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


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

In This Article

Abstract and Introduction


Non-infectious granulomatous diseases of the skin are a broad group of distinct reactive inflammatory conditions that share important similarities. As a group, they are relatively difficult to diagnose and distinguish both clinically as well as histologically. Many of these disorders have significant associations with systemic diseases that impact the patient's overall prognosis. In this update, we offer a discussion of emerging concepts and controversies in this field, as presented through evidence-based answers to seven important clinical questions regarding palisading and epithelioid granulomata. These questions offer an opportunity to review ten non-infectious granulomatous conditions that have implications for systemic disease: granuloma annulare, annular elastolytic giant cell granuloma, necrobiosis lipoidica, methotrexateinduced accelerated rheumatoid nodulosis, necrobiotic xanthogranuloma, interstitial granulomatous dermatitis, interstitial granulomatous drug reaction, palisaded neutrophilic granulomatous dermatitis, sarcoidosis, and metastatic Crohn disease. Recent clinical, epidemiologic, and laboratory studies have shed some light on these diseases, the association of these conditions with systemic disorders, and their overall prognoses.


Granulomatous reactions in the skin develop as an immune system response to an antigen, in which epithelioid macrophages and various inflammatory and immune cells congregate, often surrounded by fibrosis or a lymphocyte cuff. They are classified as infectious or non-infectious, based upon the presence or absence of an infectious pathogen that serves as the inciting antigen. However, for many of these conditions, we have a poor understanding of the inciting antigen, which may range from infectious (including live or dead microorganisms) to drugs (and/or their metabolites), or result from innate host pathology (e.g. connective tissue disease, vasculitis, or cancerous antigens).

Infectious granulomatous disorders are straightforward in that a microorganism can be identified for a relatively straightforward diagnosis and treatment, while non-infectious diseases are often more difficult to identify and treat. While many granulomatous responses have traditionally been regarded as non-infectious, it is important to acknowledge the proposed role for infection in the etiology of several of these conditions that are regarded as 'non-infectious' granulomatous disorders, such as a slow-growing infection,[1] a post-infectious immunologic response,[2] or presentation of granulomatous disease in the setting of infection.[3] Further, it is also possible that these diseases represent a cutaneous expression of infective states mediated by the immune system, such as reactive erythemas or the id reaction.[4,5]

Non-infectious granulomatous disorders encompass a challenging group of diseases both in terms of their diagnosis and in counseling patients regarding their prognosis, in addition to the possible systemic co-morbidities they may subsequently encounter. An important source of this challenge is the clinical and histologic overlap among these conditions (along with the potential for misdiagnosis due to this overlap). Table I offers a summary of each of these conditions, including both a clinical and histologic description, to clarify and distinguish among these disorders.[6–9] Importantly, several of these conditions can present both clinically and histologically with a variety of phenotypes, such as sarcoidosis, which has been noted to clinically and histologically resemble several of the other cutaneous granulomatous disorders.[10]

It is not the intent of these authors to comprehensively review and update all non-infectious granulomatous diseases, and we direct the reader to dermatologic texts and reviews for more comprehensive information.[6] In this review, we offer common clinical questions regarding these diseases, how they relate to each other, and their systemic disease co-morbidities. These putative systemic co-morbidities include associations that have been proposed in the literature, often through case reports and small case reviews; therefore, epidemiologic information regarding their co-incidence is not available at this time. For each question, the disease is briefly reviewed before embarking on an evidence-based response to the question, followed by a summary and clinical recommendations. The questions addressed are the following:

  1. Is granuloma annulare (GA) associated with hematopoietic and solid malignancy?

  2. Is necrobiosis lipoidica (NL) always associated with concurrent, antecedent, or subsequent diabetes mellitus?

  3. Is methotrexate the only cause for accelerated rheumatoid nodulosis?

  4. Is paraproteinemia in necrobiotic xanthogranuloma (NXG) always associated with an underlying malignancy?

  5. Are interstitial granulomatous dermatitis (IGD) and palisaded neutrophilic granulomatous dermatitis (PNGD) distinct conditions with overlapping features and triggers, or part of a single disease spectrum?

  6. What does skin involvement in sarcoidosis portend for systemic disease or malignancy?

  7. Why does metastatic Crohn disease persist after surgical removal of the affected bowel?


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