Correlating architectural disorder and cytologic atypia in clark (dysplastic) melanocytic nevi

Correlating Architectural Disorder and Cytologic Atypia in Clark (Dysplastic) Melanocytic Nevi CHRISTOPHER R. SHEA, MD, ROBIN T. VOLLMER, MS, MD, AND VICTOR G. PRIETO, MD, PHD Histological architecture is very important in the pathological diagnosis of Clark (also known as atypical or dysplastic) melanocytic nevi. However, few studies have attempted to quantify architectural features or to correlate them directlywith cytology. In 166 consecutive Clark nevi, the presence or absence of the following features in the intraepidermal or junctional component was recorded: (1) Archite~ ture: circumscription, symmetry, cohesiveness of nests, suprabasal melanocytes, confluence, and single-cell proliferation; (2) Cytology of melanocytes: round/euchromatic nuclei, nuclear enlargement, cell enlargement, and prominent nucleoli. Each criterion was given a value of 0 or 1, and a summation score was obtained for both architecture and cytology in each case. The chi-square test was used to determine the significance of relationships among these parameters. The degrees of architectural disorder and of cytologic atypia were positively

correlated (P = .026). Scores for both parameters were distributed over a wide range of values and were concentrated toward the low-middle portion of the spectrum. Several particular architectural and cytologic variables showed significant interdependence. Clark nevi exhibit a broad spectrum of architectural disorder and cytologic atypia, which, according to our data, generally are closely related features. Because some cases displayed a relatively high score for one parameter but a low score for the other, quantification of both parameters permits a more complete histopathologic evaluation of these lesions and may provide additional information for their clinical management. HuM PATnOL 30:500-505. Copyright © 1999 by W.B. Saunders Company Key words: nevus, dysplastic, atypical, Clark's, grading. Abbreviation: CN, Clark nevi.

Wallace H. Clark, Jr, introduced his concept of clinically and histologically atypical nevi under the designation "B-K mole syndrome" in 19781; later, he preferred "dysplastic nevus" for these neoplasms. 2 Thomas B. Fitzpatrick first proposed the term "Clark nevus" in his honor, ~ a suggestion seconded by others 4 and adopted in this article. A perennial point of contention is whether the diagnosis of Clark nevus (CN) requires cytologic atypia of melanocytes or can be rendered on architectural grounds alone. 5-7 Several papers emphasize cytologic criteria to grade CN. s-ll However, few studies have quantified architectural disorder or analyzed the correlation between these two parameters. Ira strong correlation between the degrees of architectural and cytologic abnormality should be discovered, this controversy would lose much of its force. In this study, we quantify both the degree of cytologic atypia and the extent of architectural disorder in a series of 166 consecutive CN. Our results show a wide spectrum of scores for both parameters and a significant overall correlation between the graded architectural and cytologic features. We propose that both kinds of criteria should be employed for the histopathologic evaluation of CN.

METHODS Case Material

From the Department.s of Pathology and Medicine (Dermatology), Duke University Medical Center, and Veterans Administration Medical Center, Durham, NC. Address correspondence and reprint requests to Christopher R. Shea, MD, Department of Pathology, Box 3712, Duke University Medical Center, Durham, NC 27710. Copyright © 1999by W.B. SaundersCompany 0046-8177/99/3005-0004510.00/0

500

All melanocytic nevi (n = 470) received by the Division of Dermatopathology at Duke University Medical Center between April 4, 1997 and August 1, 1997 were screened for the possible diagnosis of CN. That diagnosis was based on features apparent at scanning (20 x) magnification, namely (1) lateral extension of the junctional component at least three fete ridges beyond any dermal component; and (2) stromal response, that is, papillary dermal fibrosis and inflammation. Cases were excluded if they had (1) evidence of scarring or regression; (2) incomplete biopsy precluding adequate evaluation; or (3) features suggesting congenital onsetJ 2 Each specimen was routinely paraffin embedded, sectioned on multiple levels, and stained with hematoxylin and eosin.

Scoring of Architectural and Cytologic Features The biopsies were scored by two dermatopathologists (C.R.S. and V.G.P.) during a consensus conference. The histological parameters were selected from several proposed to be characteristic of CN, 13as follows:

Architectural Features

Circumscription. Junctional component discretely nested at both edges of lesion (score = 0), as opposed to a diffuse single-cell pattern of proliferation in at least one edge (score = 1). Symmetry. Lesions showing good overall symmetry regarding situation of junctional vis-a-vis intradermal components, relative lateral extension of the two junctional components toward edges, size of junctional nests, and stromal response (score = 0) otherwise, score = 1. Cohesion. Over 50% of junctional nests compact and cohesive (score = 0); otherwise, score = 1. (Compact nests retracting en masse away from the surrounding epidermis were considered cohesive.)

CLARK (DYSPLASTIC)MELANOCYTICNEVUS(Shea et al)

Suprabasal Melanocytes. Single or nested melanocytes present above the epidermal basal layer, either in more than two high-power fields or at the edge of the lesion (score = 1); otherwise, score = 0. Confluence. Confluence of greater than 50% of junctional melanocytic proliferation, either as bridging of melanocytic nests or as contiguous single cells (score = 1); otherwise, score = 0. Single-CellProliferation. Junctional melanocytes arranged as single cells rather than in nests in more than 20% of the lesion (score = 1); otherwise, score = 0.

TABLE 2.

Leading Clinical Diagnoses of 166 Consecutive Clark Nevi

Leading Clinical Diagnosis

Cytologic Features Cytologic f e a t u r e s were r e q u i r e d to b e p r e s e n t in g r e a t e r t h a n 50% o f m e l a n o c y t e s in e i t h e r o f t h e two h i g h - p o w e r fields with t h e m o s t atypical ceils. Nuclear Shape and Staining. Nuclei round or oval, and euchromatic (score = 0); otherwise, score = 1. Nuclear Size. Diameter of melanocyte nuclei greater than that of basal layer keratinocyte nuclei (score = 1); otherwise, score = 0. NucleolarProminence. Nucleoli prominent in greater than 50% of cells (score = 1); otherwise, score = 0. Cell Size. Melanocyte diameter more than twice that of basal-layer keratinocyte nuclei (score = 1); otherwise, score = 0. Separate summation scores of architectural and cytologic features were calculated for each nevus.

Statistical M e t h o d s Chi-square tests were used to examine associations between pairs of scores and between the architectural and cytologic summation scores. The SPLUS statistical software (Version 3.3, StatSci Division of MathSoft, Inc., 1995, Seattle, WA) was used for all analyses.

Atypical, dysplastic, irregular, unusual, growing, or changing nevus or mole (or rule out same) Nevus or mole (not otherwise specified) Lesion, pigmented lesion, or not provided Melanoma (or rule out same) Lentigo Seborrheic keratosis Basal cell carcinoma Hemangioma

No. of Cases (% Cases) 111 26 13 9 3 2 1 1

(67) (16) (8) (5) (2) (1) (1) (1)

e n c e o f j u n c t i o n a l m e l a n o c y t e s (96 cases = 58%) a n d t h e a b s e n c e o f a w e l l - n e s t e d a p p e a r a n c e at o n e o r b o t h e d g e s (95 cases = 57%) w e r e t h e m o s t f r e q u e n t aspects o f d i s o r d e r e d a r c h i t e c t u r e , f o l l o w e d by p r e s e n c e o f a single-cell p a t t e r n o f p r o l i f e r a t i o n (80 cases = 4 8 % ) . All o f t h e a b o v e o c c u r r e d m u c h m o r e f r e q u e n t l y t h a n a s y m m e t r y (30 cases = 18%), n o n c o h e s i o n o f nests (21 cases = 1 3 % ) , o r s u p r a b a s a l m e l a n o c y t e s (16 cases = 10%). Several a r c h i t e c t u r a l f i n d i n g s w e r e interd e p e n d e n t (Table 3). Specifically, t h e p r e s e n c e o f single-cell p r o l i f e r a t i o n was s t r o n g l y c o r r e l a t e d with both suprabasal location of melanocytes and poor c i r c u m s c r i p t i o n ; t h e l a t t e r two f e a t u r e s w e r e also signific a n t l y a s s o c i a t e d with e a c h other.

C y t o l o g i c Features F i g u r e s 3 a n d 4 illustrate s e l e c t e d cytologic f i n d i n g s in r e p r e s e n t a t i v e b i o p s y s p e c i m e n s . A b n o r m a l n u c l e a r s h a p e o r s t a i n i n g p a t t e r n o c c u r r e d in 117 cases ( 7 0 % ) , f o l l o w e d by i n c r e a s e d cell d i a m e t e r (103 cases = 6 2 % ) , i n c r e a s e d n u c l e a r size (41 cases = 2 5 % ) , a n d n u c l e o l a r p r o m i n e n c e (14 cases = 8%). As s h o w n in T a b l e 4 (shaded boxes), the presence of nuclei showing hyperc h r o m a t i s m o r l a c k i n g a r o u n d / o v a l s h a p e was n e g a tively a s s o c i a t e d with b o t h l a r g e n u c l e a r size a n d p r o m i nence of nucleoli.

RESULTS Case Material O n e h u n d r e d sixty-six c o n s e c u t i v e CN (23 j u n c t i o n a l a n d 143 c o m p o u n d ) m e t i n c l u s i o n a n d e x c l u s i o n c r i t e r i a a n d f o r m t h e basis o f this r e p o r t . T h e lesions were o b t a i n e d f r o m 122 p a t i e n t s (57 m a l e a n d 65 f e m a l e ) , with a m e a n a g e o f 32 years ( r a n g e , 5 to 85). D i s t r i b u t i o n o f a n a t o m i c sites a n d t h e l e a d i n g clinical d i a g n o s e s a r e given in Tables 1 a n d 2, respectively.

Architectural Features F i g u r e s 1 a n d 2 illustrate s e l e c t e d a r c h i t e c t u r a l f i n d i n g s in r e p r e s e n t a t i v e b i o p s y s p e c i m e n s . C o n f l u -

TABLE 1.

Anatomic Site Distribution of 166 Consecutive Clark Nevi

Anatomic Site

No. of Cases

(% Cases)

Trunk (NOS), back, flank, buttock, or shoulder Chest, axilla, or breast Lower extremity Abdomen Upper extremity Head or neck Perineum Not specified

78 25 19 17 16 8 1 2

(47) (15) (11) (10) (10) (5) ( 1) (1)

FIGURE 1. Prominent host response, with asymmetric location of lymphocytic infiltrate, and areas of confluence and singlecell growth pattern. 501

HUMAN PATHOLOGY

Volume30, No. 5 (May 1999)

FIGURE 3. Hyperchromatic, angulated melanocytic nuclei (mild cytologic atypia).

FIGURE2. Noncohesive melanocytic nests. Correlation of Architectural a n d C y t o l o g i c Features

DISCUSSION

Figure 5 displays the distribution of summed architectural versus cytologic scores. Chi-square analysis showed a significant overall correlation between these parameters (P = .026). Table 5 examines the associations between particular pairs of architectural and cytologic variables. A single-cell pattern of melanocytic proliferation was highly correlated with hyperchromatism or irregular shape of nuclei. Cases with large melanocytic nuclei tended also to have suprabasal melanocytes and confluent proliferation. Surprisingly, cases with large nuclei tended to be well circumscribed (negative correlation displayed in shaded box of Table 5). Multivariate Patterns

A total of 95 of 1,024 possible combinations of architectural and cytologic features occurred in this sample, with 65 patterns represented by a single nevus each (in aggregate, 39% of the total sample). Fifteen patterns occurred in two nevi each, and five patterns in three nevi each. Ten combinations were each found in more than three specimens, together making up 34% of the study sample. Table 6 presents the particulars of these 10 most common patterns, together with their frequencies.

Only a few previous studies have attempted to correlate the degrees of architectural and cytologic abnormality in CN. Balkau et aP 4 examined 334 melanocytic nevi and reported that several individual architectural features occurred at higher frequency in nevi containing cytologically atypical melanocytes, compared with nevi that completely lacked cytologic atypia. Those noteworthy features included presence of melanocytes not confined to rete ridges, variation in number of melanocytes in the basal layer, and elongation of nests with irregular margins, fusion, and bridging of rete ridges. The results were similar to our findings; however, that study did not compare the overall degrees of architectural disorder and cytologic atypia. Barnhill et a115 studied various architectural, nuclear, and cytoplasmic features in 153 clinically atypical melanocytic nevi obtained from patients with a history of melanoma. In a multivariate model, they found melanocytic hyperplasia, disarray of junctional nests, and prominent vascularity to be correlated with nuclear atypia. However, these authors did not compare architectural features with individual nuclear features (as in the current study) but rather with overall atypia.

TABLE 3. Associations Between Architectural Scores AsymNonmetric cohesive

Poorly circumscribed Asymmetric Noncohesive Suprabasal Confluent

NS

NS NS

Suprabasal

Confluent

SingleCell

P = .021 5.33

NS

P < .0001 X2 = 27.50

NS

NS

NS

NS

NS

NS

NS

P < .0001 X2 : 16.80

X2 =

NS

FIGURE 4. Large melanocytic nuclei, prominent nucleoii, abundant cytoplasm (severe cytologic atypia).

NOTE. All correlations shown are positive. P values > .05 (NS) are omitted for clarity.

502

CLARK (DYSPLASTIC) MELANOCYTIC NEVUS (Shea et al)

TABLE 4.

Associations B e t w e e n C y t o l o g i c Scores

Nuclei Large

Nucleoli Prominent

Cells Large

; ~, ~ : ~ ~ . . . . . . . . . . . . . . . . . . .

Nuclei hyperchromatic, ~.,~,~0, ~:~: ,:+ or not round/oval ~:~~ N ~?;~~:

:li~t:~l~3"~,

Nuclei large

NS

Nucleoli prominent

NS NS NS

NOTE. Negative correlations are listed within bold boxes. P values > .05 (NS) are omitted for clarity. Such atypia, defined by the presence of at least three of four criteria (pleomorphism, p r o m i n e n c e of nucleoli, large nuclei, and hyperchromatism) was identified in only 17% of their cases. O u r study shows a significant overall correlation between architectural and cytologic scores. This general c o n g r u e n c e between quite different histological attributes affirms the nosologic integrity of the Clark nevus. As a practical matter, the summation of information provided by these different parameters can be useful for accurate diagnosis; if an initial tally o f the scores shows outlying features not in accord with the

overall grade, it would be p r u d e n t to reexamine the case critically. The observed clustering of architectural and cytologic features further confirms their interrelationship. If these features (both architectural and cytologic) were all i n d e p e n d e n t of one other, the sample would be distributed randomly among the 210 = 1,024 possible combinations of these 10 binary variables (six architectural and four cytologic scores). Because this n u m b e r of combinations far exceeds the actual number of nevi tested (n = 166), most observed combinations would be represented by only a single nevus, if the null hypothesis of i n d e p e n d e n c e were true. Contrary to this hypothesis, most cases fell into clusters combining particular architectural and cytologic features (Table 6). O t h e r investigators a5,16 have also reported clustering of histological features in CN. Some o f the associations between variables were highly significant. For example, p o o r circumscription was strongly correlated with a predominantly single-cell (as opposed to nested) pattern of melanocytic proliferation (Table 3). This was to be expected, because p o o r circumscription equates to a single-cell pattern at the edge(s) of the lesion. Single-cell proliferation and suprabasal spread of melanocytes were also closely

\

\-30

\ - 2 S # cases I

\-20

FIGURE 5.

Distribution of summed architectural (0-6) versus cytologic (0-4) scores for the sample of 166 dysplastic/Clark nevi. The height of each bar is proportional to the number of nevi with a given combination of summed architectural and cytologic scores. Combinations not represented by any nevus in this series are shown as empty cells at the floor of the graphic. There is a significant positive correlation between architectural and cytologic scores (P = .026 by chi-square). The same d a t a are t a b u l a t e d in lower panel.

\ \

\

A0 ARCHITECTUR

A6

10 5

C4

CYTOLOGY

CO

A0 A1 A2 A3 A4 A5

15

CO 4 2

C1 6 13

C2 9 26

C3 1

C4 0

4

12

18

2 7

0 0

0 1

16

18

5

0

3

8

6

1

0

1

1

2

0

0

0

0

0

0

503

HUMAN PATHOLOGY TABLE 5.

Associations Between Cytologic and Architectural Scores

Asymmetric Nuclei hyperchromatic; not round/oval

Cells large

Noncohesive

Poorly Circumscribed

Suprabasal

Confluent

Single-Cell

NS

NS

P < .0002 X 2 = 14.31

NS

P = .0305 X2 = 4 . 6 8

P = .0349 X2 : 4 . 4 5

NS

NS

*

NS

NS

NS

NS

NS

NS

NS

NS

NS

NS

NS

Nuclei large Nucleoli prominent

Volume30, No. 5 (May 1999)

N O T E . N e g a t i v e c o r r e l a t i o n s a r e l i s t e d w i t h i n b o l d b o x e s ; all o t h e r c o r r e l a t i o n s s h o w n a r e p o s i t i v e . P v a l u e s > .05 ( N S ) a r e o m i t t e d clarity. B o x e s w i t h a s t e r i s k s d e n o t e c o r r e l a t i o n s o f m a r g i n a l s i g n i f i c a n c e ( . 0 6 > P > . 0 5 ) .

linked. O f interest, some other variables showed a negative correlation: for example, cases having large nuclei and p r o m i n e n t nucleoli generally did not exhibit hyperchromatic or angulated nuclei. This result indicates that CN may comprise several distinct cytologic subtypes of lesions, a notion also suggested by others. 17 Most nevi in this series were concentrated in the low to middle portion of the spectrum for both architecture and cytology. However, this observed distribution may not represent the relative prevalence of cytologic and architectural scores in unselected CN. We suspect that there exist in nature even more low-grade nevi, compared with the proportion showing moderate or severe changes; clinicians may recognize many lowgrade lesions by their gross features and manage them with clinical observation rather than biopsy. Notably, the leading clinical diagnosis was either atypical nevus or melanoma in 120 (72%) of these 166 CN, suggesting that most of our cases had significant gross irregularity that p r o m p t e d surgical intervention. Along these lines, we are currently p e r f o r m i n g a study on clinicalpathological correlation in grading nevi. No nevus in this series achieved the maximal architectural score of 6, and only one nevus had the maximal cytologic score of 4 (Fig 5). The explanation is that the most atypical melanocytic lesions diagnosed in our practice during this study period met full diagnostic criteria for malignant melanoma. In this study, we derived the cytological score from the two most atypical high-power fields. If the overall lesion showed a lesser degree of atypia, the case would be diagnosed as a nevus; however, if extreme cytologic atypia were widespread, especially in the setting of marked architectural disorder, the correct diagnosis would be melanoma. It is not surprising that severely atypical nevi and melanoma share many pathologic attributes, because t u m o r progression involves a complex sequence of stepwise molecular alterations with histologic correlates, as has been seen in many kinds of neoplasm. 18 A minority of our cases showed disparity between the degrees of cytologic atypia and of architectural disorder. All four acral nevi in this series exhibited both single-ceU and suprabasal patterns of melanocytic proliferation ( P = .015 and P < .0001, respectively), while showing only minor cytologic atypia. This finding is consonant with reports that acral nevi frequently show 504

for

aberrant architecture. 19,2°Nevi that have recurred after trauma 21 or those subjected to ultraviolet irradiation z2 also may exhibit suprabasal melanocytes; however, those settings do not pertain in the current series, because cases with features suggesting trauma were excluded. The presence of severely disordered architecture in lesions lacking obvious high-grade atypia should p r o m p t consideration of the small-cell variant of malignant melanoma. 23 Conversely, lesions exhibiting a high degree of cytologic atypia but having relatively orderly architecture also require careful examination to rule out melanoma. Based on the results of this study, at Duke we are currently grading CN by both architectural and cytologic features (Table 7). Because each criterion is assigned a score of either 0 or 1, simple addition yields summation scores for both parameters, to be graded as mild, moderate, or severe. In this series, there was overall greater than 90% agreement between the two investigators regarding grades of architecture and cytology as either mild, moderate, or severe. Grading architectural features may offer several benefits. First, it may permit better clinical-pathological correlation, because clinicians obviously can evaluate only gross and not cytologic aspects of p i g m e n t e d lesions. Furthermore, there is more agreement a m o n g pathologists regarding architectural than cytologic features of C N , 6'24 and so a TABLE 6. #

1A

11 9 8

+ . +

4

.

4 4 4 4

+ . + .

4

+

4

.

Ten Most Frequent Multivariate Patterns

2A

3A

4A

5A

6A

1C

2C

3C

4C

-

-

+ + +

+ +

+ + +

-

-

+ +

.

.

.

-

-

.

.

.

.

.

. .

+

.

.

.

.

. +

.

. . .

. --

. .

.

. . .

-

.

. .

. .

--

.

.

.

.

.

+ + + .

-

-

-

-

-

+ + +

--

+

+

--

--

+

+

-

-

+

-

+

N O T E . Architectural features: 1 A = p o o r l y c i r c u m s c r i b e d ; 2 A = asymmetric; 3A = noncohesive; 4A = suprabasal; 5A = confluent; 6 A = s i n g l e - c e l l p r o l i f e r a t i o n . Cytolog@features: 1 C = n u c l e i h y p e r c h r o marie, or not round/oval; 2C = nuclei large; 3C = nucleoli promin e n t ; 4 C = cells l a r g e . L e f t c o l u m n s h o w s n u m b e r o f c a s e s e x h i b i t i n g particular combinations of architectural and cytologic features.

CLARK (DYSPLASTIC) MELANOCYTIC NEVUS (Shea et al)

TABLE 7. Duke Grading System for Clark Nevi Architectural Disorder: Junctional component nested at both edges Good overall symmetry More than 5% of nests cohesive Suprabasal spread prominent, or present at edge Confluence of >50% of proliferation Single-cell proliferation absent or focal Sum total: Key: (0-1) = Mild; (2-3) = Moderate; (4-6) = Severe Cytologic Atypia: Nuclei round or oval, and euchromatic Nuclei > basaldayer keratinocyte nuclei Nucleoli prominent Cell diameter > 2× basal-layer keratinocyte nuclei Sum total: Key: (0-1) = Mild; (2) = Moderate; (3-4) = Severe

REFERENCES

0 Yes Yes Yes No No Yes

1 No No No Yes Yes No

0 Yes No No No

1 No Yes Yes Yes

NOTE. A separate score is obtained for architecture and cytology by assigning a value of 0 or 1 for each criterion and summing.

grading system that includes architectural criteria may prove more reproducible. Finally, and not least important, the exercise of quantifying architectural features aids recognition of those problematic lesions in which the cytologic and architectural grades are at variance. Although our grading scheme was devised primarily for research, at Duke we currently recommend that all nevi' with severe architectural disorder or severe cytologic atypia be totally excised, if clinically feasible. Because those nevi share many pathologic features with melanoma, we cannot rule out their potential for subsequent progression to malignancy if incompletely removed. The relative importance of architectural versus cytologic criteria for diagnosis of CN has been debated for years. Some authors assert the primacy of architecture. 5 Others grade as mild to moderate those CN having architectural disorder merely, and count as severe those nevi also having cytologic atypia. ~5,26 Still others, assuming a priori that nuclear cytology is the ultimate standard, suggest that solely those architectural features that are independently correlated with nuclear atypia are meaningful. 13,15 We consider that conclusion unjustified. Although genetic nuclear alterations are clearly fundamental in the progression of neoplasms to malignancy, such molecular events could be manifested as sensitively by alterations in growth pattern as by changes in the light-microscopic appearance of stained nuclei. Moreover, the range of morphological expression of fully evolved malignant melanoma is so vast 23 that we hesitate to classify melanocytic neoplasms by any arbitrary set of nuclear-cytologic features exclusively. We do not dispute the obvious importance of nuclear morphology; rather, our data indicate that architectural disorder and cytologic atypia are closely related features that together characterize CN. In summary, this series of 166 consecutive CN exhibited a wide spectrum of quantitative values for both architectural disorder and cytologic atypia. In most CN, there was a significant correlation between the grades of these parameters. We propose that both kinds of criteria are necessary for the complete histopathologic evaluation of Clark nevi and may provide additional information for their clinical management.

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