Non-infectious Granulomatous Diseases of the Skin and their Associated Systemic Diseases: An Evidence-based Update to Important Clinical Questions

Elena Balestreire Hawryluk; Leonid Izikson; Joseph C. English III

Disclosures

Am J Clin Dermatol. 2010;11(3):171-181. 

In This Article

5. Are Interstitial Granulomatous Dermatitis and Palisaded Neutrophilic Granulomatous Dermatitis Distinct Conditions with Overlapping Features and Triggers, or Part of a Single Disease Spectrum?

As described in section 1, at times GA-like granulomatous dermatitis has been classified as GA, but may have been more consistent with IGD or PNGD. Classic clinical teaching of IGD is the linear rope sign on the truck and axillae, while lesions of PNGDare generally crusted umbilicated papules on the elbows, first noted in association with RA and Churg-Strauss disease.[55,56] Classic histologic teaching describes IGD as having a sparse palisaded histiocytic infiltrate with mild neutrophilic debris and eosinophils and necrobiotic collagen, while PNGD has an intense neutrophilic and interstitial histiocytic infiltrate and there may be evidence of vasculitis. The confusion has arisen with GA-like or polymorphic-appearing confluent and annular plaques on the torso. In these patients, pathology is required to appropriately diagnose IGD or PNGD. Therefore, some clinicians recommend the terminology of granulomatous dermatitis.

Unfortunately, the published literature has noted overlap and there has been an inappropriate interchange of clinical and histologic presentations between these entities. Additionally, several authors believe that they comprise a continuum or progression of a single disease process,[57,58] as opposed to distinct conditions. The concept of a progression of disease was first offered by Chu et al.[57] in their 1994 article that presented analyses of biopsies of nine patients at various stages of disease; however, the biopsies were not prepared from a single patient at certain timepoints, which would have allowed observation of disease progression within a single subject. Sangueza et al.[58] include the following disease entities within the ''clinical and histologic spectrum of PNGD:'' linear subcutaneous bands, PNGD, IGD with cutaneous cords and arthritis, rheumatoid papules, Churg-Strauss granuloma, superficial ulcerating rheumatoid necrobiosis, necrobiotic granuloma, palisading granuloma, cutaneous extravascular necrotizing granuloma, and rheumatoid neutrophilic dermatitis, and the authors offered seven cases to add to examples of this disease spectrum. Another possibility is that these disorders represent a single disease spectrum that manifests itself differently in the skin based upon a balance between the patient's humoral and cellular immune response, such as that observed for leprosy or proposed for RA.[59] While these remain interesting possibilities, evidence in the literature is lacking.

The clinical associations of granulomatous dermatitis with autoimmune disease and lymphoproliferative disorders have been intermixed between both IGD and PNGD diagnoses in the literature. Therefore, one is obligated to search for disease. Various case studies have illustrated an association of PNGD with systemic lupus erythematosus, systemic sclerosis, RA, and connective tissue disorders, both in children and adults.[58,60–64] Similarly, IGD has been described in patients with autoimmune diseases such as arthritis, autoimmune hepatitis, and in the presence of various autoantibodies including the antiphospholipid syndrome.[65–68]However, IGDhas also been observed in patients with hematologic malignancy;[19] those taking medications such as tumor necrosis factor-a inhibitors,[69] ACE inhibitors, and diuretics;[70] and as a reaction to foods including soy products.[71]

Further confusion among these conditions has arisen with the term interstitial granulomatous drug reaction (IGDR), a condition that appears similar to macular GA and occurs more commonly on the extremities. It has a unique pathology with vacuolar interface dermatitis, atypical lymphocytes, and interstitial granulomatous changes. Like IGD, and as the name implies, IGDR is also associated with medication use. First recognized as a distinct clinical entity in 1998 by Magro et al.,[72] these authors presented 20 patients with GA-like lesions and, of the 15 patients who discontinued the implicated therapeutic agent, cutaneous findings resolved in all. IGDR can be induced by a wide variety of therapies, including common medications such as antihypertensives[73] and bowel stimulants,[74] antivirals,[75] strontium,[76] and even Chinese herbal medication.[77] IGDR resolves upon discontinuation of the offending drug; patients who are diagnosed with IGDR that does not resolve may actually have a T-cell dyscrasia or granulomatous slack skin. Associations of IGDR with autoimmune conditions or lymphoproliferative disorders have not been reported.

The assessment of clinical and histologic features is necessary to distinguish between these entities. Overall, the confusion that exists in the literature with respect to IGD and PNGD raises concern about potentially associated systemic conditions. Accordingly, as an example, it would be difficult to justify a work-up for an association of IGD, but not PNGD, with lymphoproliferative disorders. A similar clinical investigation for these conditions is warranted until more data are available.

5.1 Summary and Recommendations

Studies have not clearly demonstrated whether IGD and PNGD are part of a continuum of disease, and there is confusion in the literature despite the fact that these conditions have distinct clinical and histopathologic characteristics. All patients with suggestive symptoms should be evaluated for a drug- or allergen-induced etiology, as symptoms may remit with discontinuation if the patient has IGDR or IGD. Once this is excluded, all patients should be screened for associated autoimmune, lymphoproliferative, or malignant states.

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