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Research Letters |

Lichen Sclerosus Exhibiting Histologic Signs of Lymphedema: An Essential Factor in the Pathogenesis of Verruciform Xanthoma FREE

J. Andrew Carlson, MD, FRCPC; Grant D. Dias Carlson; Michael Murphy, MD; Angela Rohwedder, PhD
[+] Author Affiliations

Author Affiliations: Divisions of Dermatopathology and Dermatology, Department of Pathology, Albany Medical College, Albany, New York (Dr Carlson and Mr Dias Carlson); and Department of Dermatology, University of Connecticut Medical Center, Farmington (Dr Murphy). Dr Rohwedder is the owner of Bio-Med-Molec Service, a private company in Kalkar, Germany.


Arch Dermatol. 2012;148(2):260-262. doi:10.1001/archdermatol.2011.1536.
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Recently, Fite et al1 reported a series of vulvar verruciform xanthomas (VX) and attributed VX pathogenesis to disorders that injure the dermoepidermal junction (DEJ), namely lichen sclerosus (LS). While we agree that damage to the DEJ is the source of debris found in the xanthomatous macrophages of VX, the LS theory does not explain the accumulation of lipophages in the papillary dermis or the superimposition of verrucous epidermal hyperplasia —the 2 pathognomonic features of VX.

Our research group2 has recently reported evidence that VX is a complication of localized lymphedema, which has many causes, including trauma, surgery, radiation therapy, neoplasia, infection, and inflammatory dermatoses.3 Specifically, scarring due to trauma, repeated irritation, and/or chronic inflammation can obstruct lymphatics and lead to lymphostasis, histologically denoted by lymphangiectases. Regional lymphostasis, because of disrupted immune cell trafficking, creates a localized area of immunosuppression permitting latent human papillomavirus (HPV) infection to manifest as warts.4 Macrophages ingest lipid-rich debris derived from overlying damaged and/or proliferating keratinocytes and accumulate in the papillary dermis because of poor lymphatic drainage. In corollary, increased lymphatic flow leads to regression of VX.2 Based on this mechanistic framework, we sought to determine if histologic evidence of lymphedema existed in LS that would explain the relative frequent occurrence of VX in vulvar LS, 60% in the series reported by Fite et al.1

Over a 3-month period in 2011, all diagnosed cases of LS in the Department of Pathology at Albany Medical College were retrieved. Formalin-fixed paraffin-embedded sections were immunostained with antibodies to D2-40, a lymphatic specific marker (Dako; 1:200) and CD68, a macrophage marker (Ventana Medical Systems; prediluted), using an automated method (Ventana Medical Systems). Normal skin from elliptical excisions of benign and malignant skin tumors was used for controls (cases previously reported4). Lymphatic density was measured by counting the number of D2-40 expressing vessels per millimeter squared. Lymphatic vessels were categorized as dilated or collapsed; the maximal dilation of the former was measured (methods previously described4). In addition, the presence or absence of D2-40 expression by the basal layer of the epidermis and aggregates of CD68-positive cells at the DEJ were recorded. STATA software, version 11.2 (StataCorp LP), was used for statistical analysis, with significance set at P   <  .05. The institutional review board of Albany Medical College approved this study.

The Table lists the overall results of this study, revealing that LS specimens exhibited significantly 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 significantly outnumbered dilated vessels in controls (P   ≤  .03). Notably, collapsed lymphatic vessels were seen underlying the sclerotic zone, often in areas of inflammation, but lymphangiectases were found throughout the zone of sclerosis, mostly in its deep aspect, which also contained dilated blood vessels. The D2-40 expression of basal keratinocytes was frequent in LS, a phenomenon that has been described in localized lymphedema.3 Conspicuously, CD68+ macrophages could be found forming small aggregates at the DEJ in more than half of LS cases (Figure).

Place holder to copy figure label and caption
Graphic Jump Location

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 ×40 [A] and ×100 [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 ×40). 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 ×400). E, Staining with D2-40 antibodies reveals collapsed lymphatic vessels in a region of inflammation underlying the dermal sclerosis (yellow asterisk) (original magnification ×100).

Table Graphic Jump LocationTable. Increased Numbers of and Greater Dilation of Lymphatic Vessels Evidence of Lymphedema in Lichen Sclerosusa

Lichen sclerosus has been likened to an “inflammatory scar. ” Therefore, it is not surprising to find that the hallmark feature of LS, its sclerosis, which progressively replaces the upper dermis over time, disrupts lymphatic drainage by effacing the normal dermal architecture, leading to signs of lymphostasis —numerous dilated lymphatic vessels. Scarring and lymphangiectases are ubiquitous features underlying warts and are suspected pathogenic factors.4

While only a few reports of VX have documented HPV infection,1 the low frequency of detection has been attributed to the sensitivity and specificity of the methods used where low copy number of β-HPV and genital-mucosal HPV have been presumptively missed.2 Indeed, LS has been reported to harbor a high frequency of HPV genotypes.5 Thus, LS displays all the etiologic elements necessary for the formation of VX —lymphostasis and latent HPV infection. We agree with Fite et al1 that the identification of VX requires a search for a primary disorder that produces a milieu of latent or clinically evident lymphedema —an essential factor in the pathogenesis of VX.

Correspondence: Dr Carlson, Albany Medical College, 47 New Scotland Ave, MC-81, Albany, NY 12208 (CarlsoA@mail.amc.edu).

Accepted for Publication: August 28, 2011.

Author Contributions:Study concept and design: J. A. Carlson and Rohwedder. Acquisition of data: G. D. Dias Carlson. Analysis and interpretation of data: J. A. Carlson, G. D. Dias Carlson, and Murphy. Drafting of the manuscript: G. D. Dias Carlson. Critical revision of the manuscript for important intellectual content: J. A. Carlson, Murphy, and Rohwedder. Statistical analysis: J. A. Carlson and G. D. Dias Carlson. Obtained funding: J. A. Carlson. Administrative, technical, and material support: J. A. Carlson and Murphy. Study supervision: J. A. Carlson.

Financial Disclosure: None reported.

Funding/Support: This work was supported in part by clinical revenues and generous donors to the Divisions of Dermatology and Dermatopathology, Department of Pathology, Albany Medical College.

Fite C, Plantier F, Dupin N, Avril MF, Moyal-Barracco M. Vulvar verruciform xanthoma: ten cases associated with lichen sclerosus, lichen planus, or other conditions.  Arch Dermatol. 2011;147(9):1087-1092
PubMed   |  Link to Article
Lu S, Rohwedder A, Murphy M, Carlson JA. Verruciform xanthoma: localized lymphedema (elephantiasis) is an essential pathogenic factor.  J Cutan Pathol. 2011;
PubMed
Lu S, Tran TA, Jones DM,  et al.  Localized lymphedema (elephantiasis): a case series and review of the literature.  J Cutan Pathol. 2009;36(1):1-20
PubMed   |  Link to Article
Paul J, Carlson JA. Lymphangiectases are common underlying warts and in normal peritumoral skin: histologic evidence of decreased immune surveillance.  Am J Dermatopathol. 2011;33(2):152-160
PubMed   |  Link to Article
Carlson JA, Malfetano J, Rohwedder A. Genital and epidermodysplasia verruciformis associated HPV DNA is frequently found in lichen sclerosus [abstract].  J Cutan Pathol. 2000;27:552

Figures

Place holder to copy figure label and caption
Graphic Jump Location

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 ×40 [A] and ×100 [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 ×40). 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 ×400). E, Staining with D2-40 antibodies reveals collapsed lymphatic vessels in a region of inflammation underlying the dermal sclerosis (yellow asterisk) (original magnification ×100).

Tables

Table Graphic Jump LocationTable. Increased Numbers of and Greater Dilation of Lymphatic Vessels Evidence of Lymphedema in Lichen Sclerosusa

References

Fite C, Plantier F, Dupin N, Avril MF, Moyal-Barracco M. Vulvar verruciform xanthoma: ten cases associated with lichen sclerosus, lichen planus, or other conditions.  Arch Dermatol. 2011;147(9):1087-1092
PubMed   |  Link to Article
Lu S, Rohwedder A, Murphy M, Carlson JA. Verruciform xanthoma: localized lymphedema (elephantiasis) is an essential pathogenic factor.  J Cutan Pathol. 2011;
PubMed
Lu S, Tran TA, Jones DM,  et al.  Localized lymphedema (elephantiasis): a case series and review of the literature.  J Cutan Pathol. 2009;36(1):1-20
PubMed   |  Link to Article
Paul J, Carlson JA. Lymphangiectases are common underlying warts and in normal peritumoral skin: histologic evidence of decreased immune surveillance.  Am J Dermatopathol. 2011;33(2):152-160
PubMed   |  Link to Article
Carlson JA, Malfetano J, Rohwedder A. Genital and epidermodysplasia verruciformis associated HPV DNA is frequently found in lichen sclerosus [abstract].  J Cutan Pathol. 2000;27:552

Correspondence

February 1, 2012
Charlotte Fite, MD; Fran çoise Plantier, MD; Micheline Moyal-Barracco, MD
Arch Dermatol. 2012;148(2):260-262. doi:10.1001/archdermatol.2011.2085.
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