentsheets of tumor cells with grade 3 nuclei in Z33% of thelesion (diffuse grade 3 nuclei). By combining selected pos-itive and negative attributes that significantly distinguishedgroups 1 and 2 on these univariate analyses, the followingapproximate morphologic profile emerged for cases thatwere diagnosed as CCC in this study: papillae with hyali-nized cores in Z33% of the lesion, clear cells in Z33% ofthe lesion, hyperchromasia in Z33% of the lesion, theabsence of nuclear pseudostratification in >3 cells on thepapillae, the absence of nuclear pseudostratification inglands in Z33% of the lesion, the absence of diffuse grade3 nuclei, the absence of long and slender papillae in Z33%of the lesion, and glands and papillae lined by cuboidal toflat, noncolumnar cells. In the backward stepwise logisticregression analysis, 3 features from the profile that pre-dicted the confirmed CCC group included: (1) no to mini-mal (score 0 to 1, respectively) diffuse sheets of grade 3nuclei [P=0.025; 95% confidence interval (CI), 0.0266-0.363]; (2) no to minimal nuclear stratification in glandsand papillae (P=0.040; 95%CI, �0.228 to �0.0054); and(3) glands and papillae lined by cuboidal to flat, non-columnar cells (P=0.008; 95% CI, 0.0911-0.566).

TABLE 2. k Values Between Any Pair of Observers

Observers* Ob 1 Ob 2 Ob 3 Ob 4 Ob 5 Ob 6 Ob 7 Ob 8 Ob 9 Ob 10 Ob 11 Average j Values

Ob 1 NA 0.19 0.43 0.22 0.29 0.18 0.29 0.30 0.33 0.20 0.26 0.27

Ob 2 0.19 NA 0.40 0.56 0.46 0.48 0.43 0.55 0.33 0.60 0.49 0.45

Ob 3 0.43 0.40 NA 0.37 0.46 0.34 0.39 0.48 0.37 0.44 0.52 0.42

Ob 4 0.22 0.56 0.37 NA 0.50 0.57 0.55 0.63 0.43 0.53 0.50 0.49

Ob 5 0.29 0.46 0.46 0.50 NA 0.53 0.60 0.60 0.37 0.58 0.55 0.49

Ob 6 0.18 0.48 0.34 0.57 0.53 NA 0.59 0.59 0.39 0.57 0.53 0.48

Ob 7 0.29 0.43 0.39 0.55 0.60 0.59 NA 0.57 0.45 0.59 0.64 0.51

Ob 8 0.30 0.55 0.48 0.63 0.60 0.59 0.57 NA 0.55 0.67 0.64 0.56

Ob 9 0.33 0.33 0.37 0.43 0.37 0.39 0.45 0.55 NA 0.47 0.48 0.42

Ob 10 0.20 0.60 0.44 0.53 0.58 0.57 0.59 0.67 0.47 NA 0.69 0.53

Ob 11 0.26 0.49 0.52 0.50 0.55 0.53 0.64 0.64 0.48 0.69 NA 0.53

Average k values 0.27 0.45 0.42 0.49 0.49 0.48 0.51 0.56 0.42 0.53 0.53 0.46

*Observer numbers were assigned randomly.Bold value emphasize the average Kappa values are distinct from the othersNA indicates not applicable; Ob, Observer.



The number of diagnoses rendered for each of the 35cases ranged from 1 to 6 (of the 7 possible diagnostic cate-gories in Table 1, including the diagnosis deferrals). Ninecases (numbers 3, 6, 9, 13, 16, 21, 29, 30, and 32) wereclassified as being the most “diagnostically problematic” onthe basis of the fact that the panel of observers rendered atleast 4 different diagnoses for each of them. All 9 cases fellinto the aforementioned group 2 of “possible CCC” cases,indicating that each of the 9 cases was considered by at least

1 observer to represent CCC. Three (33%) of these 9 prob-lematic cases (cases 3, 16, and 29) had a similar morphologicpattern: composed predominantly or exclusively of sheets oftumor cells with variably clear cytoplasm (Figs. 3B–D). Cases9 and 13 were glandular and/or papillary proliferationswhose only CCC-like feature is the presence of clear cells,and whose composite of pathologic features was not clearlydiagnostic of another histotype (Fig. 3F). The remaining 4cases were morphologically heterogenous.

TABLE 3. Selected Morphologic Features: A Comparison of “Confirmed CCC” and “Possible CCC” Cases

Morphologic Features Group 1 (Confirmed CCC) Group 2 (Possible CCC) P

ArchitectureAny papillae present 10/14 10/13 1Any solid component present 9/14 8/13 1Any tubulocystic component present 4/14 0/13 0.098Glands present 11/14 12/13 0.59Any small round papillae 9/14 6/13 0.45Small round papillae Z33% 5/14 4/13 0.55Any long and slender papillae (>0.5mm) 2/14 7/13 0.046Long and slender papillae (>0.5mm) in Z33% of lesion 1/14 5/13 0.08Any tufting or budding 2/14 5/13 0.21Complex branching papillae 4/14 4/13 1Any papillae with hyalinized cores 6/14 3/13 0.24Papillae with hyalinized cores in Z33% of lesion 6/14 0/13 0.016Inflammatory cores 4/14 5/13 1Nuclear pseudostratification (>3 cells) on papillae 1/14 8/13 0.004

CytologyAny cells with clear cytoplasm 14/14 13/13 1Clear cells in Z33% 12/14 6/13 0.046Any cells with eosinophilic cytoplasm 12/14 12/13 1Well-defined cell membranes in glandular/papillary regions 5/14 3/13 0.68Well-defined cell membranes in solid regions 9/9 6/8 0.2Hobnail cells present 8/14 3/13 0.12Hobnail cells in Z33% of lesion 4/14 0/13 0.098Overt squamous differentiation 0/14 0/13 1Predominant cell type lining glands and papillae is cuboidal or flat 9/11 3/12 0.03Predominant cell type lining glands and papillae is columnar 2/11 9/12 0.012Any grade 3 nuclei present 5/14 11/13 0.018Diffuse grade 3 nuclei present 1/14 6/13 0.033Predominant nuclear grade: grade 2 12/14 10/13 0.65Prominent nucleoli 7/14 10/13 0.24Hyperchromasia Z33% of lesion 7/14 1/13 0.033Eccentric Nuclei 1/14 1/13 1Nuclear pseudostratification (>3 cells) in glands 6/14 8/13 0.45Nuclear pseudostratification (>3 cells) in glands in Z33% of lesion 0/14 5/13 0.016

Stroma (nonpapillary areas)Inflammatory 11/14 8/13 0.42Fibroblastic 14/14 13/13 1Hyalinized 7/14 5/13 0.70Myxoid 2/14 1/13 1

Other featuresSize of lesional area* 1.2 1.5 0.135Psammoma bodies 2/14 1/13 1Targetoid bodies 2/14 0/13 0.48Open tumor rings 1/14 0/13 1Necrosis 10/14 9/13 1Lymphovascular space invasion 0/14 4/13 0.1Myometrial invasion 7/10 8/11 1Hyaline globules 6/14 4/13 0.69Foci of intraepithelial tumor growth present in background endometrium 1/10 2/11 1Non–clear cell area present 0/14 6/13 0.014Mitotic index (per 10HPF)* 5.3 11 0.11

Fisher exact test and Student t test.



DISCUSSIONMost of the nonendometrioid histotypes of endo-

metrial carcinoma were described in the last 65 years,before which histologic grading was a much more clin-ically significant endeavor for pathologists evaluatingendometrial carcinomas than histologic typing. However,with the description of CCC and ESC and their attendantclinical implications, the accurate histotyping of endo-metrial carcinomas has evolved into an activity of para-mount clinical significance, as adjuvant treatment optionsand general prognostication may vary significantly byhistotype.22

A neoplastic lesion in the uterus that is composedpredominantly of clear cells may represent a wide varietyof lesions, including CCC or putative precursor lesions,EEC and other clear cell rich carcinomas, epithelioidsmooth muscle tumors, gestational trophoblastic tumors,perivascular epithelioid tumors (PEComa), or metastaticneoplasia.7,23–27 This differential diagnosis can be readilyresolved in the vast majority of cases by paying carefulattention to morphologic detail, clinicopathologic corre-lation, and the judicious application of immunohisto-chemistry. The few cases that cannot be so resolved are,in our experience, carcinomas, wherein the diagnostic dif-ficulty is in histotyping. There are several factors to whichthis is potentially attributable. Some traditionally CCC-associated morphologic features are not histotype specific.7

EEC not uncommonly displays cytoplasmic clarity relatedto the accumulation of glycogen, lipid, mucin, or unknownfactors.1,28,29 ESC commonly displays a significant pop-ulation of hobnail cells, and some ESCs display foci ofcytoplasmic clarity.7 Furthermore, some CCCs have beenreported to show ESC-like architectural features.30 Theimmunohistochemical marker hepatocyte nuclear factor 1bhas some diagnostic utility as a CCC marker,31 but itsspecificity for the clear cell histotype is suboptimal.32–34

Therefore, at present, ancillary studies are more useful inexcluding some histologic mimics than in supporting thediagnosis of CCC, which is almost exclusively a morpho-logic exercise.

CCC was defined in the aforementioned study ofKurman and Scully6 as a carcinoma that was “composedpredominantly of cytologically malignant clear [non-squamous] and/or hobnail cells growing in solid, tubular,papillary or cystic patterns,” indicating that the diagnosisshould be based on a composite of cytologic and archi-tectural findings. However, the diagnostic approach tocases that display a subtotal complement of features, es-pecially when encountered in a biopsy or curettage, andthe level of specificity or diagnostic weight that should beassigned to each feature in this scenario remain unclear.In the current study, we have demonstrated a moderatelevel of interobserver variability in the classification ofendometrial carcinomas with clear cells even by this panelof experienced and specialized gynecologic pathologists.Our findings suggest that there are morphologically“classic” cases of CCC at one end of the spectrum and casesthat may display only a few features that are suggestive ofthat diagnosis on the other, and the degree to which cases

that are toward the latter end of the spectrum are mergedwith the CCC group varies by observer. Given the sig-nificant differences between the histotypes of endometrialcarcinoma with regard to prognostication and therapy, ourfindings suggest the need for a better definition of inclusionand exclusion morphologic criteria for CCC and therequisite stringency of application for such criteria. Thus,we sought to comparatively describe the morphologic fea-tures of cases that did and did not display significant in-terobserver variability. The resultant morphologic profile ofour “confirmed CCC” cases (papillae with hyalinized coresin Z33% of the lesion, clear cells in Z33% of the lesion,hyperchromasia in Z33% of the lesion, the absence ofnuclear pseudostratification in >3 cells on the papillae, theabsence of nuclear pseudostratification in glands in Z33%of the lesion, the absence of diffuse sheets of grade 3 nuclei,the absence of long and slender papillae in Z33% of thelesion, and glands and papillae lined by cuboidal to flat,noncolumnar cells) should not be conceptualized as a def-inition for CCC, but as a set of morphologic features thatfavor CCC over differential considerations. More im-portantly, it is the absence of many of these features in aclear cell–rich endometrial carcinoma that should raise thepossibility of an alternative diagnosis to CCC.

One morphologic pattern that appeared to be asource of diagnostic variability was the near-exclusive orexclusively solid pattern of clear cells. This pattern wasseen in 3 (33%) of our 9 most diagnostically problematiccases, and the principal differential considerations forthese cases included CCC, UC, and grade 3 EEC. Theseare important distinctions, given the notably adverseprognostic significance of the UC diagnosis,8,35–37 theneed to preserve the biological purity of cases classified ineach category to ensure the accuracy of associatedtranslational research and clinical trials, and the fact thatUC has an association with microsatellite instability andmay occur in young women.38 One of the cases with anexclusively solid pattern (case 16) also showed foci ofsquamous differentiation (Fig. 3D), which may explainwhy the most frequent response (4 of 11) was EEC.Parenthetically, 2 groups have allowed otherwise classiccases of UC that display foci of the so-called “abruptkeratinization” to still be classified as such.36,37 Im-portantly, 10 of 11 observers did not classify the lesion incase 16 as CCC, although 3 deferred their diagnoses.Most CCCs display an admixture of histologic pat-terns,4,33 and an endometrial CCC comprised entirely ofthe solid pattern in a resection specimen would be un-usual. Solid areas were identified in 10 (71%) of our 14group 1 cases but in none was it the exclusive pattern.These solid areas were composed of cells with abundantclear to eosinophilic cytoplasm, well-defined nuclearmembranes, predominantly grade 2 nuclei, and scatteredcells with grade 3 nuclei. Other authors have previouslyreported a similar morphologic profile: “sheets of clearcells with prominent hyperchromatic nuclei, voluminousclear cytoplasm, and distinct cell borders.”4 Notably,groups 1 and 2 did not differ in a statistically significantmanner with regard to the general frequencies of these



features, suggesting that the profile is not specific andwould not be reliable in classifying a purely solid tumor asCCC if there are no other diagnostic features (Fig. 3).However, although the profile is not specific, it certainlyappears to be highly sensitive, and a significant deviationfrom this profile in the solid region of a clear cell–richendometrial carcinoma argues against a diagnosis ofCCC. UC, a differential diagnostic consideration, is typ-ically composed of sheets of discohesive, relatively mo-notonous, occasionally pleomorphic tumor cells andusually does not display cohesive cells with well-definedmembranes.8,35–37 This differential can easily be resolvedby immunohistochemical studies for pankeratins, as UCsare typically negative or show only focal or patchy pos-itivity, whereas CCC is diffusely immunoreactive.35–37

The second potential source of diagnostic variability,as was exemplified in cases 9 and 13 from the diagnosticallyproblematic group (Fig. 3F), is a histologic pattern ofglandular and/or papillary proliferations whose primaryCCC-like feature is the presence of clear cells and whosecomposite of pathologic features is not clearly diagnostic ofanother histotype. This represents another scenario whereinimmunohistochemistry may be beneficial, as EEC is usuallyestrogen receptor (ER) and progesterone receptor (PR)immunoreactive, and CCCs are usually ER and PR neg-ative.7,30 However, even if such lesions are ER and PRnegative, it is unclear whether they can be classified as CCCin the absence of other diagnostic features. In an informalpoststudy survey, the 11 observers were asked how theywould classify “an endometrial carcinoma composed ofglandular and/or papillary proliferations whose only CCC-like feature is the presence of clear cells and whose com-posite of pathologic features is not clearly diagnostic ofanother histotype.” They were given 4 options: CCC,“adenocarcinoma, unclassified or a descriptive diagnosis(such as “adenocarcinoma with clear cells”),” “undifferent-iated carcinoma,” and “other.” Eight of the 9 respondentschose the second option (adenocarcinoma, unclassified or adescriptive diagnosis (such as “adenocarcinoma with clearcells), whereas 1 chose CCC. A second question asked howthey would classify such a lesion if it displayed an im-munophenotype similar to ovarian CCC (hepatocyte nu-clear factor 1b positive, ER negative, PR negative, and p53wild type/negative). Three of 8 observers responded bysaying that they would not alter their original diagnoses,and the reason stated by all 3 was that the aforementionedimmunoprofile has not been validated in endometrial CCC.The remaining 5 responded by saying that they wouldeither change their diagnosis to CCC (n=2) or issue acommentary favoring CCC (n=3) depending on howsuggestive of CCC they believed the overall morphologicprofile of the case was. As noted previously, immuno-histochemical studies are most useful in separating differ-ential considerations. However, even after these analyses,there likely remains a group of endometrial carcinomaswith clear cells that cannot be classified by conventionalcriteria. Until the clinicopathologic features of these casesare clarified, we do not recommend that they be classified asCCC at present time.

There are some potential limitations associated withour study design, and our findings should accordingly beevaluated within the context of these limitations. First, wedid not review all endometrial carcinomas that were seenduring the search period, and reports without the “clearcell” search phrase were therefore not represented inthe results generated from the search. Cases that wereerroneously not classified as CCC, and whose morpho-logic features may have provided some insights into whythey were not classified as such, were not captured. Inaddition, the “possible CCC” cases that were capturedwould be expected to overrepresent cases signed out bypathologists whose practice patterns are to documentfeatures such as clear cells in any histotype of endometrialcarcinoma. Second, the absence of preset diagnostic cate-gories was designed to mirror the realistic clinical scenariobut probably also served to decrease interobserver agree-ment. Third, a large number of morphologic features wereevaluated in a relatively small dataset, and this may have ledto some degree of model overfitting. Although the variablesselected by this model make clinical sense, it still needs to bevalidated in a test analysis of other data, and efforts areunderway to collect this confirmatory data. Finally, only 1slide from each case was evaluated. Endometrial carcinomasmay display significant cytoarchitectural heterogeneity, andin real practice, before a diagnosis is rendered, all slidesassociated with a given case will be evaluated to put thefindings in any given one in context.

In summary, we have demonstrated that (1) thediagnosis of endometrial carcinomas with clear cells bygynecologic pathologists based solely on their morpho-logic features is associated with a moderate level ofinterobserver variability; (2) factors to which this inter-observer variability may be attributed include the overlapbetween CCC and other histotypes regarding somepotentially diagnostic morphologic features, the sub-totality of potentially diagnostic features in many cases,and specific morphologic patterns, including the near-exclusive or exclusively solid pattern of clear cells, orglandular/papillary proliferations whose only CCC-likefeature is clear cells. The latter are 2 diagnostic scenariosin which the application of ancillary testing, such as im-munohistochemistry, will likely be of maximal utility; (3)there is a morphologic profile that characterizes cases thatgynecologic pathologists more uniformly classify as CCC,and the features therein are therefore highly supportive ofthe diagnosis of CCC in an endometrial carcinoma withclear cells. Conversely, in the differential diagnosis be-tween CCC and other histotypes, the absence of themorphologic features in the aforementioned profile orbroad and significant qualitative deviations from it issuggestive of a diagnosis other than CCC.

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http://www.nccn.org

ORIGINAL ARTICLES

Acne severity grading: Determining essential clinicalcomponents and features using a Delphi consensus

Jerry Tan, MD,a Barat Wolfe, MA,b Jonathan Weiss, MD,c Linda Stein-Gold, MD,d Joseph Bikowski, MD,e

James Del Rosso, MD,f Guy F. Webster, MD,g Anne Lucky, MD,h Diane Thiboutot, MD,i Jonathan Wilkin, MD,j

James Leyden, MD,k and Mary-Margaret Chren, MDl

Windsor, Ontario, Canada; Atlanta, Georgia; Detroit, Michigan; Columbus and Cincinnati, Ohio;

Las Vegas, Nevada; Philadelphia and Hershey, Pennsylvania; and San Francisco, California

From

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Fund

Background: There are multiple global scales for acne severity grading but no singular standard.

Objective: Our objective was to determine the essential clinical components (content items) and features(property-related items) for an acne global grading scale for use in research and clinical practice using aniterative method, the Delphi process.

Methods: Ten acne experts were invited to participate in a Web-based Delphi survey comprising 3 iterativerounds of questions.

Results: In round 1, the experts identified the following clinical components (primary acne lesions,number of lesions, extent, regional involvement, secondary lesions, and patient experiences) and features(clinimetric properties, ease of use, categorization of severity based on photographs or text, andacceptance by all stakeholders). In round 2, consensus for inclusion in the scale was established forprimary lesions, number, sites, and extent; as well as clinimetric properties and ease of use. In round 3,consensus for inclusion was further established for categorization and acceptance. Patient experienceswere excluded and no consensus was achieved for secondary lesions.

Limitations: The Delphi panel consisted solely of the United States (U.S.)ebased acne experts.

Conclusion: Using an established method for achieving consensus, experts in acne vulgaris concluded thatan ideal acne global grading scale would comprise the essential clinical components of primary acnelesions, their quantity, extent, and facial and extrafacial sites of involvement; with features of clinimetricproperties, categorization, efficiency, and acceptance. ( J Am Acad Dermatol 2012;67:187-93.)

Key words: acne; consensus; Delphi; global severity; grading.

Abbreviations used:

CASS: Comprehensive Acne Severity ScaleECLA: Echelle de Cotation des L�esions d’Acn�eFDA: Food and Drug AdministrationGAGS: Global Acne Grading SystemIQR: interquartile range

INTRODUCTIONSeverity is the most important clinical feature

upon which clinicians establish recommendationsfor acne treatment.1 Unlike research settings, thepreferred method for acne severity assessment in

the Department of Medicine, University of Western Ontarioa;

epartment of Psychology, University of Windsorb; Gwinnett

ermatology PC and Gwinnett Clinical Research Center, Inc,

tlantac; Dermatology, Henry Ford Hospital, Detroitd; Derma-

logy, Ohio State University Medical Center, Columbuse; Valley

ospital Medical Center, Las Vegasf; Dermatology, Jefferson

edical College, Philadelphiag, Division of Pediatric Dermatol-

y, Cincinnati Children’s Hospitalh; Department of Dermatol-

y, The Pennsylvania State University College of Medicine,

ersheyi; unaffiliatedj; Department of Dermatology, University

Pennsylvaniak; and Department of Dermatology, University

California San Francisco.l

ing sources: None.

Conflicts of interest: A full list of disclosures for all authors may be

found at the end of the article.

Presented in part as a poster at the 22nd World Congress of

Dermatology, Seoul, Korea, May 24-29, 2011.

Accepted for publication September 1, 2011.

Reprints not available from the authors.

Correspondence to: Jerry Tan, MD, FRCPC, 2224 Walker Rd, Suite

300, Windsor, Ontario, Canada N8W5L7. E-mail: jerrytan@

bellnet.ca.

Published online October 31, 2011.

0190-9622/$36.00

� 2011 by the American Academy of Dermatology, Inc.

doi:10.1016/j.jaad.2011.09.005

187



http://dx.doi.org/10.1016/j.jaad.2011.09.005

J AM ACAD DERMATOL

AUGUST 2012188 Tan et al

clinical practice must be practical and time-efficient.Consequently, severity measures are typically basedon qualitative methods of severity grading ratherthan lesion counting. While there are currently morethan 25 acne grading systems in existence, there isneither a gold standard nor a standardized systemconsistently used in clinical practice.2

CAPSULE SUMMARY

d There are multiple scales for acneseverity grading but no singularstandard for use in research and clinicalpractice.

d American experts concluded that anideal acne scale should include primaryacne lesions, quantity, extent, and facialand extrafacial sites as clinicalcomponents; and clinimetric properties,categorization, efficiency, andacceptance as features.

d This is the initial phase in identifying/developing a standard for acne severitygrading to facilitate translation ofresearch findings to clinical practice.

The development of acnegrading systems and the rele-vant features of those inmorecommon use have been re-viewed elsewhere.1,3,4

Overall acne severity is de-pendent on lesion size, den-sity and type; and on thedistribution and intensity ofinvolvement at affected sites.5

This range of dimensionsleads to inherent complexityin developing a uniform,standardized, global severityclassification.6 Nevertheless,clinician-based global acneassessments are of particularvalue in clinical practice,where lesion counts are im-practical because of timeconstraints; and in clinical in-vestigations, where global
qualitative evaluation is considered to be a pivotaloutcome measure in clinical trials of acne treatment.7
While development of a standard for comprehen-sive acne severity evaluation has been a recognizedimperative in acne research for over a decade,1,2 thisgoal has not been achieved. Indeed, a recent sys-tematic review of clinician-based outcome measuresfor acne concluded that the current disparate arrayprohibits secondary trial data analysis, complicatesinterpretation of study results, and may compromisepatient care.8 Clearly, a standard for acne severityevaluation that is accepted by acne experts andclinicians would facilitate consistency in clinicalpractice, clinical trials, and epidemiologicalinvestigations.

The Delphi process is a group communicationmethod that provides group members equalopportunity to contribute to decision making whilereducing the negative effects of group interactions—including normative pressure from vocal or opinion-ated group members.9 Key features of this processinclude anonymity, iteration, controlled feedback,and statistical aggregation of group responses.10 Thisprocess imposes few constraints on the size or com-position of the panel11 and, when applied online, canbe used for geographically dispersed members in a

timely and cost-efficient manner. In dermatology, theDelphi process has recently been applied to establishthe core outcome domains for controlled trials andclinical recordkeeping in atopic eczema.12

On the basis of these considerations, our goal wasto determine the essential clinical components (ie,content-related items) and features (ie, scale-related

properties) of an acne sever-ity global grading scale thatmay be feasible in bothclinical practice and researchapplications by using a Web-based Delphi process forconsensus building.

METHODSThis study was a 3-phase

Delphi process facilitatedby an online survey metho-dology (Perseus SurveySolutions). Panelist re-sponses (in the form of anon-ymous judgments) regardingclinical and measurementitems essential for a globalacne severity scale relevantto practice and clinical trialswere collected at specific

time points (rounds) and disseminated back to thepanel using statistical measures of central tendencyfor further amplification and feedback. This processis outlined in Fig 1.

A panel of dermatologists with clinical and/orresearch interest in acne vulgaris were invited toparticipate. A steering panel of 4 dermatologists(J. T., J. W., J. B., and L. S. G.) with an interest inacne outcome measures was convened and re-quested to invite an additional 7 dermatologistsacknowledged as experts in acne research to partic-ipate as panel-members for this study.

Literature review, conceptualization of the re-search objective, and identification of survey meth-odology was conceived by a member of the steeringcommittee (J. T.). Accordingly, he was disqualifiedfrom serving on the response panel as his role was toelaborate the initial survey questions, disseminatethem to the panel, review feedback, and then pro-vide further iterations of the Delphi. Thus 10 derma-tologists served as Delphi panelists.

In the first Delphi round, 4 open-ended questionswere posed:a) What components are essential in an acne sever-

ity grading scale? (By components, we meanparts that make up the whole instrument.)

Fig 1. Schematic of the 3 Delphi rounds.

*Green PJ. The content of a college-level outdoor leadership

course. Paper presented at the Conference of the Northwest

District Association for the American Alliance for Health,

Physical education, Recreation, and Dance, Spokane, WA. 1982.

J AM ACAD DERMATOL

VOLUME 67, NUMBER 2Tan et al 189

b) Do any current acne severity grading scalesinclude the components you consider essential?

c) What features are important for an acne severitygrading scale? (By features, we mean qualities orproperties of the scale.)

d) Do any current acne severity grading scalesinclude the features you consider important?

Panel responses underwent content analysis, inwhich they were coded for initial themes reflectingsimilar meaning, and then grouped into conceptualcategories. For example, panelists consistently men-tioned the need for a scale to be valid, which wasplaced under the theme ‘‘validity.’’ Eventually thistheme and similar ones (such as reproducibility)were combined together under the rubric ‘‘clinimet-ric properties.’’ This process was also similar forother categories.

In the second round, a summary of initial re-sponses in addition to an online survey was distrib-uted. The panel was asked to grade the importanceof each component and feature identified in round1 by using a 7-point Likert scale (�3 extremelyunimportant to 13 extremely important). First, pan-elists rated the overall importance of the 6 majorclinical components and 4 major features. Next, theywere asked, if a particular component or feature wasto be included, to specify subcategories for inclusion.For example, for secondary lesions, they were askedto rate the importance of each of scarring, pigmen-tary changes, excoriations, and postinflammatoryerythema for inclusion. Open-ended commentswere also solicited from panelists.

Data were analyzed using SPSS version 17 formeasures of central tendency (ie, mean, mode,median) and level of dispersion (standard deviationand interquartile range [IQR]). Because SPSS doesnot handle Likert data with negative values, thisrange was converted to a 1 (extremely unimportant)to 7 (extremely important) scale for purposes ofanalysis. Cut off ranges for inclusion and exclusionwere based on precedent.13 Using the medians andIQRs, 4 outcomes were possible: consensus forinclusion (median [6, IQR \2), consensus forexclusion (median\2, IQR\2), consensus neutral(median \6 and [2, IQR \2), and no consensus(median of any number, IQR[2).

In the third round, a summary of responses fromthe second round was provided to the panel inaddition to another iteration of the online survey. Ifconsensus for definitive inclusion or exclusion hadbeen achieved for specific items after the secondround, panelists were not questioned further; ifconsensus neutral was achieved after the secondround, panelists were asked to categorically chooseinclusion or exclusion; if no consensus had beenachieved, panelists were asked to rate that item againusing the 7-point Likert scale. For the latter, the samecut off ranges and criteria for inclusion/exclusionfrom the second round were used. For items whererespondents were asked to include or exclude,consensus was defined as 70%.*

RESULTSIn the first round, panelists identified 6 clinical

components and 4 features as essential to the devel-opment of a global acne scale. Clinical componentsidentified by the panel included (a) primary acnelesions (either evaluating both inflammatory andnoninflammatory primary lesions together or sepa-rately); (b) secondary lesions (scarring, pigmentarychanges, excoriations, postinflammatory erythema;either evaluating all types of secondary lesionstogether, or separately); (c) quantity of lesions (eval-uated through counting, numerical ranges such as0-10 or 11-40, verbal descriptors such as few ormany); (d) extrafacial sites of involvement (chest,back, neck, shoulders); (e) extent of involvement(evaluated through proportion descriptors such asone third or entire, percentages at each site, generaldescriptors such as minimal or somewhat); and (f)patient experiences (acne-related quality of life,treatment-related bother). Features identified bythe panel included (a) clinimetric properties (valid-ity, reproducibility, discriminatory capacity, and re-sponsiveness); (b) efficiency (ease of use byclinicians, researchers, nursing staff, and easy toteach); (c) categorization (ability to categorize acneseverity based on photograph examples, descriptive

Table I. Clinical components and subcomponentsachieving consensus*

Clinical components

Clinical component item

(and subcomponents) Consensus

Delphi

round for

consensus

Consensus for inclusionPrimary lesions

(inflammatory andnoninflammatory)

Inclusion 2

Evaluated separately InclusionEvaluated together Exclusion

Quantity of lesions Inclusion 2Lesion counting InclusionNumerical range InclusionVerbal descriptors NeutralOther Neutral

Sites of involvement Inclusion 2Chest InclusionBack InclusionNeck InclusionShoulders InclusionOther No consensus

Extent of involvement Inclusion 2Proportion descriptors InclusionPercentage at each site No consensusGeneral descriptors No consensusOther Neutral

Consensus for exclusionPatient experiences Exclusion 3

No consensusSecondary lesions No consensus eIf secondary lesions were included:Scarring InclusionPigmentary changes InclusionExcoriations ExclusionPostinflammatoryerythema

No consensus

Other NeutralEvaluated separately InclusionEvaluated together Exclusion

*Consensus for inclusion (IN) = median $ 6; interquartile range

(IQR) # 2. Consensus for exclusion (OUT) = median # 2, IQR # 2.

Consensus neutral (NEUTRAL) = median\6 and[2, IQR\2. No

consensus (NONE) = median of any number, IQR $ 2. At round 3,

consensus to include or exclude (IN or OUT) = 70% agreement of

respondents.

Table II. Features and subfeatures for inclusion*

Features

Feature item (subfeatures) Consensus

Delphi

round for

consensus

Consensus for inclusionClinimetric properties Inclusion 2Validity InclusionReproducibility InclusionDiscriminatorycapacity

Inclusion

Responsivity InclusionEfficiency

(ease of use)Inclusion 2

For clinicians InclusionFor researchers InclusionFor nursing staff InclusionEasy to teach InclusionOther No consensus

Categorization ofseverity

Inclusion 3

Descriptive text InclusionPhoto examples InclusionBoth text and photos InclusionOther Exclusion

Acceptance Inclusion 3By researchers InclusionBy clinicians InclusionBy regulators InclusionBy patients ExclusionBy lay public ExclusionOther Exclusion

*Consensus for inclusion (IN) = median $ 6; interquartile range

(IQR) # 2. Consensus for exclusion (OUT) = median # 2, IQR # 2.

Consensus neutral (NEUTRAL) = median\6 and[2, IQR\2. No

consensus (NONE) = median of any number, IQR $ 2. At round 3,

consensus to include or exclude (IN or OUT) = 70% agreement of

respondents.

J AM ACAD DERMATOL


text, or both); and (d) acceptance (by all stake-holders including clinicians, researchers, regulators,patients, lay public). These 6 clinical components, 4features, and their respective subcategories repre-sent the complete list of items for the second andthird rounds of the Delphi. These items and theirconsensus ratings for each round of the Delphiprocess are summarized in Tables I and II.

Additionally, responses to identification of currentscales that included these clinical components and

features were collated. Two of 5 respondents indi-cated that no current scales included all essentialcomponents. Two scales14,15 were posited to includeboth the clinical components and features by onerespondent each, and one further scale16 was sug-gested by two respondents to include only thefeatures. All 10 panelists responded for the first 2rounds; however, only 9 panelists responded for thethird round. Of 54 total items identified by the panel,consensus was achieved for 31 after round 2. Afterround 3, consensus was achieved for an additional10 items, while consensus neutral was achieved for4, and no consensus was achieved for 8.

Regarding clinical components, consensus wasachieved that primary lesions (noninflammatory andinflammatory, evaluated separately), quantity of le-sions (evaluated through counting and numericalrange), extrafacial sites of involvement (specifically

J AM ACAD DERMATOL


chest, back, neck, and shoulders), and extent ofinvolvement (evaluated using proportion descriptorssuch as one third or less) should be included.Consensus for exclusion was achieved for patientexperiences whereas no consensus was obtained forsecondary lesions, although a slight majority (5 of 9)opted for exclusion (see Table I).

Regarding features, consensus was achieved forinclusion of clinimetric properties (validity, repro-ducibility, discriminatory capacity, and responsiv-ity), efficiency (ie, easy for clinicians, researchers,and nursing staff to use; and easy to teach), accept-ability (by researchers, clinicians, and regulators),and categorization of severity (through descriptivetext and/or photographic examples) (see Table II).

DISCUSSIONWhile there are a myriad of grading systems for

acne severity, none were developed with priorconsensual determination of essential content do-mains. This study used a structured method ofconsensus building, the Delphi process, to identifythe essential clinical components and features ofacne severity global grading for use both in clinicalpractice and in research. Consensus for inclusionwas achieved for the following clinical components:primary lesions, quantity, sites, and extent of in-volvement; as well as the following features: clini-metric properties, efficiency, categorization, andacceptance. Consensus for exclusion comprised pa-tient experiences. No consensus was achieved forsecondary lesions.

While two panelists identified 3 present scales thatmay contain essential clinical components and/orfeatures, further evaluation revealed shortcomings ineach. The scale by Allen and Smith14 of 8 severitygrades features text descriptions of type, quantity oflesions, and proportions of facial involvement—andincluded a separate severity scale for comedones.However, this system was limited to the face. TheEchelle de Cotation des L�esions d’Acn�e (ECLA) scaleby Dreno et al15 comprised numerical ranges ofprimary acne lesions and included extrafacial sites.However, the scale did not include proportiondescriptors of anatomical sites and was not validatedagainst another construct. The Leeds revised acnegrading system presents pictorial examples of overallseverity of facial and truncal acne; including aseparate scale for facial comedones (but not trun-cal).16 However, there was no complementary textdescribing quantity of lesions or extent of involve-ment. Subsequent analysis has shown that the facialcomponent of the scale is skewed to higher grades offacial acne severity with inadequate representationof milder forms.17 Thus these scales did not

adequately fulfill the required elements for clinicalcomponents and/or features identified in this study.In a recent review of measurement properties ofinvestigator-assessed outcome measures for acne, 9separate assessment methods were identified.8

However, when evaluated against the clinical com-ponents identified as important in this study, nonefulfilled all the criteria.

Acne lesion counting, a pivotal component ofacne clinical trial measurements and one identifiedby the panel as important for inclusion, is largelyimpractical in clinical practice. However, other itemsfor inclusion, such as a numerical range of lesionscorresponding to varying severity categories andcategorization based on descriptive text and photo-graphic standards, may be more feasible options.

Results of the current Delphi support inclusion ofextrafacial sites of involvement. Currently, however,only 3 acne grading systems explicitly include ana-tomical regions other than the face. The Leeds system(a photonumeric scale comprising 16 facial, 8 chest,and 8 back severity categories) has been usedextensively in previous epidemiological and investi-gational studies on acne.16 The Leeds system isunique in providing a separate subcategory fornon-inflammatory acne, a feature identified as es-sential in this study. The Comprehensive AcneSeverity Scale (CASS), inclusive of facial and truncalacne, has been validated with the Leeds system andan acne-specific quality-of-life instrument. This scalecomprises 6 categories and is based on a globalassessment previously used in clinical trials.17

However, this scale combines noninflammatory andinflammatory lesions into aggregate categories. TheGlobal Acne Grading system (GAGS), a quasi-quantitative scheme combining regional evaluationof 6 sites (5 facial and 1 truncal) with scores for lesiontype and number summed to provide an overallglobal score, has been proposed but has not yet beenvalidated.18 Most recently, a 5-category global scalehas been proposed.19 While shown to demonstratehigh rater reliability, this scale is limited to the face.

Surprisingly, participants in this Delphi agreed toexclude patient experiences. This finding mayreflect the focus of this expert group on clinician-determined severity, and the ready availability ofquality-of-life scales relevant to skin disease ingeneral and acne in particular. Such patient-centric measures are routinely included as a com-plement to clinician-based global acne severityassessments in clinical trials.20-25 Future researchersmay wish to evaluate whether clinicians who do notconduct research would find the inclusion of pa-tient experiences useful for an ideal acne severityscale.

J AM ACAD DERMATOL


The lack of consensus for secondary lesions mayreflect ambivalence regarding their significance inoverall severity grading.While ongoing acne scarringhas been suggested to reflect more severe acne,thereby predicating more aggressive manage-ment,5,26 a contrasting view is that secondary lesionsreflect previous, not present, activity. Thus a dynamicmeasure of increasing scarring in the presence ofongoing primary acne activity may be more relevantin this context. Consideration of the dynamic con-ceptualization of secondary lesions will require fur-ther exploration. In particular, the development of anacne scar grading system sensitive to clinically rele-vant changes in scarring would be valuable.

For the remaining items for which consensus wasnot achieved, the majority were of the ‘‘other’’category, that is, were there other means of evaluat-ing quantity of lesions, other means of evaluatingextent of involvement, or other means of categori-zation not yet suggested by the panel? The inclusionof this ‘‘other’’ category was intended to allowrespondents to contribute additional items not orig-inally identified in the first Delphi round. Whilecomments were solicited regarding these open-ended items, few panelists responded with sugges-tions, and even fewer responded that the current listbeing considered was inadequate. This implied thatthe panelists did not have other options to offer forconsideration and that item generation at round oneof the Delphi was fairly exhaustive.

The process for group decision-making can bedivided into 3 different methods: interacting (groupdiscussion with pooling of judgments, followed by amajority voting procedure or consensus decision),nominal (individuals silently and independentlygenerate their own ideas, followed by recordedpresentations of ideas, group discussion, then inde-pendent voting through a ranking or rating proce-dure), and Delphi. Unlike the former two, closephysical proximity ofmembers is not required for thelatter. Both nominal and Delphi processes have beenshown to be effective in problem-solving activitiesinvolving pooled judgment of groups. The relativeadvantages are the potential for rapid response withthe nominal process in contrast to lower costs (travel,accommodations, opportunity cost) and lesser in-convenience of the Delphi.27 For this study—thecombined need to minimize cost, maximize partic-ipation, and provide adequate time for reflection onthe issues—led us to select the Delphi process.

A potential limitation of Web-based Delphi sur-veys is the limited range of responses (ie, littleflexibility for participants to include responses un-related to the questions specifically asked). Toreduce this restriction, we solicited panel comments

and concerns with each item for every round.Additional limitations are that this U.S.-based expertpanel is not globally representative and may notadequately represent the perspective of practi-tioners. With regard to the former, a U.S.-basedacne expert panel will more likely have experiencewith acne grading systems for regulatory approval asthe U.S. Food and Drug Administration has clearlydefined recommendations regarding such outcomemeasures for trials in acne.6 Regarding the latter, ourpurpose was to clarify core dimensions relevant for asingular standard for use both in clinical practice andin research. To this end, our panel was selected onthe basis of experience in both domains.

In summary, essential clinical components andfeatures for acne severity global grading were iden-tified by a Delphi process of consensus amongclinical and research experts in acne. The clinicalcomponents for inclusion consist of the following:separate severity grading of noninflammatory andinflammatory acne lesions, incorporation of facialand extrafacial sites of involvement, determinationof extent, and categorization by descriptive text andphotographic templates. Furthermore, the expertsagreed that such an instrument should demonstraterobust clinimetric properties and be shown to beefficient in application and to be acceptable tostakeholders. Our findings should be viewed as aninitial step to guide in the identification of such ascale among those in existence, or, in its absence, inthe development of such a new standard.

Disclosures: Dr Tan is an advisory board member,speaker, consultant and/or investigator for Bayer,Cipher, Galderma, Photocure, Roche, Stiefel/GSK.Dr Webster is a consultant for Allergan, Cipher,Galderma, GSK, Medicis, Ortho, Anterios, andValecor. Dr Leyden is a consultant and advisoryboard member for Allergan, Obagi, Medicis,Galderma, Stiefel/GSK. Dr Stein-Gold is an advisoryboard member and/or investigator for Galderma,Medicis, Stiefel/GSK. Dr Thiboutot is a consultantand/or investigator for Allergan, Dow, Galderma,Intendis, Johnson and Johnson/Ortho, Medicis,Stiefel/GSK. Dr Lucky has been an investigator forGalderma, Johnson & Johnson, and Coria. DrBikowski is an advisory board member, speaker,and/or consultant for Allergan (and stockholder),Coria, Galderma, Intendis, Onset, Promius,Quinnova, Stiefel/GSK. Dr Wilkin has been a con-sultant/advisor for Allergan, Bayer, Dow, Galderma,Medicis, Photocure, Warner Chilcott, Pierre Fabre,and Promius. Dr del Rosso has been a consultant/advisor, speaker and/or investigator for Allergan,Coria, Galderma, Intendis, Medicis, OrthoNeutrogena, Ranbaxy, Stiefel, Triax, PharmaDerm,

J AM ACAD DERMATOL


and Warner Chilcott. Dr Weiss is a consultant and/orinvestigator for Anterios, Coria, Galderma, OrthoNeutrogena, Promius, Quinnova, and Stiefel/GSK.Ms Wolfe and Professor Chren have no conflicts todeclare.

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