Sarcoidosis is a multisystemic inflammatory disease that can present with various symptoms and mimic other diseases. A thorough physical examination, correct imaging tests, and targeted biopsies are required to make the diagnosis and distinguish it from different diseases. This article provides an overview of the diagnostic journey of Sarcoidosis.

What is sarcoidosis?

Sarcoidosis is an inflammatory disease that can affect different organs by causing lumps called granulomas. The immune system detects elements in the body as potentially harmful and overreacts to them, causing immune cells to encapsulate that structure, leading to granulomas.

The cause of the disease has not yet been fully discovered. However, research suggests genetic factors, autoimmune processes, past infections, or contact with certain environmental factors could cause it.¹ The prevalence of sarcoidosis in the United Kingdom is approximately 1-50 per 100,000 people, and globally, it is highest in Sweden and Canada, with approximately 150 per 100,000.²

Common symptoms and Affected organs

Sarcoidosis is a multisystem disease that can affect different body organ systems. The organ-specific symptoms can vary depending on the affected organs. Since it is an inflammatory disease, symptoms like tiredness, night sweats, weight loss, or fever often accompany the organ-specific symptoms. In some cases, sarcoidosis can be asymptomatic so the diagnosis is made through incidental findings without any symptoms after excluding other differential diagnoses.¹

Other symptoms that presented at the time of the first presentation of sarcoidosis:³

• Breathlessness
• Cough
• Fatigue
• Joint pain
• Eye symptoms
• Skin lesions
• Neurological symptoms

Physical examination, X-ray, and biopsy are necessary for further investigation when sarcoidosis symptoms show.

Physical examination

Role of physical examination

Sarcoidosis diagnosis is often complicated and delayed because it is a multisystemic disease with various symptoms and frequently mimics other conditions. When sarcoidosis is suspected, a physical examination is essential to localise all organ manifestations. Hence, the physician can do further organ-specific tests and decide on the most suitable place for a biopsy.¹

Patient history

When taking the patient's history, the doctor will ask the patient about current and past symptoms, medical history, family history, and environmental history. Possible signs and symptoms the physician will look for are in Table 1.¹

Imaging tests

If the patient's history and physical findings are consistent or suggestive of sarcoidosis, imaging tests are recommended primarily of the lungs to look for signs of pulmonary sarcoidosis, the most frequent manifestation form.¹

Chest X-ray

A chest X-ray is the subsequent investigation to perform. Depending on the findings in the chest X-ray, the stage of sarcoidosis is defined, which is decisive for the prognosis. The higher the stage, the prognosis and probability of remission deteriorate. The stages are:⁴

• Stage 0: No chest abnormalities
• Stage 1: Bilateral hilar lymphadenopathy (enlargement of the lymph nodes at both broncho vascular roots of the lungs, which are located on both sides of the heart) without parenchymal infiltrates
• Stage 2: Bilateral hilar lymphadenopathy and pulmonary infiltrates (areas of increased density of the lung tissue)
• Stage 3: Pulmonary infiltrates without bilateral hilar lymphadenopathy
• Stage 4: Pulmonary fibrosis (scarring of the lung tissue)

CT scan (computed tomography)

A CT scan is not performed routinely for diagnosis and staging of sarcoidosis. However, it is done as an additional step if needed. The advantage of a CT scan is that it shows structures from different perspectives, in fine layers and with detail. A CT scan is often used in sarcoidosis if the patient has persistent respiratory symptoms. Typical findings can be:⁴

• Enlargement of the lymph nodes in both lung roots (bilateral lymphadenopathy)
• Nodules (aggregated granulomas) in both lungs
• Scarring
• Air trapping, due to blocked exhalation ways because of scarring and inflammation
• Bronchiectasis (enlargement of the bronchi)

MRI (magnetic resonance imaging)

MRI, especially with a Gadolinium contrasting agent, can detect areas with higher cell activity, such as inflammation or tumours. In sarcoidosis, MRI detects hidden areas of sarcoidosis activity, especially in neurological structures such as the brain or the spinal cord.¹ It can be done focused on one region (for example, the heart or brain) or as a whole-body MRI to screen for sarcoidosis in any tissue.⁴ Limitations are that Gadolinium is not allowed in people with severe kidney diseases and that the findings are not specific, meaning that other high cell activity can also be detected in the MRI simultaneously. Furthermore, the air in the lung is black on the MRI, so the MRI cannot be used for sarcoidosis staging or lung examination.

PET scan (positron emission tomography)

A PET scan detects positrons emitted from a radioactive agent. The radioactive agent is typically coupled with Fluorodeoxyglucose (FDG). When injected into the body, FDG uptake will be higher in cells with high activity (tumour areas, inflammatory areas, brain), which can be detected through the positron emission in 2D like an X-ray. PET is often combined with CT or MRI so that the emission localisation can be done precisely in 3D. The PET scan is used for:⁴

• To localise Sarcoid activity in areas difficult to access (for example, heart or bone)
• To monitor disease activity under treatment (regression or persistence)
• In cases with inconclusive indications for immunosuppressive therapy after the conventional imaging techniques.

Biopsy

A biopsy of Sarcoidosis is needed to confirm the diagnosis and distinguish it from other conditions such as Tuberculosis.

Localisation of biopsies

The biopsy must be performed in tissues with nodules or sarcoid activity confirmed by physical examination (for example, sarcoidosis of skin) or imaging techniques. As sarcoidosis can involve any organ, the biopsy should be performed in the most safely accessible region with activity. Most biopsies are done in the lungs, lymph nodes, or skin.^3,4

How are the biopsies performed?

Lung biopsy

A lung biopsy can be performed using different techniques depending on the type of biopsy. Endobronchial ultrasound (EBUS) a biopsy localisation is done with an ultrasound placed on the bronchus. After localisation, the needle punctures the bronchial wall and aspirates tissue. This technique is suited for lymph node aspirations near the central hilum.

On the other hand, transbronchial biopsy perforates the bronchial wall to reach lung tissue behind the wall. Compared to needle aspiration, a much larger biopsy is performed in this method therefore there is a higher risk of complications such as pneumothorax.

finally,  mediastinoscopy is an operation that requires an operating room and general anaesthesia. The mediastinoscope is inserted into the thorax through the sternum. Compared to the first two procedures, a mediastinoscopy has the highest complication rate but also the highest diagnostic yield.⁵

Although both biopsy procedures are used as ways to better diagnose sarcoidosis, EBUS or TBNA is less invasive as a method than mediastinoscopy.

Lymph node biopsy

Depending on the localisation, a lymph node biopsy can be performed under ultrasound guidance or CT. The biopsy can mostly be done under local anaesthesia. Complications can be pain, bleeding, or local infections.

Skin biopsy

A skin biopsy is the least invasive among the others and it can be performed with local anaesthesia. Side effects could include prolonged bleeding, local infections, and remaining scars.

Pathology findings

When examined under the microscope, the biopsy tissue typical for sarcoidosis has the following characteristics:⁵

• Granulomas of aggregates of macrophages
• Inside the granulomas are multinucleated giant cells
• Granulomas are surrounded by little lymphocytes
• The centre is not necrotising and not caseating

Sometimes, if the tissue is not from an area with sarcoid activity, no findings can be found in the biopsy. This is a so-called “wrong-negative” finding.

Interpretation of results

The Diagnosis of sarcoidosis requires:⁴

• Clinical and imaging findings that are compatible with sarcoidosis
• Biopsy findings of noncaseating, non-necrotising granulomas
• Exclusion of other differential diagnoses

Since the granulomas in sarcoidosis can be similar to those in other granulomatous diseases, the most important diagnostic factors are patient history and physical findings.⁵

Summary

Sarcoidosis is a systemic inflammatory disease that forms granulomas in various organs, leading to symptoms such as fatigue, weight loss, and fever. While the exact cause is unknown, factors like genetics, autoimmunity, and environmental exposures may contribute to its development. Patients may present with symptoms affecting the lungs, skin, eyes, joints, and neurological system. 

Diagnosing sarcoidosis requires a thorough physical examination to identify organ involvement and determine the need for targeted biopsies. Factors such as patient history, past infections, family history, and environmental exposures are considered during the diagnostic process. Imaging tests such as chest X-rays, CT scans, MRI, and PET scans help evaluate the extent of organ involvement and disease progression. 

Biopsies, patient history and physical examination are essential for confirming a diagnosis of sarcoidosis and differentiating it from other conditions like tuberculosis. Biopsies can be performed in various organs affected by sarcoidosis, with lung, lymph node, and skin biopsies being commonly used.