An 86-year-old man with a history of chronic lymphocytic lymphoma presented for evaluation of a persistent erythematous, eroded eruption of the bilateral inguinal folds and gluteal cleft of 6 years' duration. The lesions were characterized by burning, stinging, and weeping. Previous treatments included systemic and topical antifungal agents, topical glucocorticoid preparations, topical immunomodulators, topical antibacterial agents, barrier creams, and various emollients, with minimal benefit. Previous biopsy findings were consistent with nonspecific spongiotic dermatitis. The results of TRUE Test (Thin-layer Rapid Use Epicutaneous Test; Allerderm Laboratories Inc, Phoenix, Arizona) allergen testing were negative. The patient denied bone pain, dyspnea, cough, abdominal pain, polydipsia, polyuria, urinary retention, fevers, chills, or weight loss. Physical examination revealed circumscribed erythematous plaques with superficial maceration and erosions involving the bilateral inguinal creases and lateral scrotum, with extension to the perineum and gluteal cleft. Erythematous papules measuring 2 to 3 mm in diameter were found at the periphery (Figure 1). There was no evidence of lymphadenopathy or hepatosplenomegaly.
Erythematous, macerated, and eroded plaque with satellite papules involving the inguinal creases and scrotum.
The differential diagnosis included Langerhans cell histiocytosis (LCH), intertrigo, contact dermatitis, nutritional deficiency, Paget disease, psoriasis, erosive lichen planus, cutaneous T-cell lymphoma, and sarcoidosis. A punch biopsy specimen revealed dense aggregates of large epithelioid cells with abundant cytoplasm and reniform nuclei filling the papillary dermis (Figure 2). Similar-appearing cells were also scattered throughout the epidermis and reticular dermis. Immunohistochemical staining of these mononuclear cells demonstrated CD1a and S-100 protein (Figure 3). A diagnosis of LCH was made.
Superficial erosion with aggregates of epithelioid cells with reniform nuclei filling the papillary dermis and extending into the epidermis (hematoxylin-eosin, original magnification ×100).
Immunohistochemical staining reveals prominent CD1a positivity of the epithelioid cell infiltrate (CD1a, original magnification ×100).
The patient underwent a complete evaluation, including determination of serum zinc levels, complete blood cell count, complete metabolic panel, skull films, chest roentgenogram, skeletal survey, and bone scan. There was no evidence of extracutaneous disease, and the results of all laboratory tests were within normal limits except for an elevated lymphocyte count, which was consistent with the patient's history of chronic lymphocytic lymphoma.
The patient had already undergone therapeutic trials of topical glucocorticoids and antibacterial agents, without improvement. He and his wife were of advanced age, with significant comorbities, and lived a significant distance from the medical center. Toxic systemic or topical treatment regimens and those requiring frequent treatment sessions were considered undesirable and made effective therapy a challenge.
Many therapies have been used for the empirical treatment of patients with both multisystem and isolated disease, with mixed results. Single-agent and multiagent chemotherapies are typically the mainstay of treatment for multisystem disease. The therapeutic approach for isolated cutaneous disease has been less uniform and is largely characterized by anecdotal reports using different systemic, topical, and UV regimens. Oral chemotherapeutic agents that have been used in cutaneous LCH have significant adverse effect profiles and may be unnecessarily aggressive, barring the failure of more conservative modalities. Topical chemotherapies can be difficult to tolerate, particularly in the genital region. Psoralen–UV-A has been used with anecdotal success in some patients, but it is difficult to deliver to skin-fold areas and requires frequent weekly treatment sessions.
Therapy with a 308-nm UV-B excimer laser (Xtrac Ultra; Photomedex, Montgomeryville, Pennsylvania) was initiated at 0.1 J/cm2 per treatment (average, 0.19 J/cm2 per treatment; range, 0.1-0.6 J/cm2) based on response and tolerance. The radiation was delivered through a liquid light guide with an 18-mm-diameter beam over a surface area ranging from 248 to 608 cm2. Treatments occurred at 3-week intervals for a total of 17 sessions at a minimal erytherma dose of 1 to 2. The patient tolerated this therapy well but did have some initial erythema and crusting, necessitating 2 weeks of topical mupirocin therapy. He was reevaluated at each treatment session and demonstrated clinically significant improvement after 3 sessions, with a 50% reduction in erythema and erosions as well as complete resolution of the burning symptoms (Figure 4). At 5 months, he was still symptom free, and there was no evidence of clinical disease. After the fifth treatment, hematoxylin-eosin staining of another biopsy specimen of the lesion revealed mild fibrosis and telangiectasias in the superficial dermis. CD1a immunostaining of a single focus of deep perieccrine cellularity demonstrated a residual nest of Langerhans cells (Figure 5).
Mild residual erythema of the inguinal crease during the third excimer laser treatment.
Nest of CD1a-positive epithelioid cells deep around an eccrine gland (CD1a, original magnification ×20).
Over the next 2 months, the patient was unavailable for follow-up treatments because of health issues. During this time, he experienced a relapse of his LCH, consistent with the histopathologic evidence of residual disease. The excimer laser appears to be effective at reducing but not eradicating the infiltrates in the deeper dermis.
Langerhans cell histiocytosis comprises a rare, clinically diverse group of disorders that are characterized by the proliferation and accumulation of abnormal Langerhans cells in various tissues, including the skin, bone, lungs, and central nervous system. Although patients of any age may be affected, it is more commonly seen in children, with an incidence of 5 to 8 per million. Incidence in adults is estimated to be 1 to 2 per million.1 There does not appear to be a racial predilection, and males may be affected slightly more often than females.2
The pathogenesis of LCH remains unclear, with features suggestive of a neoplastic, reactive, or immune dysregulation process. Support for a neoplastic process includes abnormal immature protein expression, evidence of clonality3,4 and loss of heterozygosity, and increased incidence of second related neoplasms3,5 as well as rapid infiltration and death in some cases. Furthermore, there appears to be evidence of a genetic predisposition, with 1% of affected patients having an affected primary relative, perhaps suggestive of a genetic neoplastic predisposition.3,6,7 In contrast, factors favoring a reactive process include the following: the LCH cells histologically resemble normal Langerhans cells rather than showing maturation arrest typical of malignancy; the LCH lesions retain their uniform granulomatous character in contrast to the cellular pleomorphism of a malignant neoplasm; the LCH lesions show a relatively uniform distribution instead of the typical haphazard spread of malignant neoplasms; and the LCH lesions can develop spontaneous regression, which is only rarely seen in true malignant neoplasms.3,5 Although it has been suggested that viral etiologic factors may be a source of the LCH reactive process, studies have only rarely reported Epstein-Barr virus as a possible triggering factor.8 Environmental pathogenetic factors have not been identified, except that an elevated incidence of smoking has been found in patients with pulmonary LCH.2,9-11
New theories have focused on the possibility of immune dysregulation as the underlying cause of LCH. Investigators have cited immunologic aberrations such as decreased suppressor T-cell activity and increased immunoglobulin levels within LCH lesions. Studies have also revealed a phenomenon described as a “cytokine storm,” in which increased levels of tumor necrosis factor, interleukin (IL)-3, and granulocyte-macrophage colony-stimulating factor are seen as a part of an abnormal T-cell/Langerhans cell interaction, which results in a self-perpetuating autocrine and paracrine cycle.1,12-14 Also, LCH cells appear to have persistence of immature features, such as expression of IL-2 and interferon gamma receptors, which are normally lost as a part of immunologic activation. This may be a result of elevated IL-10 production by monocytes, including macrophages.1 Ultimately, the definitive cause remains to be elucidated.
Langerhans cell histiocytosis may be broadly categorized as localized (single-system) or disseminated (multisystem) disease. The organs most commonly involved are the lungs, bones, skin, lymph nodes, liver, and central nervous system. Pituitary infiltration with resultant diabetes insipidus is characteristic and has been reported in 29.6% of patients in 1 study.2 Isolated skin disease, as in this case, is relatively rare, with reports of less than 1%2 and as high as 10%.15 Sites of cutaneous involvement predominantly include the scalp, flexural areas, external genitalia, and glabrous skin. Lesions typically manifest as reddish yellow erythematous papules, nodules, patches, and plaques with scattered erosions, ulcerations, crusting, or scale. In some cases, diagnosis may be delayed for years owing to the clinical similarity to other conditions such as seborrheic dermatitis, nutritional deficiencies, and intertrigo. Therefore, LCH must always be included in the differential diagnosis of these processes when they are unresponsive to multiple therapies.
Diagnosis of LCH is made by the demonstration of characteristic histopathologic aggregates of CD1a+ histiocytes on biopsy of bone, lung, and skin.1,2 Also, LCH lesional cells may stain positively for S-100 protein, CD31, CD68, MIB-1, peanut agglutinin, placental alkaline phosphatase, and the interferon gamma receptor. Positivity of 2 or more of these stains is considered diagnostic. Immunohistochemical staining for CD1a can be easily performed in formalin fixed, paraffin-embedded tissue and has made the use of these ancillary stains largely supportive rather than of primary use in diagnosis.
Members of the Histiocyte Society recently provided comprehensive documentation on the clinical features of LCH in adult patients.2 They found that two-thirds of patients with LCH had multisystem disease, while only one-third presented with isolated single-organ disease, usually involving the lungs, bone, or skin.2 Single-organ disease tends to have a good prognosis, while multisystem disease often carries a greater risk of morbidity and mortality.3 The overall 5-year survival rate for LCH was estimated to be 91.7%. Estimates for multisystem disease and isolated single-system disease were 92% and 100%, respectively. Interestingly, isolated pulmonary disease had the worst 5-year survival rate (87.8%).2
Because of the rarity of adult multisystem LCH, its treatment has been largely anecdotal, and only recently have there been attempts to develop uniform therapeutic regimens. To our knowledge, no clinical trials have yet been performed in the adult population. Observation, chemotherapy, local topical treatments, immunomodulatory agents, radiation therapy, and organ or bone marrow transplantation have been reported to be successful.1,9,16-18 Combination therapy with vinblastine and prednisone has been evaluated and proposed as first-line treatment for pediatric multisystem LCH2,19 as well as, more recently, adult multisystem LCH.2 This combination, however, has not shown any additional therapeutic benefit with respect to response, survival, or reactivation.1 Other systemic approaches for LCH include 2-chlorodeoxyadenosine,20,21 mercaptopurine, thalidomide,1,22,23 cyclophosphamide, cyclosporine,24 and methotrexate,25 used singly or in combination. Similarly, therapeutic approaches for isolated skin LCH have not been evaluated by clinical trials and remain anecdotal. Options include observation, psoralen–UV-A,26,27 topical nitrogen mustard,28,29 topical or intralesional steroids, thalidomide,22,30 isotretinoin,31 subcutaneous interferon,15 imiquimod,32 and topical antibacterial agents.
Ultraviolet radiation is capable of suppressing both the local and the systemic immune system in a dose-dependent fashion. This is particularly true of the UV-B wavelength range. One of the primary mechanisms by which this immunosuppression is achieved is by the depletion of Langerhans cells from the epidermis as well as by the increased release of cytokines, including IL-10 and tumor necrosis factor. This effect is exploited in the treatment of LCH. Psoralen–UV-A therapy, though less effective in depleting Langerhans cells, has deeper penetration into the dermis and is therefore most often used in the treatment of LCH. However, it is difficult to apply in a controlled, focal fashion. The use of narrowband UV-B, such as the 308-nm excimer laser, permits the direct focal application of therapy but at the expense of depth of penetration. Because the excimer only reaches the superficial papillary dermis, this limited penetration likely accounts for the persistence of disease around the deep eccrine glands in our patient.
In our case, the excimer laser did not appear, at least initially, to be curative but may have had a role in symptomatic disease control. This may be of particular benefit in those patients with health comorbidities that are so severe they would poorly tolerate more aggressive or intensive therapies. The treatments are fairly simple to administer, and the smaller handpiece spot size makes focal treatments in difficult locations relatively easy. The excimer laser may also be of benefit as an adjuvant therapy in combination with other modalities to better effect a complete response. For example, treatment with topical agents such as nitrogen mustard or imiquimod may be abbreviated and better tolerated after “debulking” of the LCH infiltrate with the excimer laser. Further studies are required to determine the role of the excimer laser in the treatment of LCH.
Correspondence: William Aughenbaugh, MD, Department of Dermatology, University of Wisconsin–Madison, 1 S Park, Seventh Floor, Madison, WI 53715 (email@example.com).
Accepted for Publication: November 29, 2007.
Author Contributions: Drs Vogel, Aughenbaugh, and Sharata had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Vogel. Acquisition of data: Vogel, Aughenbaugh, and Sharata. Analysis and interpretation of data: Vogel and Aughenbaugh. Drafting of the manuscript: Vogel and Aughenbaugh. Critical revision of the manuscript for important intellectual content: Aughenbaugh and Sharata. Study supervision: Aughenbaugh, and Sharata.
Financial Disclosure: None reported.
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