Rom J Morphol Embryol 2015, 56(3):1179–1183 R J M E ASE EPORT Romanian Journal of C R Morphology & Embryology http://www.rjme.ro/

Lichen sclerosus and annulare of the : a significant association

DANIEL VAL1), ANDRÉ COLLARD2), JOSÉ FERNANDO VAL-BERNAL3)

1)Laboratoire National de Santé, Division d’Anatomie Pathologique, Dudelange, Luxembourg 2)Service d’Urologie, Centre Hospitalier Emile Mayrisch, Niederkorn, Luxembourg 3)Department of Anatomical Pathology, Marqués de Valdecilla University Hospital, Medical Faculty, University of Cantabria and IDIVAL, Santander, Spain

Abstract Lichen sclerosus (LS) is considered to be a disease resulting of local immune dysregulation. A delayed-type hypersensitivity reaction and cell-mediated immune response are hypothesized to be the pathogenesis of (GA). The case is presented of an uncircumcised 45-year-old man who developed lesions of LS and GA in his foreskin. Both processes were treated with . GA is rarely located in the foreskin. As far as we are aware, only one previous case presented this location. We describe herein for the first time LS associated with GA in the foreskin. Both processes have a common autoimmune pattern suggesting a link between them. Although we cannot exclude that comorbidity may be a coincidence, we think this combination of lesions is not just coincidental but significantly associated through immunopathological mechanisms. Keywords: , foreskin, granuloma annulare, lichen sclerosus, penis.

 Introduction trauma, diabetes mellitus, rheumatoid arthritis, , , allergic processes, hepatitis, , Lichen sclerosus (LS) is a chronically relapsing disease , or exposure to toxic chemicals or injectable with a potential for , destructive scarring and materials. There was no history of sexually transmitted functional impairment preferentially located in the ano- disease and he was not taking any regular medication. genital skin [1]. The process is -mediated of There was no family history. Risk factors for papilloma presumed autoimmune etiology. LS can occur with con- , human immunodeficiency virus (HIV) comitant autoimmune disease, positive family history for infection or were not present. Physical examination autoimmune disease [2–4] and presence of tissue-specific of the penis revealed a serpiginous area with grouped [5]. Genital mucocutaneous LS is associated flesh-colored papules, on the cutaneous surface of the with an increased risk for squamous cell carcinoma [1, 6]. foreskin. The papules coalesced into annular plaques Granuloma annulare (GA) is a self-limited dermatosis, measuring 1.8×1.2 cm. Other zones showed white-gray, of unknown etiology, characterized by necrobiotic dermal smooth, atrophic patches and plaques extensively involving papules that have an annular configuration. Clinical variants the skin and mucosa of the foreskin. They globally of the disease include localized, generalized, perforating, measured 2.5×1.3 cm. Routine blood tests showed no subcutaneous, and erythematous (or patch) forms. Although abnormalities. The PSA (prostate-specific antigen) was the pathogenesis remains uncertain, the process possibly normal. He was treated with local Oxytetracycline and represents a delayed type hypersensitivity reaction. Vázquez- Hydrocortisone Acetate. The patient did not improve with López et al. [7] suggested that at least localized GA belongs this treatment and 44 days after he underwent circumcision to the spectrum of autoimmune diseases. Moreover, De under general anesthesia. In the intervention, an extensive Paola et al. reported the simultaneous occurrence of LS, sclerosis of the foreskin was noted. Review at 48 days after diffused GA and autoimmune thyroiditis [8]. These authors surgery showed a surgical bed in the process of healing. considered this combination not coincidental. Three fragments of foreskin measuring 2.2×1.9 cm, In this report, we document the coexistence of LS 2.3×1.3 cm, and 2.2×0.8 cm were received. The histo- and localized GA in the foreskin of a 45-year-old man, pathological study showed two separate types of lesions. and we discuss their co-morbidity. Penile GA is rare and One type showed epidermal compact ortho- an uncommon presentation of the disease. To the best of and effacement of the rete ridge pattern. Occasionally, the our knowledge, the association of LS and GA lesions in rete ridge pattern was partially conserved with presence the foreskin has not been reported. of within the basal cell layer in association with some apoptotic or hydropic keratinocytes. There was  Case report fibrosis, thickening and hyalinization of the collagen in A 45-year-old man exclusively heterosexual sought the papillary . Beneath this, there was a zone of medical advice for swelling of the glans and difficulty in moderate to scarce lymphocytic infiltration. Predominant retracting the foreskin. The patient denied any history of CD3+ lymphocytes were observed with a mixed population

ISSN (print) 1220–0522 ISSN (on-line) 2066–8279 1180 Daniel Val et al. of CD4+ and CD8+ T-cells. Telangiectases throughout the upper half of the dermis were seen (Figure 1). Significant junctional cleavage (clefting) at the dermoepidermal junction was present (Figure 2). The whole lesion showed features of lichen sclerosus in advanced stage. The other type of lesion showed foci of altered collagen bundles and deposit of basophilic mucin surrounded by palisaded macrophages, lymphocytes and occasional eosinophils in the upper- to mid-reticular dermis (Figure 3). These were well developed (Figure 4) but multinucleated giant cells were not observed. Nuclear fragments were present in the necrobiotic areas.

Figure 1 – Lichen sclerosus. Diagnostic features include Figure 2 – Lichen sclerosus. There is a subepidermal compact hyperkeratosis, loss of rete ridges, homogeneous bulla, the roof of which is formed by an acellular zone in the upper dermis, a band of chronic without rete ridges. The hyalinized dermis with a inflammatory cells lying beneath this layer, and telangiec- band-like infiltrate of lymphocytes lies at the base of tases in the upper half of the dermis (HE staining, ×100). the bulla (HE staining, ×100).

Figure 3 – Granuloma annulare. Panoramic view showing Figure 4 – Mature granuloma. The large central area of palisaded granulomas. They reveal a central area of is surrounded by palisaded macrophages with degenerated collagen and mucin deposition in the super- the long axes of their nuclei radiating outward (“picket- ficial to mid-reticular dermis (HE staining, ×40). fence pattern”), and lymphocytes (HE staining, ×100).

Multiple palisaded necrobiotic granulomas formed a with Alcian Blue (pH 2.5) (Figure 5) and colloidal iron. geographic pattern within the dermis revealing a broad The overlying epidermis showed no alterations. The lesion intense expression of CD68+ macrophages. There was a was considered a dermal (necrobiotic) palisade granuloma superficial and deep perivascular lymphocytic infiltrate. with features of localized granuloma annulare. T-cell markers (CD3, CD4 and CD8) were mainly detected Both types of lesion were completely separated without in the perivascular lymphocytic infiltrate with CD4+ pre- showing intermingled areas. dominating over CD8+ lymphocytes. The mucin stained

Lichen sclerosus and granuloma annulare of the foreskin: a significant association 1181 through systematic microvascular disease [17]. It has been postulated that LS might be an immune response triggered by a melanocytic lesion in cases in which the patients show such a concomitant pigmentary lesion. Thus, changes of LS extended beyond the melanocytic proliferation [18]. There is increasing evidence that auto- immunity plays a pathogenic role and there appears to be a genetic susceptibility to LS. An important clinical feature of LS is the association with autoimmune disorders including autoimmune thyroiditis, alopecia areata, vitiligo, pernicious anemia, rheumatoid arthritis, scleroderma, type I diabetes mellitus [2–4], immunobullous disease [19] and celiac disease [20]. Some cases are associated with a local lymphocytic [21] indicating a local immune dysregulation. Circulating IgG autoantibodies targeting extracellular matrix 1 (ECM1) protein have been reported in men with LS [5]. However, anti-ECM1 antibodies are not the causative mechanism but represent an epipheno- menon [5]. Human leukocyte antigen (HLA) DR11, DR12, and DQ7 occur more frequently in men with the disease [3]. Thus, it has been held that the origin of LS is immunologic with a mechanism of inheritance. GA is a relatively common cutaneous disorder classi- cally presenting on the dorsal aspect of hands and feet that may affect patients of all ages. Clinical presentation includes localized, generalized, subcutaneous, perforating, and patch forms. Localized GA is often asymptomatic, and usually diagnosed in patients before 30 years of age. Figure 5 – Granuloma annulare. Mucin deposition is Incidence is highest in women. Localized form constitutes demonstrated with the Alcian Blue staining (×40). 75% of cases. More than 50% of patients with this form have spontaneous resolution within two years [22]. GA  Discussion is a collagenolytic blue granuloma [23] characterized histo- pathologically by four patterns: palisading (necrobiotic) LS is more prevalent in women, but it may occur in granuloma, interstitial incomplete form, sarcoidal type, and men of all ages. There is a bimodal age incidence with pseudolymphomatous form [24]. peaks in boys and adult men. The mean age at diagnosis As far as we are aware, only 20 cases of GA of the is 42 years. The estimated prevalence may be as high as penis have been described to date [25–39] (Table 1). one in 300 men [9]. LS is a disease of the uncircumcised Table 1 – Penile granuloma annulare: review of the men. This process involves the foreskin in 70% of cases literature [1]. It is a progressive lymphocyte-mediated disease that Case / Age Location Site Associations affects epidermis and dermis skin components. Diverse [Reference] [years] etiopathogenic factors have been proposed including 1 / [25] 25 Shaft Subcutaneous No infection, environmental factors, exposure to urine, drugs, 2 / [25] 26 Shaft Subcutaneous No metabolic disease, association with melanocytic lesions, 3 / [25] 24 Shaft Subcutaneous No and [10]. Association with acid-fast bacilli, 4 / [26] 61 Shaft Dermis Asthma spirochetes and Borrelia burgdorferi has been negated 5 / [27] 50 Shaft Not reported No [10–12]. Human papilloma virus (HPV) has been detected 6 / [28] 20 Shaft Dermis No on the surface of the lesion and it has been considered as 7 / [29] 23 Shaft Subcutaneous No a “passenger” virus or an innocent bystander [10]. Hepatitis 8 / [30] 41 Shaft Dermis No C virus is highly unlikely to play an etiopathogenic role 9 / [31] 13 Shaft Subcutaneous Asthma in the process [13]. The role of Epstein–Barr virus is 10 / [31] 16 Shaft Subcutaneous Asthma unknown [14]. LS demonstrate koebnerization and can 11 / [32] 29 Shaft Subcutaneous No arise or recur at areas that have undergone trauma, surgery, 12 / [33] 13 Shaft Subcutaneous No constant friction, sunburn or radiation treatment [10]. 13 / [34] 13 Shaft Subcutaneous No Some authors consider LS a non-specific pathological 14 / [35] 13 Shaft Subcutaneous No 15 / [35] 26 Shaft Subcutaneous No response to urinary exposure in the uncircumcised male 16 / [35] 24 Shaft Subcutaneous No [15]. However, it has not been found any factor capable 17 / [36] 7 Base Subcutaneous Asthma of producing the disease in the urine. It has been reported 18 / [37] 34 Foreskin Dermis No that beta-blockers may influence the clinical expression Urethral 19 / [38] 15 Shaft Subcutaneous of LS [16], but the role of drugs in the causation of anomaly disease is not known. A case-controlled study suggested 20 / [39] 60 Glans Dermis Tuberculosis 21 / Present Lichen that elevated body mass index, diabetes mellitus, coronary 45 Foreskin Dermis artery disease and smoking were associated with LS report sclerosus

1182 Daniel Val et al. Most of these lesions were located in the shaft and skin. However, we cannot exclude that co-morbidity is they were subcutaneous. The present case is the second exclusively a coincidence. Thus, further investigations case reported in the foreskin and the only case associated are needed to better understand the etiopathogenesis. with LS. The GA was of collagenolytic (necrobiotic) granuloma type located in the dermis.  Conclusions GA has also been reported to follow viral (including HIV, Epstein–Barr virus, and herpes zoster), GA is rarely located in the foreskin. We describe for trauma, malignancy (mostly lymphoma or prostate carci- the first time LS associated with GA in the foreskin. Our noma), insect bites, tuberculosis skin tests [22], dys- case suggests that LS and GA are closely related, and that lipidemia [40] and drugs including Amlodipine, gold, both processes should be recognized as two cutaneous manifestations associated with immune dysregulation. Allopurinol, Diclofenac, Quinidine, intranasal Calcitonin Further studies need to be performed to elucidate the [41] and Thalidomide [42]. There is no significant asso- mechanisms of association of both entities. ciation with B. burgdorferi [12]. The pathogenesis of GA has been linked to the dermal dendritic macrophage Conflict of interests network, delayed hypersensitivity reaction and cell- The authors declare that they have no conflict of mediated immune response with mainly T-helper cells interests. [43]. Thus, immunohistochemistry shows predominant CD4+ cells in the lesions. These cells secrete interferon-γ, Consent tumor necrosis factor-α, and macrophage-inhibiting factors, Written informed consent was obtained from the patient causing macrophages to persist in the area. 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Corresponding author José Fernando Val-Bernal, Professor, MD, PhD, Department of Anatomical Pathology, University of Cantabria and IDIVAL, Avda. Cardenal Herrera Oria s/n, ES-39011 Santander, Spain; Phone +34 942 202520/ext. 73232, Fax +34 942 203492, e-mail: [email protected]

Received: January 6, 2015

Accepted: November 23, 2015