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    Pulmonary Sarcoidosis: A Guide for the Practicing Clinician
    Pulmonary Sarcoidosis: A Guide for the Practicing Clinician
    Pulmonary Sarcoidosis: A Guide for the Practicing Clinician
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    Pulmonary Sarcoidosis: A Guide for the Practicing Clinician

    By Marc A. Judson

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    Pulmonary Sarcoidosis: A Guide for the Practicing Clinician is a valuable resource for clinicians of varied disciplines concerning the care of the sarcoidosis patient. Sarcoidosis is a multi-system disorder and represents a major challenge to physicians. Although any organ may be involved with sarcoidosis, the lung is the most common organ affected. Chapters are written by distinguished authors who have extensive experience in caring for these patients. Detailed figures and tables are provided to guide the practicing clinician through all aspects of the condition, from clinical manifestations to treatment options. Pulmonary Sarcoidosis: A Guide for the Practicing Clinician is fully comprehensive and evidence-based and will be an essential addition to the bookshelves of all whose practice involves the care and treatment of patients with sarcoidosis.
    LanguageEnglish
    PublisherHumana Press
    Release dateOct 16, 2013
    ISBN9781461489276
    Pulmonary Sarcoidosis: A Guide for the Practicing Clinician

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      Pulmonary Sarcoidosis - Marc A. Judson

      Marc A. Judson (ed.)Respiratory MedicinePulmonary Sarcoidosis2014A Guide for the Practicing Clinician10.1007/978-1-4614-8927-6_1

      © Springer Science+Business Media New York 2014

      1. The Diagnosis of Sarcoidosis

      Marc A. Judson¹  

      (1)

      Division of Pulmonary and Critical Care Medicine, Department of Medicine, Albany Medical College, Albany, NY, USA

      Marc A. Judson

      Email: [email protected]

      Abstract

      The diagnosis of sarcoidosis is never completely secure. The diagnosis can, rarely, be made on clinical grounds without biopsy confirmation if the clinical presentation is very specific for the disease. Otherwise, histological confirmation of granulomatous inflammation is required. However, identification of granulomatous inflammation is inadequate to make the diagnosis of sarcoidosis as this histological pattern is associated with many alternative diseases. Therefore, a diligent effort must be undertaken to exclude such diseases. This effort includes obtaining a detailed medical history as well as careful examination of the biopsied material. Because sarcoidosis is a multisystem granulomatous disease of unknown cause, additional efforts must be made to identify involvement in at least two organs to confirm the diagnosis. This chapter outlines the approach and potential pitfalls in establishing a diagnosis of sarcoidosis.

      Keywords

      SarcoidosisDiagnosisEtiologyBiopsyPathology

      Introduction

      Despite the claim that the method of diagnosis of sarcoidosis has been established [1], the reality is that the diagnosis is never completely secure. Certain clinical features are typical of sarcoidosis, but none of them are specific for the diagnosis. Sarcoidosis remains a diagnosis of exclusion, and it is impossible to exclude alternative diagnoses with complete confidence. This chapter reviews the diagnostic approach and potential pitfalls in establishing a diagnosis of sarcoidosis.

      Definition

      Sarcoidosis has been defined as multisystem granulomatous disorder of unknown cause [1]. With rare exceptions (vide infra), clinicoradiologic findings without histologic evidence of granulomatous inflammation are inadequate to render a diagnosis of sarcoidosis. Histologic evidence of granulomatous inflammation is also inadequate for the diagnosis of sarcoidosis because alternative causes of granulomatous inflammation need to be excluded. It is prudent to maintain a healthy degree of skepticism that an alternative diagnosis has been overlooked [2]. The fact that the disease is multisystem implies that there must be evidence of granulomatous inflammation in at least two organs for the diagnosis of sarcoidosis to be secure.

      Diagnostic Approach

      Figure 1.1 outlines the approach to the diagnosis to sarcoidosis. This is a multistep process that usually involves the collection of clinical information, histological examination of tissue for the presence of granulomatous inflammation, exclusion of known causes of this granulomatous inflammation, and documentation that the granulomatous inflammation is present in at least two organs [2]. This diagnostic approach will be discussed in detail in the sections that immediately follow.

      A304083_1_En_1_Fig1_HTML.gif

      Fig. 1.1

      The figure outlines the diagnostic algorithm for sarcoidosis. See text for details. Adapted from [2], with permission

      Clinical Data Collection

      As with most diseases, sarcoidosis can only be considered a potential diagnosis if clinical data have been collected that exceed a certain threshold such that the diagnosis is plausible. Certain clinical findings suggest the diagnosis of sarcoidosis, although none of them is pathognomonic [2]. This process involves weighing the clinical findings that support the diagnosis of sarcoidosis against the clinical findings that tend to refute it. If sufficient clinical evidence has accumulated suggesting that sarcoidosis is a reasonable consideration, a tissue biopsy is usually indicated. Table 1.1 outlines clinical findings that are often used to gauge the likelihood of the diagnosis of sarcoidosis.

      Table 1.1

      Clinicoradiographic data supporting or weakening the likelihood of sarcoidosis

      CXR chest radiograph, SACE serum angiotensin-converting enzyme, 2× ULN two times the upper limit of normal, HRCT high resolution computer tomography

      Adapted from [2], with permission

      Demographics

      Sarcoidosis is rare before adulthood [3]. The disease usually presents before age 40, peaking in those aged 20–29 years old. There is a second smaller peak of increased incidence after age 50, especially in women [3]. The disease is slightly more frequent in women than men at a ratio of less than 2–1 [3, 4]. The disease is more prevalent in certain ethnicities such as African Americans and Northern Europeans [2–4].

      Medical History

      Patients with sarcoidosis often present with no symptoms [5]. This is especially common in white patients [6]. Therefore, sarcoidosis should be considered in asymptomatic patients with hilar adenopathy, mediastinal adenopathy, and/or diffuse parenchymal infiltrates on lung imaging [6, 7]. A family history should be elicited because the prevalence rate of sarcoidosis is much higher in first-degree relatives of sarcoidosis patients than in the general population [8]. A smoking history should be obtained as sarcoidosis is much more common in nonsmokers [9]. Potential sarcoidosis patients should be questioned about their occupational history, as the disease is common in certain occupations including firefighters [10].

      In addition, patients should be questioned concerning potential exposures that may cause diseases that may mimic sarcoidosis. Specifically, a history of active tuberculosis, latent tuberculosis infection, and tuberculosis exposure should be obtained. Patients should be questioned concerning time spent in areas where certain fungi are endemic such as the Ohio River valley where histoplasmosis is common [11]. The possibility of beryllium exposure should be explored because chronic beryllium disease (CBD) can mimic sarcoidosis radiographically [12] and histologically [13, 14]. CBD has been misdiagnosed as sarcoidosis in up to 40 % of cases [2, 15]. As most patients are unaware of potential exposures to beryllium, it is important to ask about work industries where exposure to beryllium is plausible including aerospace, nuclear weapons, electronics, jewelry, sporting goods, ceramics, and dental [16]. Furthermore, minimal beryllium exposure may lead to significant disease [17, 18]. Hypersensitivity pneumonitis (HP) is a granulomatous pulmonary disease resulting from exposure to bioaerosols that may mimic sarcoidosis. A history of exposure to birds and hot tubs should be obtained as these are the most two common exposures causing HP in the USA [19, 20].

      Evidence of Extrapulmonary Involvement

      Because sarcoidosis is a systemic disease, evidence that a disorder is present in two or more organs supports a diagnosis of sarcoidosis [2]. At presentation, 95 % of sarcoidosis patients have clinical evidence of pulmonary involvement, and more than 40 % have evidence of involvement in the skin, liver, peripheral lymph node, or eye [21]. Therefore, sarcoidosis should be considered in patients with pulmonary disease and a concomitant disorder in one of these organs.

      Radiographic Findings

      Bilateral hilar adenopathy on chest radiograph suggests the diagnosis of sarcoidosis, especially if the patient has no fever, night sweats, or weight loss [2, 7, 22]. The chest radiograph often demonstrates bilateral enlargement the hilar lymph nodes as well as concomitant enlargement of the right paratracheal lymph nodes, which is described as the 1, 2, 3 sign [23]. Findings on high resolution chest-computed tomography (HRCT) may be more specific for the diagnosis of sarcoidosis than those found on chest radiography, although they are inadequate for a diagnosis to be secured without biopsy confirmation. Typical HRCT findings that suggest sarcoidosis include parenchymal nodules and opacities that represent conglomerations of these nodules that have a perilymphatic distribution along the bronchovascular bundles as well as in subpleural locations [24–30].

      Serum Angiotensin-Converting Enzyme

      Angiotensin-converting enzyme (ACE) is produced in the epithelioid cell of the sarcoid granuloma [31], and serum ACE (SACE) levels reflect the total sarcoidosis granuloma burden [31]. Although SACE has been suggested as a diagnostic test for sarcoidosis, elevated SACE levels in isolation are inadequately sensitive or specific to reliably diagnose of exclude the disease [32]. In a review of 14 studies encompassing 4,195 patients concerning the diagnostic accuracy of SACE for sarcoidosis, the sensitivity was 77 % (range: 41–100 %) and the specificity was 93 % (range: 83–99 %) [33]. The likelihood of sarcoidosis increases in patients with higher SACE levels [33, 34], and SACE levels greater than 2 times the upper limits of normal are rarely seen in other diseases and not seen in cancer or lymphoma [32].

      Making the Diagnosis of Sarcoidosis on Clinical Grounds Without a Tissue Biopsy

      On rare occasions, the clinical presentation is so specific for sarcoidosis that the diagnosis can be made without a confirmatory tissue biopsy. These presentations are listed in Table 1.2. Even in these situations, the clinician should be diligent in terms of excluding possible, albeit unlikely, alternative diagnoses.

      Table 1.2

      Clinical presentations that may be assumed to be sarcoidosis without tissue confirmation provided additional data do not suggest an alternative diagnosis

      Adapted from [2] with permission

      Selection of a Biopsy Site

      With the exception of the rare instances where the clinical findings are highly specific for sarcoidosis (Table 1.2), the diagnosis requires a tissue biopsy (Fig. 1.1). It is in the patient’s best interest for the biopsy to be minimally invasive and associated with the least morbidity. For these reasons, superficial biopsy sites are preferred compared to visceral organs [35]. Even in patients suspected to have sarcoidosis on the basis of obvious thoracic or abdominal disease, a thorough skin, conjunctival, lacrimal gland, and peripheral lymph node examination should be performed. The patient should be questioned about the presence of scars or tattoos, because sarcoidosis skin nodules have a predilection to form in these areas. The detection of a conjunctival nodule, palpable lacrimal gland, or palpable peripheral lymph node should prompt consideration of a biopsy for diagnosis.

      When there is no clinical evidence that a superficial site is involved with sarcoidosis, a biopsy is usually attempted in an organ where sarcoidosis involvement is suspected. This is very often the lung, as pulmonary involvement occurs in more than 90 % of sarcoidosis patients early in the course of the disease [21]. The approach to lung biopsy for the diagnosis of pulmonary sarcoidosis continues to change with the advent of newer technologies. Although the diagnosis can almost always be made by mediastinoscopy when significant mediastinal adenopathy is present and by video-assisted thoracoscopic surgery when there is parenchymal lung disease, less invasive bronchoscopic procedures are usually preferred. The yield of transbronchial lung biopsy (TLB) for the diagnosis of pulmonary sarcoidosis ranges from 60 to 97 % depending on the number of biopsies taken and the presence of parenchymal disease on chest radiograph [36–42].

      Endobronchial biopsy may be positive in more than 60 % of patients with pulmonary sarcoidosis [43]. Biopsies are more frequently positive in individuals with abnormal-appearing airways [43]. Furthermore, endobronchial biopsy can be performed with TLB and increases the yield for sarcoidosis above that using TLB alone [43].

      Transbronchial needle aspiration under endobronchial ultrasound guidance (TBNA-EBUS) has been extensively evaluated as a diagnostic approach for pulmonary sarcoidosis over the last decade. The diagnostic yield is in the range of 80 % [44], and a positive result avoids the need for TLB and endobronchial biopsies if on-site cytopathology is performed. TBNA-EBUS has been shown to be superior to blind TBNA without ultrasound guidance for the diagnosis of sarcoidosis [45].

      Examination of inflammatory cells from bronchoalveolar lavage fluid (BALF) is sometimes used as a complementary test for the diagnosis of pulmonary sarcoidosis. The diagnostic accuracy of the percentage of lymphocytes and the CD4/CD8 lymphocyte subpopulation ratio in BALF have been assessed. The sensitivity, specificity, positive and negative predictive values of these BALF analyses for the diagnosis of sarcoidosis have been variable, probably because of differences in the prevalence of sarcoidosis, the prevalence of other diseases associated with BALF lymphocytosis, and the cut-off values used. In general, BALF lymphocytosis (greater than 15 % lymphocytes) has a 90 % sensitivity for the diagnosis of sarcoidosis [46, 47], although the specificity is low [46]. Table 1.3 shows the differential diagnosis of BALF lymphocytosis, and this needs to be kept in mind in order to exclude alternative causes for this finding other than sarcoidosis. The BALF CD4/CD8 ratio is increased >3.5 in 50–60 % of pulmonary sarcoidosis patients. However, the specificity of the BALF CD4/CD8 ratio criterion has approached 95 % in some [48, 49] but not all [46] studies. Some have advocated that the BALF CD4/CD8 criterion is diagnostic of sarcoidosis when there are concomitant chest imaging findings compatible with sarcoidosis [47]; however, these criteria not been formally tested. At present, the role of BALF for the diagnosis of sarcoidosis is controversial and unsettled.

      Table 1.3

      Causes of a lymphocytosis (≥15 % lymphocytes) in bronchoalveolar lavage fluid

      Granulomas can be detected histologically in any organ that is involved with sarcoidosis [35]. The biopsy of neural tissue and the heart are particularly problematic because of the potential morbidity associated with these procedures. Because patients with neurosarcoidosis will have extraneural sarcoidosis nearly 90 % of the time [50], most patients have extraneural disease from which a biopsy specimen can be obtained. Although endomyocardial biopsy is a fairly specific test for cardiac sarcoidosis in the proper clinical setting, its sensitivity is very low [51]. For this reason, endomyocardial biopsy is rarely performed for the diagnosis of sarcoidosis. Often, imaging studies are used surrogate tests for the diagnosis of neurosarcoidosis and cardiac sarcoidosis. Such studies should be interpreted cautiously as their specificity depends upon associated clinical evidence for sarcoidosis, which should almost always include previous biopsy confirmation of granulomatous inflammation of unknown cause in another organ (vide infra).

      On some occasions, the diagnosis of sarcoidosis is suspected on clinical grounds, although no specific organ is identified to biopsy. There is no established approach for this situation. Total body imaging such as positron emission tomography (PET) [52] or gallium-67 scanning [53] has been proposed in such cases to identify an organ for biopsy, although no rigorous analysis of this approach has been undertaken. Another suggested approach in this situation is to biopsy organs that are commonly affected, even in the absence of symptoms or other clinical findings suggestive or sarcoidosis involvement of that organ. Conjunctival biopsies have performed in this situation, and the yield has ranged from 27 to 55 % in patient without ocular symptoms [54–60]. In vivo confocal microscopy of the conjunctiva can detect multinucleated giant cells without the need for a biopsy, and this has also been advocated to noninvasively confirm granulomatous inflammation in sarcoidosis patients [61]. Liver biopsy demonstrates granulomas in 24–78 % of sarcoidosis patients, even when they have no symptoms attributable to the liver and normal serum liver function tests [62–64]. However, hepatic granulomas are not specific for sarcoidosis so that clinical evidence of extrahepatic sarcoidosis must be present for the diagnosis to be secure [35]. Andonopoulos and colleagues found that gastrocnemius muscle biopsy revealed granulomas in 22 consecutive patients without muscle symptoms who had bilateral hilar adenopathy on chest radiograph [65]. However, most of these patients had strong clinical evidence of sarcoidosis; furthermore, this procedure is fairly invasive. Another invasive biopsy procedure for sarcoidosis is scalene lymph node biopsy [66], which has essentially been supplanted by diagnostic biopsy of more easily accessible sites.

      Another test to consider when sarcoidosis is suspected on clinical grounds, although no specific organ is identified to biopsy is the Kveim test. This test involves the intradermal inoculation of a suspension of splenic tissue from spleen that was involved with sarcoidosis [67]. If a skin nodule develops at the inoculation site in 4–6 weeks, is biopsied, and reveals noncaseating granulomatous inflammation, this is highly specific for the diagnosis of sarcoidosis. Unfortunately, the Kveim test in not highly sensitive for the diagnosis of sarcoidosis; both the sensitivity and specificity of the test vary depending on the spleen that is used, and the suspension is not approved by the Food and Drug Administration. Therefore, the Kveim test is not approved as a standard diagnostic test for sarcoidosis.

      Figure 1.2 shows our approach to the selection of a biopsy site for the diagnosis of sarcoidosis.

      A304083_1_En_1_Fig2_HTML.gif

      Fig. 1.2

      The figure outlines the diagnostic approach to selecting a biopsy site for pathologic confirmation of granulomatous inflammation consistent with sarcoidosis. This approach emphasizes (a) selection of a relatively noninvasive biopsy site when possible; (b) biopsy of a site suspected to be clinically involved unless the biopsy would be highly invasive; (c) various approaches when no obvious organ involvement is demonstrated or only organs requiring very invasive biopsies demonstrate potential involvement

      Pathology

      Although granulomatous inflammation is necessary to establish a diagnosis of sarcoidosis in most cases, granulomas are nonspecific inflammatory reactions, and they are not diagnostic of sarcoidosis or any other granulomatous disease [2, 68]. Meticulous histological examination with appropriate staining of all biopsies should be performed to search for known causes of granulomatous inflammation, such as mycobacteria, fungi, parasites, and foreign material (e.g., talc).

      Although there are no specific histological features that are diagnostic of sarcoid granulomas, there are certain features that suggest this diagnosis. The sarcoid granuloma usually consists of a compact (organized) collection of mononuclear phagocytes (macrophages and epithelioid cells) [69]. Typically, there is no necrosis within the sarcoid granuloma; however, on occasion, there is a small to moderate amount of necrosis. Usually, giant cells fuse within the sarcoid granuloma to form multinucleated giant cells. These granulomas are typically surrounded by lymphocytes in the periphery. A variety of inclusions may be present within the sarcoid granuloma including asteroid bodies, Schaumann’s bodies, birefringent crystals, and Hamazaki–Wesenberg bodies; however these inclusions are not specific or diagnostic of sarcoidosis [68]. In particular, birefringent crystals within the sarcoid granuloma may lead to a misdiagnosis of talc granulomatosis [14]. Care must be taken to ensure that the crystal morphology and size are compatible with intravenously injected talc to ensure the diagnosis of talc granulomatosis [14].

      Exclusion of Alternative Causes of Granulomatous Inflammation

      Table 1.4 lists potential causes other than sarcoidosis for granulomatous inflammation based on the organ involved. The diagnosis of sarcoidosis requires that all these diagnoses have been excluded to a reasonable degree. As it is impossible to be completely assured that all these causes have been excluded, the diagnosis of sarcoidosis is never completely secure.

      Table 1.4

      Major pathologic differential diagnosis of sarcoidosis at biopsy

      Adapted from [2], with permission

      The exclusion of alternative causes of granulomatous inflammation requires a multifaceted approach [2]. A detailed medical history is essential to exclude potential exposure to infectious agents (e.g., tuberculosis and fungi), environmental exposures (e.g., organic bioaerosols generated from birds or hot tubs that may cause hypersensitivity pneumonitis), and occupational exposures (e.g., beryllium) (vide supra).

      In addition to the medical history, the biopsy specimen must be meticulously examined for alternative causes of granulomatous inflammation [14]. This includes a search for infectious agents and foreign materials that could induce a granulomatous reaction. At a minimum, this should include appropriate stains of histologic material for mycobacteria and fungi, and usually, cultures for these organisms as well.

      Verification of Sarcoidosis Involvement of a Second Organ

      The presence of granulomatous inflammation of unknown cause in a single organ is inadequate for the diagnosis of sarcoidosis, as, by definition, multiple organs should be involved. Examples of such single organ granulomatous diseases that are distinguished from sarcoidosis include idiopathic granulomatous hepatitis [70], that is rarely found to be sarcoidosis (extrahepatic granulomas rarely develop over time) and idiopathic panuveitis, a granulomatous uveitis confined to the eye that is common in the southeastern USA [71].

      Although granulomatous inflammation in an isolated organ is not diagnostic of sarcoidosis, treatment is usually identical to the treatment of sarcoidosis provided that alternative causes have been reasonably excluded. Therefore, it is usually not of clinical importance to search for additional organ involvement beyond a general organ screen as outlined in Table 1.5.

      Table 1.5

      Extent of workup for second organ involvement if a biopsy has revealed granulomatous inflammation consistent with sarcoidosis

      Adapted from [2] with permission

      Although the diagnosis of sarcoidosis requires strong evidence that a second organ be involved, histological confirmation of involvement in a second organ is not always required. A consensus panel of sarcoidosis experts has established clinical criteria for definite, probable, and possible organ involvement with sarcoidosis for some organs without the need for a biopsy, provided alternative causes for this clinical finding has been reasonably excluded (Table 1.6) [72].

      Table 1.6

      Clinical criteria for extrapulmonary sarcoidosis organ involvement in patients with biopsy-confirmed sarcoidosis in another organa

      aThere can be no other explanation for the clinical findings in this table for these criteria to be valid. In addition, biopsy of each of these organs would constitute definite involvement. Adapted from [72] with permission

      Other Idiopathic Multiorgan Granulomatous Syndromes

      There are other multiorgan granulomatous syndromes that are thought not to be sarcoidosis, but rather, separate clinical entities. This is a controversial issue because some consider these disorders under the penumbra of sarcoidoses syndromes. Blau’s syndrome consists of granulomatous iritis, arthritis, and skin rash [73]. The disease is a genetic disorder [74] and has an autosomal dominant pattern of inheritance with variable penetrance [73]. In contrast to sarcoidosis, most cases occur before 12 years of age. Blau’s syndrome is considered a separate entity from childhood sarcoidosis on the basis

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