Dermoscopic Features of Skin Lesions in Patients with Mastocytosis

STUDY Dermoscopic Features of Skin Lesions in Patients With Mastocytosis

Sergio Vano-Galvan, MD, PhD; Ivań A´ lvarez-Twose, MD; Elena De las Heras, MD, PhD; J. M. Morgado, Msc; Almudena Matito, MD; Laura Sańchez-Munõz, MD, PhD; Maria N. Plana, MD, PhD; Pedro Jaeń, MD, PhD; Alberto Orfao, MD, PhD; Luis Escribano, MD, PhD

Objectives: To evaluate dermoscopic features in a group factors for more symptomatic forms of the disease ac- of 127 patients with mastocytosis in the skin and to in- cording to the need for daily antimediator therapy. vestigate the relationship between different dermoscopic patterns and other clinical and biological charac- Results: Four distinct dermoscopic patterns were ob- teristics of the disease. served: yellow-orange blot, pigment network, reticular vascular pattern, and (most frequently) light-brown blot. Design: Clinical and laboratory data were compared A reticular vascular pattern was identified in all telangi- among patients with mastocytosis grouped according to ectasia macular eruptiva and some maculopapular mas- the different dermoscopic patterns. tocytosis. In turn, all patients with mastocytoma displayed the yellow-orange blot pattern. The reticular Setting: Patients were selected from the Instituto de Es- vascular dermoscopic pattern was associated with the need tudios de Mastocitosis de Castilla La Mancha and the De- for daily antimediator therapy; this pattern, together with partment of Dermatology of Hospital Universitario Ramo´n serum tryptase levels and plaque-type mastocytosis, rep- y Cajal from April 1 through September 30, 2009. resented the best combination of independent factors to predict the need for maintained antimediator therapy. Patients: Overall, 127 consecutive patients (70 females [55.1%] and 57 males [44.9%]; median age, 17 Conclusions: Dermoscopy is a feasible method for the years; range, 0-81 years) with mastocytosis in the skin subclassification of mastocytosis. Of note, a reticular vas- were included in the study. cular pattern is more frequently associated with the need for antimediator therapy. Main Outcome Measures: Evaluation of dermoscopic patterns and investigation of potential predictive Arch Dermatol. 2011;147(8):932-940

KIN IS THE MOST COMMONLY tion, telangiectasia macularis eruptiva per- involved tissue in mastocy- stans (TMEP) also has been reported as a tosis, being affected in virtu- rare subvariant of MIS characterized by red- Author Affiliations: ally all pediatric and most dish macules that occur due to underly- Department of Dermatology adult cases.1-6 Because a com- ing, dilated, dermal, thin-walled blood ves- (Drs Vano-Galvan, De las Heras, pleteS bone marrow study is required to es- sels; it is typically seen in adults.8-10 More and Jaeń) and Unidad de tablish the systemic nature of the dis- recently, (multiple) nodular and plaque- Bioestadı´stica Clıńica (Dr Plana), ease, the term mastocytosis in the skin (MIS) type skin lesions also have been de- Hospital Universitario Ramońy recently has been proposed to define those scribed.11 They have been proposed as new Cajal, Madrid, Instituto de patients (eg, children with proven cuta- variants of MIS on the basis of the under- Estudios de Mastocitosis de Castilla La Mancha, Hospital neous mastocytosis) in whom screening lying clinical and pathogenic mechanisms. Virgen del Valle, Toledo for systemic involvement has not been Although careful inspection of skin le- (Drs A´ lvarez-Twose, Matito, performed. sions frequently suffices to identify MIS, Sańchez-Mun˜ oz, Jaeń, and According to the World Health Organi- a skin biopsy followed by histologic evalu- Escribano and Mr Morgado), zation, MIS may be subclassified into 3 variation plus immunohistochemistry for Red Espan˜ ola de Mastocitosis ants: maculopapular cutaneous mastocyto- tryptase and c-kit are required to reach a (Dr A´ lvarez-Twose, Matito, sis (MPCM) (also known as urticaria final diagnosis.12 Histologic criteria for the Sańchez-Mun˜ oz, Orfao, and pigmentosa [UP]), diffuse cutaneous mas- diagnosis of MIS include the presence of Escribano and Mr Morgado), tocytosis, and solitary mastocytoma of the large aggregates (Ͼ15 cells per cluster) of Servicio General de Citometrıá, skin.7 The most common variant is MPCM, tryptase-positive mast cells (MCs) or scat- Centro de Investigacioń del Cańcer/Instituto de Biologıá which is found in children and adults with tered MCs exceeding 20 cells per micro- ϫ 13,14 Molecular y Celular del Cańcer, mastocytosis; diffuse cutaneous mastocy- scopic high-power ( 40) field. In a and Department of Medicine, tosis and solitary mastocytoma of the skin variable percentage of cases, c-kit muta- Universidad de Salamanca, are less frequently observed and typically are tion at codon 816 also is detected in le- Salamanca (Dr Orfao), Spain. restricted to pediatric patients. In addi- sional skin.15,16

ARCH DERMATOL/ VOL 147 (NO. 8), AUG 2011 WWW.ARCHDERMATOL.COM 932

©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 Corrected on August 23, 2011 Dermoscopy is a noninvasive technique based on in Table 1. Classification of Cutaneous Mastocytosis vivo epiluminescence microscopy, which provides rapid 11 and easy evaluation of the colors and microstructure of by Hartmann and Henz the epidermis, the dermoepidermal junction, and the papillary dermis, none of which are visible to the naked eye. Classification of Cutaneous Mastocytosis In recent years, dermoscopy has emerged as a simple and 1. Maculopapular cutaneous mastocytosis useful tool for the diagnosis of melanocytic and nonme- 2. Plaque-type cutaneous mastocytosis 3. Nodular cutaneous mastocytosis/mastocytoma (ie, solitary lanocytic skin lesions, and it has proven to be especially or multiple) 17 useful for early recognition of malignant melanoma. Sev- 4. Diffuse cutaneous mastocytosis eral diagnostic algorithms based on the use of dermos- 5. Telangiectatic cutaneous mastocytosis copy have been developed for melanocytic and nonmelanocytic skin lesions. However, currently, information regarding the dermoscopic patterns of skin lesions in mastocytosis is scanty and restricted to individual case re- ferent dermoscopic patterns were identified, and each pa- ports or very small patient series.18,19 In this study, we tient’s lesions were classified into 1 of these 4 subgroups. report on the dermoscopic patterns of a large series Subsequently, the potential relationship between the dermo- (n=127) of patients with mastocytosis and the relation- scopic patterns identified and specific clinical variants of the disease, sBt levels, and the severity of MC mediator symptoms ship between those patterns and the clinical and biologi- was investigated. cal characteristics of the disease. The interobserver and intraobserver reproducibility was as- sessed for each dermoscopic pattern evaluated for a lesion in METHODS all 127 patients. The evaluation of dermoscopic patterns was masked from clinical data. Digital dermoscopic images were obtained from all patients by 4 investigators (S.V.-G., I.A´ .-T., A.M., PATIENTS AND CLINICAL and L.E.), and the dermoscopic images were evaluated by 3 der- AND LABORATORY EXAMINATIONS matologists (S.V.-G., E.D.L.H, and P.J.) who established the pre- dominant dermoscopic pattern in each case. Regarding intra- Overall, 127 consecutive patients (70 females [55.1%] and 57 observer reproducibility, 1 of the dermatologists (S.V.-G.) males [44.9%]; median age, 17 years; range, 0-81 years) with evaluated each lesion and reevaluated all of them 3 months later. MIS who were referred to the Instituto de Estudios de Mas- Regarding interobserver reproducibility, 2 dermatologists tocitosis de Castilla La Mancha or the Department of Derma- (E.D.L.H. and S.V.-G.) independently evaluated the same le- tology of Hospital Ramo´n y Cajal from April 1 through Sep- sions, and the results were compared. tember 30, 2009, were included in the study. Among the 127 patients, 61 (48.0%) were younger than 14 years and 66 (52.0%) were adults (median [range] age at the time of dermoscopy, 3 STATISTICAL ANALYSES years [0-11 years] and 38 years [15-81 years], respectively). In all patients except those with mastocytoma who had typical For all continuous variables, median and range were calculated but for categorical variables, frequencies were reported. clinical features at arrival, the diagnosis of MIS was estab- ␹2 lished on the basis of a skin biopsy specimen. Median (range) The Mann-Whitney and tests were used to assess the statistical significance of differences observed between groups for time from disease onset to inclusion in the study was 11 years ␬ (3-60 years) in adults and 1 year (0-8 years) in children continuous and categorical variables, respectively. The sta- Ͻ tistics were calculated to assess interobserver and intraob- (P .001). The study was approved by the local ethics com- ␬ mittees, and each participant gave informed consent before en- server agreement. With regard to the interpretation of sta- tering the study, according to the tenets of the Declaration of tistics, a value of 1.00 indicates perfect agreement, values greater Helsinki. than 0.80 are considered excellent, values between 0.61 and Classification of MIS was performed in all patients after care- 0.80 are good, values between 0.40 and 0.60 are fair, and val- ful examination of the skin following the criteria proposed by ues less than 0.40 are poor. To identify the best combination of independent factors associated with each subgroup of pa- Hartmann and Henz (Table 1).11 Serum baseline tryptase (sBt) measurement was performed using a commercially available tients, multivariate (ie, logistic regression) analysis was per- technique (CAP; Phadia AB, Uppsala, Sweden); clinical symp- formed. For multivariate analyses, only those variables that showed statistically significant differences in the univariate study toms suggesting the release of MC mediators (eg, pruritus, flush- Յ ing, abdominal cramping, diarrhea, nausea or vomiting, and were included in the model. P .05 was considered statisti- anaphylaxis) also were recorded. The severity of mastocytosis- cally significant. For all statistical analyses, the SPSS 15.0 sta- related symptoms was subsequently graded in 2 different sub- tistical software package (SPSS Inc, Chicago, Illinois) was used. groups according to the need for antimediator therapy (AMT) on a daily basis. RESULTS

DERMOSCOPY CLINICAL VARIANTS OF MIS

Mastocytosis skin lesions were examined by 2 independent der- Overall, the different subtypes of MIS observed in the 127 matologists trained in dermoscopy (S.V.-G. and E.D.L.H.) using patients studied were MPCM in 90 patients (70.9%), a DermLite instrument (3Gen LLC, Dana Point, California) at 10-fold magnification. No pressure was applied to avoid col- nodular mastocytosis (NM) in 11 patients (8.7%), soli- lapse of the capillaries. In those patients who displayed mul- tary mastocytoma in 11 patients (8.7%), plaque-type mas- tiple skin lesions, 2 or more lesions were evaluated. According tocytosis (PM) in 8 patients (6.3%), and TMEP in 7 pa- to the dermoscopic findings (eg, background color and the pres- tients (5.5%). All patients except those with solitary ence or absence of reticular lines or vessels), as many as 4 dif- mastocytoma displayed multiple skin lesions. Table 2

ARCH DERMATOL/ VOL 147 (NO. 8), AUG 2011 WWW.ARCHDERMATOL.COM 933

©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 Corrected on August 23, 2011 Table 2. Number (Percentage) of Different Variants of Lesions in Patients With Mastocytosis in the Skin Grouped According to Age and Sex

Children Adults

Boys Girls Total Male Female Total Variant (n=38) (n=23) (N=61) (n=19) (n=47) (N=66) MPCM (n=90) 19 (54.3) 16 (45.7) 35 (100) 16 (29.1) 39 (70.9) 55 (100) NM (n=11) 6 (60.0) 4 (40.0) 10 (100) 0 1 (100) 1 (100) Solitary mastocytoma (n=11) 9 (81.8) 2 (18.2) 11 (100) 0 0 0 PM (n=8) 4 (80.0) 1 (20.0) 5 (100) 2 (66.7) 1 (33.3) 3 (100) TMEP (n=7) 0 0 0 1 (14.3) 6 (85.7) 7 (100)

Abbreviations: MPCM, maculopapular cutaneous mastocytosis; NM, nodular mastocytosis; PM, plaque-type mastocytosis; TMEP, telangiectasia macularis eruptiva perstans.

gives the distribution of the different clinical variants ac- 5 with NM (45.5%), and 3 with PM (37.5%). A reticular cording to patient sex and age. vascular pattern was seen in all adult patients with TMEP and in 11 (7 adults and 4 children); of 90 patients with DERMOSCOPIC FEATURES MPCM (12.2%) finally, a yellow-orange blot was observed in all patients with mastocytoma and in 6 of 11 After careful examination of skin lesions, 4 dermo- with NM (54.6%). scopic patterns were identified (Figure 1) and named as follows: light-brown blot (51 patients [40.2%]), pig- SERUM TRYPTASE ment network (41 patients [32.3%]), reticular vascular (18 patients [14.2%]), and yellow-orange blot (17 pa- The median (range) sBt level was 9 ng/mL (1-508 ng/ tients [13.4%]). In our study, the intraobserver and the mL) with significantly (PϽ.001) higher values in adults interobserver agreement for the assignment of a dermo- compared with children (median, 24.5 vs 6 ng/mL, re- scopic pattern for each lesion were excellent (␬=0.87, spectively). Of interest, sBt levels were significantly higher PϽ.001, and ␬=0.80, PϽ.001, respectively). Of note, in in patients with a reticular vascular pattern vs those with all patients who displayed multiple skin lesions, a pre- the light-brown blot (P=.02), pigment network (P=.02), dominant dermoscopic pattern was identified. The light- or yellow-orange blot profile (PϽ.001) (median, 24.5 vs brown blot pattern was characterized by a light- 10 ng/mL, 9 ng/mL, and 5.4 ng/mL, respectively) brownish diffuse blot without any other identifiable (Figure 4A), with the level in those with the yellow- features; pigment network lesions showed fine brown re- orange blot profile being significantly lower than in those ticular lines, similar to those observed in some melano- with the light-brown blot (P=.02) and pigment net- cytic lesions. In turn, lesions with a reticular vascular pat- work patterns (P=.04). Of note, all these differences lost tern consisted of thin reticular telangiectasias on a mild their statistical significance when adult and pediatric pa- erythematous base with sparse vessels dotted through- tients were separately considered except for the higher out. Finally, yellow-orange blot lesions were character- sBt levels found among children with reticular vascular ized by a yellowish to orange faded color with an ill- vs yellow-orange blot patterns (10.5 vs 5.2 ng/mL; P=.03). defined margin. Of interest, the dermoscopic patterns Figure 4B shows differences in sBt levels between the observed for different skin lesions of the same patient were distinct clinical forms of MIS. Of interest, sBt levels were similar. The histologic correlation of each dermoscopic significantly higher in the TMEP group (median, 84.9 ng/ pattern is illustrated in Figure 2. mL) vs all other groups except for the patients with PM Table 3 gives the distribution of the 4 dermoscopic (MPCM, 21.7 ng/mL [P=.001]; NM, 9.8 ng/mL [P=.003]; patterns among adult and pediatric patients. The reticu- and solitary mastocytoma, 4.2 ng/mL [PϽ.001]). Con- lar vascular pattern was observed in 14 of the 66 adults versely, sBt levels in patients with mastocytoma were sig- (21.2%) and 4 of the 61 children (6.6%) (P=.02), but the nificantly lower than those of the remaining disease groups yellow-orange blot pattern was more frequently found (P=.001). When dividing all patients into adult or pe- in children than adults (26.2% vs 1.5%; PϽ.001). By con- diatric groups, differences in sBt levels were restricted trast, no significant differences in the frequency of the to TMEP vs MPCM (84.9 vs 21.7 ng/mL; P=.009) and light-brown blot or the pigment network patterns were PM vs MPCM (288 vs 21.7 ng/mL; P=.005) in adults; observed in adults compared with children (37.9% vs however, in children, only patients with mastocytoma 42.6% and 39.4% vs 24.6%, respectively; P=.61 and P=.08, showed significantly lower sBt levels compared with all respectively). Figure 3 shows the frequency of each der- other groups except patients with PM. moscopic pattern observed among the distinct MIS variants. A light-brown blot pattern was observed in approxi- NEED FOR ANTIMEDIATOR THERAPY mately half of all patients with MPCM lesions (43 of 90; [47.8%]), 3 of 11 patients with NM (27.3%), and 5 of 8 In 75 patients (59.1%), mastocytosis-related symptoms were patients with PM (62.5%). In turn, a pigment network mild or absent, and patients did not need AMT or only pattern was identified in 36 patients with MPCM (40.0%), needed it on demand; conversely, in the remaining 52

ARCH DERMATOL/ VOL 147 (NO. 8), AUG 2011 WWW.ARCHDERMATOL.COM 934

C D

E F

G H

Figure 1. Examples of the 4 different dermoscopic patterns identified in patients with mastocytosis in the skin. A, In a 9-year-old boy, maculopapular cutaneous mastocytosis with a light-brownish blot were observed on dermoscopy without any identifiable dermoscopic structure (ie, the characteristic light-brown blot pattern). B, In a 7-year-old boy, maculopapular cutaneous mastocytosis and a light-brown blot were observed on dermoscopy. C, In a 25-year-old woman, maculopapular cutaneous mastocytosis and fine brown reticular lines were observed on dermoscopy, typical of the pigment network pattern. D, In a 57-year-old man, maculopapular cutaneous mastocytosis and a pigment network pattern were observed on dermoscopy. E, In a 59-year-old woman, maculopapular cutaneous mastocytosis and thin reticular telangiectasias on a mild erythematous base with sparse vessels dotted throughout were observed on dermoscopy (ie, the reticular vascular dermoscopic pattern). F, In a 46-year-old woman, telangiectatic mastocytosis and a reticular vascular dermoscopic pattern were observed on dermoscopy. G, In a 9-month-old boy, solitary mastocytoma manifesting as a yellowish to orange discoloration with an ill-defined margin was observed on dermoscopy (ie, the yellow-orange blot dermoscopic pattern). H, In a 4-month-old girl, solitary mastocytoma and a yellow-orange blot were observed on dermoscopy.

ARCH DERMATOL/ VOL 147 (NO. 8), AUG 2011 WWW.ARCHDERMATOL.COM 935

C D

Figure 2. Histologic correlation with the 4 dermoscopic patterns (hematoxylin-eosin, original magnification ϫ40). A, The light-brown pattern showed mild and homogeneous hyperpigmentation of the basal layer associated with a dense dermal infiltrate of mast cells with scattered eosinophils. B, The pigmented network pattern correlated with a marked hyperpigmentation of the basal layer, more marked on the rete ridges, associated with a slight dermal infiltrate of mast cells. C, The main histopathologic feature of lesions with reticular vascular pattern was the dilation of the blood vessels. D, The yellow-orange blot pattern showed a dense infiltration of mast cells along the papillary and reticular dermis.

patients (40.9%), daily need for AMT was observed due to needed daily AMT was significantly higher among adults maintained symptoms. The percentage of patients who compared with children (51.5% vs 29.5%; P=.01) and in

ARCH DERMATOL/ VOL 147 (NO. 8), AUG 2011 WWW.ARCHDERMATOL.COM 936

©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 Corrected on August 23, 2011 Table 3. Number (Percentage) of Dermoscopic Patterns According to Patient Age and Sex

Children Adults

Boys Girls Total Men Women Total Pattern (n=38) (n=23) (N=61) (n=19) (n=47) (N=66) Light-brown blot (n=51) 17 (65.4) 9 (34.6) 26 (100) 6 (24.0) 19 (76.0) 25 (100) Pigment network (n=41) 7 (46.7) 8 (53.3) 15 (100) 11 (42.3) 15 (57.7) 26 (100) Reticular vascular (n=18) 3 (75.0) 1 (25.0) 4 (100) 2 (14.3) 12 (85.7) 14 (100) Yellow-orange blot (n=17) 11 (68.8) 5 (31.2) 16 (100) 0 1 (100) 1 (100)

100 Light-brown blot A Pigment network 175 80 Reticular vascular Yellow-orange blot 150

125 60

100 40 No. of Cases 75

50 20 Serum Tryptase, ng/mL Serum Tryptase, 25 0 MPCM NM PM Mastocytoma TMEP 0 Subtype of MIS Light-Brown Pigment Reticular Yellow-Orange Blot Network Vascular Blot (n = 51) (n = 41) (n = 18) (n = 17) Figure 3. Relative distribution of the different dermoscopic patterns Dermoscopic Pattern observed among the patients with mastocytosis in the skin (MIS) (n=127), grouped according to the distinct forms of the disease. MPCM indicates B maculopapular cutaneous mastocytosis; NM, nodular mastocytosis; 600 PM, plaque-type mastocytosis, and TMEP, telangiectasia macularis eruptiva perstans. 500

those patients with increased sBt levels of 10 ng/mL or 400 greater compared with patients with sBt levels less than 10 ng/mL (66.7% vs 15.6%; PϽ.001) independent of the age 300 Ͻ group (65.3% vs 11.8% [P .001] in adults and 71.4% vs 200 17.0% [PϽ.001] in children). Regarding the association Serum Tryptase, ng/mL Serum Tryptase, between AMT and the clinical forms of the disease, pa- 100 tients with PM needed continuous AMT more frequently than all other groups (87.5% vs 37.8%; P=.008), but none 0 of the patients with solitary mastocytoma (compared with TMEP MPCM NM PM Mastocytoma 44.8% of all other clinical forms of MIS; P=.003) required (n = 7) (n = 90) (n = 11) (n = 8) (n = 11) AMT on a daily basis. Subtype of MIS Regarding dermoscopic patterns (Table 4), the need Figure 4. Median serum baseline tryptase levels in patients with mastocytosis for daily AMT was higher among patients with a reticu- in the skin (MIS) (n=127). Patients are grouped according to the different lar vascular pattern vs all other dermoscopic patterns dermoscopic patterns identified (A) and the distinct skin variants of the disease (77.8% vs 34.9%; P=.001); in contrast, only 17.6% of pa- (B). MPCM indicates maculopapular cutaneous mastocytosis; NM, nodular tients with a yellow-orange blot pattern needed daily AMT mastocytosis; PM, plaque-type mastocytosis; and TMEP, telangiectasia macularis eruptiva perstans. Error bars indicate SD. (compared with 44.5% of patients with other dermoscopic patterns). Of note, of those 17 patients (11 with mastocytoma and 6 with NM) with a yellow-orange blot lar vascular pattern vs other dermoscopic profiles (81.8% pattern, the patients with NM needed continuous AMT vs 32.9%; P=.003). In line with these findings, a reticu- more frequently than patients with mastocytoma (50.0% lar vascular pattern also was more frequently associated vs 0%; P=.03). In contrast, no significant differences were with daily need for AMT (compared with all other cases) observed in the daily need for AMT among the 18 pa- when adults (78.6% vs 44.2%; P=.02) and children (75.0% tients with a reticular vascular pattern (81.8% of pa- vs 26.3%; P=.07) were separately considered. tients with MPCM compared with 71.4% of patients with In univariate analysis, the following variables were in- TMEP; PϾ.99). However, when patients with MPCM cluded: clinical form (ie, MPCM, PM, NM, TMEP, and were separately considered, a higher frequency of need mastocytoma), dermoscopic pattern (ie, light-brown blot, for daily AMT was observed among those with a reticu- pigment network, reticular vascular, and yellow-orange

ARCH DERMATOL/ VOL 147 (NO. 8), AUG 2011 WWW.ARCHDERMATOL.COM 937

©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 Corrected on August 23, 2011 blot), sBt level, and age group (ie, adults and children). patterns reported in this study showed histologic corre- Multivariate analysis of predictive disease features for the lation with UP and TMEP, respectively. Several years be- need for daily AMT (Table 5) showed that the combi- fore, Arpaia et al19 had described the dermoscopic pat- nation of sBt level (ie, Ͼ10 ng/mL), PM, and a reticular tern of a solitary maculopapular mastocytosis lesion as vascular pattern was the most informative independent a delicate pale pigmented network. We report on the larg- factor; of note, no patients displayed all 3 factors simul- est series of dermoscopic patterns observed in mastocy- taneously. On the basis of these results, a scoring sys- tosis described so far in the literature. Overall, 4 clearly tem was built that proved to have high efficiency (posi- distinguishable dermoscopic patterns were identified: tive predictive value, 0.9; 95% confidence interval [CI], light-brown blot, pigment network, reticular vascular, and 0.78-1.03; negative predictive value, 0.69; 0.60-0.78) to yellow-orange blot. properly classify patients with MIS according to the need The light-brown blot pattern was the most frequent for AMT when at least 2 of those factors are simultane- dermoscopic pattern in our series. It accounted for a large ously present (Ն2 of 3). These results contrast with pre- proportion of all patients with MPCM and PM. Dermo- dictive values observed when 1 or more of those factors scopic findings in these patients were similar to those ob- Ն are present (score of 1 of 3) (positive predictive value, served in acral nevus20 and some actinic lentigos (S.V.-G. 0.65; 95% CI, 0.53-0.76; negative predictive value, 0.86; et al, unpublished data, January 2009). 0.78-0.95). In turn, dermoscopic features of patients with a pigment network pattern were consistent with previously COMMENT reported data pertaining to mastocytosis, and they have been related to the potential accumulation of melanin in To our knowledge, only 1 study in a small series of pa- the basal layer of the epidermis due to proliferation of tients with mastocytosis (ie, 3 patients with TMEP and MC within the dermis.21 This pattern typically is seen in 3 with UP) has been published so far,18 in which 2 dif- melanocytic lesions, but it also can be detected in non- ferent dermoscopic patterns were described (ie, a pig- melanocytic lesions other than mastocytosis, such as der- ment network and a vascular pattern). Of interest, the 2 matofibroma,22 solar lentigo,23 pigmented seborrheic keratoses,24 accessory nipple,25 Kaposi sarcoma,19 and even healthy skin.26 In our series, the pigment network pat- Table 4. Need for Antimediator Therapy Among Patients tern was present in approximately one-third of all pa- With Mastocytosis in the Skin With Different Dermoscopic Patterns tients with mastocytosis, with a slight predominance among those with MPCM and PM, similar to the light- Need for Antimediator Therapy brown blot pattern profile. Thin telangiectasias detected in the reticular vascu- No Need Daily lar pattern occur due to the presence of numerous pro- or on Demand, Basis, liferating vessels within the papillary dermis, which could Patient Group No. (%) No. (%) reflect local release of MC-derived angiogenic factors.27 Light-brown blot The vascular dermoscopic pattern has been previously Children (n=26) 18 (69.2) 8 (30.8) 28 Adults (n=25) 12 (48.0) 13 (52.0) described in clear cell acanthoma, nonpigmented ec- 29,30 31 Total (n=51) 30 (58.8) 21 (41.2) crine poromas, squamous cell carcinoma, amela- Pigment network notic melanoma,32 and porocarcinoma.33 Of interest, this Children (n=15) 10 (66.7) 5 (33.3) pattern of thin telangiectasia is not seen commonly in these Adults (n=26) 17 (65.4) 9 (34.6) other conditions. In our series, a reticular vascular pat- Total (n=41) 27 (65.9) 14 (34.1) Reticular vascular tern, in which MCs are typically located around dilated Children (n=4) 1 (25.0) 3 (75.0) capillaries of the superficial plexus of the upper dermis, Adults (n=14) 3 (21.4) 11 (78.6) was systematically found in patients with TMEP and in Total (n=18) 4 (22.2) 14 (77.8) a small proportion of those with MPCM. Yellow-orange blot The yellow-orange blot dermoscopic pattern has been Children (n=16) 14 (87.5) 2 (12.5) reported in a wide variety of skin lesions characterized Adults (n=1) 0 1 (100) Total (n=17) 14 (82.4) 3 (17.6) by a xanthogranulomatous dermal infiltrate, which include juvenile xanthogranuloma,34 sebaceous hyperplasia,35,36 reticulohistiocytoma, xanthomatous dermatofi-

Table 5. Univariate and Multivariate Analyses of Predictive Factors for the Need for Daily Antimediator Therapy

Univariate Analysis Multivariate Analysis

Predictive Factor Patients, No. (%) RR (95% CI) P Value HR (95% CI) P Value Adult mastocytosis 34 (51.5) 2.5 (1.2-5.3) .01 NA NA Serum tryptase level Ͼ10 ng/mL 42 (66.7) 10.8 (4.6-25.4) Ͻ.001 8.8 (3.6-21.7) Ͻ.001 Plaque-type mastocytosis 7 (87.5) 11.5 (1.4-96.7) .02 13.6 (1.3-137.3) .03 Reticular vascular pattern 14 (77.8) 6.5 (2.0-21.3) .002 4.6 (1.2-17.0) .02

Abbreviations: CI, confidence interval; HR, hazard ratio; NA, not applicable; RR, relative risk.

ARCH DERMATOL/ VOL 147 (NO. 8), AUG 2011 WWW.ARCHDERMATOL.COM 938

©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 Corrected on August 23, 2011 broma, and adult xanthogranuloma.37 Of interest, in our sis. However, these patterns are not totally specific for series, a similar yellow-orange blot pattern was system- MIS, so the diagnosis needs to be confirmed by the re- atically observed among children with mastocytoma and sults of a skin biopsy in most cases. The dermoscopic pat- in approximately half of all patients with NM. terns, in combination with sBt levels and the clinical forms Also, a clear association between the subtype of MIS of MIS, also provide useful information for the identifi- and these dermoscopic patterns is demonstrated. On the cation of more symptomatic forms of the disease that will basis of these observations, a question remained regard- require daily AMT. Strict and prospective follow-up of ing the potential effect of such patterns on the behavior patients can allow the possibility of detecting changes in of the disease and the severity of MC mediator release– dermoscopic patterns throughout the evolution of the dis- associated symptoms. In this regard, our results clearly ease (ie, children with a progressive decrease in skin le- show that high sBt levels (ie, Ͼ10 ng/mL), together with sions) or for the follow-up of response of skin lesions to a PM and the presence of a reticular vascular dermo- different therapies, such as psoralen–UV-A, cytoreduc- scopic pattern, are highly predictive of the daily need for tive, or targeted therapies. AMT. Currently, it is well known that sBt levels corre- late with the overall MC burden38,39; in fact, an sBt level Accepted for Publication: October 26, 2010. higher than 20 ng/mL is highly suggestive of systemic in- Correspondence: Luis Escribano, MD, PhD, Instituto de volvement in MIS, and it is 1 of the 4 World Health Or- Estudios de Mastocitosis de Castilla La Mancha, Hospi- ganization minor criteria for diagnosis of systemic mas- tal Virgen del Valle, Carretera de Cobisa s/n, Toledo tocytosis.7 Furthermore, increased sBt levels also have been E-45071, Spain ([email protected]). associated with the severity of MC mediator release symp- Author Contributions: Drs Escribano and Orfao had full toms not only in mastocytosis but also in allergic dis- access to all the data in the study and take responsibility eases.40-42 In our study, sBt levels were higher in adults for the integrity of the data and the accuracy of the data compared with children, in accordance with a higher fre- analysis. Study concept and design: Vano-Galvan, A´ lvarez- quency of systemic involvement and a longer follow-up Twose, De las Heras, Jaeń, Orfao, and Escribano. Acqui- since the onset of the disease in adults. Nevertheless, sition of data: Vano-Galvan, A´ lvarez-Twose, De las Heras, higher sBt levels were associated with a more frequent Morgado, Matito, Sańchez-Mun˜ oz, and Escribano. Analy- need for daily AMT in the adult and pediatric groups. In sis and interpretation of data: Vano-Galvan, A´ lvarez- line with these findings, multivariate analysis showed that Twose, De las Heras, Morgado, Sańchez-Mun˜ oz, Plana, sBt levels but not patient age proved to be a powerful in- and Jaeń.Drafting of the manuscript: Vano-Galvan, A´ lvarez- dependent predictive factor of the need for daily AMT, Twose, Matito, and Jaeń. Critical revision of the manu- supporting the notion that tryptase levels by themselves script for important intellectual content: Vano-Galvan, A´ l- are a powerful predictive factor of a more symptomatic varez-Twose, De las Heras, Morgado, Sańchez-Mun˜ oz, disease. Plana, Jaeń, Orfao, and Escribano. Statistical analysis: In line with previous observations,18 all patients with Vano-Galvan, A´ lvarez-Twose, and Plana. Obtained fund- TMEP in our series showed a reticular vascular dermo- ing: Orfao and Escribano. Administrative, technical, and scopic pattern. However, this pattern also was detected material support: Morgado, Matito, and Sańchez- in some patients with MPCM; of interest, these latter pa- Mun˜ oz. Study supervision: Vano-Galvan, A´ lvarez- tients more frequently required daily AMT than other pa- Twose, De las Heras, Morgado, Sańchez-Mun˜ oz, Jaeń, Or- tients with MPCM. Overall, the presence of a reticular fao, and Escribano. vascular pattern was associated with an increased need Financial Disclosure: None reported. for daily AMT; on the basis of these findings, it could be Funding/Support: This work was supported by grant PS hypothesized that in combination with other variables, 09/00032 from Fondo de Investigaciones Sanitarias of the dermoscopy could provide additional help in the iden- Ministerio de Sanidad y Consumo (Dr Escribano) and tification of patients at risk for more severe symptoms, grants FISCAM 2007/36 and FISCAM 2008/46 from Junta independently of tryptase levels or the clinical subtype de Comunidades de Castilla La Mancha (Dr Escribano). of MIS, as confirmed in our study by multivariate analy- Dr Vano-Galvan was the beneficiary of a Jorge Fran- sis. Another disease features that proved to be associ- cisco Tello Mun˜ oz scholarship supported by the Agen- ated with more severe symptoms was the clinical form cia Laıń Entralgo, Community of Madrid. of MIS; PM was associated with a higher proportion of patients receiving daily AMT, but solitary mastocytoma REFERENCE was less symptomatic, with no patients needing daily AMT. At least in adults, this could occur due to a higher 1. Soter NA. The skin in mastocytosis. J Invest Dermatol. 1991;96(3)(suppl):32S- MC burden, as supported by the extremely higher sBt lev- 39S. els observed within this group of patients. 2. Kettelhut BV, Metcalfe DD. Pediatric mastocytosis. Ann Allergy. 1994;73(3):197- A limitation of our study is that patients previously 207. 3. Longley J, Duffy TP, Kohn S. The mast cell and mast cell disease. J Am Acad diagnosed as having mastocytosis were evaluated. A fu- Dermatol. 1995;32(4):545-564. ture prospective study including dermoscopy evalua- 4. Alto WA, Clarcq L. Cutaneous and systemic manifestations of mastocytosis. Am tion at the time of disease diagnosis may clarify whether Fam Physician. 1999;59(11):3047-3054, 3059-3060. dermoscopy may predict better evaluation in the future. 5. Katsamba AD, Karpouzis AJ, Koumantaki-Mathioudaki E, Jorizzo JL. Mastocy- tosis with skin manifestations: current status. J Eur Acad Dermatol Venereol. 1999; The results of this study reveal that 4 dermoscopic pat- 13(3):155-165. terns were evident in MIS, which can be easily evalu- 6. Soter NA. Mastocytosis and the skin. Hematol Oncol Clin North Am. 2000;14(3): ated in the diagnostic workup of cutaneous mastocyto- 537-555, vi.

ARCH DERMATOL/ VOL 147 (NO. 8), AUG 2011 WWW.ARCHDERMATOL.COM 939

©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 Corrected on August 23, 2011 7. Horny HP, Metcalfe DD, Bennet JM, et al, Swerdlow SH, Campo E, Harris NL, by pigmented seborrheic keratoses: a finding which is not uncommon in et al eds. Mastocytosis. In: WHO Classification of Tumours of Haematopoietic dermoscopy. Dermatol Surg. 2002;28(8):776-779. and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research 25. Oztas MO, Gurer MA. Dermoscopic features of accessory nipples. Int J Dermatol. and Cancer; 2008:54-63. 2007;46(10):1067-1068. 8. Parkes Weber F, Rast H. Telangiectasia macularis eruptiva perstans: a telangi- 26. Scope A, Marghoob AA, Chen CS, Lieb JA, Weinstock MA, Halpern AC; SONIC ectatic and relatively pigmentless variety of urticaria pigmentosa of adults. Acta Study Group. Dermoscopic patterns and subclinical melanocytic nests in normal- Derm Venereol (Stockh). 1935;16:216-224. appearing skin. Br J Dermatol. 2009;160(6):1318-1321. 9. Allen BR. Telangiectasia macularis perstans. Br J Dermatol. 1978;99(suppl 16): 27. Reed JA, Albino AP, McNutt NS. Human cutaneous mast cells express basic fi- 28-29. broblast growth factor. Lab Invest. 1995;72(2):215-222. 10. Sarkany RPE, Monk BE, Handfield-Jones SE. Telangiectasia macularis eruptiva 28. Bugatti L, Filosa G, Broganelli P, Tomasini C. Psoriasis-like dermoscopic pat- perstans: a case report and review of the literature. Clin Exp Dermatol. 1998; tern of clear cell acanthoma. J Eur Acad Dermatol Venereol. 2003;17(4):452- 23(1):38-39. 455. 11. Hartmann K, Henz BM. Classification of cutaneous mastocytosis: a modified con- 29. Altamura D, Piccolo D, Lozzi GP, Peris K. Eccrine poroma in an unusual site: a sensus proposal. Leuk Res. 2002;26(5):483-486. clinical and dermoscopic simulator of amelanotic melanoma. J Am Acad Dermatol. 12. Valent P, Akin C, Escribano L, et al. Standards and standardization in mastocy- 2005;53(3):539-541. tosis: consensus statements on diagnostics, treatment recommendations and 30. Avile´s-Izquierdo JA, Vela´zquez-Tarjuelo D, Lecona-Echevarrı´a M, La´zaro- response criteria. Eur J Clin Invest. 2007;37(6):435-453. Ochaita P. Dermoscopic features of eccrine poroma [in Spanish]. Actas 13. Garriga MM, Friedman MM, Metcalfe DD. A survey of the number and distribu- Dermosifiliogr. 2009;100(2):133-136. tion of mast cells in the skin of patients with mast cell disorders. J Allergy Clin 31. Nicolino R, Zalaudek I, Ferrara G, et al. Dermoscopy of eccrine poroma. Dermatology. Immunol. 1988;82(3, pt 1):425-432. 2007;215(2):160-163. 14. Wolff K, Komar M, Petzelbauer P. Clinical and histopathological aspects of cu- 32. Bugatti L, Filosa G, De Angelis R. The specific dermoscopical criteria of Bowen’s taneous mastocytosis. Leuk Res. 2001;25(7):519-528. disease. J Eur Acad Dermatol Venereol. 2007;21(5):700-701. 15. Longley BJ Jr, Metcalfe DD, Tharp M, et al. Activating and dominant inactivating 33. Blum A, Metzler G, Bauer J. Polymorphous vascular patterns in dermoscopy as c-KIT catalytic domain mutations in distinct clinical forms of human mastocytosis. a sign of malignant skin tumors: a case of an amelanotic melanoma and a Proc Natl Acad Sci U S A. 1999;96(4):1609-1614. porocarcinoma. Dermatology. 2005;210(1):58-59. 16. Bodemer C, Hermine O, Palme´rini F, et al. Pediatric mastocytosis is a clonal dis- 34. Palmer A, Bowling J. Dermoscopic appearance of juvenile xanthogranuloma. ease associated with D816V and other activating c-KIT mutations. J Invest Dermatol. Dermatology. 2007;215(3):256-259. 2010;130(3):804-815. 35. Bryden AM, Dawe RS, Fleming C. Dermatoscopic features of benign sebaceous 17. Argenziano G, Mordente I, Ferrara G, Sgambato A, Annese P, Zalaudek I. Der- proliferation. Clin Exp Dermatol. 2004;29(6):676-677. moscopic monitoring of melanocytic skin lesions: clinical outcome and patient 36. Zaballos P, Ara M, Puig S, Malvehy J. Dermoscopy of sebaceous hyperplasia. compliance vary according to follow-up protocols. Br J Dermatol. 2008;159 Arch Dermatol. 2005;141(6):808. (2):331-336. 37. Cavicchini S, Tourlaki A, Tanzi C, Alessi E. Dermoscopy of solitary yellow le- 18. Akay BN, Kittler H, Sanli H, Harmankaya K, Anadolu R. Dermatoscopic findings sions in adults. Arch Dermatol. 2008;144(10):1412. of cutaneous mastocytosis. Dermatology. 2009;218(3):226-230. 38. Schwartz LB, Irani AM. Serum tryptase and the laboratory diagnosis of sys- 19. Arpaia N, Cassano N, Vena GA. Lessons on dermoscopy: pigment network in temic mastocytosis. Hematol Oncol Clin North Am. 2000;14(3):641-657. nonmelanocytic lesions. Dermatol Surg. 2004;30(6):929-930. 39. Sperr WR, Jordan J-H, Fiegl M, et al. Serum tryptase levels in patients with mas- 20. Saida T, Koga H. Dermoscopic patterns of acral melanocytic nevi: their varia- tocytosis: correlation with mast cell burden and implication for defining the cat- tions, changes, and significance. Arch Dermatol. 2007;143(11):1423-1426. egory of disease. Int Arch Allergy Immunol. 2002;128(2):136-141. 21. Yadav S, Vossaert KA, Kopf AW, Silverman M, Grin-Jorgensen C. Histopatho- 40. Schwartz LB, Metcalfe DD, Miller JS, Earl H, Sullivan T. Tryptase levels as an logic correlates of structures seen on dermoscopy (epiluminescence microscopy). indicator of mast-cell activation in systemic anaphylaxis and mastocytosis. N Engl Am J Dermatopathol. 1993;15(4):297-305. J Med. 1987;316(26):1622-1626. 22. Zaballos P, Puig S, Llambrich A, Malvehy J. Dermoscopy of dermatofibromas: a 41. Ludolph-Hauser D, Rue¨ff F, Fries C, Scho¨pf P, Przybilla B. Constitutively raised prospective morphological study of 412 cases. Arch Dermatol. 2008;144(1): serum concentrations of mast-cell tryptase and severe anaphylactic reactions 75-83. to Hymenoptera stings. Lancet. 2001;357(9253):361-362. 23. Haas N, Hermes B, Henz BM. Detection of a novel pigment network feature in 42. Haeberli G, Bro¨nnimann M, Hunziker T, Mu¨ller U. Elevated basal serum tryptase reticulated black solar lentigo by high-resolution epiluminescence microscopy. and Hymenoptera venom allergy: relation to severity of sting reactions and to Am J Dermatopathol. 2002;24(3):213-217. safety and efficacy of venom immunotherapy. Clin Exp Allergy. 2003;33(9): 24. De Giorgi V, Massi D, Stante M, Carli P. False “melanocytic” parameters shown 1216-1220.

ARCH DERMATOL/ VOL 147 (NO. 8), AUG 2011 WWW.ARCHDERMATOL.COM 940

©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 Corrected on August 23, 2011 Bordeaux CEDEX, France (fanny.morice-picard rich domains of the LDL receptor gene are a cause of familial hypercholesterolemia. @chu-bordeaux.fr). Hum Genet. 2002;111(6):501-510. Author Contributions: Dr Morice-Picard had full access 5. Cariou B, Ouguerram K, Zaı¨r Y, et al. PCSK9 dominant negative mutant results in increased LDL catabolic rate and familial hypobetalipoproteinemia. Arterio- to all the data in the study and takes responsibility for the scler Thromb Vasc Biol. 2009;29(12):2191-2197. integrity of the data and the accuracy of the data analysis. 6. Braverman N, Lin P, Moebius FF, et al. Mutations in the gene encoding 3 beta- Study concept and design: Morice-Picard and Taıëb. Acqui- hydroxysteroid-delta 8, delta 7-isomerase cause X-linked dominant Conradi- sition of data: Morice-Picard, Kostrzewa, Wolf, Benlian, Hu¨nermann syndrome. Nat Genet. 1999;22(3):291-294. Taıëb, and Lacombe. Analysis and interpretation of data: 7. Traupe H, Has C. The Conradi-Hu¨nermann-Happle syndrome is caused by mu- Morice-Picard, Kostrzewa, and Benlian. Drafting of the manu- tations in the gene that encodes a 38-37 sterol isomerase and is biochemically related to the CHILD syndrome. Eur J Dermatol. 2000;10(6):425-428. script: Morice-Picard and Taıëb. Critical revision of the manu- 8. Ausavarat S, Tanpaiboon P, Tongkobpetch S, Suphapeetiporn K, Shotelersuk V. script for important intellectual content: Morice-Picard, Two novel EBP mutations in Conradi-Hu¨nermann-Happle syndrome. Eur J Kostrzewa, Wolf, Benlian, Taıëb, and Lacombe. Adminis- Dermatol. 2008;18(4):391-393. trative, technical, and material support: Wolf. Study super- 9. Steijlen PM, van Geel M, Vreeburg M, et al. Novel EBP gene mutations in Conradi- vision: Taıëb and Lacombe. Hu¨nermann-Happle syndrome. Br J Dermatol. 2007;157(6):1225-1229. Financial Disclosure: None reported. 10. Aughton DJ, Kelley RI, Metzenberg A, Pureza V, Pauli RM. X-linked dominant Additional Contributions: We are indebted to the pa- chondrodysplasia punctata (CDPX2) caused by single gene mosaicism in a male. Am J Med Genet A. 2003;116A(3):255-260. tients. 11. Sutphen R, Amar MJ, Kousseff BG, Toomey KE. XXY male with X-linked dominant chondrodysplasia punctata (Happle syndrome). Am J Med Genet. 1995; REFERENCES 57(3):489-492. 12. Shirahama S, Miyahara A, Kitoh H, et al. Skewed X-chromosome inactivation causes intra-familial phenotypic variation of an EBP mutation in a family with X-linked 1. Derry JMJ, Gormally E, Means GD, et al. Mutations in a delta 8-delta 7-sterol isomerase in the tattered mouse and X-linked dominant chondrodysplasia punctata. dominant chondrodysplasia punctata. Hum Genet. 2003;112(1):78-83. Nat Genet. 1999;22(3):286-290. 13. Has C, Seedorf U, Kannenberg F, et al. Gas chromatography-mass spectrometry 2. Happle R. Lyonization and the lines of Blaschko. Hum Genet. 1985;70(3):200-206. and molecular genetic studies in families with the Conradi-Hu¨nermann-Happle 3. Chevy F, Humbert L, Wolf C. Sterol profiling of amniotic fluid: a routine method syndrome. J Invest Dermatol. 2002;118(5):851-858. for the detection of distal cholesterol synthesis deficit. Prenat Diagn. 2005; 14. Has C, Bruckner-Tuderman L, Mu¨ller D, et al. The Conradi-Hu¨nermann-Happle 25(11):1000-1006. syndrome (CDPX2) and emopamil binding protein: novel mutations, and so- 4. Amsellem S, Briffaut D, Carrie´ A, et al. Intronic mutations outside of Alu-repeat- matic and gonadal mosaicism. Hum Mol Genet. 2000;9(13):1951-1955.

Correction

Errors in Byline, Author Affiliations, and Author Con- tributions. In the Study titled “Dermoscopic Features of Skin Lesions in Patients With Mastocytosis” by Vano- Galvan et al, published in the August issue of the Ar- chives (2011;147[8]:932-940), errors occurred in the byline and the Author Affiliations section on page 932 and in the Correspondence and Author Contributions sections on page 939. In the byline, the names of 2 of the coauthors should have read “Elena De las Heras, MD, PhD” and “Maria N. Plana, MD, PhD.” The corrected spellings of those surnames also should have been re- flected in the Author Affiliations and Author Contribu- tions sections.

ARCH DERMATOL/ VOL 147 (NO. 9), SEP 2011 WWW.ARCHDERMATOL.COM 1076