Case 4 -

Chronic Actinic Dermatitis Steven R. Tahan Beth Israel Deaconess Medical Center Boston, MA

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Clinical History 22 year old male with a several month history of pruritic erythematous scaly plaques initially on the posterior and sides of neck that spread to the anterior neck, upper chest, and later face, upper trunk, and arms. Lesions are well demarcated and sharply cut-off at the collar. The eruption worsened in summer. Case 4 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 4 - Figure 1 Case 4 - Figure 2 Case 4 - Figure 3 Case 4 - Figure 4 Case 4 - Figure 5 Case 4 - Figure 6 Case 4 - Figure 7 Case 4 - Figure 8 Case 4 - Figure 9a CD4 Case 4 - Figure 9b CD8 Case 4 - Figure 9c CD5 Case 4 - Figure 9d CD7 Histology and Molecular Work-up H&E sections show a predominantly spongiotic dermatitis combined with lymphocyte tagging along the dermo-epidermal interface, focal lymphocyte exocytosis, focal papillary dermal fibrosis, and superficial to deep dermal perivascular lympho-histiocytic infiltrate. Some lymphocytes have irregular nuclear contours. Immunohistochemical stains reveal a predominantly T-cell (CD3+) infiltrate with CD4+:CD8: ratio of approximately 1:1. No significant loss of CD5 and CD7 expression by the T-cells is appreciated. DNA was amplified from paraffin sections, and no clonal rearrangement of the T-cell gamma receptor was detected. Differential and Final Diagnosis The presentation of a cutaneous eruption beginning in light-exposed areas characterizes this disorder in the group of a photo-aggravated dermatoses. This broad spectrum of disorders that includes polymorphous light eruption, auto-immune connective tissue diseases, porphyrias, DNA repair defects (xeroderma pigmentosum), solar urticaria, contact photo-allergic dermatitis, and drug induced photo-allergic dermatitis, and chronic actinic dermatitis/actinic reticuloid (etiology unknown). The histologic picture combines spongiosis with prominent lymphocyte tagging along the dermo-epidermal junction, patchy papillary dermal fibrosis, and a superficial perivascular lymphocytic infiltrate. Polymorphous light eruption, in contrast, is typically markedly edema, particularly in early phases, and lacks features of chronicity. Cutaneous manifestation of auto-immune connective tissue diseases exhibit more significant vacuolar interface degeneration with apoptosis, cytoid body formation, follicular keratin plugging, thickening of the basement membrane zone, deep perifolliculitis, and increased dermal mucins. Porphyrias are characterized by hyaline thickening of vessel walls and the basement membrane zone, often with subepidermal bulla. Eruptions of xeroderma pigmentosum show a mild non-specific perivascular lymphocytic infiltrate, telangiectasias, and prominent melanin pigmentation along basal layers of the epidermis with foci of hypomelanization. Solar urticaria is pauci-inflammatory with edema. Photo-allergic dermatitis, either in response to a contactant or systemic trigger, usually includes eosinophils among the inflammatory infiltrate. Chronic actinic dermatitis is an idiopathic reaction triggered by light, and best fits the pathologic changes combining eczematous features and lymphocytic infiltrate. The presence of lymphocyte tagging along the dermo-epidermal junction, foci of lymphocyte epidermotropism, cellular enlargement, sometime with nuclear infoldings, papillary dermal fibrosis, and chroncity raise some concern for a T-cell dyscrasia/evolving mycosis fungoides . The CD4:CD8 ratio of 1:1 with retention of CD5 and CD7 expression, and absence of a clonal T-cell gamma receptor rarrangement, however, argue against mycosis fungoides. Despite the somewhat early age of onset in this individual, the final diagnosis is chronic actinic dermatitis ("actinic reticuloid"). Historical Recognition of Chronic Actinic Dermatitis Chronic actinic dermatitis (CAD, synonyms, photosensitivity dermatitis, persistent light reaction, actinic reticuloid, photosensitive eczema) is a persistent, often chronic eczematous eruption triggered by exposure to light [1]. It was first described by Haxthausen in 1933 in a patient who developed a persistent hypersensitivity reaction to light following intravenous injection of trypaflavine. In the 1960s similar reactions were described with other drugs and following contact to household substances [2, 3]. In 1969 the condition was reported in a severe form with widespread cutaneous involvement and designated "actinic reticuloid" [4]. This was followed by reports of milder forms under the appellations "photosensitive eczema" and "photosensitivity dermatitis" [5]. In 1979 this spectrum of disorders was grouped under the umbrella name "chronic actinic dermatitis" [6]. Epidemiology CAD occurs in worldwide distribution and affects individuals of all skin colors. It is most common among older men living in temperate climates. No familial tendency has been recognized. It may develop in normal skin or in patients with a history of endogenous eczema, photoallergic or allergic contact dermatitis, and unusually oral drug hypersensitivity, or polymorphous light eruption (see below). Some patients have allergic contact sensitivity to airborne allergens including plant antigens, fragrances, or topical lotions. Clinical Manifestations The eruption is characterized by an eczematous pruritic eruption on light exposed areas such as the scalp, face, back and sides of neck, upper chest, dorsal aspects of arms and hands. A past history of atopy, allergic contact dermatitis, seborrheic dermatitis, or polymorphous light eruption, is not uncommon [7, 8]. Commonly there is a sharp cut-off at lines of clothing and sparing of upper eyelids, skin beneath earlobes, web spaces, and other sun-protected areas. Lesions are pruritic and can be patchy or confluent, papular or plaque-like, often with lichenification. Ezcema of the palms and soles may develop. In some individuals lesions may spread to covered areas and even lead to erythroderma. Severely affected individuals can experience pruritus, lymphadenopathy, atypical lymphocytes in peripheral blood, alopecia, palmarplantar hyperkeratosis, and onychodystrophy. These cases can bear close resemblance to Sezary syndrome. Malignant transformation has been claimed, but not convincingly demonstrated. Rare cases of erythrodermic cutaneous T cell lymphoma have been reported to exhibit photosensitivity [9]. Histology CAD exhibits variable pathology ranging from interface dermatitis to florid spongiotic dermatitis with psoriasiform epidermal hyperplasia, atrophy, or combinations of these [10]. Characteristically there is a moderately dense perivascular and interstitial dermal infiltrate of medium-sized lymphocytes, often with foci of epidermotropism or tagging along the dermal-epidermal junction. Some lymphocytes can have convoluted and even cerebriform nuclei. These cells are often epidermotropic and may form Pautrier-like microabscesses, resembling mycosis fungoides. The presence of eosinophils in the infiltrate can raise consideration for, but is not diagnostic of, a drug or topical allergic etiology. Chronic older lesions have variable, often marked acanthosis, variable scaling, and papillary dermal fibrosis. Sometimes Pautrier's-like lymphocyte collections develop within the epidermis. In the papillary dermis vertically streaked fibrosis, occasional stellate fibroblasts, and small multinulcleated cells, sometimes referred to as Montgomery giant cells are present. In the deeper dermis there can be dense perivascular aggregates of predominantly T-cells with admixed histiocytes, eosinophils, and sometimes plasma cells. In severe CAD, there may be prominent, albeit focal, lymphocyte exocytosis with some cells exhibiting irregular nuclear contours. The predominance of CD8+ phenotype and absence of clonal T-cell gamma receptor rearrangements (see below) is helpful in distinguishing these cases from mycosis fungoides (MF). Immunophenotype Immunophenotyping of infiltrating T cells can be very helpful in distinguishing CAD/actinic reticuloid from mycosis fundgoides [11]. In CAD, the CD4 subpopulation of T cells is nearly equal or less than the CD8 population in contrast toCTCL where in most cases, CD4 cells out number CD8 cells by nearly 10 fold (except for the uncommon cases of CD8+ mycosis fungoides). This difference is accentuated in peripheral blood samples where CD4/CD8+ ratio was in a recent study found to range from 0.3 – 1.6 in CAD/actinic reticuloid compared to a range of 0.9 – 92 in Sezary syndrome. Clonality Studies Molecular studies using PCR in combination with denaturing gradient gel electrophoresis for assessment of clonal T cell receptor gamma gene rearrangements have consistently shown an absence of clonal rearrangements in actinic reticuloid [11, 12]. Pathogenesis The pathogenesis of CAD is not well understood. The clinical features, nature and pattern of dermal inflammatory infiltrate, cytokine production, and adhesion molecule activation are all very similar to those of allergic contact dermatitis. This is a delayed-time hypersensitivity response, and it appears that the CAD represents a reaction to a photo-activated endogenous cutaneous autoantigen [13, 14]. Some studies have suggested that the ultraviolet radiation absorber may be DNA or an associated molecule [15]. Summary CAD is diagnosed by means of a combination of clinical findings, abnormal response of clinically normal skin to exposure to light irradiation, and supporting histologic findings. Inducing wavelengths are in the UVB range in most patients, but for some in the UVA and visible light spectrums. Anti-nuclear anti-Ro and anti-La antibody titers are normal, as are blood, urine, and stool porphyrin concentrations. In drug and chemical photosensitivity, history of exposure to an inducing substance supported by positive patch testing is required. Mycosis fungoides is usually not, but may occasionally be mildly photosensitive. Of note, Sezary-like cells can be found in circulating blood in erythrodermic CAD, but a low CD4:CD8 ratio and absence of T-cell clonality will help to steer the diagnosis away from MF. Key words Actinic reticuloid Chronic actinic dermatitis Persistent light reaction Photo-eczema References Hawk JLM and Lim HW. Chronic actinic dermatitis, in Bologna, Lorizzo, Rapini (eds). Dermatology. Edinburgh: Mosby, 2003:1371-1373. Wilkinson DS . Two cases of photodermatitis due to tetrachlorsalicylanilide (TCSA). Proc R Soc Med. 1961 Sep;54:817-8. Jillson OF, Baughman RD. Contact photodermatitis from bithionol. Arch Dermatol 1963 Oct; 88:409-18. Epstein SS, Taylor FB.Photosensitizing compounds in extracts of drinking water. Science. 1966 Oct 14;154(746):261-3. Hawk JLM, Magnus IA. Chronic actinic dermatitis – an idiopathic photosensitivity syndrome including actinic reticuloid and photosensitive eczema. Br J Dermatol 1979; 101 (suppl 17):24. Menage HduP, Hawk JLM. The idiopathic photodermatoses: chronic actinic dermatitis (photosensitivity dermatitis/ actinic reticuloid syndrome). In JLM Hawk (ed). Photodermatology. London:Arnold, 1999:127-42. Dawe RS, Ferguson J. (2003) Diagnosis and treatment of chronic actinic dermatitis. Dermatol Ther, 16, 45-61. Russell SC, Dawe RS, Collins P, et al. The photosensitivity dermatitis and actinic reticuloid syndrome (chronic actinic dermatitis) occurring in seven young atopic dermatitis patients. Br J Dermatol 1998;138, 496-501. Morris SD, Hawk JLM, Rusell-Jones R, et al. Severe photosensitivity in four patients with erythrodermic cutaneous T-cell lymphoma. Br J Dermatol 2002; 147:36. Toonstra J. Actinic reticuloid. Semin Diagn Pathol 1991;8:109. Bakels V, Van Oostveen JW, Preesman AH, Meijer CJ, and Willemze R. Differentiation between actinic reticuloid and cutaneous T cell lymphoma by T cell receptor gamma gene rearrangement analysis and immunophenotyping. (1998) J Clin Pathol. February; 51(2): 154–158. Du Peloux Menagé H, Whittaker SJ, Ng YL, et al. Analysis of T-cell receptor genes in chronic actinic dermatitis: no evidence of clonality. J Invest Dermatol 1992;98:546. Hawk JLM, Lim HW. Chronic actinic dermatitis. In Lim: HW, Honigsmann H, Hawk JLM, eds. Photodermatology. New York: Informa Healthcare: 2007:169. Hawk JLM, Young AR, Ferguson J. Cutaneous photobiology. In Burns DA, Breathnach SM, Cox N, Griffiths C, eds. Rook/Wilkinson/Ebling Textbook of Dermatology, 7th ed. Oxford:Blackwell Science, 2004:24.1. Menage HduP, Harrison GI, Potten CS, et al. The action spectrum for induction of chronic actinic dermatitis is similar to that for sunburn inflammation. Photochem Photobiol 1995;62:976.