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NEW DEVELOPMENTS IN MEDICAL RESEARCH

CLINICAL MANIFESTATIONS, PATHOPHYSIOLOGY, DIAGNOSTIC METHODS, IMAGING AND INTERVENTION IN SARCOIDOSIS

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NEW DEVELOPMENTS IN MEDICAL RESEARCH

CLINICAL MANIFESTATIONS, PATHOPHYSIOLOGY, DIAGNOSTIC METHODS, IMAGING AND INTERVENTION IN SARCOIDOSIS ALI NAWAZ KHAN EDITOR

New York

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Copyright © 2016 by Nova Science Publishers, Inc. All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. We have partnered with Copyright Clearance Center to make it easy for you to obtain permissions to reuse content from this publication. Simply navigate to this publication’s page on Nova’s website and locate the “Get Permission” button below the title description. This button is linked directly to the title’s permission page on copyright.com. Alternatively, you can visit copyright.com and search by title, ISBN, or ISSN. For further questions about using the service on copyright.com, please contact: Copyright Clearance Center Phone: +1-(978) 750-8400 Fax: +1-(978) 750-4470 E-mail: [email protected]

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Published by Nova Science Publishers, Inc. † New York

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CONTENTS Preface

vii

Chapter 1

A Pathologist’s Approach to Pulmonary Sarcoidosis Hanaa Bamefleh

Chapter 2

Clinical Manifestations, Diagnostic Methods and Management of Pulmonary Sarcoidosis Nahid Sherbini, Hamdan Al-Jahdali and Ali N. Khan

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The Chest Radiograph in the Diagnosis and Staging of Thoracic Sarcoidosis Zeid Al-Ani and Syahminan Suut

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Chapter 3

1

Chapter 4

The Role of HRCT in Pulmonary Sarcoidosis Carolyn Allen Carolyn, Ali Nawaz Khan and Ayan Sabih

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Chapter 5

Saprophytic Aspergillosis (Aspergilloma) Sumaira Macdonald, Abeeku Afedzi Hammond and Ali Nawaz Khan

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Chapter 6

Genitourinary Manifestations of Sarcoidosis: Symptomatology and Diagnostic Imaging of Genitourinary Sarcoidosis Ali Nawaz Khan, Shyam Sunder Koteyar Shyam Sunder Radha Krishna, Anthony Kodzo-Grey Venyo and Ayan Sabih

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Contents

Chapter 7

Cardiac Sarcoidosis Prabhakar Rajiah

Chapter 8

Imaging of Neurosarcoidosis Rekha Siripurapu and Amit V. Herwadkar

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Chapter 9

Sarcoidosis of Spine: Clinical Profile and Imaging Amit V. Herwadkar and Rekha Siripurapu

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Chapter 10

Radionuclides in the Diagnosis and Management of Sarcoidosis Durr-e-Sabih, Ali Nawaz Khan and Ayan Sabih

Chapter 11

The Role of PET/CT in Sarcoidosis Ghulam Mustafa Shah Syed

Chapter 12

Ocular Manifestations of Sarcoidosis: Presentation, Diagnosis, Findings, and Treatment Ali Afzal Bodla

Index

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143 157

187 199

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PREFACE Sarcoidosis is a multisystem granulomatous disease of unknown etiology that is characterized by noncaseous epithelioid cell granulomas, which may affect almost any organ in the body. Intrathoracic involvement is common and accounts for most of the morbidity and mortality associated with this disease. The diagnosis is based on the total exclusion of other granulomatous disorders. The organs that are commonly involved are the lymph nodes, lungs, liver, spleen, skin, and eyes; these organs can be involved individually or in combination. The correlation of the clinical, radiological features along with the pathologic finding of non-caseating epithelioid cell granulomas is vital to establish the diagnosis. There is no single precise cause attributed to the causation of this disease. Genetic factors are suspected due to the observation of racial groups such as African Americans, West Indians and Asians who have a higher prevalence of sarcoidosis. Familial sarcoidosis is well-known, which may be attributed to genetic factors or the sharing of a similar environment. Environmental factors may also play a role by involving the uptake and processing of unknown antigens by the respiratory system. Occasional patients with sarcoidosis have an association with primary biliary cirrhosis, where the granulomas in both diseases look similar. Patients receiving treatment with anti-retroviral therapy or interferon alpha might have pulmonary granulomas as in HIV-infected patients and leukemia patients retrospectively. Sarcoidosis is more prevalent and is a more severe disease in blacks in the United States of America. Twothirds of patients with sarcoidosis resolve spontaneously without specific treatment. Therapeutic measures, when required, rely on immune suppression. Sarcoidosis can present to a variety of medical specialists including primary health care physicians, pulmonologists, dermatologists,

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rheumatologists, ophthalmologists, nephrologists, urologists, neurologists, and neurosurgeons to name a few. As the symptoms are varied in sarcoidosis, the differential diagnosis includes most non-specific systemic disorders. A chest radiograph (CXR) is usually the first diagnostic imaging study in patients with respiratory symptoms. A CXR is a non-invasive modality, widely available, easy to interpret and when correlated with the clinical findings, may be the only imaging required to diagnose pulmonary sarcoidosis. A CXR is also the most commonly used imaging technique for follow-up in patients with established diagnosis, and is reproducible and cost efficient. Conventional chest radiography, however, has its limitation as it may be normal in 5-10% of patients with established sarcoidosis. In 25-30% of patients, the radiologic changes are nonspecific or atypical reducing the plain film sensitivity. In such cases, High-Resolution CT (HRCT) is useful in clarifying the diagnosis providing crucial information on extent of the disease. HRCT, unlike a plain radiograph, can readily differentiate active inflammation from irreversible fibrosis.

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In: Clinical Manifestations, Pathophysiology … ISBN: 978-1-63485-832-8 Editor: Ali Nawaz Khan © 2016 Nova Science Publishers, Inc.

Chapter 1

A PATHOLOGIST’S APPROACH TO PULMONARY SARCOIDOSIS* Hanaa Bamefleh, MBchB, FRCPC, FIAC, MME Anatomic Pathology and Pulmonary Pathology, King Abdulaziz Medical City (KAMC), Riyadh, Saudi Arabia King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS)

ABSTRACT Sarcoidosis is a multisystem granulomatous disease, of unknown etiology that is characterized by noncaseous epithelioid cell granulomas, which may affect almost any organ in the body. Intrathoracic involvement is common and accounts for most of the morbidity and mortality associated with this disease. The diagnosis is based on the total exclusion of other granulomatous disorders. The organs that are commonly involved are lymph nodes, the lungs, liver, spleen, skin, and eyes; organs that can be involved individually or in combination. The correlation of the clinical, radiological features along with the pathologic finding of non-caseating epithelioid cell granulomas is vital to establish the diagnosis. There is no single precise cause attributed to the causation of this disease. Genetic factors are suspected due to the observation of

*

Edited by Dr. Ali Nawaz Khan MBBS, MRCS, FRCR, FRCP Consultant Radiologist/Professor Honorary North Manchester General Hospital M8 5RB. [email protected]

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Hanaa Bamefleh racial groups such as African Americans, West Indians and Asians who have a higher prevalence of sarcoidosis.

INTRODUCTION Sarcoidosis is a disease that involves multiple organ systems of the body. It is characterized by the formation of granuloma enhanced by cellular hypersensitivity at the sites involved. The cause of this disease is yet to be clearly identified. The organs that are commonly involved are lymph nodes, the lungs, liver, spleen, skin and eyes. These organs can be involved individually or in combination. The correlation of the clinical, radiological features along with the pathologic finding of non-caseating epithelioid cell granulomas is helpful to establish the diagnosis. However, exclusion of other known causes of granulomatous disease has to be done [1].

ETIOLOGY There is no single precise cause attributed to the causation of this disease. Genetic factors are suspected due to the observation of racial groups such as Black Americans, West Indians and Asians who have more prevalence of this disease. Moreover, association with major histocompatibility complex (MHC) particularly class II, MHC alleles is observed. Certain HLA alleles appear to confer susceptibility to sarcoidosis, such as HLA DR11, 12, 14, 15 and 17 while others confer with protective effect such as HLA DR 1DR4 and possibly HLA DQ 0202 [2]. Familial sarcoidosis is well-known which could be attributed to genetic factors or sharing the same environment. The above attributes to two-thirds of the susceptibility and the latter contribute to only one third. Environmental factors might play a role by involving the uptake and processing of unknown antigens by the respiratory system. Occasional patients with sarcoidosis have an association with primary biliary cirrhosis where the granulomas in both diseases look similar. Patients receiving treatment with anti-retroviral therapy or interferon alpha might have pulmonary granulomas as in HIV-infected patients and leukemia patients retrospectively. In some patients, acid-fast bacterial L-forms have been cultured from the blood of patients with sarcoidosis. In others, molecular probes for mycobacterial nucleic acid on

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granulomatous tissues from patients with sarcoidosis gave positive results. However, positive cultures from patient’s blood are unique. Distribution of organs involved by sarcoidosis and tuberculosis is different (e.g., uveitis is more common in sarcoidosis and not seen in tuberculosis). This observation makes mycobacterial tuberculosis as an unlikely cause of sarcoidosis [1]. Other agents suggested having a role in the causation of sarcoidosis which includes Mycobacterium tuberculosis, other mycobacterial, Propionibacterium acnes, Borrelia burgdorferi, mycoplasma, herpes virus, Epstein-Barr virus, Coxsackie B virus, Cytomegalovirus, inorganic agents such as aluminum, zirconium and talc, and organic agents such as pine pollen [1]. Sarcoidosis, following lymphoma, has been reported by London et al. He described 14 cases previously unpublished and 25 cases already published in the literature. All developed sarcoidosis following lymphoproliferative disease; Hodgkin’s and non-Hodgkin’s lymphoma were equally presented. Sarcoidosis in those patients was of mild intensity and rarely required treatment [3]. The immunologic reaction of patients with sarcoidosis is unusual, as tuberculin skin reaction is negative despite contact with tubercle bacilli. This status is known as anergy. It is found that the ratio of the suppressor T-cells (CD8) to the helper T-cells (CD4) is increased in the blood in sarcoidosis where it is the reverse in the bronchoalveolar lavage fluid [CD8: CD4 ratio increase in blood, CD8: CD4 ratio decreased in the lavage fluid]. The latter finding in the lavage is compatible with the finding of the tissue granulomas. In the acute phase of the disease, there is an increase in the CD4 helper T-cells which release cytokines such as interleukin-2, interferon-gamma, and interleukin-16. These attract other mononuclear cells leading to granuloma formation. The cytokine interleukin-2 is associated with poor prognosis the transforming growth factor – beta is related to spontaneous remission [1].

PATHOLOGICAL FINDINGS The characteristic histologic finding in sarcoidosis is a granuloma. A sarcoid granuloma is non-necrotizing (immune granuloma), distributed along bronchovascular bundles, lymphatic roots in the pleura and the interlobular septae. These granulomas typically occur within areas of sclerotic fibrosis [4]. They affect the upper lobes in an otherwise unremarkable lung tissue; airspace granulomas are rare. Early biopsy shows only interstitial lymphocytic infiltrate that is transient. However, at this stage patients are usually

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asymptomatic, and biopsies are seldom done. Early and late lesions are usually focal and diffuse lymphocytic infiltrate is not a feature of sarcoidosis [1]. Typical sarcoid granulomas resemble early tubercles but without caseation necrosis. In some cases, tiny spotty central necrosis can be seen affecting a portion of only a small percentage of granulomas. Rare instances of classic sarcoidosis may exhibit significant and even confluent areas of necrosis. The first detailed description of necrosis in sarcoidosis was provided by Ricker and Clark in 1949. They reviewed 300 cases wherein they found a varied amount of necrosis in 35% of the cases. Zittergruen found necrosis to be more prevalent in biopsy material obtained from a patient with recent onset of sarcoidosis [5]. The granuloma is composed of epithelioid cells haphazardly arranged without the formation of peripheral palisading. Among these cells, multinucleated giant cells of either Langhans-type or foreign-body type can be seen within the center of the granuloma. The giant cells may contain distinctive cytoplasmic inclusions; Schaumann and or asteroid bodies, but these two bodies are not pathognomonic of sarcoidosis and can be seen in other granulomatous inflammation. Schumann bodies are residues of lysosomes and asteroid bodies are aggregates of intermediate vimentin microfilaments that are arranged radially to give a stellate appearance. The lymph nodes draining the involved organ may contain small brown bodies derived from lysosomal ceroid pigment, along with numerous non-necrotizing sarcoid granulomas [1].

The Macrophage/Epithelioid Cell The epithelioid cells which form the granulomas are derived from macrophages by a transformation process. During which the phagosomes and lysosomes of the macrophages are replaced by cytoplasmic organelles more in keeping with a secretory cell. The immature epithelioid cells contain rough endoplasmic reticulum which is a structure needed for the production of protein. Also, Golgi apparatus and storage vesicles are found. They appear early and later with maturation they predominate. The mature cells secrete proinflammatory cytokines and fibrogenic cytokines such as transforming growth factor beta, tumor necrosis factor alpha, RANTES and nitric oxide synthase. Moreover, these cells have in their cytoplasm angiotensin converting enzyme; this explains its high level in the serum in patients with sarcoidosis. Within the

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granulomas, final hydroxylation of Vitamin D occurs leading to its activation and consequently to hypercalcemia [1].

The Lymphocytes The immunohistochemical study confirms that the T-helper CD4 lymphocytes predominate within the granuloma, and the T-suppressor CD8 lymphocytes are fewer in number and are located peripherally. The T-helper lymphocytes are mainly of the Th1 type as suggested by cytokine studies. They produce interleukin-2 and interferon gamma. Antigens presenting reticular cells are also found at the periphery of the granulomas, but B-lymphocytes are observed between granulomas [1].

THE GRANULOMAS The granulomas are located in sites rich in lymphatics; about the centriacinar bronchovascular bundle, the interlobular septae, and the pleura. Due to this location, a bronchial biopsy usually provides sufficient tissue for establishing the diagnosis. Sometimes the granulomas around the bronchi can also extend to the arteries and veins leading to granulomatous angiitis or large elastic arteritis. Also, venules and lymphatics may be affected. Because the veins have a thinner wall, they are most commonly affected. These findings explain why some patients may have a veno-occlusive disease and sometimes right heart failure. In rare occasions, sarcoidosis is associated with disseminated visceral giant cell arteritis [1]. Conglomerate-type of sarcoidosis occurs when the granulomas are numerous to the extent that they fuse and form a large mass of sarcoid tissue embedded in refractile eosinophilic collagen. A narrow rim of lymphocytic inflammation is typically seen at the periphery of these confluent nodules. Granulomas may resolve spontaneously or heal by fibrosis, and if this will occur, then honeycomb-pattern of the lung will evolve that might contain calcified Schaumann bodies. At this stage, tissue biopsy will not be able to identify the underlying etiology. But before these stages are reached, biopsies usually show active and healed granulomas indicating that the unknown agent is continuously affecting the lungs. In some patients, only fibrosis is seen without granulomas, and this means that the patients have reached advanced stage while being asymptomatic [1].

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VASCULITIS IN SARCOIDOSIS Granulomatous vasculitis is considered significant histologic finding in classic sarcoidosis. Many reports in the literature since 1944 confirm this finding in classic sarcoidosis. The large series of reported cases are found in these references; Carrington et al. 1976 (n-47), Rosen1977 (n-128), Kitaichi and Izumi 1984 (53%), Yamaguchi et al. in 1986 (n-75, 48%), Takemura et al. 1991(n-174, 53%), Takemura e 1992 (n-40, 100% all autopsy cases). Venous and lymphatic involvement is more than arterial involvement due to a thinner wall of the vessels. Pulmonary hypertension associated with granulomatous vasculitis is rare but few case reports are now available in the literature. Also, a few number of case reports of sarcoidosis simulating pulmonary veno-occlusive disease due to an involvement of the pulmonary vessels are released. Examination of the elastic stains on lung tissue sections is necessary. It will demonstrate fragmentation of the elastic fibers of the involved blood vessel, and this step helps to establish the diagnosis of sarcoid vasculitis. Based on the preceding, it seems reasonable to conclude that the real incident of granulomatous pulmonary angiitis/vasculitis in classic sarcoidosis approaches 100 [5].

Morphological Types of Sarcoidosis Necrotizing sarcoid granulomatosis (NSG) and nodular sarcoidosis (NS): Yale Rosen has reviewed the literature on NSG from 1973 to 2003 and the literature on NS from 1952 to 2003. He found 103 cases of necrotizing sarcoid granulomatosis and 111 instances of nodular sarcoidosis. Pathologic findings: Both categories have granulomas in 100% of instances. The vasculitis and necrosis are seen in 100% of NSG. Thus, it is named necrotizing and granulomatous. The Vasculitis is described as lymphocytic in just a few cases; both arteries and veins can be involved. The necrosis is small or large and is seen within the granuloma. It may be coagulative or caseous but not suppurative. In few cases, granulomatous vasculitis has led to focal infarct. Overall, the description of the pathologic findings in this reviewed literature for NSG was found to be lacking in detail concerning the extent of necrosis, proportion of granulomas exhibiting necrosis, type of necrosis present and whether infarction if present was associated with vascular

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occlusion due to granulomatous vasculitis. Moreover, it creates confusion by using the term caseation necrosis microscopically, while it is a perfect description term. It contradicts the description of sarcoid granulomas as defined by the 1999 American Thoracic Society statement on sarcoidosis. {The characteristic lesion of sarcoidosis is a discrete compact, non-caseating epithelioid cell granuloma. Granulomas may occasionally exhibit focal coagulative necrosis} [5]. The summary of the review for NS shows necrosis present in 14% of cases and vasculitis in 14%. None of the cases have both necrosis and vasculitis. In the cases that stain for acid-fast bacilli and culture for bacteria were performed, all were reported negative. Unfortunately in a significant number of those cases reported in the literature, there was no mention of cultures or microorganism stains [5].

SPECIMEN ACQUISITION Tissue Samples The best procedure for tissue diagnosis is bronchial; transbronchial biopsies obtained during bronchoscopy. As the granulomas are typically seen immediately beneath the airway mucosa, the diagnostic yield is usually high. As to the ideal number of biopsies to be taken, Gilman and coworkers suggest four biopsies to be taken to increase the chances of obtaining a positive tissue sample by 90% [4]. False negative results can be seen as endobronchial lesions are present in only 40% of patients with Stage I sarcoidosis and 70% of patients with Stage II or III disease. Alternatively, an open lung biopsy may be required to obtain adequate tissue for evaluation if there are no peripheral or endobronchial lesions. Pleural involvement is rare. Therefore, it is not recommended for biopsy [2]. A biopsy of lymph node, skin or parotid gland can show the nonnecrotizing granulomas. But biopsy from skin lesion such as erythema nodosum is not advisable for because it will show panniculitis a morphologic feature not diagnostic for sarcoidosis [2]. Other procedures that might be used for obtaining tissue are wedge resection, segmentectomy, lobectomy, needle biopsy, intrathoracic or extra thoracic lymph node biopsies. Some patients are diagnosed incidentally after an autopsy. Vascular involvement in sarcoidosis is observed in patients

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exposed to open lung biopsy or autopsy studies; procedures that involve examination of large tissue samples [2]. In a study of 151 patients done by Gayal et. al. comparing Transbronchial needle aspiration (TBNA), endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA), transbronchial lung biopsy (TBLB) and endobronchial biopsy (EBB), he concluded that Bronchoscopic biopsy is a valuable tool for the diagnosis of sarcoidosis. Transbronchial and endobronchial biopsies provide the best yield in the diagnosis, particularly when the mucosa is abnormal. However, to maximize the diagnostic yield, it is advised to combine TBLB and conventional TBNA and EBB or EBUS-TBNA [6].

Cytology Samples The lymph nodes can be sampled via ultrasound-guided bronchoscopic fine needle aspiration. However, as seen above, the best yield is obtained by a combination of tissue biopsy with cytology. The diagnosis of sarcoidosis can be confirmed when the bronchoalveolar lavage (BAL) cell count result shows the following: Decreased CD8 suppressor T lymphocytes, increased in CD4/CD8 ratio and low levels of neutrophils and eosinophils (less than 1%). The importance of BAL in confirming the diagnosis and excluding the need for tissue biopsy is demonstrated in the findings of Winterbauer et al.’s study of 600 BAL specimens from patients evaluated for clinical suspicion of sarcoidosis. He found that the triad of CD4/CD8 ratio of more than 2, 1% or fewer neutrophils, and 1% or fewer eosinophils, gave a sensitivity of 59%, specificity of 94%, positive predictive value of 73% and negative predictive value of 90% in distinguishing sarcoidosis from all other diseases [2]. They compared these results with the gold standard of transbronchial biopsy where 22 of 27 patients with confirmed sarcoidosis had positive findings of non-caseating granulomas on transbronchial biopsy. (The other five cases have biopsy proving non-caseating granuloma at a different body site) [2]. Transbronchial biopsy has a sensitivity of 81%, specificity of 95% positive predictive value of 95% and negative predictive value of 95% in distinguishing sarcoidosis from all other diseases. This study suggests that this predictive triad may have similar results to transbronchial biopsy particularly in specificity and ruling out sarcoidosis. And in this case, a tissue biopsy may

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be excluded [2]. Although this conclusion is valid, however, most centers rely more on tissue biopsies and cytology samples obtained by TBLB, TBNA, EBB and EBUS-TBNA in various combination depending upon availability, coast, and experience [6]. Sun et al. studied 284 mediastinal and hilar lynch node aspirates by EBUS-TBNA in 111 patients, and he concluded that EBUS-TBNA is a safe procedure for the diagnosis of sarcoidosis, with higher diagnostic yield in stage I than stage II. In order, to obtain a higher diagnostic yield especially if the rapid on-site evaluation is not available, aspiration should be taken from the largest mediastinal lymph node or hilar lymph node accessible and 3- 5 passes should be attempted [7]. Oda et al. did a study on 33 patients with clinical diagnosis of sarcoidosis. He applied to flow cytometry on the T lymphocytes obtained from broncho alveolar lavage sample. He got an accurate estimate of the ratio of T helper: T suppressor lymphocytes. Moreover, he compared this finding to the mediastinal lymph node aspiration using EBUS. The final sample was subjected to immunohistochemistry with CD4 and CD8 antibodies. The ratio was calculated and compared with a sample from the lavage. Correlation between the ratios of the two sample types was statistically significant. Furthermore, the finding of granulomas in the mediastinal lymph node aspirate confirmed the diagnosis of sarcoidosis [8].

Differential Diagnosis Sarcoidosis is a diagnosis of exclusion. It is reached only after ruling out other causes of lung granulomas particularly infections agents. Diagnosis is made based on criteria from the American Thoracic Society (ATS), and the World Association of Sarcoidosis and other Granulomatous Disorders (WASOG). These criteria mandate the presence of clinic radiologic findings suggestive of sarcoidosis, presence of tissue non-necrotizing epithelioid granulomas and the exclusion of known causes of granulomatous reactions [3]. The most important differential diagnosis is tuberculosis. So it is important for each granulomatous lung disease even in the absence of necrosis to apply Ziehl-Neelson stain for acid fast bacilli (Mycobacterium tuberculosis) to exclude this infection. Molecular study of tubercle bacilli is also helpful if the special stains are negative [1].

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Hasso and colleagues performed a retrospective study of lung tissue granulomas where special stains are negative, and 11% showed positive microbiologic culture, in these cases the clinical and radiologic findings were of low to intermediate suspicion of sarcoidosis. As might be expected, necrosis in granulomas was more frequently associated with culture-positive cases. The presence of caseation necrosis favors tuberculosis over sarcoidosis. However, the presence of Schaumann bodies and asteroid bodies, as well as involvement of blood vessels favors sarcoidosis. Foreign-body reaction can resemble sarcoidosis. Therefore, polarizing filters are needed to examine histologic sections looking for the foreign material (fragmented Schaumann bodies are also birefringent). Sarcoid granulomas are more diffuse and florid, involving both lungs and foreign-body granulomas tend to be more localized [1]. Aspiration pneumonia can be associated with granuloma formation, but these tend to resemble foreign-body type granulomas with characteristic multinucleated giant cells, often containing foreign material (partially digested food). Lymph nodes draining tumors may show sarcoid granulomas; sometimes they are seen close to the tumor and may even mask it. Lymphoma is known to be associated with granulomas that can be so extensive to the extent that the lymphoma can be overlooked, and the diagnosis of granulomatous disease is interpreted as the cause of the lymphadenopathy [1]. Extrinsic allergic alveolitis (EAA) is associated with granulomas that are usually poorly formed and not discrete tight well formed as in sarcoidosis. They are few, located in a diffuse chronic interstitial pneumonia. In sarcoidosis, the granulomas are located in relatively normal alveolar septae. The late stage of EAA will have no granulomas similar to sarcoidosis but in the latter burned out granulomas can sometimes be seen. Furthermore the ratio of Helper: suppressor T lymphocytes in broncho alveolar lavage are high in sarcoidosis but low in EAA [1]. Chronic berylliosis is indistinguishable from sarcoidosis on histopathologic grounds. Like sarcoidosis, chronic berylliosis produces fibrosis of variable severity and has distinct granulomas with giant cells. Chronic berylliosis may produce large, centrally hyalinized nodules which can mimic resolved lesion of histoplasmosis or burned out confluent sarcoid granuloma. When granulomas are less prominent, chronic berylliosis may also simulate hypersensitivity pneumonitis histopathologically. Lymphoid interstitial pneumonia can be considered in the differential diagnosis of sarcoidosis as it may have poorly formed granulomas, but it

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usually express a very prominent diffuse interstitial pneumonitis, and lymph node involvement is absent [1, 4].

Laboratory Findings The complete blood count may show leukopenia, anemia, thrombocytopenia or pancytopenia. Liver enzymes, alkaline phosphatase, and immunoglobulin, may be elevated. Hypercalciuria is defined as urinary calcium to creatinine ratio of more than 0.2 for normal patients over the age of two years with relatively normal body mass index. Elevated angiotensin converting enzymes is not diagnostic due to false positive results. However, it is found to be elevated in over 75% of cases of sarcoidosis further supporting the diagnosis [2]. Biomarkers in Future Directions The advances in molecular biology and computerized laboratory medicine may help by providing more precise diagnostic tests to confirm the clinical and radiologic suspicion of sarcoidosis and to differentiate it from other clinically overlapping entities such as idiopathic pulmonary fibrosis. Several works in proteomics, blood transcriptional signature are ongoing to help distinguish pulmonary sarcoidosis from tuberculosis and other mimickers [2]. Course of the Disease The course of the disease is chronic with a progression of 10-30% of the cases. Spontaneous remission may occur in nearly 2/3 of the patients. Serious extra pulmonary involvement, cardiac, central nervous system and hepatic may occur in 4-7% of the patients [5]. Some patients may develop lymphoma after sarcoidosis, Brinker in 1986 named this sarcoid-lymphoma syndrome. In this case, patients develop lymphoma after sarcoidosis and the patients have a chronic active form of sarcoidosis, suggesting that chronicity is a risk factor for lymphoma. The latter is supported by the finding of increased risk of Hodgkin’s lymphoma by 14.1% in patients with sarcoidosis in Scandinavia in a population-based case control study [3, 9, 10].

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The typical sarcoid granulomas are located around the bronchovascular bundles; the image demonstrates a granuloma adjacent to a blood vessel (large arrow), magnification X 200. The giant cells sometimes contain asteroid bodies as seen in the inset X 400. Original slide is Hematoxylin and Eosin (H&E) stain.

REFERENCES [1]

[2] [3]

[4]

Pathology of the lung. Bryan Corrin, Andrew G Nicholson. Third edition. 2011. Churchill Livingstone, Elsevier. ISBN 978-0-7020-33698. Robert Heinle, Christopher Chang. Diagnostic criteria for sarcoidosis, Autoimmunity Reviews. 13 (2014) 383-387. Jonathan London, Aurelie Grados, Christophe Ferme et al. Sarcoidosis Occurring After Lymphoma, Report of 14 Patients and review of the Literature. Medicine, Volume 93, number 21, November 2014 (www.md-journal.com). Practical pulmonary pathology, a diagnostic approach. Kevin Leslie and Mark R. Wick. Elsevier Saunders. 2011. ISBN. 978-1-4160-5770-3.

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Yale Rosen, Four Decades of Necrotizing Sarcoid Granulomatosis; What Do We Know Now? Arch Pathology Lab Med-Vol139, February 2015. [6] Abhishek Goyal, Dheeraj Gupta, Ritesh Agarwal et al, Value of Different Bronchoscopic Sampling Techniques in Diagnosis of Sarcoidosis; A prospective Study of 151 Patients. J Bronchol Intervent Pulmonol. Volume 21, Number 3, July. 2014. (www.bronchology.com). Lippincott Williams and Wilkins. [7] Jiayuan Sun, Huizhen Yang, Jiajun Teng et al. Determining Factors in Diagnosing [8] Pulmonary Sarcoidosis by Endobronchial Ultrasound- Guided Transbronchial Needle Aspiration. Ann Thorac Surg. 2015; 99: 441-6. [9] Keishi Oda, Hiroshi Ishimoto, Kazuhiro Yatera. Relationship between the ratios of CD4/CD8 T-lymphocytes in the broncho alveolar lavage fluid and lymph nodes in patients with sarcoidosis. Respiratory Investigation. 52 (2014) 179-183. [10] Brincker H. The sarcoidosis-lymphoma syndrome, Br J Cancer. 1986; 54:467-473. [11] Landgren O, Engels EA, Pfeiffer RM, et al. Autoimmunity and susceptibility to Hodgkin’s Lymphoma: a population –based casecontrol study in Scandinavia. J Natl Cancer. 2006; 98:1321-1330.

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In: Clinical Manifestations, Pathophysiology … ISBN: 978-1-63485-832-8 Editor: Ali Nawaz Khan © 2016 Nova Science Publishers, Inc.

Chapter 2

CLINICAL MANIFESTATIONS, DIAGNOSTIC METHODS AND MANAGEMENT OF PULMONARY SARCOIDOSIS Nahid Sherbini1, Hamdan Al-Jahdali1, and Ali Nawaz Khan2 1

Department of Medicine, Pulmonary Division, King Saud University for Health Sciences, King Abdulaziz Medical City - Riyadh, Saudi Arabia 2 North Manchester General Hospital, Manchester, UK

ABSTRACT Sarcoidosis is a multisystem granulomatous disease, of unknown etiology that is characterized by noncaseous epithelioid cell granulomas, which may affect almost any organ in the body. Intrathoracic involvement is common and accounts for most of the morbidity and mortality associated with this disease. The diagnosis is based on the total exclusion of other granulomatous disorders. The organs that are commonly involved are lymph nodes, the lungs, liver, spleen, skin, and 

Corresponding author: Dr. Hamdan AL-Jahdali MD.FRCPC, FCCP, Adjunct Professor- McGill University, Professor Pulmonary and Sleep Medicine- King Saud University for Health Sciences, Head of Pulmonary Division, Medical Director of Sleep Disorders Center, King Abdulaziz Medical City, Riyadh, PO Box 101830*11665, Tel: work: +96612520088 Ext 17597, 17531, Mobil Tel: +966505224271, E-mail. [email protected]

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Nahid Sherbini, Hamdan Al-Jahdali and Ali Nawaz Khan eyes; organs that can be involved individually or in combination. The correlation of the clinical, radiological features along with the pathologic finding of non-caseating epithelioid cell granulomas is vital to establish the diagnosis. There is no single precise cause attributed to the causation of this disease. Genetic factors are suspected due to the observation of racial groups such as African Americans, West Indians and Asians who have a higher prevalence of sarcoidosis.

INTRODUCTION Sarcoidosis is one of the important diseases in pulmonary medicine practice; it is a multisystem granulomatous disorder of unknown cause characterized by the presence of non-caseating granulomas which typically affects young individuals [1, 2]. The granulomas occur in many organs, but the most frequently affected sites are the lungs in approximately 90% of cases, other sites include lymph nodes, skin, eyes, and liver. The majority of the patients are asymptomatic at presentation with bilateral hilar adenopathy. Spontaneous resolution occurs many of cases, but progressive lung disease occurs in around 25 percent [1]. The incidence of sarcoidosis varies among geographical regions and races [3]. The diagnosis of sarcoidosis requires clinical and radiographic findings compatible with the diagnosis [4], histologic confirmation of granulomatous inflammation and exclusion of other causes of granulomatous disease. The treatments of pulmonary sarcoidosis have not been standardized. Many indications need to explore by the assessment before starting corticosteroid that is considered the standard of care for sarcoidosis patients. The different lines of treatment are necessary because of a significant steroid toxicity, many drugs are studied and will be reviewed here. Here, we did an overview of the clinical manifestations, diagnostic methods and an updated managements lines of pulmonary sarcoidosis.

CLINICAL MANIFESTATION The clinical findings of sarcoidosis are related to the affected organ but still not specific for the disease, and the diagnosis may need a confirmatory biopsy showing non-caseating granulomatous inflammation and exclusion of other alternative causes.

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The classical population are 20 and 60 years of age; the disease is more prevalent and with earlier onset in blacks than in whites [5]. Both genders and all races still may be affected. The incidence and prevalence of the disease are not known. With the difficulty to be estimated for several reasons such as the variability of the presentations of the illness and existence of more common granulomatous diseases (e.g., tuberculosis and fungal infection) in some areas of the world. Sarcoidosis most frequently involves the lung in approximately 90% of the cases, but up to 30% of patients present with extra-pulmonary manifestations of sarcoidosis Table 1 [6]. Different types of lung involvement are recognized, but classically interstitial lung disease and nodular infiltrate with or without calcification. Other less common pulmonary manifestations include pneumothorax, pleural involvement, and pulmonary hypertension. Table 1. Differential diagnosis of sarcoidosis Infections

Vasculitis

hypersensitivity pneumonitis Organic agents PneumoconiosisInorganic agents Immunological disorders Drug reactions Foreign materials Miscellaneous

Bacteria, chlamydia, fungi, metazoa, mycobacteria (M. tuberculosis and atypical mycobacteria), protozoa, rickettsia, spirochetes, viruses Bronchocentric granulomatosis, Churg-Strauss syndrome, granulomatosis with polyangiitis (formerly known as Wegener’s granulomatosis), necrotizing sarcoid granulomatosis Farmers’ lung, bird fanciers’ lung

Aluminium, beryllium, silica, talc, titanium, zirconium Crohn’s disease, hypogammaglobinemia, Langerhans cell histiocytosis, primary biliary cirrhosis Malignancy Carcinoma, Hodgkin’s disease, non-Hodgkin’s lymphoma methotrexate, etanercept, infliximab, azacytidine, oxaliplatin, amoxicillin, sirolimus, fluoxetine Granulomatous histiocytic necrotizing lymphadenitis (Kikuchi-Fujimoto disease), granulomatous lesions of unknown significance (GLUS syndrome)

Main manifestations are the common respiratory symptoms include a dry cough, shortness of breath and chest pain; these are frequently accompanied by fatigue, fever, and weight loss [7]. Other symptoms include skin lesions

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Nahid Sherbini, Hamdan Al-Jahdali and Ali Nawaz Khan

(particularly around tattoos or scars), visual symptoms, dry eyes or mouth, parotid enlargement, syncope, palpitations or arthralgia and arthritis. Evidence show that patients may have symptoms for more than 3 months before clinical diagnosis [8]. The physical examination should target all systems, chest findings show fine crackles in the presence of pulmonary parenchymal involvements, but not commonly found. Wheezing is important because it can highlight the presence of endobronchial lesion or traction bronchiectasis with scaring in advanced chronic lung diseases. Digital clubbing is rare and typically associated with advanced fibrosis.

APPROACH TO DIAGNOSIS Clinical, laboratory and radiological correlation with an exclusion of other causes and involvement of more than one organ system are needed for a diagnosis of sarcoidosis. Some important evidence establishes approach for diagnosis of sarcoidosis [2], but the reality is that the diagnosis of sarcoidosis is still not an easy task in many of the cases and can be challenging [9]. There are some important known classical clinical features of sarcoidosis but usually non-specific for the diagnosis. Other diseases, such as asthma, ILD, pulmonary tuberculosis, can mimic the presentation of sarcoidosis. The combination of non-caseating granulomas in one organ classically lung or skin and clinical evidence of other sarcoidosis manifestations such as hypercalcemia and bilateral hilar enlargement aid in confirming sarcoidosis diagnosis. Initial evaluation of patients with possible sarcoidosis includes Full history, physical examination, laboratory tests, ECG, chest radiographs, pulmonary function tests and ophthalmology evaluation. Starting with the results of Complete blood count and the differential which may reveal leukopenia and \or anaemia in around 10% of patients, liver function tests for possible hepatic involvement, glucose, electrolytes, blood urea nitrogen, creatinine, serum calcium, and hypercalciuria in urinalysis all should be screened in sarcoidosis. Hypergammaglobulinemia occurs in 30 80% of the cases and a positive rheumatoid factor may be found. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) is mildly elevated in most of the sarcoidosis patients but does not differentiate them from other causes of inflammation. Few studies revealed high CRP indicate a better response to therapy [10, 11]. The serum angiotensin-converting enzyme (ACE) level is elevated in 75% but has limited clinical use due to poor sensitivity and specificity [12]. Angiotensin-converting enzyme (ACE) is

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produced in the epithelioid cell of the granuloma [13] and one evidence shows that serum ACE levels reflect the granuloma burden in sarcoidosis [14]. However, the diagnostic and prognostic value of the serum ACE is questionable. Another study of 1,941 patients with sarcoidosis, 1,575 healthy control subjects, and 1,355 patients with other diseases, the sensitivity of an elevated serum ACE for the diagnosis of sarcoidosis was 57%, the specificity 90%, positive predictive value 90%, but negative predictive value only 60%. Other causes of raised serum ACE include hyperthyroidism, tuberculosis and fungal infections [15]. ACE monitoring has been proposed as a means to follow the course of the disease. However, the level of ACE does not correlate with the severity of the disease [16, 17]. Positive Tuberculin Skin Testing (TST) or an interferon gamma release assay (IGRA) favours a diagnosis of Mycobacterium tuberculosis, knowing diminished skin test reactivity is expected in sarcoidosis. Arterial blood gases may be normal, or may reveal hypoxemia and hypocapnia (hyperventilation) or hypercapnia [18].

Histopathology The main pathological findings raise from development and accumulation of (non-caseating) granulomas, collections of macrophages, epithelioid cells and CD4+ lymphocytes, but these findings are still not specific for the disease. This persistent granulomatous inflammation will cause the tissue injury and in the late stages of the disease, fibrosis. The commonly known organs involved are lungs the findings are presence of granulomas in the alveolar septa, the walls of bronchi, and adjacent to the pulmonary arteries and veins, alveolitis which involves the interstitium more than the alveolar spaces and accumulation of inflammatory cells, including monocytes, macrophages, and lymphocytes and central fibrinoid necrosis may be seen [19]. The existence of large amounts of necrosis suggests an alternate diagnosis or necrotizing sarcoid granulomatosis [20]. Sarcoid-like histopathologic changes can be seen in lymph nodes from patients with neoplastic diseases such as Hodgkin disease and other lymphoproliferative disorders, germ cell testicular tumors, breast cancer, renal cell carcinoma, leiomyosarcoma, and ovarian mucinous cystadenoma, among others [21]. Thus, caution is advised when patients present with sarcoid-like granulomas in a lymph node, but without other typical features of sarcoidosis. Other important organs affected are eyes and skin; several studies suggest that the disease results from a response to

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environmental antigens affecting these organs [22]. Still the aetiology of sarcoidosis remains unknown, and its pathogenesis incompletely understood.

Radiology Pulmonary imaging plays an important role in the diagnosis of sarcoidosis, starting with a chest radiograph, which is often followed by HighResolution Computed Tomography (HRCT). All patients with possible sarcoidosis should have a chest radiograph. The presence of bilateral hilar adenopathy is a classic finding in sarcoidosis, which is classically symmetrically enlarged (in ~50% of cases), or the right may be slightly more prominent Figure 1. True unilateral adenopathy is uncommon (