Clinical and radiological features of extra-pulmonary sarcoidosis: a pictorial essay
Insights into Imaging volume 7, pages 571–587 (2016)
The aim of this manuscript is to describe radiological findings of extra-pulmonary sarcoidosis. Sarcoidosis is an immune-mediated systemic disease of unknown origin, characterized by non-caseating epitheliod granulomas. Ninety percent of patients show granulomas located in the lungs or in the related lymph nodes. However, lesions can affect any organ. Typical imaging features of liver and spleen sarcoidosis include visceromegaly, with multiple nodules hypodense on CT images and hypointense on T2-weighted MRI acquisitions. Main clinical and radiological manifestations of renal sarcoidosis are nephrolithiasis, nephrocalcinosis, and acute interstitial nephritis. Brain sarcoidosis shows multiple or solitary parenchymal nodules on MRI that enhance with a ring-like appearance after gadolinium. In spinal cord localization, MRI demonstrates enlargement and hyperintensity of spinal cord, with hypointense lesions on T2-weighted images. Skeletal involvement is mostly located in small bone, showing many lytic lesions; less frequently, bone lesions have a sclerotic appearance. Ocular involvement includes uveitis, conjunctivitis, optical nerve disease, chorioretinis. Erythema nodosum and lupus pernio represent the most common cutaneous manifestations encountered. Sarcoidosis in various organs can be very insidious for radiologists, showing different imaging features, often non-specific. Awareness of these imaging features helps radiologists to obtain the correct diagnosis.
• Systemic sarcoidosis can exhibit abdominal, neural, skeletal, ocular, and cutaneous manifestations.
• T2 signal intensity of hepatosplenic nodules may reflect the disease activity.
• Heerfordt’s syndrome includes facial nerve palsy, fever, parotid swelling, and uveitis.
• In the vertebrae, osteolytic and/or diffuse sclerotic lesions can be found.
• Erythema nodosum and lupus pernio represent the most common cutaneous manifestations.
Sarcoidosis is a multi-systemic disorder of unknown cause, pathologically characterized by the accumulation of inflammatory cells forming non-caseating granulomas. Lesions can be located in any organ but in about 90 % of patients, granulomas affect the lungs or the related lymph nodes .
According to Geize et al., sarcoidosis can be encountered in extra-pulmonary locations, in approximately 30 % of cases . Moreover, the study entitled “A Case Control Etiologic Study of Sarcoidosis” (ACCESS) provided an accurate analysis regarding distribution of the disease: in 736 sarcoidosis cases, 699 patients showed thoracic disease, and 368 out of the 736 patients had concomitant extra-thoracic disease [3–5]; isolated extra-pulmonary disease was found only in a small percentage of cases (2 %) [3, 5].
The systemic location of the disease can be very insidious for radiologists: a wide variety of imaging features are found, often non-specific, which can mimic other pathological conditions [6, 7]. Therefore, the aim of this pictorial essay is to describe the most important clinical features and the main radiological findings of sarcoidosis in various organs, in order to help radiologists in the identification of the disease.
The disease affects young men and women aged between 25 and 40 years, without major differences in ethnicity. Some studies do show a greater incidence in females . In about 30 % of cases, there is a second peak incidence from 50 to 65 years of age. This second peak mostly affects women showing clinical characteristics that differ from those of younger patients [9, 10]. The annual incidence varies widely from country to country. In northern Europe it is about 5-40/100,000, which represents the highest value reported; in Japan the incidence is lower, with a value of about 1-2/100,000. Afro-Americans are the most affected (35.5/100,000), whereas white Americans have an incidence of 10.9/100,000 .
Normally, sarcoidosis shows a variable clinical course; it may also exhibit different extra-thoracic manifestations. These vary widely according to ethnicity: for example, involvement of the eye, liver, bone marrow, extra-thoracic lymph nodes, and skin has been more statistically associated with African Americans than with Caucasians [3, 5].
Cardiac and ocular diseases are frequently encountered in Japanese patients, erythema nodosum in northern Europeans, and ocular and granulomatous skin involvement in black patients [11–13]. In addition, regarding cutaneous lesions, Lupus pernio has been frequently observed in Puerto Ricans.
Extra-thoracic sarcoidosis involves females more frequently than males .
Extra-pulmonary sarcoidosis: clinical and imaging features
Extra-pulmonary sarcoidosis has been found in 30 % of patients with the disease . The most common site reported in the paper by Gezer et al. is the abdomen, which includes liver, spleen, biliary tree, peritoneum, and lymphatic sarcoidosis .
The cutaneous system and the eyes are involved with a frequency of 25 % [14, 15]. Following data reported in the paper by Rao et al., the third most affected organ is the eye, with a frequency of involvement ranging from 10 to 60 % . However, according to data reported by Koyama et al., ocular sarcoidosis is found with higher frequency, being about 80 % . Skin lesions are found in 20 to 35 % of patients with sarcoidosis [11, 17, 18]; similarly, a frequency of 25 % for cutaneous involvement has been reported in other papers [16, 19].
The following sections below describe more in detail clinical and radiological features of systemic sarcoidosis (Table 1), focusing on abdominal, neural, musculo-skeletal, cutaneous, ocular, and cardiac manifestations.
Hepatic sarcoidosis occurs with a prevalence of 1-40/100,000; it generally involves young people . The disease is underestimated: indeed, involvement of hepatic parenchyma is encountered—in autopsy specimens—in 50–80 % of cases . In 2–60 % of patients, laboratory tests show abnormal levels, indicating an organ dysfunction . Portal hypertension, cirrhosis and chronic cholestatic disease are rarely reported from patients with hepatic sarcoidosis .
Commonly, imaging demonstrates hepatomegaly, with homogeneous appearance of parenchyma ; very often, this radiological feature is associated with splenomegaly and enlargement of abdominal lymph nodes , which are encountered close to the liver hilus or in celiacal region. However, in 5–15 % of cases, multiple nodular granulomas, ranging from 1 to 2 mm to several centimeters in diameter, become visible on CT and MRI . Nodular involvement—according to Karagiannidis et al.—can be detected in low percentage (<5 % of cases) .
Granulomatous lesions are located in the portal and periportal spaces of hepatic sinuses and generally exhibit “an identical stage of maturation” [20, 23]. They may be seen as round or oval shaped hypoechoic nodules at ultrasound (Fig. 1), involving hepatic parenchyma in a diffuse or limited form. These nodules are hypodense on CT images and show a low signal on MRI scan, especially in T2-weighted fat-saturated acquisitions. The nodules are generally hypointense on gadolinium-enhanced T1-weighted acquisitions [23–25]. However, signal intensity depicted on T2-weighted images reflects the degree of activity of disease: nodules can appear hyperintense in case of inflammation, due to oedema and high vascular permeability (Fig. 2) . Similarly, on diffusion weighted imaging (DWI) acquisition, nodules with inflammation appear as high signal intensity lesions, with restriction on apparent diffusion coefficient (ADC) map. Fibrotic nodules show low signal on T2-weighted and diffusion sequences .
Splenic sarcoidosis is generally associated with lung disease; however, normal chest radiography is observed in one quarter to one third of patients with splenic sarcoidosis . Splenic involvement has been reported in a variable percentage, ranging from 24 to 59 % of biopsies [28–30]; at autopsy, the frequency of sarcoid lesions in the splenic parenchyma is about 41 % .
Patients can be asymptomatic, or complain of fever, weight loss, and malaise [21, 32]. In the series reported by Warshauer et al., splenomegaly has been found in one third of cases . Hepatic and splenic contemporary involvement has been reported in 5–15 % of cases .
Splenic sarcoidosis can be present in a homogeneous fashion or in a nodular pattern [2, 27, 33]. At ultrasound, splenic lesions may be detected as small nodules, with hypoechoic attenuation in comparison to surrounding parenchyma. On CT images, lesions are generally revealed as small hypodense nodules after contrast administration (Fig. 3); nodules can be larger than 1 cm in size, with a tendency to confluence (Fig. 4).
On MRI acquisitions, nodular lesions show low signal in all sequences ; the visualization reaches an optimal level on T2-weighted acquisition with fat suppression and in the early gadolinium-enhanced T1 images (Fig. 5) [34, 35]. It has recently pointed out that MRI is able to monitor the activity of the disease. On T2-weighted images, nodules can appear hyperintense in cases of inflammation due to oedema and high vascular permeability; also, on DWI acquisitions, inflammation of nodules show high signal intensity, with restriction on ADC map .
Among abdominal sarcoidosis, autopsy revealed only a small percentage of cases (5 %) located in pancreatic tissue, intestinal tract, and testes . The gastric antrum is the area most frequently involved . Along the gastrointestinal tract, small ulcerations and mucosal thickening can be observed.
The biliary tree may be involved in extra-hepatic or intra-hepatic pattern. Granulomatous lesions develop in the portal triad, causing a cholestatic pattern.
Extra-hepatic involvement of the biliary tree can be caused by multiple small granuloma of the wall; the radiological appearance in these cases may simulate a cholangiocarcinoma; in many cases, the biliary tree may be compressed by enlarged abdominal nodes.
According to Koyama et al., in 6 % of cases parotid glands may have sarcoidosis involvement; generally, the disease is found bilaterally, with enlargement of glands . An inhomogeneous pattern can be observed on enhanced CT images (Fig. 7); increased T2-signal intensity and nodular lesions are observed on MRI acquisitions (Fig. 8). Increased uptake of Gallium-67 reproduces the typical “Panda” sign, even if this radionuclide accumulation is also described in other pathological entities (lymphoma and HIV infection) .
Lymphatic and peritoneal sarcoidosis
Lymphatic abnormalities have been already described as abdominal manifestations of sarcoidosis, consisting of “lymphadenopathy or increased number of normal sized nodes” ; lymph nodes are generally 1–2 cm in size. In a previous experience, abdominal adenopathy was reported in approximately 30 % of patients; in these case series, adenopathy was defined as “two or more nodes with a short axis diameter greater than 6 mm” .
Enlarged nodes can be observed in different locations: in the periportal region, close to the liver hilus (Fig. 9), or between portal vein and vena cava. They can be found adjacent to the celiac trunk or pancreas (Fig. 10), or in a paraaortic disposition. Lymph nodes are also found around iliac vessels, or in the mesentery. A diffuse abdominal nodes involvement can be observed (Fig. 11). Necrosis or calcifications are rare in sarcoidosis .
Lymphatic involvement is frequently associated with pulmonary disease, and this can be very helpful for radiologists in order to achieve a correct diagnosis. When the disease is limited to the lymphatic system in mediastinum and in the abdomen, a differential diagnosis from other disorders, e.g. lymphoma, may be very difficult.
Peritoneal sarcoidosis is extremely rare [2, 38–41]. It can appear with ascites and multiple nodules: these imaging features—as reported by Gezer et al.—should be differentiated from other pathological conditions, which include carcinomatosis, tuberculosis, and fungal infections .
In sarcoidosis, the real incidence and prevalence of renal involvement is difficult to establish, because the disease can occur in a variable manner; in most cases, it has been found in 35 to 50 % of patients . Main clinical manifestations are nephrolithiasis, nephrocalcinosis, nephrogenic diabetes insipidus, renal insufficiency, and acute interstitial nephritis with or without granuloma; however, many patients with renal involvement are asymptomatic.
The increased levels of 1,25-dihydroxyvitamin, produced by mononuclear cells trapped in pulmonary alveoli, determines a greater absorption of calcium: this leads to hypercalcemia and consequential nephrolithiasis and nephrocalcinosis .
The prevalence of interstitial nephritis in sarcoidosis oscillates from 7 to 27 % [44, 45]. The renal involvement may be with or without granuloma. Granuloma interstitial nephritis is the typical histological finding and is defined “naked with no cuff of inflammatory cells with presence of asteroid bodies and calcification” . This lesion differs form tuberculosis granuloma for the absence of necrosis.
Enhanced CT images may show signs of interstitial nephritis [21, 47, 48] with the typical “striated nephrogram” represented by ill-defined hypodense lines into the renal parenchyma. Diffusion MRI sequences show interstitial nephritis as hyperintense areas, with signal restriction on apparent diffusion coefficient map.
Rarely, radiological features of renal sarcoidosis can be represented by granulomatous pseudotumour; these lesions are generally incidentally discovered during CT examination. They can appear as hypo-, iso-, or hypeattanuating areas on unenhanced CT scans; after contrast administration, they are hypodense to the surrounding renal parenchyma (Fig. 12) . Differential diagnosis includes lymphoma or other tumours. On MRI acquisition, lesions show heterogeneous signal on unenhanced sequences and appear hypointense on early and delayed images acquired after gadolinium administration .
The urinary manifestations of sarcoid nephritis are nonspecific: the alterations of the urine analysis are similar to those of chronic tubular pathologies. Biopsy is the only way to make a diagnosis, showing normal glomeruli with interstitial infiltration of mononuclear cells and non-caseating granulomas; occasionally, it may be also depicted with glomerular disease [49, 50].
Central nervous system (CNS) involvement is reported in 25 % of cases at autopsy; in a post-mortem series, neural sarcoidosis was detected with a frequency of 14–27 % [51–54]. Symptoms due to neurosarcoidosis are not frequently observed, being encountered in less than 10 % of patients .
The disease shows a special predilection for the basal cisterna of the brain; cranial nerve involvement is frequent, influencing the clinical manifestation of disease. Facial nerve palsy, for example, is a typical manifestation of brain sarcoidosis in young adults . It may be associated with chronic fever, swelling of parotid gland and uveitis, configuring the typical “Heerfordt’s syndrome” (Fig. 13).
Diagnosis of sarcoidosis can be performed following the criteria reported in the study by Pawate et al., in which the presence of neurosarcoidosis is evaluated as definite, probable, and possible. According to their criteria , the disease is graded as “definite” when detected on histological specimens. It is labelled as “probable” when: a) laboratory tests are positive for CNS inflammation (elevated levels of cerebrospinal fluid protein or MRI features compatible with neurosarcoidosis) b) detection of systemic sarcoidosis (positive histology and/or least two indirect indicators from gallium scan, chest imaging and serum angiotensin-converting enzyme); the disease is considered possible when previous criteria are not satisfied .
Lesions appear hyperintense on T2-weighted MRI images, located in the superficial and deep white matter; sometimes, these imaging features may resemble lesions of multiple sclerosis . Also grey matter lesions are generally hyperintense on T2-weighted sequences. In the series reported by Pawate et al., contrast-enhancing parenchymal white matter lesions were found in 10 out of 54 cases (19 %) .
Dural thickening is generally isointense to the grey matter on T1-weighted acquisitions, hypointense on T2-weighted sequences, with contrast enhancement after gadolinium injection .
Leptomeningeal localizations are more visible after contrast injection, showing increased enhancement (Fig. 14) . As reported by Urih et al., and subsequently by Christoforidis et al. , leptomeningeal infiltration involves frequently the suprasellar and frontal basal meninges.
Nodules can be solitary or multiple, showing enhancement after contrast injection with a ring-like appearance in the activity phase: this appearance can simulate glioblastoma or metastases. An intracranial mass presentation has been also reported in the literature, simulating a brain neoplasm .
Spinal sarcoidosis is reported in about 4–28 % of cases; it occurs predominantly in old people and has a poor prognosis . The disease may be intramedullary or extramedullary. Junger et al. distinguish four stages of disease: 1) leptomeningeal enhancement; 2) fusiform spinal cord enlargement; 3) focal or diffuse intramedullary disease; 4) spinal cord atrophy .
MRI features of stage 1 and 2 disease include leptomeningeal thickening, with hyperintense signal on enhanced T1-weigheted images . In cervical and thoracic regions, intramedullary lesions appear hypointense in T2-weighted MRI sequences with hyperintensity of the associated oedema; they show enhancement (Fig. 15) on T1-weighted images after contrast injection .
The skeletal system represents a rare localization of sarcoidosis . Radiological features of skeletal locations have been described for the first time in 1910 by Rieder [62, 63]. It occurs in a variable range of percentages, from 9 % up to 39 % . However, its frequency can be underestimated, because bone lesions are often asymptomatic ; frequently, the disease is misdiagnosed, being interpreted as metastatic lesions .
The disease generally involves hands and feet, which have been reported in several reviews as the most affected locations [62, 64]. On conventional radiography, lesions produce a lacy pattern of osteolytic areas in the digits (Fig. 16) [19, 66–68]; cortical erosions and pathological fractures may be observed .
Large bones and axial skeleton involvement is uncommon; however, the disease may be encountered in ribs, long bones, skull and vertebrae. Axial skeleton disease, without pulmonary lesions, is rarely reported .
Lesions of large bone and axial skeleton can be detected as radiolucent (Fig. 17) or sclerotic areas (Fig. 18) . Sclerotic areas are well depicted on CT images, consisting of hyperdense homogeneous areas, round or oval in shape (Fig. 18); osteolysis produces a hypodense appearance, and differential diagnosis from metastatic lesions is required. The MRI appearance of bone lesions is heterogeneous. Vardahanabuhuti et al. described how lesions can appear as bone marrow infiltration areas, “round, cannonball-like or intramedullary lesions”; lesions can reproduce a “starry sky appearance” . Sarcoid lesions show high signal intensity on T2-weighted images, high-density proton sequences and STIR acquisitions; on T1-weighted images, lesions are generally hypointense.
In patients with sarcoidosis, skeletal FDG uptake can be observed (Fig. 19); these increased sites of metabolic activity are not specific. In combination with thoracic features of sarcoidosis, bone sites of increased uptake can be interpreted as “skeletal sarcoidosis” . Muscle involvement is frequently misdiagnosed, being reported as chronic myopathy, acute myositis, or pseudotumour .
Ocular involvement occurs in approximately 25–60 % of patients with systematic sarcoidosis, more frequently in the third decade (first peak of incidence) and between the sixth and the seventh decade (second peak of incidence) . This may represent the initial manifestation of the disease , or may co-exist with asymptomatic systemic disease and can be vision-threatening.
In most cases (about 20 %), uveitis is the first common manifestation: symptoms that patients complain of include tearing, photophobia, pain, infection, lacrimation, redness. However, these symptoms can be absent: “silent uveitis” is very insidious because it may produce permanent ocular damage before treatment. The common type of uveitis is often anterior in black patients, posterior in white patients, specifically in elderly female patients [72–74]. Blindness in at least one eye occurs in about 10 % of patients and the main cause is cystoid macular oedema [75, 76].
In the anterior segment, conjunctivitis occurs in 7–70 % of the patients with ocular sarcoidosis and, together with lacrimal gland involvement, is usually asymptomatic. The sarcoidosis granulomas in the eyes have the appearance of yellow “millet-seed” nodules. When the disease involves the posterior part of the eyes, it is frequently associated with neurological manifestations: optic nerve disease, cranial nerve palsies, encephalopathy, and disorders of the hypothalamus and pituitary gland [77, 78].
Other manifestations of ocular sarcoidosis include granulomatous iridocyclitis, retinal periphlebitis and chorioretinis; foci of retinal involvement are generally revealed by fluorangiography as “punched-out” lesions (Fig. 20). In 7 to 17 % of cases of ocular sarcoidosis occur conjunctival follicles [79, 80].
Erythema nodosum is the most common nonspecific cutaneous lesion of sarcoidosis. In most cases it occurs with subcutaneous erythematous nodules (Fig. 21a), often observed on anterior tibia, accompanied by systemic symptoms, such as fever, malaise or polyarthralgias .
The term “specific” is misleading, because clinically lesions are not specific to sarcoidosis, and the only way to make a diagnosis is biopsy. Papule (Fig. 21b) is the most common specific cutaneous lesion of sarcoidosis: although the face is the main location, it may occur anywhere and may be of various colours. Larger and flat-topped plaques (Fig. 21c) are very frequent and can be single or multiple; the lesions are located on the face, trunk or extremities.
A characteristic clinical manifestation of cutaneous sarcoidosis is lupus pernio (Fig. 21d): it appears as chronic and indurated papules or plaques in the middle-face, particularly the alar rim of the nose.
The diagnosis of cutaneous sarcoidosis is performed with histological examination of a cutaneous biopsy, which shows the presence of sarcoidal granuloma without any cornoid lamella.
Sarcoidosis characteristic granulomatous lesion manifests in any part of the heart, but the myocardium is most frequently involved . In order of frequency, the areas most affected are the left ventricular wall, interventricular septum, papillary muscles, right ventricula and atria [88, 89]. Valvular involvement is rare, but the impaired functioning of the cardiac valves may occur after sarcoid reaction of the papillary muscles [88, 90]. Pericardium involvement may be present, rarely determining constrictive pericarditis .
Gadolinium-enhanced cardiac MRI allows us to detect differences between normal tissue and altered tissue, the latter displaying areas of focal enhancement, particularly in the myocardial wall or subepicardial region (Fig. 22) [92, 93]. In addition, other MRI findings include mural oedema, pericardial effusion, myocardial or pericardial thickening and segmental wall motion abnormalities.
Radionuclide scans with gallium, citrate, and thallium are used for diagnosis and follow-up in patients with cardiac sarcoidosis [94, 95]. PET-CT is a technique for diagnosis of active involvement of cardiac sarcoidosis and can be used for the thoracic and extra-thoracic stage of the disease .
Abdominal, neural, musculo-skeletal, cutaneous, ocular and cardiac sarcoidosis has extremely variable clinical features; their imaging findings can often simulate other diseases, namely malignancies. Sarcoidosis should be considered in the differential diagnosis of multiple lesions of brain, abdomen and bones in patients with suspected or proved disease.
In patients with pulmonary sarcoidosis, a careful evaluation of patients’ symptoms is mandatory in order to identify other locations of the disease. Radiologists, correlating imaging and clinical-pathologic findings, play an important role in diagnosis and follow-up of the disease, in order to reduce its morbidity and mortality.
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This article is based on electronic poster published in EPOS: F. Roccasalva, S. Palmucci, M. Piccoli, G. Cappello, R. O. A. Siverino, S. Puglisi, S. Torrisi, V. Vindigni, C. Vancheri. (2015) Imaging features of extra-thoracic sarcoidosis: a pictorial essay. EPOS™ Poster presented at ECR 2015. doi: 10.1594/ecr2015/C-2049.
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Palmucci, S., Torrisi, S.E., Caltabiano, D.C. et al. Clinical and radiological features of extra-pulmonary sarcoidosis: a pictorial essay. Insights Imaging 7, 571–587 (2016). https://doi.org/10.1007/s13244-016-0495-4