cine, University of Chicago, Chicago, Illinois (Drs Mann, fection to manifest as warts.4 Macrophages ingest lipid- Petronic-Rosic, and Shea). rich debris derived from overlying damaged and/or Correspondence: Dr Duffy, Department of Dermatol- proliferating keratinocytes and accumulate in the papil- ogy, University of Utah, 30 N 1900 E, 4A330 SOM, Salt lary dermis because of poor lymphatic drainage. In corol- Lake City, UT 84132 ([email protected]). lary, increased lymphatic flow leads to regression of VX.2 Author Contributions: All authors had full access to all Based on this mechanistic framework, we sought to deter- of the data in the study and take responsibility for the mine if histologic evidence of lymphedema existed in LS integrity of the data and the accuracy of the data analy- that would explain the relative frequent occurrence of VX sis. Study concept and design: Mann. Acquisition of data: in vulvar LS, 60% in the series reported by Fite et al.1 Mann. Analysis and interpretation of data: Duffy, Mann, Petronic-Rosic, and Shea. Drafting of the manuscript: Mann. Methods. Over a 3-month period in 2011, all diagnosed Critical revision of the manuscript for important intellec- cases of LS in the Department of Pathology at Albany tual content: Duffy, Mann, Petronic-Rosic, and Shea. Ad- Medical College were retrieved. Formalin-fixed paraffin- ministrative, technical, and material support: Mann. Study embedded sections were immunostained with antibod- supervision: Duffy, Petronic-Rosic, and Shea. ies to D2-40, a lymphatic specific marker (Dako; 1:200) Financial Disclosure: None reported. and CD68, a macrophage marker (Ventana Medical Sys- Funding/Support: This study was supported in part by tems; prediluted), using an automated method (Ven- the Section of Dermatology, Department of Medicine, Uni- tana Medical Systems). Normal skin from elliptical ex- versity of Chicago. cisions of benign and malignant skin tumors was used Role of the Sponsors: The sponsors had no role in the for controls (cases previously reported4). Lymphatic den- design and conduct of the study; in the collection, analy- sity was measured by counting the number of D2-40 ex- sis, and interpretation of data; or in the preparation, re- pressing vessels per millimeter squared. Lymphatic ves- view, or approval of the manuscript. sels were categorized as dilated or collapsed; the maximal Additional Contributions: We are indebted to Yves dilation of the former was measured (methods previ- Lussier for performing statistical analysis on the data. ously described4). In addition, the presence or absence of D2-40 expression by the basal layer of the epidermis 1. Fung MA. Terminology and management of dysplastic nevi: responses from 145 dermatologists. Arch Dermatol. 2003;139(10):1374-1375. and aggregates of CD68-positive cells at the DEJ were re- 2. Tripp JM, Kopf AW, Marghoob AA, Bart RS. Management of dysplastic nevi: corded. STATA software, version 11.2 (StataCorp LP), a survey of fellows of the American Academy of Dermatology. J Am Acad was used for statistical analysis, with significance set at Dermatol. 2002;46(5):674-682. Ͻ 3. Goodson AG, Florell SR, Boucher KM, Grossman D. Low rates of clinical re- P .05. The institutional review board of Albany Medi- currence after biopsy of benign to moderately dysplastic melanocytic nevi. JAm cal College approved this study. Acad Dermatol. 2010;62(4):591-596. 4. Kmetz EC, Sanders H, Fisher G, Lang PG, Maize JC Sr. The role of observa- tion in the management of atypical nevi. South Med J. 2009;102(1):45-48. Results. The Table lists the overall results of this study, revealing that LS specimens exhibited signifi- cantly more dilated lymphatics and greater dilation of lymphatic vessels than did controls. In addition, dilated lymphatics significantly outnumbered collapsed vessels in LS samples, whereas collapsed lymphatics signifi- Lichen Sclerosus Exhibiting Histologic Signs cantly outnumbered dilated vessels in controls of Lymphedema: An Essential Factor in the (PՅ.03). Notably, collapsed lymphatic vessels were Pathogenesis of Verruciform Xanthoma seen underlying the sclerotic zone, often in areas of in- flammation, but lymphangiectases were found through- ecently, Fite et al1 reported a series of vulvar ver- out the zone of sclerosis, mostly in its deep aspect, ruciform xanthomas (VX) and attributed VX which also contained dilated blood vessels. The D2-40 R pathogenesis to disorders that injure the dermo- expression of basal keratinocytes was frequent in LS, a epidermal junction (DEJ), namely lichen sclerosus (LS). phenomenon that has been described in localized While we agree that damage to the DEJ is the source of lymphedema.3 Conspicuously, CD68ϩ macrophages debris found in the xanthomatous macrophages of VX, could be found forming small aggregates at the DEJ in the LS theory does not explain the accumulation of li- more than half of LS cases (Figure). pophages in the papillary dermis or the superimposi- tion of verrucous epidermal hyperplasia—the 2 pathog- Comment. Lichen sclerosus has been likened to an “in- nomonic features of VX. flammatory scar.” Therefore, it is not surprising to find Our research group2 has recently reported evidence that that the hallmark feature of LS, its sclerosis, which pro- VX is a complication of localized lymphedema, which has gressively replaces the upper dermis over time, disrupts many causes, including trauma, surgery, radiation therapy, lymphatic drainage by effacing the normal dermal archi- neoplasia, infection, and inflammatory dermatoses.3 Spe- tecture, leading to signs of lymphostasis—numerous di- cifically, scarring due to trauma, repeated irritation, and/or lated lymphatic vessels. Scarring and lymphangiectases chronic inflammation can obstruct lymphatics and lead to are ubiquitous features underlying warts and are sus- lymphostasis, histologically denoted by lymphangiecta- pected pathogenic factors.4 ses. Regional lymphostasis, because of disrupted immune While only a few reports of VX have documented HPV cell trafficking, creates a localized area of immunosuppres- infection,1 the low frequency of detection has been attrib- sion permitting latent human papillomavirus (HPV) in- uted to the sensitivity and specificity of the methods used

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©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Table. Increased Numbers of and Greater Dilation of Lymphatic Vessels Evidence of Lymphedema in Lichen Sclerosusa

Patient CD68؉ Sex, F/M, Total LVs, Collapsed Maximum at DEJ, D2-40؉ Sample Type Patient Age, y No. Site No./mm2b LVs/mm2b Dilated LVs/mm2b Dilation, mmb %c BK, % Lichen sclerosus 61 (16) (24-84) 16/2 14 Genital, 4 8.2 (4.4) (2.0-19.0) 2.7 (1.4) (0-6.0) 5.5 (3.3) (0.7-13) 0.05 (0.02) (0.03-0.12) 56 61 (n = 18) trunk Normal skin 56 (22) (17-86) 5/4 4 Genital, 5 6.6 (5.6) (2.2-18.5) 3.8 (2.4) (1.0-8.5) 2.7 (3.3) (0-10.0) 0.03 (0.01) (0-0.05) 0 0 (n=9) trunk P valued .23 .05 .08 .21 .07 .03 .02 .005 .002

Abbreviations: BK, basal keratinocytes; DEJ, dermoepidermal junction; LVs, lymphatic vessels. aUnless otherwise noted, data are reported as mean (SD) (range) values. bD2-40–expressing vessels counted. cClusters of CD68ϩ macrophages at the DEJ. dBoldface type indicates significant difference, P Ͻ .05.

A B C D

Figure. Immunohistopathologic specimens. A and B, An advanced lesion of stereotypical lichen sclerosus exhibits a vertically oriented, dilated lymphatic vessel with irregular valves in the deepest region of the sclerosis (hematoxylin-eosin, original magnifications ϫ40 [A] and ϫ100 [B]). C, Staining with D2-40 antibodies shows expression by epidermal basal keratinocytes (single yellow arrow), and dilated lymphatics with the deep aspect of the sclerosis are evident (double-headed yellow arrow); a non-D2-40–dilated vessel (vein) is found in the mid dermis (black arrow), signifying concomitant disruption of blood flow in addition to lymphatic drainage (note that a small dilated lymphatic is found adjacent to the dilated vein) (original magnification ϫ40). D, Staining with CD68 antibodies labels a cluster of macrophages at the dermoepidermal junction overlying the sclerosis—the putative site of lipophage accumulation in verruciform xanthoma (original magnification ϫ400). E, Staining with D2-40 antibodies reveals collapsed lymphatic vessels in a region of inflammation underlying the dermal sclerosis (yellow asterisk) (original magnification ϫ100).

where low copy number of ␤-HPV and genital-mucosal HPV Accepted for Publication: August 28, 2011. have been presumptively missed.2 Indeed, LS has been re- Author Affiliations: Divisions of Dermatopathology and ported to harbor a high frequency of HPV genotypes.5 Thus, Dermatology, Department of Pathology, Albany Medi- LS displays all the etiologic elements necessary for the for- cal College, Albany, New York (Dr Carlson and Mr Dias mation of VX—lymphostasis and latent HPV infection. We Carlson); and Department of Dermatology, University of 1 agree with Fite et al that the identification of VX requires Connecticut Medical Center, Farmington (Dr Murphy). a search for a primary disorder that produces a milieu of Dr Rohwedder is the owner of Bio-Med-Molec Service, a latent or clinically evident lymphedema—an essential fac- private company in Kalkar, Germany. tor in the pathogenesis of VX. Correspondence: Dr Carlson, Albany Medical College, J. Andrew Carlson, MD, FRCPC 47 New Scotland Ave, MC-81, Albany, NY 12208 (CarlsoA Grant D. Dias Carlson @mail.amc.edu). Michael Murphy, MD Author Contributions: Study concept and design: J. A. Carl- Angela Rohwedder, PhD son and Rohwedder. Acquisition of data: G. D. Dias Carl-

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©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 son. Analysis and interpretation of data: J. A. Carlson, G. The second hypothesis advanced by Carlson et al is that D. Dias Carlson, and Murphy. Drafting of the manu- the verrucous epidermal hyperplasia that is a hallmark of VX script: G. D. Dias Carlson. Critical revision of the manu- could be related to an HPV infection. This HPV infection may script for important intellectual content: J. A. Carlson, Mur- have been facilitated by the lymphostasis, the source of the dis- phy, and Rohwedder. Statistical analysis: J. A. Carlson rupted immune-cell trafficking and consequently of localized and G. D. Dias Carlson. Obtained funding: J. A. Carlson. immunosuppression. This interesting assumption is not cor- Administrative, technical, and material support: J. A. Carl- roborated either by the pathologic features of VX or by the avail- son and Murphy. Study supervision: J. A. Carlson. able virologic data. Indeed, we found that the verrucous hy- Financial Disclosure: None reported. perplasia of VX had specific, almost pathognomonic, histologic Funding/Support: This work was supported in part by features that differ from those of HPV infections: wedge- clinical revenues and generous donors to the Divisions shaped parakeratosis forming deep invaginations into the ac- of Dermatology and Dermatopathology, Department of anthotic epithelium and exhibiting a characteristic orange hue Pathology, Albany Medical College. under hematoxylin-eosin stain; and neutrophilic infiltrate at the junction between the superficial parakeratotic layers and 1. Fite C, Plantier F, Dupin N, Avril MF, Moyal-Barracco M. Vulvar verruci- form xanthoma: ten cases associated with lichen sclerosus, lichen planus, or the underlying stratum spinulosum. In addition, neither koilo- other conditions. Arch Dermatol. 2011;147(9):1087-1092. cytes nor atypia were observed. 2. Lu S, Rohwedder A, Murphy M, Carlson JA. Verruciform xanthoma: local- In our retrospective study, no HPV search was per- ized lymphedema (elephantiasis) is an essential pathogenic factor. J Cutan Pathol. 2011. formed. However, the data collected from the literature are 3. Lu S, Tran TA, Jones DM, et al. Localized lymphedema (elephantiasis): a case mainly negative, even though very sensitive methods were series and review of the literature. J Cutan Pathol. 2009;36(1):1-20. 3 4. Paul J, Carlson JA. Lymphangiectases are common underlying warts and in used. A few cases with a positive HPV search have been re- 4 normal peritumoral skin: histologic evidence of decreased immune surveillance. ported, but these findings could have been incidental: HPV Am J Dermatopathol. 2011;33(2):152-160. may be present on normal vulvar or oral mucosa in as many 5. Carlson JA, Malfetano J, Rohwedder A. Genital and epidermodysplasia ver- 5 ruciformis associated HPV DNA is frequently found in lichen sclerosus as 23.3% of the cases. [abstract]. J Cutan Pathol. 2000;27:552. Charlotte Fite, MD Franc¸oise Plantier, MD Micheline Moyal-Barracco, MD In reply Author Affiliations: Departments of Dermatology (Drs We appreciate the interest of Carlson et al in our article on 1 Fite and Moyal-Barracco) and Pathology (Dr Plantier), vulvar VX as well as their comment about the possible etio- Assistance Publique des Hoˆpitaux de Paris (APHP), Hos- logic roles of lymphostasis and HPV. Our 10 vulvar VX cases pital Cochin, Paris Descartes University, Paris, France. were all associated with another vulvar condition, mainly Correspondence: Dr Fite, APHP, Department of Derma- LS but also lichen planus (2 cases), vulvar radiodermatitis tology, 27 rue du Faubourg Saint-Jacques, Paris, 75014 (1 case), and Paget disease (1 case). Our findings sustain France ([email protected]). the hypothesis of Zegarelli et al2 that damage to the epithe- lium—particularly of the DEJ, in our opinion, could trig- 1. Fite C, Plantier F, Dupin N, Avril MF, Moyal-Barracco M. Vulvar verruci- form xanthoma: ten cases associated with lichen sclerosus, lichen planus, or ger the following cascade: (1) entrapment of epithelial cells other conditions. Arch Dermatol. 2011;147(9):1087-1092. in the papillary dermis; (2) subsequent degeneration of these 2. Zegarelli DJ, Zegarelli-Schmidt EC, Zegarelli EV. Verruciform xanthoma: fur- cells and lipid formation; (3) engulfment of released lipids ther light and electron microscopic studies, with the addition of a third case. Oral Surg Oral Med Oral Pathol. 1975;40(2):246-256. by macrophages; and (4) accumulation of foam cells be- 3. Ers¸ahin C, Szpaderska AM, Foreman K, Yong S. Verruciform xanthoma of tween the rete ridges. the penis not associated with human papillomavirus infection. Arch Pathol Carlson et al object that this hypothesis does not explain Lab Med. 2005;129(3):e62-e64. 4. Khaskhely NM, Uezato H, Kamiyama T, et al. Association of human papillo- why macrophages accumulate in the papillary dermis. We mavirus type 6 with a verruciform xanthoma. Am J Dermatopathol. 2000; think that the superficial location of the xanthomatous cells 22(5):447-452. 5. Llamas-Martı´nez S, Esparza-Go´mez G, Campo-Trapero J, et al. Genotypic de- can be explained by the fact that the papillary dermis is the termination by PCR-RFLP of human papillomavirus in normal oral mucosa, part of the dermis, which is the closest of the damaged epi- oral leukoplakia and oral squamous cell carcinoma samples in Madrid (Spain). dermis. The poor lymphatic drainage reported by Carlson Anticancer Res. 2008;28(6A):3733-3741. et al in 14 genital and 4 trunk LS cases could account for the accumulation of macrophages in the papillary dermis. However, to confirm this hypothesis one should demon- strate the following: (1) that all the other conditions asso- ONLINE FIRST ciated with mucosal or cutaneous VX are associated with lymphostasis (eg, Paget disease, lichen planus, graft-vs- Efficacy and Safety of Apremilast host disease, discoid lupus erythematosus, pemphigus vul- in Chronic Cutaneous Sarcoidosis garis, recessive dystrophic epidermolysis bullosa, lichen planus, epidermal nevus); (2) that lymphostasis is not just entoxifylline, a phosphodiesterase type 4 inhibitor, an incidental finding related to inflammation, whatever its is reported to be effective for the treatment of sar- cause. In addition, if an increased number and dilation of P coidosis.1 However, the adverse events associated lymphatic vessels is present in most LS cases, these abnor- with this drug have limited its general use. Apremilast is a malities cannot alone explain alone the occurrence of VX new phosphodiesterase type 4 inhibitor that blocks the syn- with LS. Indeed, VX only exceptionally occurs concomi- thesis of proinflammatory cytokines and chemokines, such tantly with LS. as tumor necrosis factor, interferon ␥, and the interleukins

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