You are in: eMedicine Specialties > Radiology > CHEST Sarcoidosis, ThoracicArticle Last Updated: Apr 4, 2008AUTHOR AND EDITOR INFORMATIONSection 1 of 11
  Author: Ali Nawaz Khan, MBBS, FRCS, FRCP, FRCR, LRCP, Chairman of Medical Imaging, Professor of Radiology, NGHA, King Fahad National Guard Hospital, King Abdulaziz Medical City, Riyadh, Saudi Arabia Ali Nawaz Khan is a member of the following medical societies: American Institute of Ultrasound in Medicine, Radiological Society of North America, Royal College of Physicians, Royal College of Physicians and Surgeons of the United States, Royal College of Radiologists, and Royal College of Surgeons of England Coauthor(s): Sarah Al Ghanem, MBBS, Consulting Staff, Department of Medical Imaging, King Fahad National Guard Hospital, Riyadh, Saudi Arabia; Klaus L Irion, MD, PhD, Consulting Staff, The Cardiothoracic Centre Liverpool NHS Trust, The Royal Liverpool University Hospital, UK; Sumaira MacDonald, MBChB, PhD, MRCP, FRCR, Lecturer, Sheffield University Medical School; Endovascular Fellow, Sheffield Vascular Institute; Margaret Aird, MBChB, FRCR, Consulting Staff, Department of Radiology, Wythenshawe Hospital; Carolyn M Allen, MB, BCh, MRCP, FRCR, CCST, Consultant Radiologist, Department of Clinical Radiology, North Manchester General Hospital, UK Editors: Judith K Amorosa, MD, FACR, Clinical Professor and Program Director, Department of Radiology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School; Consulting Staff, Department of Radiology, Robert Wood Johnson University Hospital; Bernard D Coombs, MB, ChB, PhD, Consulting Staff, Department of Specialist Rehabilitation Services, Hutt Valley District Health Board, New Zealand; W Richard Webb, MD, Chief of Thoracic Imaging, Professor, Department of Radiology, University of California at San Francisco; Robert M Krasny, MD, Consulting Staff, Department of Radiology, The Angeles Clinic and Research Institute; Barry H Gross, MD, Professor, Department of Radiology, University of Michigan Medical School; Professor, University of Michigan Cancer Center Author and Editor Disclosure Synonyms and related keywords: Boeck sarcoid, Besnier-Boeck-Schaumann, lupus pernio, benign granulomatous sarcoid, Jungling's sarcoidosis, Jungling sarcoidosis, Mortimer's sarcoidosis, Mortimer sarcoidosis, Schaumann's sarcoidosis, Schaumann sarcoidosis, non-caseating granuloma, noncaseating granuloma INTRODUCTIONSection 2 of 11
  BackgroundSarcoidosis is a multisystemic granulomatous disease of unknown etiology with variable presentation, prognosis, and progression. Caesar Boeck first coined the term sarcoid in 1899 to describe one of the skin lesions of sarcoidosis because of its histologic resemblance to a sarcoma. In 1905, Boeck described a series of patients with sarcoid who presented with cough and nasal granulomas. These findings suggested the systemic nature of the disease. In 1915, Kusnitski and Bittorf described chest radiographic abnormalities in a patient with sarcoidosis. Sarcoidosis almost always affects the respiratory system. Most patients present with the classic combination of bilateral hilar lymphadenopathy, parenchymal disease of the lung, and eye or skin lesions; however, virtually any organ in the body may be involved. At diagnosis, about 50% of patients are asymptomatic, 25% complain of cough or dyspnea, and 25% have or develop eye symptoms or skin lesions (eg, such as erythema nodosum, lupus pernio, plaques or scars). When present, constitutional symptoms include weight loss, fatigue, weakness, and malaise. Symptoms of pulmonary involvement, such as dry cough and shortness of breath, develop in 20-30% of patients. Bilateral hilar lymphadenopathy is the most common radiographic finding. Other radiographic findings include interstitial lung disease; occasional calcification of affected lymph nodes; and rarely, pleural effusions and thickening. In general, sarcoidosis is a self-limiting subclinical process in 60-70% of cases. About 20-30% of patients are left with a variable degree of permanent lung damage. In 10-15% of the patients, sarcoidosis can become chronic. The incidence of ocular involvement is about 20-30%. Because the disease so often involves thoracic structures, chest radiography plays a crucial role in the diagnosis, staging, and follow-up of sarcoidosis. The diagnosis is established when the clinical and radiographic findings are supported by histologic evidence of widespread noncaseating epithelioid cell granulomas in more than 1 organ or a positive Kveim-Stiltzbach skin test result. For excellent patient education resources, visit eMedicine's Lung and Airway Center and Cold and Flu Center. Also, see eMedicine's patient education articles Collapsed Lung, Flu in Adults, and Coughs. PathophysiologyEtiology The etiology of sarcoidosis is unknown. Granulomatous inflammation is invariably present; some have speculated that this disease is a response to inhaled foreign material. Thoracic sarcoidosis is currently viewed as a disorder of immune regulation, but the antigenic agent or agents responsible for the disease remain elusive. A deranged cellular immune response to an unidentified antigen, such as atypical tuberculosis (TB) or pine pollen, is possible. Mycobacterium species and, less likely, gram-negative bacteria have been implicated. However, cultures from affected tissue are almost always sterile. Additionally, no evidence suggests host-to-host transmission of the disease. However, some evidence implicates abnormal immune function. The bronchoalveolar lavage fluid in patients with sarcoidosis contains an increased number of lymphocytes, especially the CD4 subset in patients with active sarcoidosis. The ratio of helper T cells to suppresser T cells is abnormal. Cell-mediated immunity is stimulated in the lung, resulting in the formation of characteristic epithelioid cell granulomas. Activated alveolar macrophages and T lymphocytes play an important role in the development of sarcoidosis. T cells are responsible for an accumulation of CD4 cells and the release of interleukin (IL)–2 at sites of disease activity. This may be clinically manifest by an inverted CD4/CD8 ratio. In sarcoidosis, a variety of biochemical mediators are released; these include IL-1 (a T-cell activator), fibronectin (fibroblast chemotactic factor), and alveolar macrophage-derived growth factor (stimulates fibrosis). The T-lymphocyte population includes a higher proportion of T-helper cells as compared with the population in normal lungs. These activated T cells release IL-2 (which stimulates the growth of T-helper or cytolytic cells), monocyte chemotactic factor (which attracts circulating monocytes), and immune interferon (which activates polyclonal B cells). The production of TH1 cytokines, such as interferon and tumor necrosis factor (TNF), is also increased, with an associated increase in TNF receptors. TNF propagates inflammation; this has been demonstrated by the affective use of anti-TNF agents in the treatment of sarcoidosis. B cells also play a role, as shown by B-cell hyperreactivity with immunoglobulin production. The process described above may resolve spontaneously, or it may progress to form the noncaseating granulomas, which is the histologic hallmark of sarcoidosis. Progression of the granulomatous process to fibrosis may occur in 10-15% of patients.1 Histologic findings Alveolitis is the earliest pathologic manifestation of sarcoidosis. The earliest change is an infiltrate of lymphocytes and histiocytes in the alveolar septa, which eventually progress to the typical granulomatous lesions. The intrathoracic involvement is characteristically most pronounced in peribronchovascular, interlobular septal, and pleural areas. This process affects the upper lobes of the lungs more severely. The inflammatory response is a nongranulomatous interstitial pneumonitis involving the alveolar walls. T lymphocytes recruit macrophages, which lose their motility and are transformed into epithelioid cells. Conglomeration of these epithelioid cells, lymphocytes, peripheral fibroblasts, and multinucleated giant cells become interstitial granulomas. A fine network of reticular fibers is also present. Minimal central necrosis may rarely occur. Sarcoid granulomas are widely distributed. They congregate in lymph nodes and in organs rich with lymphoid tissues. In the lung, the granulomas are interstitial, located in the subpleural, septal, perivascular, and peribronchial spaces. In 10-20% of patients with sarcoidosis, interstitial granulomas progress to pulmonary fibrosis. The histologic hallmark of sarcoidosis is the noncaseating granuloma, but this finding is by no means specific. These granulomas are the result of a nonspecific cell-mediated response and indistinguishable from those found in berylliosis, TB, leprosy, hypersensitivity pneumonitis, Crohn disease, primary biliary cirrhosis, fungal disease, and local sarcoid reactions seen in lymph node–draining neoplasms and sites of chronic inflammation. Thus, the diagnosis of sarcoidosis is established by exclusion. Staging The clinical staging of sarcoidosis is based on the pattern of chest radiographic findings: (a) stage 0 is a normal chest radiograph; (b) stage I, lymphadenopathy only; (c) stage II, lymphadenopathy and lung parenchymal disease; (d) stage III, parenchymal lung disease only; and (e) stage IV, pulmonary fibrosis. At presentation, approximately 5-10% of patients have stage 0 disease; 50%, stage I; 25-30%, stage II; and 15%, stage III. Although most cases of sarcoidosis either regress or remain stable, 10-15% progress to pulmonary fibrosis. Generally, pulmonary function worsens with an increasing stage of disease, but radiologic staging does not correlate well with the severity of pulmonary function abnormalities. Often, the radiographic abnormalities appear worse than the degree of functional impairment actually present. Extrapulmonary thoracic manifestations Sarcoidosis predominantly affects the lungs, both clinically and radiologically. However, sarcoidosis can affect virtually any organ. Autopsy studies have shown cardiac involvement in 25% of cases, but symptoms and imaging findings occur in only 10% of patients with cardiac involvement. One half of patients with abnormal electrocardiographic results are asymptomatic. Ventricular arrhythmias, heart block, congestive failure, angina, constrictive pericarditis, left ventricular aneurysm formation, and sudden cardiac death due to granulomatous inflammation of the cardiac conduction pathways have all been reported. Pericardial involvement is rare; when present, it usually occurs because of the direct extension of myocardial disease. Frequency of organ involvement The frequency of organ involvement varies considerably in different series. Rates may be as follows:
FrequencyUnited StatesIn the United States, the prevalence of sarcoidosis is 5-40 cases per 100,000 population. However, it was not until the mid 1940s that a large number of cases were identified during mass chest radiography screening for the Armed Forces; before this, the high prevalence of sarcoidosis had not been recognized in North America. Sarcoidosis was once considered rare, but it is now the most common fibrotic lung disease; it occurs often enough in the United States for Congress to have declared a national Sarcoidosis Awareness Day in 1990. Because sarcoidosis may mimic other diseases, its prevalence can only be estimated. About 5 in 100,000 white individuals in the United States have sarcoidosis. The disease occurs more frequently among African Americans, probably affecting 40 per 100,000 population. Overall, the rate appears to be 20 cases per 100,000 population in cities on the East Coast; the rate is somewhat lower in rural locations. However, some investigators believe that these figures greatly underestimate the percentage of the US population with sarcoidosis. InternationalSarcoidosis occurs worldwide. The true prevalence of sarcoidosis is difficult to determine because the disease is often asymptomatic and frequently does not come to medical attention. Thoracic sarcoidosis is found with varying frequency in virtually every country of the world. Sarcoidosis appears to be more common and more severe in certain geographic areas. Reports are subject to error because the surveillance and criteria for diagnosis vary from country to country. The prevalence is higher in countries with temperate climates: In the United States, the incidence is 10-40 cases per 100,000 population; in the United Kingdom, 20-30 per 100,000; in Scandinavia, 64 per 100,000; and in Japan, 10-20 per 100,000. The overall incidence in Europe is 19 cases per 100,000 population; in Bulgaria, 1.4 per 100,000; in Spain, 0.04 per 100,000; and in Sweden, 64 per 100,000. In tropical climes, the incidence is lower: In Africa, Southeast Asia, India, Central America, and South America, the incidence is less than 10 cases per 100,000 population. Mortality/MorbidityThe overall mortality rate that is directly related to sarcoidosis is 5%. Patients may die from right-sided heart failure, respiratory failure, or massive hemoptysis. A small number of patients die from sudden cardiac death due to direct granulomatous involvement of the conduction pathways and myocardium. Regarding morbidity, the 3 major complications of pulmonary sarcoidosis are mycetoma formation, fibrosis, and right-sided heart failure.
RaceSarcoidosis occurs in all races. Nevertheless, the risk is greater in young African American adults, especially women, and in those of Scandinavian, German, Irish, or Puerto Rican origin.
SexGlobally, a male-to-female ratio of approximately 2:1 is reported.
AgeSarcoidosis mainly affects people aged 20-40 years, and the disease typically manifests in the third or fourth decade of life. However, the age range of patients extends from preadolescence to the seventh decade.
Clinical DetailsClinical presentationUsually, sarcoidosis occurs without symptoms. Although physical findings are normal, abnormalities are seen on the chest radiograph. Pulmonary dyspnea on exertion, cough (dry or productive), chest pain, and hemoptysis (rare) occur in 50% of cases. Approximately 50% of patients with sarcoidosis are asymptomatic at diagnosis; 25% complain of dyspnea and a persistent cough, which can be among the first symptoms of sarcoidosis; and 25% have extrathoracic symptoms, which are usually related to the skin or eyes. Constitutional symptoms, such as malaise weight loss, loss of appetite, and fever occur less commonly.2, 3, 4, 5 Löfgren syndrome Löfgren syndrome is an acute form of sarcoidosis that occurs with an acute febrile illness accompanied by erythema nodosum; hilar lymphadenopathy; malaise; arthropathy; and, occasionally, uveitis and parotitis. Löfgren syndrome is common in Scandinavian patients; it is uncommon in African American and Japanese patients. Skin involvement Skin lesions, including those due to erythema nodosum or lupus pernio, and skin plaques or scars are found in around 30% of patients with sarcoidosis. Skin lesions can be subdivided into nonspecific types and specific types (which histologically reveal noncaseating granulomas). Papular sarcoidosis is the most common specific skin lesion. These lesions are red or brown-to-purple skin papules; they are seen most commonly on the face or on extensive surfaces of the arm and legs (see Images 1 and 2). Papular rash is often associated with the acute form of sarcoidosis and, generally, a good prognosis. Lupus pernio is a specific form of cutaneous sarcoidosis. It is characterized by indurated, bluish-purple elevations that mainly affect the nose and digits (see Image 3). Lupus pernio resembles lesions seen in acute cold injury (hence the name pernio). Lupus pernio is characteristically seen in African American individuals. The cosmetic effect of these skin lesions may prompt patients to seek medical attention. These lesions are frequently associated with serious systemic disease, including involvement of the upper respiratory tract, pulmonary fibrosis, chronic uveitis, and bone cysts. Subcutaneous nodules are often a manifestation of chronic disease; however, they may appear any time in the course of disease. These nodules involve the limbs and trunk. The lesions are usually 0.5-2.0 cm in diameter, subcutaneous, firm, nontender, mobile, and red-brown to purple in color. They are generally not a prognostic indicator. The plaques of cutaneous sarcoidosis are round or oval, annular or arciform, and red-brown to purple. These lesions usually affect the trunk and limbs. Plaques are frequently associated with persistent pulmonary involvement. Preexisting, healed scars may become purple and indurated due to infiltration by sarcoid granulomas. Erythema nodosum is characterized by erythematous nodules that are usually multiple, bilateral, and tender; they are mostly located on the anterior aspect of the lower limbs. These lesions are nonspecific manifestations of sarcoidosis. The prevalence of erythema nodosum varies widely in different parts of the world, affecting 10% of American patients or less and 30% of European patients. It has a predilection for female patients, particularly those of Scandinavian, Irish, or Puerto Rican origin. Erythema nodosum is often associated with arthropathy of the ankles, elbows, wrists, and hands. Erythema nodosum usually resolves, but other skin problems can persist. Eye involvement Approximately one quarter of patients with sarcoidosis have eye involvement at some time during the course of the disease. Eye disease is more common in children than in adults. Eye involvement may be asymptomatic, but 5% of patients with sarcoidosis present with eye symptoms. Almost any part of the eye can be affected, including the eyelids, cornea, conjunctiva, uveal tract, sclera, retina, and lens. Symptomatic patients may present with conjunctival injection, photophobia, and unilaterally or bilaterally blurred vision. Rarely, cataracts, glaucoma, and blindness result. Lacrimal and salivary gland involvement may occur, even in the absence of ocular lesions. Slitlamp examination may reveal symptomatic, as well as asymptomatic, ocular involvement. Involvement of other organs Sarcoidosis may affect almost any organ of the body, but the lungs, skin, and eyes are most frequently involved. Besides the lungs and lymph nodes, structures more likely than others to be affected by sarcoidosis are the liver, skin, heart, nervous system, and kidneys, in decreasing order of frequency. Patients may have symptoms related to the specific organ affected. Patients may be asymptomatic or have nonspecific constitutional symptoms. Symptoms may also vary with the chronicity of the disease, with the activity status of the disease, and with the extent of granulomatous involvement. Heart failure due to cardiomyopathy is a rare occurrence.6 Heart block and sudden death may occur. Approximately 25% of patients have noncaseating granulomas within the heart at autopsy, but fewer than 5% have clinical cardiac disease (see Images 4-6). An elevated alkaline phosphatase level suggests hepatic involvement. Although liver involvement is common, it rarely is clinically relevant. Diagnostic evaluationBiopsy The diagnosis is established by obtaining biopsies of affected organs and by excluding other granulomatous conditions, such as fungal disease and TB, and other causes of lymphadenopathy, such as neoplasia. The central nervous system is affected in 1-5% of patients with sarcoidosis; this involvement can lead to neurologic problems. Sarcoid granulomas can appear in the brain, spinal cord, and facial and optic nerves. Facial paralysis and other symptoms of nerve damage require prompt treatment. Other cranial nerve palsies and hypothalamic/pituitary dysfunction may occur. Lymphocytic meningitis is the most common neurologic manifestation. Laboratory testing Laboratory findings in sarcoidosis include leukopenia and hypercalcemia. Hypercalcemia and hypercalciuria are due to hydroxylation of 25-dihydroxy vitamin D in macrophages, which results in increased intestinal absorption of calcium. Persistent hypercalcemia can lead to nephrocalcinosis. Hypercalcemia is seen in about 10-13% of patients, whereas hypercalciuria is 3 times more common. However, the findings of leukopenia, hypercalcemia, and hypercalciuria are nonspecific. Angiotensin-converting enzyme (ACE) is a product of macrophages and, therefore, an indicator of granuloma burden in the tissues. ACE levels are elevated in the serum and may be correlated with disease activity. The diagnostic value of elevated levels of ACE is limited by a 40% false-negative rate and a 10% false-positive rate. Its value lies in monitoring the response to treatment or the clinical course of the disease. Immunologic testing The immunologic imbalance in sarcoidosis may clinically manifest as impaired immunologic function. Cell-mediated immunity is enhanced at sites of disease activity, but it is depressed systemically. Patients may exhibit hypergammaglobulinemia caused by T-cell lymphokine stimulation of B lymphocytes. The Kveim test involves an intradermal injection of a sodium chloride suspension of human sarcoid spleen or lymph nodes. Although the Kveim test is specific, it is limited by the unavailability of the antigen, a 4- to 6-week reaction time, and variability in the interpretation of results. The Kveim test is rarely used in the United States because the US Food and Drug Administration (FDA) has approved no antigen. However, a few hospitals and clinics may have some standardized test that has been privately prepared for their own use. Pulmonary function testing In sarcoidosis, abnormal pulmonary function test (PFT) results may be indistinguishable from those seen with other interstitial lung diseases. Such results include reduced lung volume, reduced diffusing capacity, and a normal or supranormal ratio of forced expiratory volume in 1 second to forced vital capacity. The extent of PFT abnormalities is related to the severity of lung involvement by granulomatous disease and fibrosis. In acute sarcoidosis, no functional impairment may be detectable; however, if the disease progresses, pulmonary physiologic findings may indicate restrictive and obstructive airway disease. Low lung compliance results from diffuse interstitial disease. A generalized reduction in volume throughout all lobes and segments is reflected in decreased vital capacity, decreased residual volume, and decreased total lung capacity (restrictive lung disease). With endobronchial lesions or peribronchial fibrosis, PFTs may show a decreased flow rate caused by increased airway resistance (obstructive airway disease). Diffusion abnormalities may be assessed by performing the carbon monoxide diffusion capacity test. These are routinely used in evaluation and follow-up. Cardiopulmonary exercise testing Cardiopulmonary exercise testing can be used to assess the extent of pulmonary involvement. It is a sensitive test for identifying and quantifying the extent of disease. Results of cardiopulmonary exercise testing also may suggest cardiac involvement that otherwise is not evident. Bronchoalveolar lavage is performed by means of bronchoscopy, which allows evaluation of the alveolar cell population. In healthy nonsmokers, more than 90% of alveolar cells found in the lavage fluid are macrophages, 9% are lymphocytes, and less than 1% are polymorphs. In a patient with sarcoidosis, the percentage of lymphocytes increases to 40%, whereas the percentage of macrophages decreases to 60%. The increased number of T lymphocytes is associated with an increase in the ratio of T-helper cells to T-suppressor cells. These findings are nonspecific and may also be found in drug-induced lung toxicity, pneumoconiosis, and amyloidosis. In accordance with the position statement of the American Thoracic Society, all patients should undergo annual ECG testing. If patients report palpitations, they should undergo a through evaluation with at least a Holter monitor. Disease progressionThe progress of sarcoidosis is unpredictable, but certain clinical features may determine the ultimate prognosis. The sudden onset of systemic symptoms, such as weight loss and general malaise, usually indicates that the course of sarcoidosis is relatively short and mild. Dyspnea and, possibly, skin sarcoidosis often suggest that the sarcoidosis will be more chronic and severe. Racial characteristics also determine the ultimate prognosis. White patients are more likely to develop the milder form of the disease. In black individuals, sarcoidosis tends to have a more chronic and severe form. Differential diagnosisThe clinical manifestations of sarcoidosis are protean and may mimic different pathologies. Therefore, the differential diagnosis is wide and includes the following: (1) neoplasia, such as lymphoma and metastases (lymphangitis carcinomatosa); (2) TB and fungal infections; and (3) inflammation secondary to immune response, including idiopathic pulmonary fibrosis, hypersensitivity pneumonitis, berylliosis, silicosis, talcosis, asbestosis, and autoimmune diseases (eg, systemic lupus erythematosus, scleroderma, rheumatoid arthritis, ankylosing spondylitis). Laboratory findings of leukopenia and hypercalcemia are nonspecific and have a wide differential diagnosis. Preferred ExaminationWhen chest radiographic results are correlated with the clinical findings, chest radiography may be the only imaging required.7 Routine chest CT scanning is not usually indicated and adds little to patient care. Approximately 60-70% of patients with sarcoidosis have characteristic radiologic findings. In 25-30% of patients, the radiologic changes are nonspecific or atypical, and in 5-10% of patients, the chest radiograph is normal. Thus, approximately 30-40% of patients can benefit from a CT scan. CT is more sensitive than radiography in the detection of lymphadenopathy and subtle parenchymal disease. High-resolution CT (HRCT) is useful in differentiating active disease from fibrosis. HRCT results are well correlated with the yield of biopsy. The accumulation of gallium-67 (67Ga) is a sensitive but nonspecific indicator of active inflammation in patients with sarcoidosis. Gallium-67 avidity alone cannot be used to establish a diagnosis of sarcoidosis, and this finding has a limited correlation with the patient's clinical status. However, 67Ga scintigraphy is useful in identifying extrathoracic sites of involvement, in detecting active alveolitis, and in assessing response to treatment.8 Gallium-67 scans have low sensitivity and specificity as a diagnostic test; therefore, they are used infrequently. Gallium-67 scanning is useful in patients in whom the clinical picture remains confusing despite the presence of noncaseating granulomas in biopsy specimens, and it may useful in differentiating chronic hypersensitivity pneumonitis from sarcoidosis.9, 10, 11, 12, 13, 14, 15, 16, 17, 18 No large imaging studies are available to assess sarcoid cardiac involvement. Some have suggested a combined use of 67Ga and thallium scans. However, the number of studies that have reported on this technique have been small and subject to significant bias. Moreover, because of patchy sarcoid cardiac involvement, endomyocardial biopsy, which is regarded as a standard technique in the diagnosis, is subject to sampling error.19 Mycetomas may occur in more than 50% of patients with stage IV sarcoidosis and apical bullous disease. Although mycetomas may be clinically silent, hemoptysis is common. Life-threatening hemoptysis may be managed with the angiographic localization of bleeding and concurrent bronchial artery embolization in a minority of patients. Bronchial necrosis is more frequently encountered when absolute alcohol is used for embolization. The diagnosis is most confidently established when the clinicoradiologic findings are supported by histologic evidence of widespread noncaseating granulomas. Limitations of TechniquesThe limitation of all techniques is the nonspecificity of most methods of diagnostic imaging. A chest radiograph can be normal in biopsy-proven sarcoidosis. A false-positive diagnosis may occur with a variety of granulomatous diseases. Problems may also arise with the biopsy material. CT is expensive both in terms of money and the radiation burden. Gallium-67 scanning is also limited by nonspecificity, and the scans may show normal uptake in established disease. Gallium-67 scanning is also time-consuming and expensive. In a study in 31 patients, Okada et al performed a correlative analysis of longitudinal changes in bronchoalveolar lavage, 67Ga scanning, serum ACE activity, chest radiographic findings, and PFT results in pulmonary sarcoidosis.20 The investigators found that, in terms of the usefulness for estimating disease activity, differences in the 4 indicators were negligible. They concluded that a chest radiograph and serum angiotensin-converting enzyme (ACE) levels sufficiently reflect disease activity and that, at present, routine evaluation with 67Ga scanning and bronchoalveolar lavage is not necessarily indicated in the long-term management of patients with pulmonary sarcoidosis. DIFFERENTIALSSection 3 of 11
Other Problems to Be ConsideredNeoplasia - Lymphoma and metastases (lymphangitis carcinomatosa) Causes of noncaseating granulomas on biopsy Berylliosis Hilar infiltrates RADIOGRAPHSection 4 of 11
FindingsRadiographic staging Characteristic radiographic appearances are reported in approximately 60-70% of patients with sarcoidosis. The radiographic changes in thoracic sarcoidosis are usefully classified into 5 groups or stages:
Radiographic findings Hilar and/or mediastinal lymphadenopathy is found in the majority of patients with sarcoidosis; this is the most common finding. The most frequent presentation is bilateral hilar and right paratracheal lymphadenopathy. Left paratracheal and aortopulmonary window lymph nodes are also frequently involved, but they may be difficult to detect on a standard posteroanterior (PA) chest radiograph. Atypical lymphadenopathy may rarely affect the paratracheal, subcarinal, aortopulmonary window, and retroazygous nodes unaccompanied by hilar lymphadenopathy. Radiographic evidence of anterior mediastinal adenopathy is seen in less than 10% of cases. The posterior mediastinum is least commonly involved. The findings of isolated lymphadenopathy in the anterior or posterior mediastinal compartments should raise the possibility of diagnoses other than sarcoidosis. Isolated unilateral hilar lymphadenopathy is an unusual manifestation of sarcoidosis, occurring in only 1-3% of patients. Patients older than 50 years may present with atypical mediastinal lymphadenopathy. Mediastinal lymphadenopathy with no associated hilar lymphadenopathy or unilateral hilar lymphadenopathy occurs more frequently in such older patients. Dystrophic calcification of involved lymph nodes is related to duration of disease, occurring in 3% of cases after 5 years and in 20% after 10 years. Calcification can be amorphous, punctate, popcornlike, or eggshell.21 Parenchymal changes from interstitial lung involvement may mimic airspace disease. On plain radiographs, parenchymal disease may show a variety of radiographic patterns, including fine nodular; reticulonodular; acinar (poorly marginated, small to large nodules or coalescent opacities); and, rarely, focal (solitary nodule or mass). In sarcoidosis, acinar opacities or interstitial granulomas may coalesce to give the appearance of the alveolar form of sarcoidosis, and an air bronchogram may be exhibited. Patients older than 50 years have a higher prevalence of solitary and multiple masslike opacities in the lung at their first presentation. In such older patients, the prevalence of atelectasis may be higher. Cavitation of sarcoid parenchymal lesions occurs rarely; it is found in fewer than 1% of patients. When cavitation occurs, TB and fungal infections need to be ruled out. Necrotizing sarcoid granulomatosis is a variant of sarcoidosis that is predominantly an angiitis rather than an alveolitis; it is more likely to give rise to cavitating pulmonary nodules, particularly in a peripheral, pleural-based location. Mycetomas develop in more than 50% of patients with stage IV sarcoidosis and apical bullous disease. The earliest manifestations of mycetoma formation are adjacent pleural thickening or apparent thickening of the wall of a bulla. Later, an intracavitary, gravity-dependent mass (Mounod sign) may be seen. Although mycetomas may be clinically silent, hemoptysis is common. Life-threatening hemoptysis that requires surgical intervention or angiographic localization of bleeding with concurrent bronchial artery embolization occurs in a minority of patients. Involvement of the pleura by the granulomatous process may result in small to moderate effusions. These effusions usually resolve in 2-3 months, as shown on radiographs. Pleural thickening may result and usually involves the lower chest. In stage IV sarcoidosis, when fibrosis supervenes, hilar retraction, decreased lung volume, and honeycomb lung may be present. Bullous disease airtrapping and diaphragmatic tenting may also be seen. Pulmonary arterial hypertension and right heart failure may develop as a result of extensive interstitial fibrosis. Radiographic findings include a prominent main pulmonary artery, enlarged right and left pulmonary arteries, right ventricular enlargement, and attenuation of peripheral vessels. Any part of the airway can be affected from the epiglottis to the bronchioles. Tracheal stenosis is rare. Mediastinal lymphadenopathy may extrinsically compress bronchi, or bronchial obstruction may result from endobronchial granulomas. Bronchiectasis or frank occlusion and/or stenosis may develop as a result of scarring and fibrosis. Cardiac involvement is usually difficult to detect on plain radiography. The radiologic signs of cardiac sarcoidosis are nonspecific and include enlarged cardiopericardial silhouette, signs of pulmonary venous hypertension, arterial pulmonary hypertension, and heart failure. Degree of ConfidenceChest radiography is a noninvasive test that is universally available. When correlated with the clinical findings, it may be the only imaging required. In most patients, sarcoidosis has a characteristic appearance on plain chest radiographs. In approximately one quarter of patients, the radiologic changes are nonspecific or atypical, and the chest radiograph is normal in a minority. However, the course of parenchymal disease is unpredictable, and no radiographic criteria exist to distinguish reversible from irreversible parenchymal changes until irreversible fibrosis has been long standing. Miller and Putman compared chest radiographs to 67Ga scans in 85 studies in 51 patients with biopsy-proven sarcoidosis.22 They found that chest radiography compared favorably with other staging methods in detecting the alveolitis phase of sarcoidosis and that the examination was reproducible, noninvasive, and cost-efficient. False Positives/NegativesThe chest radiograph may be normal in 5-10% of patients. In 25-30% of patients, the radiologic changes are nonspecific or atypical. In some patients, atypical lymphadenopathy lymphomas can mimic fungal infections, TB, and cancer. Left paratracheal and aortopulmonary window lymph nodes are less frequently involved, but they may be difficult to detect on a standard PA chest radiograph. End-stage lung parenchymal disease may be indistinguishable from lung disease of many other causes. A miliary pattern on a chest radiograph can be indistinguishable from patterns seen with TB, fungal infections, histiocytosis, and miliary metastases. Sarcoidosis rarely causes pleural effusions; when they do occur, they can be indistinguishable from pleural effusions of other causes. CT SCANSection 5 of 11
FindingsCT is more sensitive than chest radiography in the detection of mediastinal lymphadenopathy, and HRCT shows subtle parenchymal lung disease with advantage. Left paratracheal, aortopulmonary window, and anterior mediastinal nodes are more readily demonstrated with CT. With 1- to 1.5-mm sections and a high-spatial-frequency reconstruction algorithm, HRCT produces excellent images of the anatomic regions affected by the granulomatous process. Early acinar patterns, parenchymal nodules, and nodular consolidation are more clearly defined on these scans than on chest radiographs.23, 24, 25, 26, 27, 28 In sarcoidosis, HRCT findings include areas of ground-glass attenuation; subpleural nodules; perivascular nodules, which appear as beading and irregular thickening of bronchovascular bundles; and thickening of interlobular septa. The nodules, which correspond to coalescent interstitial granulomas, have irregular margins. The foci of ground-glass attenuation may represent areas of active alveolitis or diffuse microscopic interstitial granulomas that cannot be demonstrated on HRCT scans (see Images 12-13).29, 30, 31, 32, 33, 34 Stage IV sarcoidosis is often associated with upper lung fibrosis, which is depicted well with HRCT. The findings include honeycombing, bullae and cyst formation, and bronchiectasis. HRCT findings of fibrosis include lung distortion with posterior displacement of the main and upper lobe bronchi, traction bronchiectasis, abnormal central conglomeration of hilar and perihilar structures, and upper lobe conglomerate masses (see Images 14-17). Degree of ConfidenceCT can sometimes demonstrate focal parenchymal involvement in patients with stage 0 or I radiographic findings. However, HRCT results may be normal in the presence of microscopic disease. In patients with sarcoidosis, CT findings include relatively symmetric and diffuse involvement of mediastinal and hilar lymph nodes, as well as thickened bronchovascular bundles. To a lesser extent, subpleural small nodules may be seen along with interlobular septal thickening. Centrilobular attenuating areas can be detected as thickened peripheral bronchovascular bundles. On CT scans, ground-glass areas usually represent an accumulation of many granulomas in the interstitium, but they may not indicate an alveolitis. False Positives/NegativesHilar and/or mediastinal lymphadenopathy is not specific for sarcoidosis, and similar findings may occur in lymphoma, leukemia, metastases, and fungal and viral infections. With HRCT, the classification of diffuse lung parenchymal disease is based on 4 distributions: centrilobular, perilobular, panlobular, and nonlobular. The centrilobular is seen in airway diseases such as Mycoplasma pneumonia, TB, bronchiolitis, and interstitial lung diseases (eg, sarcoidosis, lymphangitic carcinomatosis, chronic interstitial pneumonias). Perilobular patterns are seen in sarcoidosis, lymphangitic carcinomatosis, non-Hodgkin lymphoma, and chronic interstitial pneumonias. A panlobular distribution is seen in advanced stages of interstitial lung diseases, such as lymphangitic carcinomatosis and sarcoidosis. A nonlobular pattern is typically seen in Pneumocystis carinii pneumonia but may occur in other interstitial lung diseases, such as sarcoidosis. MRISection 6 of 11
FindingsMendelson and associates examined 15 patients with sarcoidosis by using MRI.35 The T2 signal intensity of mediastinal lymphadenopathy varied, with no characteristic pattern noted. Three of 4 patients with bright lymph nodes on T2-weighted images had stage I disease, but low-intensity lymph nodes were also seen. In their study, the subcarinal nodes were best depicted on coronal images.36, 37, 38 MRI is also useful in characterizing osseous involvement with sarcoid, particularly in the spine.39 Degree of ConfidenceAs yet, MRI has not supplanted CT in the evaluation of thoracic sarcoidosis. Technical difficulties still exist with MRI, and cardiorespiratory movement remains a problem in thoracic imaging. In patients with chronic infiltrative lung disease, MRI appears equal to CT in the demonstration of areas of airspace opacification, but it is inferior to CT in the assessment of fine lung-parenchymal anatomy or fibrosis. MRI has a potential role in the evaluation of pericardial and/or myocardial involvement. MRI is not useful in distinguishing the lymphadenopathy of sarcoidosis from that of other entities, but it is useful for defining the anatomic extent of the disease and for differentiating enlargement of the pulmonary artery from lymphadenopathy. False Positives/NegativesMRI cannot be used to distinguish mediastinal sarcoid lymphadenopathy from mediastinal lymph node enlargement that results from other causes. NUCLEAR MEDICINESection 7 of 11
FindingsGallium-67–avid disease has been reported in more than 90% of cases of pulmonary involvement. A lambda pattern of uptake in the parahilar, infrahilar bronchopulmonary, and mediastinal lymph nodes has been described in 72% patients with intrathoracic sarcoidosis. Symmetric uptake in the parotid and lacrimal glands also occurs in 79% of the patients (see Images 18-19). One or both of the aforementioned patterns of uptake occurs in approximately 90% of patients. This pattern of activity does not usually occur in patients with lymphoma. The only exception is in patients who have undergone head and neck radiation therapy and who have subsequently developed radiation sialoadenitis. Scans in these patients may show symmetric 67Ga uptake that produces the panda sign.40, 41 Degree of ConfidenceGallium-67 scanning is more sensitive than a chest radiography in determining the degree and variation of pulmonary sarcoidosis activity, in evaluating response to therapy, and in foreseeing relapses. Gallium-67–avid disease has been reported in more than 90% of cases of pulmonary involvement, although 67Ga avidity is nonspecific. However, 67Ga scans may be useful as a baseline study at the time of diagnosis. If results of 67Ga scintigraphy are initially positive, negative findings from a subsequent 67Ga scan obtained during the course of treatment suggest that alveolitis has resolved. The accumulation of 67Ga is a sensitive but nonspecific indicator of active inflammation in patients with sarcoidosis. Gallium-67 avidity cannot be used alone to establish a diagnosis of sarcoidosis, and it has a limited correlation with the clinical status. However, 67Ga scintigraphy is useful in identifying extrathoracic sites of involvement, detecting active alveolitis, and assessing the response to treatment. Gallium-67 scans have low sensitivity and specificity as a diagnostic test. Gallium 67 scanning is useful in patients in whom the clinical picture remains confusing despite the presence of noncaseating granulomas in biopsy specimens, and scanning may useful in differentiating chronic hypersensitivity pneumonitis from sarcoidosis. Gallium-67 avidity alone cannot be used to establish a diagnosis of sarcoidosis. False Positives/NegativesGallium 67 is normally localized in the liver, spleen, bone marrow, bone, and growth plates. A lesser degree of normal accumulation occurs in the salivary and lacrimal glands and in the breast tissue. Gut activity is related to small-bowel excretion and, partly, biliary excretion. Both Hodgkin and non-Hodgkin lymphomas, lung cancers, melanomas, infections, and inflammations are 67Ga–avid and can potentially cause false-positive results for sarcoidosis. False-negative 67Ga scans may occur in up to 10% patients. In patients with lymphoma who have undergone head and neck radiation therapy, the uptake of 67Ga in the neck may be similar to that in patients with sarcoidosis. ANGIOGRAPHYSection 8 of 11
FindingsSee Intervention, below. INTERVENTIONSection 9 of 11
Controversy exists regarding optimal treatment. More than 75% patients with sarcoidosis require only symptomatic treatment, such as with nonsteroidal anti-inflammatory drugs.42 Around 10% of patients require treatment for extrapulmonary disease, and 15% of patients with persistent lung disease may require some form of treatment.43 Drug treatmentCorticosteroids, immunosuppressives, and miscellaneous are used to treat pulmonary sarcoidosis. Corticosteroids Corticosteroids remain the mainstay of treatment. Generally, prednisone is given daily and then tapered over a 6-month period. This approach is considered adequate for pulmonary disease. The dose given to the patients is debated. Some patients may require low-dose long-term steroids. Steroids can relieve symptoms and suppress inflammation and granuloma formation. The indications for steroid treatment include involvement of the central nervous system, ocular involvement, cardiac involvement, hypercalcemia, and nephrocalcinosis. The decision to treat pulmonary sarcoidosis with steroids remains a subject of debate and is based on clinical, physiologic, and radiologic findings. The initial response to steroid treatment does not, however, preclude the progression to pulmonary fibrosis and death. Drug therapies, such as treatment with steroids and other anti-inflammatory medications, have their own risks of morbidity and mortality, and long-term monitoring is usually required. In more than 70% of patients, the disease regresses within 2 years of the initial onset regardless of treatment. In some patients, sarcoidosis progress relentlessly, and they may require long-term medication. Corticosteroid use may be associated with increased relapse rates. High-dose inhaled corticosteroids are an option, but conclusive evidence that this treatment is effective is lacking. Corticosteroids may be beneficial for cardiac disease, but they may result in aneurysm formation.44 Immunosuppressives Noncorticosteroid agents are being used more frequently. These agents include methotrexate or other alternatives, such as cyclosporine, pentoxifylline, and azathioprine. These may be successful alternatives to prednisone and are steroid-sparing agents. Miscellaneous Hydroxychloroquine may be used for cutaneous lesions, hypercalcemia, neurologic sarcoidosis, and bone lesions. Nonsteroidal anti-inflammatory drugs are indicated for the treatment of arthralgias. ProcedureBiopsy Tissue diagnosis is required in most patients. Biopsy specimens can be obtained from the lungs or extrapulmonary sites. Transbronchial biopsy via fiberoptic bronchoscopy has a diagnostic yield of 85% when 4 samples are obtained. Occasionally, mediastinoscopy, thoracoscopy, or thoracotomy for node or lung biopsy may be required. Some asymptomatic patients who do not require treatment may be monitored without a biopsy. Observation may be sufficient only for patients who have a classic presentation, are asymptomatic, and can ensure close follow-up. Results may be positive, even in the setting of normal chest radiographic findings. If treatment is to be given for sarcoidosis, tissue confirmation is essential. The classic histologic finding is the presence of noncaseating granulomas with special stains negative for fungus and mycobacteria. Massive hemoptysis, defined as the expectoration of more than 600 mL of blood in 48 hours, may complicate a mycetoma. Surgical resection of the cavity is the treatment of choice. Contraindications to surgery include bilateral advanced lung disease, large transpleural blood vessels, failure to identify the bleeding site, and continued hemoptysis after previous surgery. Bronchial artery embolization is a valuable technique in patients with persistent hemoptysis who are not surgical candidates. Bronchial artery embolization Before bronchial artery embolization is attempted, angiography is performed to assess the bronchial arterial anatomy, the nonbronchial systemic blood supply to the mycetoma, and the presence and extent of any contribution of blood supply from the pulmonary artery. The technique involves selective bronchial artery catheterization with a femorovisceral 5F end-hole catheter. After preliminary bronchial angiography is performed, the catheter is securely inserted into the bronchial artery to be embolized. A coaxial catheter may be required for more selective and more distal placement. Various embolic agents can be used; the simplest material is polyvinyl alcohol (PVA), a particulate agent that is available in a variety of sizes. Because mycetomas can derive their blood supply from the intercostal arteries, the thyrocervical trunks and pulmonary arteries may also need to be selectively embolized. Percutaneous CT or fluoroscopically guided intracavitary injection of a paste containing glycerin and amphotericin B or other fungal agents has been successful in the treatment of aspergillomas and chronic necrotizing aspergillosis. The fungal ball partially or completely resolves in 75% of patients. The intracavitary instillation of sodium or potassium iodide has also been used successfully in the treatment of hemoptysis in patients who are not surgical candidates. Chest pain may occur, particularly after intercostal artery embolization. Rarely, mild dysphagia may occur as a result of an interruption of blood supply to the mid esophagus. This dysphagia is self-limiting and resolves spontaneously. Transverse myelitis and bronchial necrosis are the most serious complications; fortunately, these are rare. Most case reports of transverse myelitis are historical and are probably related to contrast agent toxicity. Nontarget embolization leading to infarction is also reported. This complication is less likely to occur when a superselective approach with end-hole catheter is used. Disease course and prognosisThe course and prognosis of sarcoidosis are correlated with the mode of disease onset, the patient's race, and the presenting stage. An acute onset of disease, so-called Löfgren syndrome, usually occurs as a self-limiting condition that resolves spontaneously, whereas an insidious onset may be followed by relentless progressive fibrosis. The disease resolves within 1-2 years in 60% of patients presenting with stage I disease, in 46% with stage II disease, and in 12% with stage III disease. Non-white patients tend to have more extrathoracic manifestations and, therefore, a more guarded prognosis. Overall, two thirds of African American patients with sarcoidosis require treatment, compared with one third of white patients.45 Medical/Legal Pitfalls
MULTIMEDIASection 10 of 11
REFERENCESSection 11 of 11
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