Apart from intrathoracic lymph nodes and lung, the most frequent sites of sarcoidosis involvement include peripheral lymph nodes, eyes, skin and liver, each being noted in about 10–25% of cases in most series [
1‐
4,
9]. Virtually any organ may be affected by sarcoidosis but the frequency and degree of impairement is variable according to localizations. Overall, extrathoracic manifestations occur in about half of the cases and in this setting are associated with intrathoracic involvement in 80–90% cases. Extrathoracic localizations can be confined to one organ or be multiple and diversely combined.
The frequency of
ocular sarcoidosis is comprised between 10 and 50% according to published studies. This wide range is due to recruitment bias in series reported by ophtalmologists and to epidemiological factors with an increased incidence in Japanese patients [
27]. Any part of the eye may be involved in sarcoidosis. Macroscopic nodules of the conjunctiva are seen in 6–40% of cases and allow evidence of granulomas in 67% of cases [
27]. Anterior uveitis can be an initial, acute and symptomatic (red eyes, photophobia and blurred vision) manifestation but it can also be asymptomatic and have a chronic course justifying a systematic eye investigation including a slit lamp examination. Similarly, intermediate uveitis can be symptomatic or not. Posterior uveitis is encountered in up to 28% of cases with eye sarcoidosis and it may be associated with neurologic involvement. Optic neuropathy is very rare but it may provoke a rapid and definitive loss of vision in the absence of immediate and adequate systemic treatment. Lacrimal involvement may lead to sicca keratoconjonctivitis, while bilateral enlargement of lacrimal gland is unfrequent.
Skin manifestations of sarcoidosis are heterogeneous. Erythema nodosum is a non specific association of sarcoidosis realizing typically Löfgren's syndrome in the presence of bilateral hilar lymphadenopathy. The incidence of Löfgren's syndrome varies according to epidemiological factors (see "Epidemiology"). The frequency of specific skin manifestations of sarcoidosis ranges from 10 to 40% cases [
28]. They appear at any stage of the disease and can remain strictly isolated in one third of cases [
28]. The clinical picture of skin sarcoidosis is variegated: maculopapular lesions of various size, changes of old scars, lupus pernio, plaque formation, subcutaneous lesions
etc. Skin lesions supply a plain and proper site for biopsy with the exception of erythema nodosum. Lesions of the face such as lupus pernio are very unpleasant and often linked with a longstanding evolution of sarcoidosis and osseous and sinonasal localizations. They are often difficult to control with treatments.
Liver involvement
while granulomas are found in up to 60–80% of liver biopsy specimens, abnormalities of biological tests, primarily cholestasis, are evidenced in only about 20% of cases. Clinical enlargement of the liver is far less frequent. Chronic intrahepatic cholestasis, hepatic dysfunction, cirrhosis and portal hypertension are all severe but rare complications of sarcoidosis.
Localizations of sarcoidosis in heart, central nervous system, larynx or kidney are less frequent but potentially serious.
Cardiac involvement of sarcoidosis appears to be much more frequent in Japanese population, particularly in females > 50 years, than in Europeans and Americans in which it concerns approximatively 5% of cases [
29,
30]. It can occur at any point of time during the course of sarcoidosis. The left ventricular myocardium and, more specifically, the interventricular septum and the free left lateral wall are the most frequently involved structures in sarcoidosis. Main relevant signs include atrio-ventricular block, complete right bundle branch block (which is notably frequent and suggestive), ventricular hyperexcitability, ventricular tachycardia, left ventricular dysfunction and sudden death. The diagnosis of cardiac sarcoidosis is often a challenging issue for physicians. Serial electrocardiogram (ECG) during evolution survey, echocardiography, 24-h Holter monitoring of ECG, Thallium scan, MRI and and
18FDG PET can be helpful tools for diagnosis (29,30). Endomyocardial biopsy is theoretically the most confident mean to ascertain the diagnosis but in clinical practice it lacks sensitivity and it is an invasive procedure, which constitutes major limitations. Thus, the diagnosis of cardiac sarcoidosis usually relies on the conjunction of multiple arguments: (i) evidence of sarcoidosis, (ii) presence of cardiac abnormalities compatible with cardiac sarcoidosis and (iii) exclusion of any other cause of cardiac disease.
Any part of the
nervous system can be involved in sarcoidosis with a frequency around 10% [
31,
32]: meninges, central nervous system, cranial nerves and peripheral nerves. Aseptic meningitis can cause symptoms such as fever or headache and be associated with central nervous system manifestations or cranial neuropathy but can also be asymptomatic. Central nervous system manifestations are most frequent in Caucasians. Various clinical expression can be observed: neuro-endocrine symptoms, psychiatric symptoms, seizures, cognitive abnormalities, hydrocephalia, spinal cord impairment and various neurologic deficits. Brain and spinal cord MRI are the most sensitive tests to diagnose central nervous system sarcoidosis and guide therapeutical management. Cranial neuropathies prevale in Black patients. Although all cranial nerves can be concerned, seventh nerve palsy is the most common sign followed by optic neuropathy and involvement of the eighth and fifth nerves. Heerfordt's syndrome which associates uveitis, parotid gland enlargement, fever and cranial neuropathy, usually seventh nerve palsy, is highly suggestive of sarcoidosis. The diagnosis of neurosarcoidosis relies on the conjunction of: (i) confirmed sarcoidosis, (ii) neurologic involvement compatible with neurosarcoidosis and (iii) exclusion of an alternative neurologic disorder.
Clinically significant involvement of
kidneys is extremely rare, cited in 0.7% of cases [
9,
33]. Histology typically reveals granulomatous interstitial nephritis. Biology shows decreased creatinine clearance and low or absent proteinuria. Sarcoidosis can also produce urinary lithiasis and nephrocalcinosis while the relations between diverse forms of glomerulonephritis which are very uncommon and sarcoidoisis are very unclear.
Parotid enlargement is seen in 5–10% of cases. Sarcoidosis of the
upper respiratory tract occurrs in 0.7 and 6 % and may assume various features in relation to the involvement of sinonasal mucosa, pharynx and larynx. Laryngeal sarcoidosis is potentially serious by provoking airway obstruction. Sinonasal sarcoidosis is well-recognised to be a chronic and recalcitrant form of the disease, which is associated with lupus pernio in half cases [
34,
35]. Typically, patients complain of chronic crusting rhinitis but sinonasal involvement can occasionally lead to bone lysis and eventually disfiguiring saddle nose [
35].
Articular involvement may be acute and transient or chronic and persistent [
36]. Yet, whilst joint pains occur in 25–39% of patients with sarcoidosis, deforming arthritis is rare.
Osseous involvement is associated with characteristic abnormalities on radiography [
36]. Sarcoidosis usually affects small joints of the hands and feet, knees, ankles, elbows and wrists. Sympomatic muscle involvement is particularly unfrequent (1.4–2.3% cases).
Gastrointestinal tract is involved in less than 1.0%. The stomach is the most commonly involved part of gastronintestinal tract, sometimes diagnosed incidentally [
37]. Sarcoidosis of the small intestine and colon is much rarer and may mimic Crohn's disease. Pancreas and peritoneal localizations are exceptional.
Splenic enlargement is observed in 5–10%, it is usually minimal and asymptomatic and causes rarely decrease in the count of platelets, red and white cells [
37]. In the absence of splenomegaly, hematological alterations may be exceptionally due to a granulomatous infiltration of the bone marrow or to an autoimmune process, mainly hemolytic anemia or thrombopenia [
37]. However, the most frequent abnormality is lymphopenia, which mechanism is a redistribution of blood T cells to sites of disease.