Increased diagnosis of thin superficial spreadingmelanomas: A 20-year study

Jason E. Frangos, MD,a Lyn M. Duncan, MD,b Adriano Piris, MD,b Rosalynn M. Nazarian, MD,b

Martin C. Mihm, Jr, MD,d Mai P. Hoang, MD,b Briana Gleason, MD,e Thomas J. Flotte, MD,f

Hugh R. Byers, MD,g Raymond L. Barnhill, MD,h and Alexa B. Kimball, MD, MPHc

Boston, Massachusetts; Sacramento, San Luis Obispo, and Los Angeles, California; and Rochester,

Minnesota

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Background: Diagnostic practice by dermatopathologists evaluating pigmented lesions may have evolvedover time.

Objectives: We sought to investigate diagnostic drift among a group of dermatopathologists asked to re-evaluate cases initially diagnosed 20 years ago.

Methods: Twenty nine cases of dysplastic nevi with severe atypia and 11 cases of thin radialgrowthephase melanoma from 1988 through 1990 were retrieved from the pathology files of theMassachusetts General Hospital. All dermatopathologists who had rendered an original diagnosis for any ofthe 40 slides and the current faculty in the Massachusetts General Hospital Dermatopathology Unit wereinvited to evaluate the slide set in 2008 through 2009.

Results: The mean number of melanoma diagnoses by the 9 study participants was 18, an increase from theoriginal 11melanoma diagnoses. Amajority agreedwith the original diagnosis of melanoma in all 11 cases. Incontrast, a majority of current raters diagnosedmelanoma in 4 of the 29 cases originally reported as dysplasticnevus with severe atypia. Interrater agreement over time was excellent (kappa 0.88) and fair (kappa 0.47) forcases originally diagnosed as melanoma and severely atypical dysplastic nevus, respectively.

Limitations: The unbalanced composition of the slide set, lack of access to clinical or demographicinformation, access to only one diagnostic slide, and imposed dichotomous categorization of tumors werelimitations.

Conclusions: A selected cohort of dermatopathologists demonstrated a general trend toward the reclassifi-cation of prior nonmalignant diagnoses of severely atypical dysplastic nevi as malignant but did not tend torevise prior diagnoses of cutaneous melanoma as benign. ( J Am Acad Dermatol 2012;67:387-94.)

Key words: dermatopathology; diagnostic drift; dysplastic nevi; epidemiology; melanoma; melanomaepidemic.

he worldwide incidence of cutaneous mela- incidence has been precipitous; in 2006, the age-

T noma has been increasing over the last cen-tury.1-6 In the United States, the increase in

the Department of Dermatology, Harvard Medical School,

stona; Dermatopathology Unit, Pathology Service,b and De-

rtment of Dermatology,c Massachusetts General Hospital,

ston; Department of Dermatology, Brigham and Women’s

ospital, Bostond; Diagnostic Pathology Medical Group, Sacra-

entoe; Division of Anatomic Pathology,MayoClinic, Rochesterf;

esternDermatopathology, San Luis Obispog; andDepartments

Pathology and Laboratory Medicine, David Geffen School of

edicine at University of California, Los Angeles.h

first two authors contributed equally to this article.

orted by departmental research funds from the Dermatopa-

ology Unit and Department of Dermatology, Massachusetts

eneral Hospital, Boston, MA.

adjusted incidence rate of cutaneous melanoma forboth sexes was 21 per 100,000 per year, as compared

Conflicts of interest: None declared.

Presented in part at the Third Melanoma Pathology Symposium of

the International Melanoma Pathology Working Group in

Sydney, Australia, November 7, 2010.

Accepted for publication October 4, 2011.

Reprint requests: Jason E. Frangos, MD, Department of

Dermatology, Massachusetts General Hospital, 55 Fruit St,

Bartlett Hall, 6th Floor, Boston, MA 02114. E-mail:

pigmentedlesionstudy@gmail.com.

Published online December 12, 2011.

0190-9622/$36.00

� 2011 by the American Academy of Dermatology, Inc.

doi:10.1016/j.jaad.2011.10.026

387

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SEPTEMBER 2012388 Frangos et al

with 13 per 100,000 in 1990.7 Although the incidenceof melanoma has been rapidly increasing over thepast half century, overall mortality has not increasedsignificantly; the age-adjusted yearly death rate formelanoma for both sexes in the United States hasfluctuated between 2.6 and 2.8 per 100,000 between1990 and 2006.7 A number of researchers have

CAPSULE SUMMARY

d Over the past few decades, melanomaincidence has increased while mortalityhas remained relatively static. Changesin diagnostic practice bydermatopathologists might contributeto the discrepancy between incidenceand mortality.

d The results of this study provide somesupport for the hypothesis thatdiagnostic drift in the histopathologicdiagnosis of melanoma may haveoccurred, ie, dermatopathologists maybe more likely to make a diagnosis ofmelanoma today in biopsy specimensdiagnosed as dysplastic nevi with severeatypia 20 years ago.

d These results underscore the need foradditional research toward finding moreobjective methods of diagnosingmelanoma.

questioned the validity ofthe measured increase in theincidence of melanoma andsome have proposed that thedisparity between the rates ofincrease in incidence andmortality may, at least inpart, be caused by an in-crease in the number ofearly-stage melanomas orother factors.8-16

One possible explanationfor such an increase in thenumbers of early-stage mel-anomas is that dermatopa-thologists’ threshold forrendering a diagnosis of mel-anoma has changed overtime. These shifts, potentiallycaused by factors such asevolution in the understand-ing of the biology of mela-noma, increased vigilance inthe face of heightened legalliability, or changes in theuse of histologic criteria,

may result in the diagnosis of melanoma in tumorsthat would have been diagnosed as atypical nevi inthe past.17 In the following study, we have addressedthe possibility of diagnostic drift via the use ofmelanocytic tumors diagnosed some 20 years agoand herein re-examined 20 years later in a blindedfashion. The recent review was performed by theoriginal diagnosticians and also by dermatopatholo-gists who did not diagnose the cases 20 years ago.

METHODSThe case cohort was composed of tumors in the

diagnostic spectrum from dysplastic nevus withsevere atypia to thin radial growthephase superficialspreading melanoma. The electronic files of theJames Homer Wright Laboratories of Pathology atthe Massachusetts General Hospital (MGH) weresearched for cases with the terms ‘‘dysplastic nevus’’and ‘‘severe atypia’’ or ‘‘superficial spreading malig-nant melanoma’’ (SSMM) for the years 1988 to 1990.This computer search identified 190 cases of com-pound dysplastic nevus with severe atypia and thin

superficial spreading melanoma in 1988, 1989, and1990 (Spitz nevi; spindled cell nevi; blue nevi; in situmelanomas; melanomaswith Clark level III, IV, or IV;and outside consults were not included).

These reports described 110 cases of dysplasticnevus with severe or moderate to severe atypia, 59cases of SSMM Clark level II, and 21 cases of SSMM

Clark level II/III. The glassslides for these 190 caseswere requested from the ar-chives. Case retrieval waslimited by missing, broken,or unretrievable slides (filedrawer rusted shut). Eightycases were retrieved: the first20 available consecutivecases of dysplastic nevus forthe years 1988 through 1990and the first 10 available con-secutive cases of SSMM Clarklevel II or II/III for the years1989 and 1990. Forty casesfor which all diagnostic slideswere available were thenselected.

One representative slidewas chosen from each of 29cases of dysplastic nevi and11 cases of superficialspreading melanoma byone of the authors (L. M.D.). The slides were random-ized, stripped of unique

identifiers, and renumbered 1 to 40. The originalreported diagnoses were subjected to a dichoto-mous categorization whereby they were designatedeither ‘‘melanoma’’ or ‘‘not melanoma’’ wherein allslides of dysplastic nevi were considered not mela-noma; this resulted in 29 cases of not melanoma and11 cases of melanoma. All study methods andprocedures including the provision and use ofhistoric pathological specimens were approved bythe MGH Institutional Review Board (protocol num-ber: 2008P0153).

Dermatopathologists recruited to participate inthe study included those who originally diagnosedthe cases 20 years ago and current faculty in theMGHDermatopathology Unit. Participating dermatopa-thologists were independently provided with thebox of 40 labeled slides in 2008 through 2009 and ascore sheet that asked for a binary diagnostic choice:melanoma or not melanoma, and a space to addadditional comments about the slides if they sodesired. No clinical or demographic data were pro-vided to the dermatopathologists.

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The free-marginal Cohen kappa coefficient wasused to determine the degree of overall agreementbetween contemporary diagnoses made by the studydermatopathologists in 2008 or 2009. The Cohenkappa coefficient was also used as a measure ofinterrater agreement between contemporary andoriginal diagnoses, and was ascertained by compar-ing the diagnoses of each dermatopathologist in2008 and 2009 against the diagnoses originally ren-dered in 1988 through 1990.

The Cohen Kappa coefficient ranges from �1.0 to1.0. Interpretation of the kappa statistic was carriedout according to the approach prescribed byAltman18 in which less than 0.20 indicates poorinterrater agreement; 0.21 to 0.40, fair agreement;0.41 to 0.60, moderate agreement; 0.61 to 0.80, goodagreement; and 0.81 to 1.0 is considered an indica-tion of excellent agreement.

RESULTSThe readers included current MGH Dermato-

pathology faculty and most of the original diagnos-ticians. Of the original 6 dermatopathologists whodiagnosed one or more of the study cases 20 yearsago, 4 participated in this re-evaluation. Of the twowho did not participate, one declined the invitation;the other is no longer alive.

In the recent review, all study participants diag-nosed more melanomas than the 11 melanomadiagnoses originally reported for this study cohort.The mean number of melanoma diagnoses for all 9graders was 18 (range 12-23) (Table I).

There were 7 instances where dermatopatholo-gists disagreed with their own original diagnosisfrom 20 years ago. All 7 instances were changes indiagnosis from benign to malignant (Table I).

The mean free-marginal kappa value describinginterrater agreement (the degree of agreement be-tween individual study participants and the originaldiagnosing dermatopathologist) for all study slideswas 0.58 (range 0.1-0.75) (Table II). When compar-ing interrater agreement for cases originally diag-nosed as melanoma, the mean free-marginal kappawas 0.88 (range 0.45-1.0) (Table II). For cases orig-inally diagnosed not melanoma, the mean free-marginal kappa was 0.47 (range �0.03 to 0.79)(Table II).

The free-marginal kappa value representing over-all agreement among study participants for casesoriginally diagnosed as melanoma was 0.77.Unanimous agreement with the original diagnosiswas achieved in 55% of these cases (Fig 1). In 36% ofslides originally diagnosed as melanoma, 8 of 9 ratersagreed with the original diagnosis. In 9% of slides, 7of 9 raters agreed with the original diagnosis. The

majority of observers agreed with the original diag-nosis of melanoma in 100% of cases.

For cases originally diagnosed as severely atypicaldysplastic nevus, or other nonmelanoma descriptor,the free-marginal kappa value representing overallagreement was 0.28. There was unanimous agree-ment with the original diagnosis in 14% of thesecases (Fig 1). In 24% of cases originally diagnosed asseverely atypical, 8 of 9 raters agreed with theoriginal diagnosis. In 15% of cases originally diag-nosed as dysplastic nevus, 7 of 9 raters agreed withthe original diagnosis; and in 14% of cases, 6 of 9observers agreed with the original diagnosis. Themajority of observers agreed with the original diag-nosis of not melanoma in 86% of cases (25/29).However, in 14% of cases (4/29), a majority of ratersoverturned the original diagnosis of dysplastic nevusand placed these cases into a melanoma category. Intwo of these 4 cases the original diagnostician rereadthe case as melanoma.

Mean kappa values were also calculated exclud-ing outlier rater H. These calculations led to interrateragreement (the degree of agreement between thecontemporary diagnosis by individual study partic-ipants and the original diagnosis) for all study slidesof 0.64 (vs 0.58 including rater H), interrater agree-ment among study participants for cases originallydiagnosed as melanoma of 0.93 (vs 0.88), andinterrater agreement for cases originally diagnosedas severely atypical dysplastic nevus of 0.53 (vs 0.47).Excluding rater H led to overall agreement amongthe contemporary study participants for cases orig-inally diagnosed as melanoma of 0.86 (vs 0.77including rater H) and overall agreement for casesoriginally diagnosed as severely atypical dysplasticnevus of 0.34 (vs 0.28).

DISCUSSIONThe chief aim of this research was to determine

whether histologic evaluation by dermatopatholo-gists of melanocytic tumors in the diagnostic spec-trum ranging from severely atypical dysplastic nevusto thin superficial spreading melanoma has signifi-cantly changed over a 20-year period. This study hasdemonstrated 3 principal findings concerning a se-lect group of dermatopathologists practicing at amajor medical center. First, there is ample disagree-ment about the diagnostic status of tumors originallydiagnosed in 1988 through 1990 as dysplastic neviwith severe atypia. Second, therewas a general trendtoward the reclassification of these severely atypicalmelanocytic tumors as melanoma by all study partic-ipants. In the re-evaluation of a study set thatcontained 11 original diagnoses of melanoma, themean number of contemporarymelanoma diagnoses

Table I. Original (1988-1990) and contemporary (2008-2009) diagnoses in 40 melanocytic tumors

Slide No. Original reader Original diagnosis

Contemporary dermatopathologist reader

A B C D E F G H I

1 K 0 0 0 0 0 0 0 1y 0 02* A 1 1 1 1 1 1 1 1 0x 13 C 0 0 0 0 0 0 0 0 0 04 D 0 0 0 0 0 0 0 0 0 05 A 0 0 1y 1y 1y 0 1y 1y 1y 06 B 0 0 1y,z 0 0 0 0 0 0 07* C 1 1 1 1 1 1 1 1 1 18 D 0 0 0 0 1y,z 0 0 1y 0 1y

9 D 0 0 0 0 0 1y 1y 0 0 010* B 1 1 1 1 0x 1 1 1 1 111 B 0 1y 0 0 0 0 0 0 0 012 B 0 1y 1y,z 1y 0 0 0 1y 1y 013 A 0 0 1y 0 0 1y 0 1y 1y 014* J 1 1 1 1 1 1 1 1 0x 115 A 0 1y,z 1y 1y 0 0 1y 0 1y 016* D 1 1 1 1 1 1 1 1 1 0x

17* C 1 1 1 1 0x 1 1 1 0x 118* B 1 1 1 1 1 1 1 1 1 119 C 0 1y 1y 0 0 1y 1y 0 0 020 A 0 0 1y 1y 1y 0 1y 0 1y 021 K 0 0 0 0 0 0 0 0 1y 022 A 0 1y,z 0 1y 0 0 1y 0 1y 023 J 0 1y 0 0 0 0 1y 0 1y 024 A 0 0 1y 1y 0 0 1y 0 1y 025 A 0 0 1y 1y 0 0 0 0 1y 026 C 0 0 1y 0 0 0 0 1y 1y 027 C 0 0 0 1y,z 0 1y 0 0 0 028 C 0 1y 0 0 0 0 0 0 1y 029 A 0 0 0 0 0 0 0 0 0 1y

30 A 0 1y,z 0 0 0 1y 0 1y 0 1y

31 B 0 0 0 0 0 0 0 0 0 032 C 0 0 0 0 0 0 0 1y 1y 033 C 0 0 0 0 0 0 1y 0 0 1y

34* B 1 1 1 1 1 1 1 1 1 135* C 1 1 1 1 1 1 1 1 1 136 C 0 0 0 0 0 0 0 0 1y 037 A 0 0 0 0 0 0 0 0 0 038* C 1 1 1 1 1 1 1 1 1 139 J 0 0 0 0 0 0 0 0 1y 040* A 1 1 1 1 1 1 1 1 1 1Melanoma total 11 19 21 19 12 16 20 19 23 14

Cases were originally diagnosed as benign and called benign on rereview unless otherwise noted.

Eleven dermatopathologists are coded as A-K; original readers J and K did not participate in 2008-2009 study. Nine dermatopathologists

coded as A-I reviewed study slides in 2008-2009 and were asked to provide dichotomous categorization: 0 = not melanoma and 1 =

melanoma. Four dermatopathologists (A-D) rendered original diagnosis on at least one study slide.

*Cases originally diagnosed as melanoma and called melanoma on rereview.yDiagnoses changed from benign to malignant.zContemporary diagnoses that differed from original diagnosis made by same dermatopathologist.xDiagnoses changed from malignant to benign.

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by the 9 study participants was 18. Using the majorityrules or consensus diagnosis, 4 cases in this cohortdiagnosed as severely atypical dysplastic nevi 20years ago would be diagnosed as melanoma today.Third, there are adequate levels of agreement about

the malignancy status of tumors originally diagnosedas melanoma in 1988 through 1990; of the 11 slidesoriginally diagnosed as melanoma there was unani-mous agreement among participating dermatopa-thologistswith the original diagnosis for 55%of cases.

Table II. Agreement between original diagnosis and recent diagnosis for each dermatopathologist (kappastatistic)

A B C D E F G H I Mean

vs All original 0.6* 0.5y 0.6* 0.75* 0.75* 0.55y 0.6* 0.1z 0.75* 0.58*vs Original melanoma 1.0x 1.0x 1.0x 0.64y 1.0x 1.0x 1.0x 0.45y 0.82* 0.88*vs Original not melanoma 0.45y 0.31k 0.45y 0.79* 0.7* 0.38k 0.45y �0.03z 0.72* 0.47*

Kappa value of 1.0 indicates perfect agreement. Value of # 0 indicates no agreement except to chance.

Mean kappa values were also calculated excluding outlier rater H: adjusted interrater agreement for all study slides was 0.64 (vs 0.58

including rater H), 0.93 (vs 0.88) for cases originally diagnosed as melanoma, and 0.53 (vs 0.47) for cases originally diagnosed as severely

atypical dysplastic nevus.

*Good agreement with original diagnosis when original diagnosis was not melanoma.yModerate agreement with original diagnosis when original diagnosis was melanoma.zPoor agreement with original diagnosis when original diagnosis was not melanoma.xExcellent agreement with original diagnosis when original diagnosis was melanoma.kFair agreement.

Fig 1. Histologic findings in selected cases. A to C, Case 7: all observers agreed with originaldiagnosis of melanoma. D to F, Case 31: all observers agreed with original diagnosis ofdysplastic nevus. G to I, Case 15: originally diagnosed as not melanoma, 5 contemporaryobservers diagnosed as melanoma. (Hematoxylin-eosin stain; original magnifications: 310 (A,D, G); 320 (B, E, H); and 340 (C, F, I).

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At least 7 of the 9 observers agreed with the originaldiagnosis of melanoma for all cases.

This study corroborates previous research dem-onstrating the difficulty in achieving consensus inthe interpretation of melanocytic tumors in thediagnostic spectrum ranging from severely atypicaldysplastic nevus to thin superficial spreading mela-noma.19-25 The vigorous debate that began over 20years ago regarding the histologic criteria for thediagnosis of dysplastic nevi continues to this day.26-35

Since this debate began, several studies have dem-onstrated that the existing histologic criteria allow forreproducible distinction of most dysplastic nevi frommelanoma.19-25,36,37 With regard to the group ofpathologists in the current study (4 of whom wereauthors in one of the previous citations addressingthe histopathologic grading of dysplastic nevi), bothcytologic and architectural features contribute to adiagnosis of severe atypia. Cytologic features includenuclear enlargement greater than the size of a

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mid-epidermal keratinocyte nucleus, alterations innuclear chromatin distribution, changes in the sizeand number of nucleoli, and increased or absentcytoplasm. Low-level pagetoid intraepidermal growthpattern is the most common architectural featureassociated with severe atypia. Nevertheless, thesestudies and others point out that there still exists greatdifficulty in arriving at high rates of interobserveragreement for cases that exist in the spectrum ofseverely atypical nevus and thin radial growthephasemelanoma. In addition to possible shifts in diagnosticcriteria, the increased incidence of lawsuits claiming amissed diagnosis of melanoma may influence derma-topathologists toward the diagnosis of melanoma incases of melanocytic tumors in the diagnostic spec-trum ranging from severely atypical dysplastic nevusto superficial spreading melanoma. In a Californiastudy, a false-negative diagnosis of melanoma consti-tuted themost common reason for filing amalpracticeclaim against a pathologist.38

A generalization of the results of this study islimited by a number of factors including the unbal-anced composition of the study set, the small cohortof dermatopathologists, the absence of access toclinical or demographic information, the access toonly one diagnostic slide, the imposed dichotomouscategorization of tumors, and the potential biasassociated with microscopic interpretation as partof a research study rather than for patient carepurposes.

Cases originally diagnosed as melanoma com-prised only 28% of the total slide set. The likelihoodof detecting a change in both directions is thereforebiased toward the set of dysplastic nevi trending tomalignancy. The cases of dysplastic nevi selected forthis study were biased toward those difficult casesthat exist on the borderline of diagnosis betweenbenign and malignant, but were reported as benign.The original reports for the dysplastic nevi used inthis study often contained language that temperedthe diagnosis with caveats and admonitions to per-form conservative re-excision. In 8 of 29 cases, theoriginal diagnosing dermatopathologist, though ren-dering an ultimate diagnosis of dysplastic nevus,added notes that expressed equivocation about thediagnosis. Only one of these 8 cases was diagnosedas melanoma by a majority of the contemporaryraters in our study (case 15). In 6 of these 8 cases,comments indicated ‘‘early transformation to mela-noma cannot be ruled out’’ or ‘‘verges on melanomabut the changes are insufficient for a diagnosis ofmelanoma.’’ In two of these 8 cases the commentindicated that ‘‘a pre-existing regressed melanomacannot be excluded.’’ In contrast, none of thepathology reports for the superficial spreading

melanomas expressed any equivocation about thediagnosis. In trying to select melanomas that were atthe end of the histologic spectrum with severelyatypical dysplastic nevi, no selection criterion otherthan Clark level was applied to the melanoma cases.

This study examined the behaviors of 9 dermato-pathologists all of whom have served as faculty in theMGH Dermatopathology Unit. The results reportedhere may or may not be representative of thepractices of dermatopathologists in general.

The imposed dichotomy in tumor classificationmay have biased the results of this study. Althoughthe limitation placed on participating dermatopa-thologists in this study to render a diagnosis of eithermelanoma or not melanoma made comparison be-tween study participants relatively simple, it madecomparison with the original diagnosis problematic.Descriptive diagnostic interpretations and the finegradations of language used to characterize melano-cytic tumors allow for highly nuanced diagnoses thatguide treatment more than the simple categorizationof a tumor as benign or malignant. Furthermore, inrecent years there has been a general trend to usemore formally an intermediate category for melano-cytic tumors in the diagnostic spectrum ranging fromseverely atypical dysplastic nevus to superficialspreading melanomaein particular that of melano-cytic tumor with uncertain malignant potential.Indeed, in this study some of the participants issuedcomments such as ‘‘borderline case’’ and ‘‘predictlack of consensus.’’ However, these comments weremade about cases for which there was consensus andfor those with no consensus. Two observers com-mented on the need for age, site, and clinicalappearance to render a definitive diagnosiseonereviewer commented on 10 cases this way, the otheron two. The remaining reviewers did not commenton the need for age; nevertheless, we do appreciatethat these clinical parameters are important in theevaluation of atypical melanocytic tumors. This wasclearly a diagnostically challenging set of cases asindicated by these comments. Even in the face ofthese challenges, it seems reasonable to expect thatthere is some threshold, albeit subjective, for ren-dering the diagnosis of melanoma, a threshold thatappears to have shifted in the group of observerswho had the opportunity to revisit cases 20 yearslater.

Previously published explanations for the in-crease in the incidence of melanoma have includedascertainment biases such as an increase in biopsyrate,12 changes in histopathologic criteria,10,11,39-41

and the existence of a nonmetastasizing form of thinmelanoma.13,14,40,42,43 Because dissecting out thepotential causes of this increase is complicated, the

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impact of changes in dermatopathology practice, ifany, is difficult to quantify.

The results of this study provide support for thehypothesis that dermatopathologists are more likelyto diagnose thin superficial spreading melanoma inbiopsy specimens that were reported as dysplasticnevi with severe atypia in the past, eg, some 20 yearsago.

The authors are grateful to Barrett Goodspeed for hisassistance with searching the MGH Pathology Databaseand to ChristineWitham for her assistancewith the locationand acquisition of the original glass study slides.

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