A framework for exclusion of alternative diagnoses in sarcoidosis

Abstract

Sarcoidosis is a multisystem granulomatous syndrome that arises from a persistent immune response to a triggering antigen(s). There is no "gold standard" test or algorithm for the diagnosis of sarcoidosis, making the diagnosis one of exclusion. The presentation of the disease varies substantially between individuals, in both the number of organs involved, and the manifestations seen in individual organs. These qualities dictate that health care providers diagnosing sarcoidosis must consider a wide range of possible alternative diagnoses, from across a range of presentations and medical specialties (infectious, inflammatory, cardiac, neurologic). Current guideline-based diagnosis of sarcoidosis recommends fulfillment of three criteria: 1) compatible clinical presentation and/or imaging 2) demonstration of granulomatous inflammation by biopsy (when possible) and, 3) exclusion of alternative causes, but do not provide guidance on standardized strategies for exclusion of alternative diagnoses. In this review, we provide a summary of the most common differential diagnoses for sarcoidosis involvement of lung, eye, skin, central nervous system, heart, liver, and kidney. We then propose a framework for testing to exclude alternative diagnoses based on pretest probability of sarcoidosis, defined as high (typical findings with sarcoidosis involvement confirmed in another organ), moderate (typical findings in a single organ), or low (atypical/findings suggesting of an alternative diagnosis). This work highlights the need for informed and careful exclusion of alternative diagnoses in sarcoidosis.

Keywords: Diagnosis; Differential diagnosis; Sarcoidosis.

Fig. 1.

More aggressive testing is considered based on the breadth of the differential and the potential harms of misdiagnosis. Less aggressive testing is considered when the presentation is typical and the disease severity allows for monitoring off treatment or less toxic treatment regimens. Informed patient preference can tip the balance toward more or less aggressive testing based on patient values.

Fig. 2.. Pulmonary Sarcoidosis:

Partially calcified mediastinal lymphadenopathy (A), perilymphatic bilateral nodules (B), pulmonary fibrosis (C), and a nodular lesion mimicking lung cancer (D) as manifestations of pulmonary sarcoidosis.

Fig. 3.

Well-formed non-caseating sarcoidosis granuloma with limited involvement of surrounding interstitium (A), necrotizing infectious granuloma (B), poorly formed hypersensitivity pneumonitis granuloma accompanied by interstitial chronic inflammation (C), Surgical lung biopsy showing lymphangitic distribution of sarcoidosis granulomas (D).

Fig. 4.. Ocular Sarcoidosis:

Anterior uveitis (A), intermediate uveitis (B), posterior uveitis (C) and retinal nerve involvement (D) associated with ocular sarcoidosis.

Fig. 5.. Cutaneous Sarcoidosis:

lupus pernio (A), papules (B), finger erosion (C), and a tattoo reaction (D) as manifestations of cutaneous sarcoidosis.

Fig. 6.. Neurosarcoidosis:

leptomeningeal enhancement (A), dural thickening (B), ocular nerve involvement (C) and spinal cord edema (D) in patients with neurosarcoidosis.

Fig. 7.. Cardiac Sarcoidosis:

demonstration of complementary roles of cardiac MRI and PET for evaluation of areas of decreased perfusion (delayed enhancement in panel A) vs. active inflammation (FDG uptake in panel B).