Jonathon Hutchinson, an English physician, first described sarcoidosis in 1877 (1). Over the last few decades, substantial progress has been made to better define the clinical, radiological, immunological, and pathological features of sarcoidosis. The diagnosis of sarcoidosis is based on three major criteria: clinical presentation compatible with sarcoidosis, presence of non-necrotizing granulomatous inflammation in one or more tissue samples, and the exclusion of alternative causes of granulomatous disease. The American Thoracic Society recently published an official clinical practice guideline in which a panel of experts discuss and summarize evidence-based diagnosis of sarcoidosis (2). Despite advancements clinicians often remain challenged in reaching a diagnosis of sarcoidosis.

Along with sarcoidosis, granuloma formation is a feature of other chronic interstitial lung diseases such as chronic beryllium disease (CBD) and hypersensitivity pneumonitis (HP).

When presented with a patient with sarcoidosis and worsening shortness of breath, an assessment for pulmonary embolism (PE) and pulmonary hypertension (PH) is warranted. PE and sarcoidosis associated pulmonary hypertension (SAPH) may often be misdiagnosed as an exacerbation of sarcoidosis.

Sarcoidosis, as with other chronic inflammatory conditions, has been associated with an increased risk of venous thromboembolism (VTE) (71–73). Swigris et al. reported a greater than 2-fold higher risk of pulmonary embolism in patients with sarcoidosis when compared to the general population (74). In addition to PE, thrombosis secondary to localized inflammation has also been reported in the literature. Mural thrombosis in myocardial sarcoidosis, cerebral vein thrombosis in neurosarcoidosis and thoracic vein thrombosis in mediastinal sarcoidosis have all been reported (75–77). While the precise mechanism is not yet defined, chronic inflammation associated with sarcoidosis likely predisposes to endothelial cell injury with the inflammatory cytokines activating the coagulation cascade (78–80). Extrinsic vascular compression at a mediastinal or hilar level may lead to venous stasis thus progressing to localized thrombosis (77). Up to 38% of sarcoidosis patients demonstrate the presence of antiphospholipid antibodies (81). The use of glucocorticoids further increases the risk of VTE (82).

Fischer et al. reported elevated pulmonary-artery pressure in 6–23% of patients at rest and in as many as 43% with exertion (83). SAPH has been reported in up to 74% of patients with advanced sarcoidosis (84, 85). In one case-series, Schorr et al. reported a 7-fold increased risk for death over a 3-year follow-up in patients with SAPH (86). Pulmonary fibrosis leading to obliteration of the pulmonary vessels is considered the most common mechanism for developing PH (84). SAPH is classified as World Health Organization (WHO) group 5 due to its complex and multifactorial mechanisms (87). The optimal management for pulmonary hypertension in sarcoidosis is not well-defined. Along with treatment directed at active sarcoid inflammation (corticosteroid and steroid-sparing agents), therapy should focus on correcting hypoxia when present and managing comorbidities such as sleep apnea and cardiac dysfunction. Reduced diffusing capacity of the lung for carbon monoxide (DLCO) correlates with the severity of SAPH (88). Currently, the use of pulmonary hypertension specific therapy for the management of SAPH is controversial, and thus far pulmonary arterial hypertension specific therapies have not been approved (89, 90). Lung transplantation may also be considered in this high risk group. A reduced DLCO (<35% predicted) and a 6MWD of <300 m are associated with worse transplant-free survival. Oksana et al. identified preservation of FEV1/FVC ratio as an independent risk factor for worsened outcomes (91).

Any part of the nervous system may be involved in sarcoidosis. Neurological involvement occurs in 5–15% of patients and often precedes the diagnosis of sarcoidosis in up to 74%. Neurological Involvement most commonly affects cranial nerves (Cranial nerve VII and II are most common), the hypothalamus and the pituitary gland followed by the meninges, brainstem, spinal cord are less frequently involved (92–96).

Neurosarcoidosis can mimic other neurologic diseases including neoplasm (lymphoma, metastasis) (97), infectious etiologies (meningoencephalitis) (98) and other inflammatory diseases (angiitis/vasculitis, demyelinating disorders). Neurosarcoidosis can present as multiple supratentorial and/or infratentorial masses (35%) or solitary masses (15%) (99). The differential diagnosis includes gliomas, primary B cell lymphoma, metastatic disease, infarct, and demyelinating disease. Motor dysfunction is present in up to 50% of cases. Patients can demonstrate neuropsychiatric manifestations such as depression, psychoses, dementia, poor concentration, and hallucinations (100–102).

Harrel et al. first described hypercalcemia associated with sarcoidosis in 1939 and since then abnormal calcium metabolism is considered a key feature of sarcoidosis. Hypercalcemia in sarcoidosis is secondary to an uncontrolled synthesis of 1,25-dihydroxy vitamin D3 by macrophages present in granulomas. The increased 1,25 dihydroxyvitamin D3 leads to increased intestinal absorption of calcium that leads to increased resorption of calcium in the bone (139, 140). The most common manifestation of abnormal calcium metabolism is hypercalciuria which is prevalent in ~40–62% (119). Patients often provide a history of nephrolithiasis.

In the kidney, untreated hypercalcemia causes afferent arteriole vasoconstriction and inhibition of sodium-potassium ATPase causing a decrease in glomerular filtration rate and urinary sodium wasting, polyuria, and dehydration. Increased intracellular calcium overload and tubular obstruction by calcium precipitates may lead to tubular necrosis. Renal consequences of hypercalcemia and hypercalciuria are frequently reversible, however, long-standing hypercalciuria may lead to nephrocalcinosis and permanent changes (141, 142).

Once hypercalcemia is detected, serum albumin, ionized calcium, and 24-h urine collection for calcium excretion should be measured. In cases of progressive renal impairment, 24 h creatinine clearance, and abdominal ultrasound should also be performed to exclude nephrolithiasis or nephrocalcinosis. Primary hyperparathyroidism should routinely be ruled out. Histologic confirmation of sarcoidosis may be required to exclude lymphoma as it has the propensity to present with hypercalcemia associated with lymphadenopathy (143).

Table 5 highlights the laboratory diagnostics and management of hypercalcemia associated with sarcoidosis.

Asymptomatic and mild hypercalcemia detected in a patient presenting with acute sarcoidosis requires no further assessment, and studies suggest that monitoring the response to corticosteroid therapy is an acceptable practice. Management is aimed to prevent long term renal and bone complications. Patients are advised to maintain a fluid intake of >2 l per day, minimize their exposure to sunlight, and avoid vitamin D. Severe hypercalcemia is fairly responsive to steroids. Corticosteroids achieve normocalcemia by inhibiting the enzyme 1-α-hydroxylase, reducing gastrointestinal calcium absorption, inhibiting osteoclast function, and decreasing the production of parathyroid hormone-related protein (PTHrP) by the macrophages (31, 144–147). Early recognition and treatment of abnormal calcium metabolism associated with sarcoidosis is important as long-standing untreated hypercalcemia can progress to irreversible renal failure. It is imperative to consider the implication of the use of corticosteroids in patients as it further increases the risk of developing glucocorticoid-induced osteoporosis (148).

Sarcoid-like reaction (SLR) is defined as the presence of non-caseating epithelioid cell granuloma lesions of sarcoidosis without accompanying systemic symptoms. Sarcoid-like reactions are histologically indistinguishable from systemic sarcoidosis (149).

SLRs can be observed in patients with various malignancies. The lesions can be adjacent to the primary tumor, in the tumor itself or adjacent to the local draining lymph nodes (136, 150). SLRs occur in 4.4% of carcinomas, in 13.8% of patients with Hodgkin's disease, and in 7.3% of cases of non-Hodgkin lymphomas (151). Developing SLRs adjacent to the tumor sites may be due to a local reaction to tumor products or immunological response to an antigenic trigger. SLRs far from tumor sites may represent a host immune response to the soluble circulating tumor antigenic factors perhaps by acting as a type of auto-Kveim reagent (136, 152, 153).

Both SLRs and malignancy demonstrate increased uptake of 18F-fluorodeoxyglucose (FDG) on PET scan, which makes it difficult to distinguish the two. Though PET scans may be useful in selecting possible biopsy sites to search for malignancy, they have no role in differentiating between these two entities. There are no specific markers or radiographic patterns to distinguish SLRs from systemic sarcoidosis or from malignancy (153–156). SLRs may have an improved prognosis as a few studies have reported that SLR is self-limited (151, 157, 158). The occurrence of malignancy and sarcoidosis concomitantly is unusual but a few cases have been reported (158, 159). The development of hilar and/or mediastinal lymphadenopathies in patients with a history of malignancy should prompt considering SLRs. Biopsies of affected tissue are often required to rule out cancer recurrence.

Drug-induced sarcoidosis-like reactions (DISR) can be defined as a granulomatous tissue reaction, indistinguishable from sarcoidosis, that occurs at the same time as initiation of a potential offending drug (160). DISR can be associated with typical sarcoid-like manifestation including bilateral hilar lymphadenopathy, uveitis, hypercalcemia, cutaneous lesions, elevated serum ACE levels, and FDG uptake on PET scans (161–165). A variety of drugs have been implicated as causing DISRs including immune checkpoint inhibitors, tumor necrosis factor (TNF)-α antagonists, interferons (IFN), and antiretroviral drugs. It is unclear if the etiology of DISR is that of a sarcoid-like reaction per se or a result of an impaired immune system leading to the development of sarcoidosis while on drug therapy (160).

Although TNF-α is known to play an important role in the formation and stabilization of sarcoid granulomas, surprisingly DISRs have been reported with the use of TNF-α antagonists therapy. Most commonly reported with etanercept, DISRs occur with any of the TNF-α antagonists. The average time to occurrence of DISRs is 24 months after drug initiation with almost 60% of patients requiring treatment (166). Treatment requirements range from 0 to 59.2% in reported cases of DISR, depending on the class of drug implicated (Table 6).

DISRs may mimic other clinical manifestations of sarcoidosis such as infections, drug and autoimmune reactions, and neoplasms. In select cases, DISR can resolve with discontinuation of the offending drug (160, 167). DISRs that are not associated with significant symptoms, organ dysfunction, or quality of life impairment, do not often require treatment. In cases where treatment is required, standard sarcoidosis treatment regimens can be utilized (160).

SLRs have been reported after joint replacement surgery and after silicone breast implant placement (180, 181). These reactions are postulated to be due to an autoimmune inflammatory syndrome induced by adjuvants (ASIA). The pathogenesis of the development of ASIA is not clearly defined but one proposed mechanism involves adjuvants (i.e., silicone, mineral oil, hyaluronic acid) chronically stimulating the immune pathway and preventing antigens from being degraded which can then enhance the antigen exposure to the antigen-presenting cells (APC) (182, 183). Definitive treatment requires the removal of the prosthetic implant.

In 1929, Bernstein was the first to recognize cardiac involvement in sarcoidosis. Granulomas in cardiac sarcoidosis (CS) most often involve the conduction system and can potentially involve any part of the heart including the pericardium and myocardium (184). Depending upon the location and extent of granulomatous inflammation, clinical manifestation range from asymptomatic conduction abnormalities to fatal heart block and ventricular arrhythmia and congestive heart failure (CHF). In CS, CHF is the second most frequent cause of death after sudden cardiac death. Pericardial effusions are infrequent in CS and rarely progress to cardiac tamponade (184, 185).

A timely diagnosis of CS is often difficult as it may present with clinical features and radiographic findings overlapping with other cardiac disorders. Plain chest radiographs may appear normal. Some of the common mimickers of CS cardiomyopathy include amyloidosis and other infiltrative diseases, non-ischemic and ischemic cardiomyopathy, right ventricle infarction, lymphocytic myocarditis, connective tissue diseases associated cardiomyopathy, vasculitis (Takayasu arteritis and Wegener granulomatosis), Chagas disease, hypertrophic cardiomyopathy, and other infectious causes associated with cardiomyopathy (e.g., rheumatic fever, syphilis, fungal infections, and TB) (186–192).

Echocardiographic abnormalities, present in up to 24–77% of CS patients, range from non-specific findings to more sarcoid associated findings such as thinning of the basal anterior septum, regional wall aneurysm, diastolic dysfunction, or motion wall abnormalities in a non-coronary artery distribution (193). Impaired regional peak systolic longitudinal strain on strain echocardiography has been described and associated with cardiovascular events (194).

Thallium 201 scintigraphy can be used to help distinguish the ischemic disease from sarcoidosis or other infiltrative diseases. The reverse distribution phenomenon on rest and exercise thallium described as defects detected in the resting phase during thallium scanning that disappears or decreases in size during exercise or after dipyridamole infusion (195). Cardiac PET scanning may be combined with MRI to further define CS involvement. The sensitivities of cardiac PET and MRI with contrast are about the same for detecting myocardial involvement. Late gadolinium enhancement (LGE) on MRI generally cannot distinguish scar from inflammation while FDG uptake implies active inflammation (196, 197). Cardiac PET scanning is particularly useful in patients unable to undergo cardiac MRI because of the presence of implantable cardiac devices or renal failure where gadolinium is contraindicated.

Infrequently, granulomatous infiltration of the myocardium can result in myocardial thickening which can morphologically mimic hypertrophic cardiomyopathy but unlike CS, which is characterized by inflammation and edema, T2-weighted MRI features not typically seen in hypertrophic cardiomyopathy. Areas of Late gadolinium- enhancement (LGE) in CS are more likely to be patchy and mid myocardial.

For cardiac amyloid which is a consideration for unexplained infiltrative disease, both 99mTcpyrophosphate scanning and tissue biopsy (fat pad) showing apple-green birefringence at polarizing light microscopy are distinguishing features (198–200). In patients with CS and extracardiac involvement lymph node or lung biopsy is typically targeted but in cases of negative extracardiac biopsy or isolated CS, MRI, or PET directed endomyocardial biopsy may be required. Electro-anatomic mapping can also be used to choose cardiac sites for biopsy (201, 202).

CS can be managed with corticosteroids and when necessary inotropic, vasodilator, and antiarrhythmic medications. Automatic Implantable Cardioverter Defibrillator (AICD) or cardiac pacing may have a role. Cardiac transplantation although rare can be considered in younger patients with advanced end-stage cardiac failure. No difference in outcome has been reported when transplants are done for CS (203–206).

Common variable immunodeficiency syndrome may be complicated by granulomatous lymphocytic interstitial lung disease (GLILD) (205). The presence of sarcoidosis like lesions associated with hypogammaglobulinemia should suggest a diagnosis of CVID as up to 8–22% of patients with CVID can present with GILD (207–209). In a retrospective analysis more than two-thirds of CVID patients with radiographic evidence of interstitial lung disease had GLILD. GLILD was also frequently reported with dyspnea and splenomegaly. These patients can present with a clinical picture that mimics sarcoidosis and misdiagnosis can delay the treatment for CVID (IVIG), which in the presence of GLILD portends a poorer prognosis. Steroid therapy can further worsen CVID (208, 210–212).

Key clinical features that should alert one to the diagnosis of CVID include a history of recurrent infections (213) and a concurrent diagnosis of autoimmune diseases. Concurrent autoimmune disease occurs much less frequently in sarcoidosis than CVID. Sarcoidosis is more commonly associated with uveitis and skin disease whereas CVID patients more frequently have autoimmune cytopenias. Comparing GLID to sarcoidosis, chest CT scans had more air bronchogram, halo signs, and smooth bordered nodules in the CVID group. Bronchoalveolar lavage (BAL) revealed lower T-cell CD4: CD8 as well in the CVID group (214, 215).

With the aid of B cell immunophenotyping, granulomas associated with CVID reveal a severe reduction in switched memory B cells and a high level of CD21 low B cells. Immunoglobulin perfusions are considered the treatment of choice for CVID (216). Measurement of serum immunoglobulins should be considered when a history of recurrent infections is given and should be considered in any patient with granulomatous disease, even if the clinical and radiological presentation appears typical for sarcoidosis (217).

As illustrated by the numerous diseases that sarcoidosis can imitate, sarcoidosis deserves the reputation of “The Great Mimicker.” The purpose of this review the most common diseases that should be considered when sarcoidosis enters the differential diagnoses. Aside from the time lost for adequate treatment of the disease present, both using immunosuppressive drugs in a state that appears to be sarcoidosis or conversely failing to adequately treat sarcoidosis with its proper treatment regimen will lead to adverse outcomes. The authors herein described common pitfalls in the diagnostic process and how to avoid them in order to provide, to the best of our ability, an accurate diagnosis for a condition that continues to baffle, elude, and mislead clinicians.

All authors contributed equally in data collection, interpretation, paper writing, editing, and review.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.