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

6. What Does Skin Involvement in Sarcoidosis Portend for Systemic Disease or Malignancy?

Sarcoidosis is a systemic granulomatous disease that involves non-caseating granulomas in a variety of organs, such as lungs (90%), lymph nodes (up to 90%), liver and spleen (50–80%), musculoskeletal system (39%), eyes (30–50%), skin (25%), endocrine system (17%), nerves (5–10%), and heart (5%), and may infiltrate virtually any organ, as previously reviewed.[78] Cutaneous manifestations can occur at any stage, but most often occur at disease onset.

Cutaneous sarcoidosis can present with a variety of lesions and has been described as the 'great imitator' in dermatology.[79] The extent of skin lesions did not correlate with the extent of visceral involvement in a prospective study by Veien et al.;[80] however, some lesions can offer implications about overall disease prognosis. Sarcoidosis skin lesions that contain typical sarcoid granulomas are regarded as 'specific' and are most commonly characterized by small maculopapular lesions; the most characteristic and chronic specific lesion is lupus pernio. Mana et al.[81] suggested that patients with lupus pernio have a protracted sarcoidosis course compared with those with macular, papular, or subcutaneous lesions, and there has been an association of lupus pernio with more severe respiratory disease. This was supported by a study of 170 patients, which suggested that patients with lupus pernio had more lung involvement than patients with erythema nodosum.[82]

The hallmark of acute and benign sarcoidosis is a 'non-specific' reactive inflammatory lesion, such as erythema nodosum, which is associated with a more favorable prognosis of disease.[81] Erythema nodosum lesions are found in patients with Lofgren syndrome, a type of acute sarcoidosis. While patients with erythema nodosum lesions typically resolve more quickly, 16% of sarcoidosis patients with erythema nodosum lesions still had a chronic disease course in one retrospective study of 818 patients.[83] Another cutaneous disease form, subcutaneous sarcoidosis, has a significant association with systemic sarcoidosis, according to a 2006 retrospective analysis of 33 patients in the literature in addition to 21 patients at the authors' institution, with systemic disease most often manifesting as bilateral hilar adenopathy, but also including pulmonary, arthritic, neuropathic, renal, and ophthalmologic disease.[84] Sarcoidosis of the bone is also often diagnosed in patients with skin findings; in a collection of 24 patients described by Neville et al.,[85] incidental bone findings were found in 50% of patients with lupus pernio and 41% of patients with other cutaneous disease types. Aside from the cautious optimism offered by the presence of erythema nodosum lesions, the various cutaneous sarcoidosis lesions do not provide specific information about overall systemic disease prognosis, and any lesion suspicious for cutaneous sarcoidosis or erythema nodosum should prompt a work-up for underlying bone or systemic involvement.

As reviewed by Cohen and Kurzrock,[86] sarcoidosis and malignancy can be found simultaneously in a variety of patients. Sarcoidosis may serve as a paraneoplastic syndrome (with sarcoidosis diagnosed within 1 year of neoplasm diagnosis); occur in the sarcoidosis-lymphoma syndrome, in which the patient also has or develops a hematologic malignancy; or present in patients who have or develop solid tumors, most frequently skin, liver, lung, cervical/uterine, and testicular neoplasms. Various data support or dispute a relationship between the two conditions. In the 1970s, a collection of data from Danish sarcoidosis patients initially suggested an increased prevalence of malignancy,[87] though the analysis was disputed. In a later follow-up in 1998, the Danish patient data set suggested no increased incidence of cancer.[88] Other data have been more suggestive of a relationship between sarcoidosis and malignancy. A 1995 linkage analysis of retrospective data including 243 sarcoidosis patients and a tumor registry revealed that sarcoidosis and malignancy may be related in >25% of patients with both conditions.[89] A Swedish retrospective cohort study suggested that sarcoidosis imparts a significantly increased cancer risk in affected organs.[90]

Various theories have been postulated that speculate an etiologic relationship between the two disorders. Sarcoidosis may involve an immunologic defect that leads to the development of malignancy;[91] conversely, sarcoidosis may represent a systemic reaction to malignancy.[89] Brincker[92] later offered several alternative potential mechanisms: that increased lymphocyte mitosis in sarcoidosis may increase a risk of malignant transformation; sarcoidosis immunologic changes may impart decreased tumor rejection or resistance against tumor-causing viruses; or chemotherapy may cause antigen release that may trigger sarcoidosis. Sarcoidosis occurring subsequent to chemotherapy in Hodgkin disease patients has been reported,[93,94] and it is speculated to be triggered by a potentially increased immune response or by unmasking of antigens by chemotherapy.[94] Regardless of a potential association or mechanism, a very wide variety of hematologic and solid tumors has been described in patients with sarcoidosis.[86]

As a distinct clinical entity, 'sarcoid reactions' occur in patients who do not meet the criteria for systemic sarcoidosis, but develop non-caseating epithelioid granulomas. It has been suggested that sarcoid reactions portend a positive prognosis in oncology patients with Hodgkin lymphoma[95] and gastric carcinoma; however, similarly to sarcoidosis, sarcoid reactions have also been reported in patients with a wide variety of hematologic and solid tumors,[86] and broader prognostic data are not available.

6.1 Summary and Recommendations

Generally, skin lesions have no prognostic significance in sarcoidosis, and the presence of erythema nodosum or any cutaneous sarcoidal granulomas should prompt a search for systemic sarcoidosis. However, the presence of erythema nodosum may justify cautious optimism about a speedy or spontaneous disease resolution or a mild disease course. A causal relationship between sarcoidosis and malignancy has not been supported by the literature; however, given the documented associations, one should be attentive to possible development of malignancy in sarcoidosis patients. Current evidence does not justify the evaluation for underlying malignancy in the absence of symptoms or physical findings suggestive of malignancy in patients presenting with cutaneous sarcoidosis.

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....