Review Article
Pictorial review of intrathoracic manifestations of progressive systemic sclerosis Hamdan AL-Jahdali, Prabhakar Rajiah1, Carolyn Allen2, Shyam Sunder Koteyar2, Ali Nawaz Khan2
Department of Medicine, King Saud University For Health Sciences, Riyadh, Saudi Arabia 1 Cardiothoracic Imaging Case Western Reserve University, University Hospitals of Cleveland, Cleveland, Ohio, USA, 2 North Manchester General Hospital and Clinical Director, Acute Pennine NHS Trust, Crumpsal, Manchester, UK Address for correspondence: Dr. Dr. Ali Nawaz Khan, Consultant Radiologist and Professor (Hon), North Manchester General Hospital, Acute Pennine NHS Trust, Crumpsal, Manchester M8 6RB, UK. E-mail: drkhan1966@ msn.com Submission: 06-12-2013 Accepted: 03-03-2014
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Website: www.thoracicmedicine.org DOI: 10.4103/1817-1737.140121
Abstract: Intra-thoracic manifestations of progressive systemic sclerosis (PSS) are not well known particularly the imaging features, which forms the basis of accurate and timely diagnosis. The aim of this study is to familiarize the physicians and radiologists with these features. The diagnosis can remain elusive because of the non-specific nature of symptoms which mimic many common conditions. Thus, the diagnosis of PSS can be missed leading to continuous morbidity if the correct imaging is not pursued. The authors examined the records of rheumatology patient referrals of over a 5 year period. A hundred and seventy patients with systemic sclerosis and mixed connective tissue disorders were chosen for detailed study of the imaging available, which form the basis of this review. The images included conventional chest radiographs, digital radiographs computed radiography (CT) and high resolution computed tomography (HRCT). Where applicable computed pulmonary angiography (CTPA) and radionuclide scans were also interrogated. Key words: Imaging, mixed connective tissue disorders, progressive systemic sclerosis, systemic sclerosis
Introduction
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rogressive systemic sclerosis (PSS) is a connective tissue disease associated with small vessel arterial vasculopathy, inflammatory and immunological processes. The peak incidence is between 45 and 64 years of age.[1] Women are predominantly affected. The cause of PSS is not known. Black Americans suffer from more severe disease as compared to White Americans.[1] The original name of scleroderma was coined because of the hard skin that accompanies the disorder. The disease is termed limited when the hands and face only are involved. Limited disease is at lower risk of visceral involvement although pulmonary hypertension is more common.[2-5] PSS is diffuse disease with multiorgan involvement associated with skin, and inflammatory changes. Three subgroups are described: a. Classical type; b. CREST syndrome; and c. Overlap syndromes associated with other connective tissue disorders such as rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis and polymyositis.[6] The lungs are commonly involved in PSS with a frequency second only to the skin. Esophageal dismotility is common. Respiratory symptoms occur, in a very few cases, as a presenting manifestation. Clinical signs of pulmonary involvement are non-specific and include shortness
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of breath on exertion and subsequently also at rest. Other symptoms reported are non-productive cough, atypical chest pain, fatigue, and dyspnea.[7] Abnormalities of lung function include a restrictive ventilatory defect, airflow obstruction, and reduced carbon monoxide diffusion, which may be an isolated early finding. Interstitial lung fibrosis associated with honeycombed lung is the most common lung parenchymal abnormality on a chest radiographs. Heart enlargement and pulmonary artery dilatation are a common finding on imaging. High-resolution computed tomography (HRCT) can detect asymptomatic disease in PSS. Bronchoalveolar lavage shows an increase in total cell count; there are predominantly lymphocytic cells in alveolitis. The two distinct lung disease patterns on studies on live subjects and autopsy studies: 1. Interstitial lung disease and 2. Pulmonary vascular disease. Pulmonary hypertension may occur in the absence of interstitial lung disease, particularly in patients with limited disease. The overall mortality is reported as 50% at 7 years, with pulmonary complications as the major cause of death.[8] PSS carries the highest mortality among patients with collagen vascular disease, with pulmonary arterial hypertension the leading cause of death. Among patients with PSS, the prevalence of confirmed pulmonary arterial hypertension is around 10-16%.[9] 193
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Interstitial lung fibrosis The incidence of lung involvement in PSS is 74-95% on autopsy series.[10] Lung involvement is less common in CREST syndrome than other types of systemic scleroses [Figure 1]. Interstitial fibrosis occurs in 20-65% of PSS (8, 10). Restrictive pulmonary function tests with a decreased diffusing capacity may precede clinical or radiographic changes.[11,12] Restrictive ventilatory defect, airflow obstruction, and reduced carbon monoxide diffusion may predate lung fibrosis.[11,12] Interstitial lung fibrosis associated with honeycombed lung is the most common lung parenchymal abnormality on a chest radiographs. Figures 2-12 show different patterns of lung fibrosis. High-resolution computed tomography (HRCT) can detect asymptomatic disease in PSS.[8]
extensive esophageal involvement compared with patients with PSS without pulmonary fibrosis.[15-17] It has been postulated that increased episodes of gastroesophageal reflux in these patients could be responsible for the development of pulmonary fibrosis. Although the exact mechanism, of pulmonary fibrosis, remains elusive the authors go on to suggest that these patients with gastroesophageal reflux should be considered for anti-reflux therapy. Figures 2,4-6,9 and 11 showing dilated oesophagus with recurrent aspiration and lung fibrosis. Pulmonary hypertension Pulmonary hypertension (PH) is common and affects 50% of patients with CREST and 33% patients with PSS at
Oesophageal dysmotility Esophageal dysmotility is a common finding and occurs in 74% of cases and may be associated with aspiration pneumonia.[13,14] Recent work indicates that pulmonary fibrosis and gastroesophageal reflux associated with PSS has more a
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Figure 2: 46 year old male with PSS. (a and b) CXR shows volume loss and basal reticular changes suggestive of interstitial lung disease. (c) Axial CT scan shows basal reticular changes, ground glass opacification and traction bronchiectasis in a pattern that is suggestive of NSIP (nonspecific interstitial pneumonia). Note the dilated lower esophagus suggestive of dysmobilty. (d) Prone high resolution CT shows persistent ground glass opacities, reticular changes and traction bronchiectasis, confirming the presence of fibrosis. (e) Coronal CT scan shows the basal distribution of fibrotic changes in PSS Figure 1: PSS is considered limited when involvement is restricted to the distal extremities and face. The limited form is associated with a lower risk of visceral involvement; however, pulmonary hypertension is more common
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b Figure 3: 55 year old female with PSS. (a) Axial supine HRCT shows areas of honeycombing and traction bronchiectasis in the left upper lobe in a patient with proved PSS. (b) Prone CT in the same patient confirms the persistence of the fibrotic lesions 194
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Figure 4: 48-year-old female with PSS. (a) Axial CT scan shows the presence of volume loss and patchy areas of ground glass opacities in the lower lobes. There is also esophageal dilation, indicating dysmotility. (b) Coronal CT scan shows scattered areas of ground glass opacities associated with volume loss and traction bronchiectasis in a patient with scleroderma. (c) Axial CT scan with soft tissue window shows esophageal dilation. (d) Axial CT scan at a higher level and in soft tissue window show dilated pulmonary arteries, due to pulmonary hypertension Annals of Thoracic Medicine - Vol 9, Issue 4, October-December 2014
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Figure 5: 58-year-old male with PSC. (a) Chest radiograph shows volume loss of lungs and bilateral diffuse, predominantly peripheral and basilar areas of reticular opacities indicative of fibrosis. (b) Axial CT scan shows basal reticular changes in a peripheral distribution along with traction bronchiectasis and architectural distortion. There is also esophageal dilation (c) Coronal CT shows basal and peripheral ground glass opacities, reticular changes, architectural distortion and traction bronchiectasis. (d) Esophagogram shows dilated esophagus due to dysmotility
Figure 6: A PA chest radiograph and axial CT scans in 51-year old male with PSS showing basal fibrotic changes (CXR) a dilated thickened lower esophagus (red arrow), patchy subpleural ground glass, mild bronchial wall thickening, cysts and an air bronchogram (yellow)
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b Figure 7: (a) A PA chest radiograph on 57-year old lady with PSS showing incidental dextrocardia. (b) Axial CT scans showing bilateral reticular basal shadowing due to pulmonary fibrosis
Figure 9: PA chest radiograph on a 67-year female with PSS showing minor bronchial wall thickening at the lung bases also shown on axial CT scans, also note the minor lung fibrosis, and fluid within the lower esophagus Annals of Thoracic Medicine - Vol 9, Issue 4, October-December 2014
Figure 8: Pulmonary hypertension in patient with PSS. (a) Black blood, T2 weighted MRI, image shows dilated pulmonary arteries. (b) Axial steady state free precession (SSFP) image shows dilated pulmonary arteries due to pulmonary arterial hypertension
Figure 10: PA chest radiograph and axial CT scan of a 52-year old male patient with PSS that presented with breathlessness, showing extensive pleural thickening. An old unrelated rib fracture is noted on the right. Also note coarse subpleural fibrosis 195
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angiography.[18] PH is usually secondary to lung parenchymal disease, but primary PH may occur. [19,20] Although large pulmonary arteries and cardiomegaly may be seen on the chest radiographs the, finding is non- specific.[18,21,22] [Figures 4d and 8] Infections Tyndall et al.[23] studied the causes and predictors of mortality in systemic sclerosis (SSc). They obtained questionnaires on 234 of 284 fatalities. 55% of deaths were attributed directly to SSc and 41% to non-SSc causes. Amongst the non-SScrelated causes, infections (33%) and malignancies (31%) were followed by cardiovascular causes (29%). Shalev et al.[24] reviewed the medical records of nine patients with diagnosis of scleroderma (8 female, 1 male), admitted to the intensive care unit between 1991 and 2002. They concluded that the outcome of scleroderma patients admitted to the ICU was extremely poor. Infectious complication was the most common cause of death in these patients. A major contributory factor to this poor outcome was dependent on the severity of the underlying visceral organ involvement, particularly
Figure 11: HRCT of 53 year old man, with PSS showing bilateral basal pleural thickening and minor bronchiectasis. Also note the ground glass appearance and air within the esophagus due to gastroesophageal reflux
Figure 13: Axial CT, at the level of the pulmonary arteries on a patient with known PSS showing extensive mediastinal lymphadenopathy. Other causes of adenopathy were excluded on mediastinoscopy and biopsy. Note the thickened and dilated esophagus. 196
severe pulmonary fibrosis. The severity of this involvement is a poor outcome predictor.[24] Mediastinal lymphadenopathy Gordonson J and associates, [25] first described a patient with mediastinal lymphadenopathy and undifferentiated connective tissue disease. The histology of the lymph node showed follicular hyperplasia with plasmacytosis, a finding seen in rheumatoid arthritis. The lymphadenopathy resolved 10 months after the patient was first seen, but the mixed connective tissue disease persisted [Figures 13 and 14]. Lymphadenopathy is prevalent in patients with SSc and interstitial lung disease regardless of clinical subtype or interstitial pattern. Wechsler et al, [26] found mediastinal lymphadenopathy in 50% of patients with diffuse cutaneous SSc and 40% in patients with limited cutaneous SSc. The authors also describe a significant association of between lymphadenopathy and interstitial lung disease. 2% patients had a ground-glass parenchymal pattern of interstitial disease and 74% had honeycomb pattern. Warrick and associates[27] studied 17 patients with early systemic sclerosis (SSc) that underwent
Figure 12: Axial CT showing a soft tissue density mass in posterior right lower dorsal paravertebral gutter in a patient with known PSS. Note subpleural fibrosis, subpleural cysts/bullae and minor bronchiectasis. Biopsy revealed an adenocarcinoma
Figure 14: Axial CT scans, on another male patient with known PSS showing mediastinal lymphadenopathy (red arrow). Note the dilated esophagus Annals of Thoracic Medicine - Vol 9, Issue 4, October-December 2014
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HRCT of the chest to evaluate dyspnea and/or abnormal pulmonary function tests. Mediastinal lymphadenopathy was detected in 41% of the patients. The authors postulate that ground glass opacities on HRCT may reflect active alveolitis, and mediastinal lymphadenopathy associated with SSc lung disease may be a consequence of pulmonary inflammation.[27] Bhalla and associates,[28] found asymptomatic esophageal dilatation in 80% and mediastinal adenopathy in 60% patients in, scleroderma. The results of their study suggest that CT is useful in the detection of mediastinal adenopathy and asymptomatic esophageal involvement in patients with scleroderma. The findings can help to narrow the differential diagnosis in patients in whom CT shows diffuse interstitial lung disease. [28] G a r b e r a n d a s s o c i a t e s [29] f o u n d t h a t m e d i a s t i n a l lymphadenopathy occurs frequently in patients with SSc, at HRCT particularly if lung involvement is extensive. Their study found mediastinal lymphadenopathy in in 32% patients with lung involvement but in only 8% patients no lung parenchymal disease. The prevalence of mediastinal lymphadenopathy increase with more extensive lung involvement, but there is a poor correlation with the CT appearance and concurrent erythrocyte sedimentation rate. Yoshioka[30] reports a case SSc a 77-year old woman with general fatigue that presented with and mediastinal lymphadenopathy preceding skin changes and lung fibrosis. Mediastinal lymphadenopathy was diagnosed by chest computed tomography before the skin and lung involvements of SSc were discovered. The mediastinal lymphadenopathy resolved with the development of lung fibrosis.[30] Pericardial effusions/myocardial disease The radiological features of scleroderma pericarditis with effusion were first described by Steinberg and Rothbard[31] and later by Nasser WK and associates.[32] Thompson, Pope[33] using a casecontrol format, recruited 37 patients with scleroderma and no known cardiac disease to determine the frequency of pericardial and pleural effusions in scleroderma. Echocardiograms and chest radiographs were performed patients. Age- and gender-matched controls had echocardiograms performed which were read by a cardiologist, blinded to the diagnosis. Pleural effusions were identified in 7% (4/58) of the cohort of scleroderma patients and were more frequent in diffuse disease (10%). A total of 17% (4/23) of diffuse and 4% (1/23) of limited scleroderma patients had evidence of pericardial effusions.[31] The authors concluded that pericardial effusions do occur in scleroderma without evidence of clinical cardiac dysfunction and are more common in diffuse scleroderma. Pericardial effusion associated with scleroderma is usually asymptomatic. The incidence of pericardial involvement in scleroderma is about 50% on autopsy series. Asymptomatic pericarditis occurs in 16% of patients with diffuse disease and 30% of patients with limited scleroderma. A case of scleroderma associated large pericardial effusion, which antedated the other clinical and serologic features of scleroderma.[34] Pleural effusions in scleroderma occur in 70%.[31] Abu-Shakra and associates[35] describe a case of diffuse scleroderma associated with a large pleural effusions, pericardial effusion and subsequent renal failure. Histology of the pericardium and pleura revealed the presence of leukocytoclastic vasculitis.[35] The authors suggest pleuropericarditis in systemic sclerosis may occur as a consequence of vasculitis and large pericardial effusions may predispose to oliguric renal failure.[35] [Figures 15-17]. Annals of Thoracic Medicine - Vol 9, Issue 4, October-December 2014
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b Figure 15: Cardiac involvement in 53 year old female with PSS. (a) Short-axis view of delayed enhancement MRI shows patchy areas of linear mid myocardial enhancement (straight arrows) in the mid ventricular septum and the lateral wall. There is also a moderate sized circumferential pericardial effusion (curved arrow). (b) 3 chamber delayed enhancement MRI shows patchy areas of linear mid myocardial enhancement (straight arrows) and a circumferential pericardial effusion (curved arrow)
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Figure 16: Pericarditis in 42-year-old male patient with PSS. (a) 4 chamber black blood T1 weighted image shows thickening of pericardium, more prominently surrounding the lateral wall of the left ventricle (arrow), consistent with pericarditis. (b) 4-chamber delayed enhancement image shows circumferential delayed enhancement of the pericardium, consistent with pericardial inflammation
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Figure 17: Pericardial effusion in 49-year-old male with PSS. (a) 4 chamber blackblood double inversion recovery sequence areas of loculated pericardial effusion (straight arrows) surrounding the heart. (b) Short axis STIR image in the same patient shows heterogeneous high signal in the pericardial fluid (straight arrow). There is also myocardial edema (arrowheads) in the ventricle indicating myocardial involvement
Cardiac tamponade Inoue et al.[36] describe, a 42-year old Japanese woman with mixed connective tissue disease who developed fulminant hepatic failure and hepatic encephalopathy. Echocardiography revealed a massive pericardial effusion associated with cardiac 197
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tamponade. Bezerra et al.[37] also described a case of fulminant hepatic failure due to cardiac tamponade associated with mixed connective tissue disease. An extremely rare case of cardiac tamponade as an initial manifestation of undifferentiated connective tissue diseases has been reported.[38] The report described a case of a middle-aged man who presented with symptoms of fatigue, exertional dyspnea and orthopnea. His physical exam was significant for anasarca, elevated JVP and pulsus paradoxus. Chest X-ray showed pleural effusions and cardiomegaly the EKG revealed pulses alternans and a transthoracic echocardiography showed a large pericardial effusion associated with circulatory compromise.[36] Right heart catheter study revealed features of cardiac tamponade. Once diagnosed these patients carry the risk developing CDT within 5 years of disease onset and should be followed up in clinic periodically.[36] Briasoulis and associates,[39] report a case of a 24-year old woman admitted with a new onset heart failure and features of cardiac tamponade. Further investigations revealed progressive mixed connective tissue disease associated with severe hypothyroidism. Despite early recognition prompt recognition and prompt treatment with glucocorticoids, thyroxin, metoprolol, lisinopril, furosemide, and milrinone, the patient deteriorated and died within 4 weeks. Pleural disease Pleuritis/pleural effusion/thickening is a general finding in PSS. Pleuritic chest pain occurs in 40% patients. This is common, with pleuritic chest pain in 40%, but radiographic signs of thickening and effusions are less common.[13,14] Diffuse pleural thickening is seen in 20% on HRCT significant effusions are uncommon.[11,12,14,21] There is no pattern to the pleural thickening in mixed connective tissue disease [Figures 10 and 11]. Pleural effusions Taormina and associates [21] analyzed the chest film manifestations of 73 PSS patients which were sub-grouped on the basis of previously described criteria. Radiographic abnormalities, either interstitial lung disease or pleural effusion, were present as follows: Pleural effusions were found in 18% (8/44); CRST/CREST, 0% (0/9); and PSS-overlap syndromes, 75% (15/20). Pericardial effusion associated with scleroderma is usually asymptomatic. The incidence of pericardial involvement in scleroderma is about 50% on autopsy series. Asymptomatic pericarditis occurs in 16% of patients with diffuse disease and 30% of patients with limited scleroderma. A case of scleroderma associated large pericardial effusion, which antedated the other clinical and serologic features of scleroderma.[34] Pleuropulmonary disease and pleural effusions is a common feature of several connective tissue diseases. Pleural effusions in connective tissue disease are non-specific and require exclusion of other causes such as infection. In particular, rheumatoid nodules may mimic infectious and neoplastic lung diseases. In rheumatoid pleural effusions, a needle biopsy may reduce the likelihood of infection or malignancy. Pleural effusions caused in SLE and rheumatoid arthritis (RA) has characteristics on pleural fluid analysis that aid in diagnosis,[40,41] but other causes of effusion may complicate the issue and must be excluded. Moreover, drugs used in connective tissue disease may cause interstitial disease, increase susceptibility to infection, or both. This complicates differential diagnosis. Acute lupus pneumonitis and SLErelated alveolar hemorrhage are usually fulminant processes, 198
often associated with fever.[40,41] Highland, Heffner[42] reviewed the association of pleural effusions and interstitial parenchymal lung disease and the recent reports of occurrence of effusions to include systemic sclerosis, polymyositis-dermatomyositis, several drugs, and several miscellaneous causes of interstitial lung disease.[42] The effusions require a clinical evaluation to exclude complications of therapy and coexisting conditions unrelated to the underlying interstitial lung disease. Pulmonary hypertension is an independent risk factor for pleural effusion irrespective of connective tissue disease. Pleural effusions frequently occur with pulmonary hypertension. A study by Luo et al.[43] in patients with idiopathic and heritable PH demonstrated that pleural effusions frequently occur in patients with isolated right-sided heart failure.[43] The authors found 39.3% patients with PAH associated with CTD had pleural effusions, 45.1% with scleroderma and 27.8% with mixed connective tissue disease. The elevation of tumor markers in SLE, RA, or diabetes mellitus has been reported recently. Kimura and associates[41] report a female patient with PSS and pleuritis that demonstrated a high level of CA125 in her pleural effusion and blood serum. The authors measured the serum levels of CA125 and CA19-9 in 27 female patients with collagen diseases including SLE, PSS, dermatomyositis and Sjögren syndrome, and 11 healthy females as controls. All 27 patients showed no elevation CA125 and CA19-9 as compared with the healthy controls, there was any evident elevation of CA19-9 or CA125 levels in collagen diseases except in the reported case. Elevated serum CA125 may be one of the indicators of pleural effusion in collagen disease. Diffuse alveolar hemorrhage Diffuse alveolar haemorrhage is a rare but potentially serious complication of PSS and may occur with a systemic vasculitis or rarely with isolated pulmonary capillaritis.[44-47] Griffin and co-workers,[44] have described a case of a 41-year-old man with PSS that developed severe diffuse alveolar haemorrhage and died. The authors emphasize the importance of diffuse alveolar haemorrhage as a rare but potentially serious complication of connective tissue disease that should not be overlooked. Chaer and co-workers[45] report a 38-year-old woman with limited cutaneous systemic sclerosis and pulmonary fibrosis with diffuse alveolar hemorrhage during the course of her disease. The patient responded to steroids. Pulmonary thromboemboli in systemic sclerosis Mizoguchi et al. [48] employed ELISA and VDRL tests in order to detect Anticardiolipin antibodies (ACL) antibodies in sera samples obtained from 105 patients with SLE, RA, scleroderma, dermatomyositis, primary Sjögren’s syndrome, vasculitis and pulmonary thromboemboli. ACL antibodies were detected in 4 patients out of 11 scleroderma, 1 patient out of 7 vasculitis, 2 patients out of 5 primary Sjögren’s syndrome, and 3 patients out of 6 pulmonary thromboemboli. Mizoguchi and co-workers[49] have reported a case of recurrent pulmonary embolism due to intracardiac thrombi in systemic sclerosis. Pulmonary endothelium plays an important role in the mechanism of PAH. A study by Peled and co-workers[50] postulates that a systemic component of endothelial dysfunction might be involved in idiopathic, scleroderma-associated and chronic Annals of Thoracic Medicine - Vol 9, Issue 4, October-December 2014
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thromboembolic PAH that is correlated with disease severity [Figure 18]. Lung neoplasms Houser and Jonsson SM(50) reported a case of lung cancer associated with PSS and conducted a brief review. Richards RL & Miline JA[51] reported two cases in which cancer was associated with PSS. The authors reviewed 4 other cases previously reported. They found no evidence of an intimate association between malignant disease in general and PSS such as found dermatomyositis. In only one of the six patients, a bronchial carcinoma and the cutaneous and vascular changes of PSS develop together in a patient with previously normal lungs. In the other 5 patients, the lung manifestations of PSS preceded the lung cancer by a number of years, and in these pathological changes of the primary disease were present in parts of the lungs unaffected by tumour. The authors concluded that there was good evidence that PSS may predispose to the development of cancer of the lung. Adzić et al.[52] reviewed 375 patients; with CTD six of these (25%) had PSS. The authors analysed lung cancer (LC) stage, clinical presentation, histological type, patients’ smoking status, method of diagnosis, treatment applied, and disease outcome. The majority of CTD patients who developed lung cancer were diagnosed at an advanced stage and had poor survival. Efforts for early detection of LC in CTD patients’ group are warranted. Lung cancer is the most frequent cancer seen in patients with PSS, followed by breast cancer. Cancer is associated with PSS in between 3.6 and 10.7% of patients.[53] The diagnosis of PSS may occur before, concurrent with, or after the diagnosis of malignancy. Risk factors for the development of malignancy in patients with PSS are female gender, increased age, and diffuse systemic sclerosis. There is no consistent relationship with autoantibodies such as anticentromere and antitopoisomerase and the risk of developing cancer in PSS.[54] In a study by Colaci et al.[55] in which two thousand and 40 patients with PSS were reviewed and concluded that systemic sclerosis is a risk factor for cancer, particularly smoking- and alcohol-related cancers. Men with systemic sclerosis is at a higher cancer risk than women. Both primary and secondary cancer preventive measures are needed in the care of patients with systemic sclerosis. In their study results from an Italian rheumatologic center and review of the literature Colaci et al.[56] confirmed the higher frequency of lung cancer among PSS patients compared to the general population, particularly within patients’ subset with serum anti-Scl70 antibodies and lung involvement. [Figures 12,19,20,21-25] Neuromuscular respiratory failure in PSS Peripheral neuropathy may be a cause of ventilatory muscle weakness found in MCTD and systemic lupus. Martyn and co-workers[57] reported a 34-year-old female patient with MCTD who developed severe pulmonary and neuromuscular complications. She presented initially with myasthenia gravis and then polymyositis, profound peripheral neuropathy, and respiratory muscle failure. Eventually she died despite aggressive immunosuppressive therapy and plasmapheresis. Autopsy revealed spinal cord changes secondary to a peripheral neuropathy and signs of neurogenic atrophy confined to the respiratory muscles.[57] [Figure 26]. Annals of Thoracic Medicine - Vol 9, Issue 4, October-December 2014
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Figure 18: CT images showing major but non-occlusive pulmonary embolism in a patient with known PSS. Figure a and b are axial and coronal CT scans showing multiple pulmonary emboli (red arrows). Figures c and d are from the same patient showing pulmonary emboli associated with pulmonary fibrosis
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Figure 19: (a) PA chest radiographs of a patient with known PSS that presented with a weight loss of 3.2 kg and left shoulder pain. The two radiographs are 6 months apart. Figure b show a suggestion of a mass lesion at the right cardiophrenic angle (red arrow)
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b Figure 20: a and b are from the same patient as in the previous two figures confirming a mass at the right cardiophrenic angle associated with pulmonary fibrosis and destruction of the left scapular blade (red arrow) highly suggestive of a metastatic deposit. The patient is awaiting a biopsy for tissue typing
Bronchiectasis and bronchiolitis obliterans organizing pneumonia (BOOP) Bronchiectasis has been reported in 14% in, association with MCTD on HRCT usually secondary to traction of the airway secondary to from fibrosis or due to recurrent aspiration and infection[58] [Figures 2-5]. 199
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Figure 21: Coronal images of a patient with MCTD and peripheral neuropathy. This patient had paradoxical movement of the diaphragm on fluoroscopy and non-existent thoracic excursion in keeping with neuropathy. Note the extensive pulmonary fibrosis, multiple cysts/bullae, pleural thickening and the elevated right hemidiaphragm
Figure 23: Pre and post contrast axial CT scans showing the right posterior gutter mass and mediastinal lymphadenopathy. Note the dilated esophagus (the same patient as in the previous figure). Also see the following three figures showing PET/CT images
Figure 25: PET/CT coronal and axial images showing biopsy proved, adenocarcinoma, associated with PSS. Note the intense radionuclide uptake within the tumor and mediastinal lymph nodes and a tiny metastatic deposit within segment 2 of the liver. The images are from the same patient as in the previous three figures. Also note the dilated and thickened lower esophagus 200
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Figure 22: (a) Axial CT scan shows basal fibrotic changes (curved arrows) and a welldefined mass in the anterior aspect of the left upper lobe (straight arrow). (b) FDG-PET image shows high uptake in the lesion in the left upper lobe (straight arrow), indicative of malignancy. There is also high uptake in left hilar lymph node (curved arrow), indicative of metastasis. (c) Fused PET-CT image shows high uptake in the tumor and left hilar lymph node. (d) Fused PET-CT image shows high uptake in the lymph node. The tumor was biopsy proven to be moderately differentiated adenocarcinoma
Figure 24: PET/CT showing biopsy proved, adenocarcinoma, associated with PSS. Note the intense radionuclide uptake within the tumor and mediastinal lymph nodes and a tiny metastatic deposit within segment 2 of the liver. The images are from the same patient as in the previous two figures. Also note the dilated and thickened lower esophagus
Figure 26: PET/CT axial images showing biopsy proved adenocarcinoma, associated with PSS. Note the intense radionuclide uptake within metastatic mediastinal lymph nodes. The images are from the same patient as in the previous four figures Annals of Thoracic Medicine - Vol 9, Issue 4, October-December 2014
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There is an ever growing list of pathologies associated with BOOP. Bridges and co-workers[58] described two cases associated with PSS with rapidly evolving pulmonary infiltrates, which upon biopsy showed histologic findings of BOOP. As BOOP responds to steroid therapy it is important to differentiate BOOP from SSC and other connective tissue disorders.[58,59] Taylor JG and Bolster MB[59] presented three cases of biopsy-proven BOOP in patients with PSS and MCTD. BOOP and PSS alveolitis have similar findings on spirometry, radiographs, and BAL; the definitive diagnosis of BOOP was made by open lung biopsy. As PSS alveolitis and BOOP are treated differently, histological diagnosis of BOOP is required.
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Summary Intra-thoracic manifestations of PSS are not well known. Imaging features are the key to diagnosis and the basis of accurate and timely intervention. The study illustrates the whole spectrum of intrathoracic manifestations of PSS and aims to familiarize the physician and radiologist with these features.
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How to cite this article: AL-Jahdali H, Rajiah P, Allen C, Koteyar SS, Khan AN. Pictorial review of intrathoracic manifestations of progressive systemic sclerosis. Ann Thorac Med 2014;9:193-202. Source of Support: Nil, Conflict of Interest: None declared.
Annals of Thoracic Medicine - Vol 9, Issue 4, October-December 2014
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Pictorial review of intrathoracic manifestations of progressive systemic sclerosis Hamdan AL-Jahdali, Prabhakar Rajiah1, Carolyn Allen2, Shyam Sunder Koteyar2, Ali Nawaz Khan2
Department of Medicine, King Saud University For Health Sciences, Riyadh, Saudi Arabia 1 Cardiothoracic Imaging Case Western Reserve University, University Hospitals of Cleveland, Cleveland, Ohio, USA, 2 North Manchester General Hospital and Clinical Director, Acute Pennine NHS Trust, Crumpsal, Manchester, UK Address for correspondence: Dr. Dr. Ali Nawaz Khan, Consultant Radiologist and Professor (Hon), North Manchester General Hospital, Acute Pennine NHS Trust, Crumpsal, Manchester M8 6RB, UK. E-mail: drkhan1966@ msn.com Submission: 06-12-2013 Accepted: 03-03-2014
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Website: www.thoracicmedicine.org DOI: 10.4103/1817-1737.140121
Abstract: Intra-thoracic manifestations of progressive systemic sclerosis (PSS) are not well known particularly the imaging features, which forms the basis of accurate and timely diagnosis. The aim of this study is to familiarize the physicians and radiologists with these features. The diagnosis can remain elusive because of the non-specific nature of symptoms which mimic many common conditions. Thus, the diagnosis of PSS can be missed leading to continuous morbidity if the correct imaging is not pursued. The authors examined the records of rheumatology patient referrals of over a 5 year period. A hundred and seventy patients with systemic sclerosis and mixed connective tissue disorders were chosen for detailed study of the imaging available, which form the basis of this review. The images included conventional chest radiographs, digital radiographs computed radiography (CT) and high resolution computed tomography (HRCT). Where applicable computed pulmonary angiography (CTPA) and radionuclide scans were also interrogated. Key words: Imaging, mixed connective tissue disorders, progressive systemic sclerosis, systemic sclerosis
Introduction
P
rogressive systemic sclerosis (PSS) is a connective tissue disease associated with small vessel arterial vasculopathy, inflammatory and immunological processes. The peak incidence is between 45 and 64 years of age.[1] Women are predominantly affected. The cause of PSS is not known. Black Americans suffer from more severe disease as compared to White Americans.[1] The original name of scleroderma was coined because of the hard skin that accompanies the disorder. The disease is termed limited when the hands and face only are involved. Limited disease is at lower risk of visceral involvement although pulmonary hypertension is more common.[2-5] PSS is diffuse disease with multiorgan involvement associated with skin, and inflammatory changes. Three subgroups are described: a. Classical type; b. CREST syndrome; and c. Overlap syndromes associated with other connective tissue disorders such as rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis and polymyositis.[6] The lungs are commonly involved in PSS with a frequency second only to the skin. Esophageal dismotility is common. Respiratory symptoms occur, in a very few cases, as a presenting manifestation. Clinical signs of pulmonary involvement are non-specific and include shortness
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of breath on exertion and subsequently also at rest. Other symptoms reported are non-productive cough, atypical chest pain, fatigue, and dyspnea.[7] Abnormalities of lung function include a restrictive ventilatory defect, airflow obstruction, and reduced carbon monoxide diffusion, which may be an isolated early finding. Interstitial lung fibrosis associated with honeycombed lung is the most common lung parenchymal abnormality on a chest radiographs. Heart enlargement and pulmonary artery dilatation are a common finding on imaging. High-resolution computed tomography (HRCT) can detect asymptomatic disease in PSS. Bronchoalveolar lavage shows an increase in total cell count; there are predominantly lymphocytic cells in alveolitis. The two distinct lung disease patterns on studies on live subjects and autopsy studies: 1. Interstitial lung disease and 2. Pulmonary vascular disease. Pulmonary hypertension may occur in the absence of interstitial lung disease, particularly in patients with limited disease. The overall mortality is reported as 50% at 7 years, with pulmonary complications as the major cause of death.[8] PSS carries the highest mortality among patients with collagen vascular disease, with pulmonary arterial hypertension the leading cause of death. Among patients with PSS, the prevalence of confirmed pulmonary arterial hypertension is around 10-16%.[9] 193
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Interstitial lung fibrosis The incidence of lung involvement in PSS is 74-95% on autopsy series.[10] Lung involvement is less common in CREST syndrome than other types of systemic scleroses [Figure 1]. Interstitial fibrosis occurs in 20-65% of PSS (8, 10). Restrictive pulmonary function tests with a decreased diffusing capacity may precede clinical or radiographic changes.[11,12] Restrictive ventilatory defect, airflow obstruction, and reduced carbon monoxide diffusion may predate lung fibrosis.[11,12] Interstitial lung fibrosis associated with honeycombed lung is the most common lung parenchymal abnormality on a chest radiographs. Figures 2-12 show different patterns of lung fibrosis. High-resolution computed tomography (HRCT) can detect asymptomatic disease in PSS.[8]
extensive esophageal involvement compared with patients with PSS without pulmonary fibrosis.[15-17] It has been postulated that increased episodes of gastroesophageal reflux in these patients could be responsible for the development of pulmonary fibrosis. Although the exact mechanism, of pulmonary fibrosis, remains elusive the authors go on to suggest that these patients with gastroesophageal reflux should be considered for anti-reflux therapy. Figures 2,4-6,9 and 11 showing dilated oesophagus with recurrent aspiration and lung fibrosis. Pulmonary hypertension Pulmonary hypertension (PH) is common and affects 50% of patients with CREST and 33% patients with PSS at
Oesophageal dysmotility Esophageal dysmotility is a common finding and occurs in 74% of cases and may be associated with aspiration pneumonia.[13,14] Recent work indicates that pulmonary fibrosis and gastroesophageal reflux associated with PSS has more a
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Figure 2: 46 year old male with PSS. (a and b) CXR shows volume loss and basal reticular changes suggestive of interstitial lung disease. (c) Axial CT scan shows basal reticular changes, ground glass opacification and traction bronchiectasis in a pattern that is suggestive of NSIP (nonspecific interstitial pneumonia). Note the dilated lower esophagus suggestive of dysmobilty. (d) Prone high resolution CT shows persistent ground glass opacities, reticular changes and traction bronchiectasis, confirming the presence of fibrosis. (e) Coronal CT scan shows the basal distribution of fibrotic changes in PSS Figure 1: PSS is considered limited when involvement is restricted to the distal extremities and face. The limited form is associated with a lower risk of visceral involvement; however, pulmonary hypertension is more common
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b Figure 3: 55 year old female with PSS. (a) Axial supine HRCT shows areas of honeycombing and traction bronchiectasis in the left upper lobe in a patient with proved PSS. (b) Prone CT in the same patient confirms the persistence of the fibrotic lesions 194
d
Figure 4: 48-year-old female with PSS. (a) Axial CT scan shows the presence of volume loss and patchy areas of ground glass opacities in the lower lobes. There is also esophageal dilation, indicating dysmotility. (b) Coronal CT scan shows scattered areas of ground glass opacities associated with volume loss and traction bronchiectasis in a patient with scleroderma. (c) Axial CT scan with soft tissue window shows esophageal dilation. (d) Axial CT scan at a higher level and in soft tissue window show dilated pulmonary arteries, due to pulmonary hypertension Annals of Thoracic Medicine - Vol 9, Issue 4, October-December 2014
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Figure 5: 58-year-old male with PSC. (a) Chest radiograph shows volume loss of lungs and bilateral diffuse, predominantly peripheral and basilar areas of reticular opacities indicative of fibrosis. (b) Axial CT scan shows basal reticular changes in a peripheral distribution along with traction bronchiectasis and architectural distortion. There is also esophageal dilation (c) Coronal CT shows basal and peripheral ground glass opacities, reticular changes, architectural distortion and traction bronchiectasis. (d) Esophagogram shows dilated esophagus due to dysmotility
Figure 6: A PA chest radiograph and axial CT scans in 51-year old male with PSS showing basal fibrotic changes (CXR) a dilated thickened lower esophagus (red arrow), patchy subpleural ground glass, mild bronchial wall thickening, cysts and an air bronchogram (yellow)
a a
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b Figure 7: (a) A PA chest radiograph on 57-year old lady with PSS showing incidental dextrocardia. (b) Axial CT scans showing bilateral reticular basal shadowing due to pulmonary fibrosis
Figure 9: PA chest radiograph on a 67-year female with PSS showing minor bronchial wall thickening at the lung bases also shown on axial CT scans, also note the minor lung fibrosis, and fluid within the lower esophagus Annals of Thoracic Medicine - Vol 9, Issue 4, October-December 2014
Figure 8: Pulmonary hypertension in patient with PSS. (a) Black blood, T2 weighted MRI, image shows dilated pulmonary arteries. (b) Axial steady state free precession (SSFP) image shows dilated pulmonary arteries due to pulmonary arterial hypertension
Figure 10: PA chest radiograph and axial CT scan of a 52-year old male patient with PSS that presented with breathlessness, showing extensive pleural thickening. An old unrelated rib fracture is noted on the right. Also note coarse subpleural fibrosis 195
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angiography.[18] PH is usually secondary to lung parenchymal disease, but primary PH may occur. [19,20] Although large pulmonary arteries and cardiomegaly may be seen on the chest radiographs the, finding is non- specific.[18,21,22] [Figures 4d and 8] Infections Tyndall et al.[23] studied the causes and predictors of mortality in systemic sclerosis (SSc). They obtained questionnaires on 234 of 284 fatalities. 55% of deaths were attributed directly to SSc and 41% to non-SSc causes. Amongst the non-SScrelated causes, infections (33%) and malignancies (31%) were followed by cardiovascular causes (29%). Shalev et al.[24] reviewed the medical records of nine patients with diagnosis of scleroderma (8 female, 1 male), admitted to the intensive care unit between 1991 and 2002. They concluded that the outcome of scleroderma patients admitted to the ICU was extremely poor. Infectious complication was the most common cause of death in these patients. A major contributory factor to this poor outcome was dependent on the severity of the underlying visceral organ involvement, particularly
Figure 11: HRCT of 53 year old man, with PSS showing bilateral basal pleural thickening and minor bronchiectasis. Also note the ground glass appearance and air within the esophagus due to gastroesophageal reflux
Figure 13: Axial CT, at the level of the pulmonary arteries on a patient with known PSS showing extensive mediastinal lymphadenopathy. Other causes of adenopathy were excluded on mediastinoscopy and biopsy. Note the thickened and dilated esophagus. 196
severe pulmonary fibrosis. The severity of this involvement is a poor outcome predictor.[24] Mediastinal lymphadenopathy Gordonson J and associates, [25] first described a patient with mediastinal lymphadenopathy and undifferentiated connective tissue disease. The histology of the lymph node showed follicular hyperplasia with plasmacytosis, a finding seen in rheumatoid arthritis. The lymphadenopathy resolved 10 months after the patient was first seen, but the mixed connective tissue disease persisted [Figures 13 and 14]. Lymphadenopathy is prevalent in patients with SSc and interstitial lung disease regardless of clinical subtype or interstitial pattern. Wechsler et al, [26] found mediastinal lymphadenopathy in 50% of patients with diffuse cutaneous SSc and 40% in patients with limited cutaneous SSc. The authors also describe a significant association of between lymphadenopathy and interstitial lung disease. 2% patients had a ground-glass parenchymal pattern of interstitial disease and 74% had honeycomb pattern. Warrick and associates[27] studied 17 patients with early systemic sclerosis (SSc) that underwent
Figure 12: Axial CT showing a soft tissue density mass in posterior right lower dorsal paravertebral gutter in a patient with known PSS. Note subpleural fibrosis, subpleural cysts/bullae and minor bronchiectasis. Biopsy revealed an adenocarcinoma
Figure 14: Axial CT scans, on another male patient with known PSS showing mediastinal lymphadenopathy (red arrow). Note the dilated esophagus Annals of Thoracic Medicine - Vol 9, Issue 4, October-December 2014
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HRCT of the chest to evaluate dyspnea and/or abnormal pulmonary function tests. Mediastinal lymphadenopathy was detected in 41% of the patients. The authors postulate that ground glass opacities on HRCT may reflect active alveolitis, and mediastinal lymphadenopathy associated with SSc lung disease may be a consequence of pulmonary inflammation.[27] Bhalla and associates,[28] found asymptomatic esophageal dilatation in 80% and mediastinal adenopathy in 60% patients in, scleroderma. The results of their study suggest that CT is useful in the detection of mediastinal adenopathy and asymptomatic esophageal involvement in patients with scleroderma. The findings can help to narrow the differential diagnosis in patients in whom CT shows diffuse interstitial lung disease. [28] G a r b e r a n d a s s o c i a t e s [29] f o u n d t h a t m e d i a s t i n a l lymphadenopathy occurs frequently in patients with SSc, at HRCT particularly if lung involvement is extensive. Their study found mediastinal lymphadenopathy in in 32% patients with lung involvement but in only 8% patients no lung parenchymal disease. The prevalence of mediastinal lymphadenopathy increase with more extensive lung involvement, but there is a poor correlation with the CT appearance and concurrent erythrocyte sedimentation rate. Yoshioka[30] reports a case SSc a 77-year old woman with general fatigue that presented with and mediastinal lymphadenopathy preceding skin changes and lung fibrosis. Mediastinal lymphadenopathy was diagnosed by chest computed tomography before the skin and lung involvements of SSc were discovered. The mediastinal lymphadenopathy resolved with the development of lung fibrosis.[30] Pericardial effusions/myocardial disease The radiological features of scleroderma pericarditis with effusion were first described by Steinberg and Rothbard[31] and later by Nasser WK and associates.[32] Thompson, Pope[33] using a casecontrol format, recruited 37 patients with scleroderma and no known cardiac disease to determine the frequency of pericardial and pleural effusions in scleroderma. Echocardiograms and chest radiographs were performed patients. Age- and gender-matched controls had echocardiograms performed which were read by a cardiologist, blinded to the diagnosis. Pleural effusions were identified in 7% (4/58) of the cohort of scleroderma patients and were more frequent in diffuse disease (10%). A total of 17% (4/23) of diffuse and 4% (1/23) of limited scleroderma patients had evidence of pericardial effusions.[31] The authors concluded that pericardial effusions do occur in scleroderma without evidence of clinical cardiac dysfunction and are more common in diffuse scleroderma. Pericardial effusion associated with scleroderma is usually asymptomatic. The incidence of pericardial involvement in scleroderma is about 50% on autopsy series. Asymptomatic pericarditis occurs in 16% of patients with diffuse disease and 30% of patients with limited scleroderma. A case of scleroderma associated large pericardial effusion, which antedated the other clinical and serologic features of scleroderma.[34] Pleural effusions in scleroderma occur in 70%.[31] Abu-Shakra and associates[35] describe a case of diffuse scleroderma associated with a large pleural effusions, pericardial effusion and subsequent renal failure. Histology of the pericardium and pleura revealed the presence of leukocytoclastic vasculitis.[35] The authors suggest pleuropericarditis in systemic sclerosis may occur as a consequence of vasculitis and large pericardial effusions may predispose to oliguric renal failure.[35] [Figures 15-17]. Annals of Thoracic Medicine - Vol 9, Issue 4, October-December 2014
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b Figure 15: Cardiac involvement in 53 year old female with PSS. (a) Short-axis view of delayed enhancement MRI shows patchy areas of linear mid myocardial enhancement (straight arrows) in the mid ventricular septum and the lateral wall. There is also a moderate sized circumferential pericardial effusion (curved arrow). (b) 3 chamber delayed enhancement MRI shows patchy areas of linear mid myocardial enhancement (straight arrows) and a circumferential pericardial effusion (curved arrow)
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Figure 16: Pericarditis in 42-year-old male patient with PSS. (a) 4 chamber black blood T1 weighted image shows thickening of pericardium, more prominently surrounding the lateral wall of the left ventricle (arrow), consistent with pericarditis. (b) 4-chamber delayed enhancement image shows circumferential delayed enhancement of the pericardium, consistent with pericardial inflammation
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Figure 17: Pericardial effusion in 49-year-old male with PSS. (a) 4 chamber blackblood double inversion recovery sequence areas of loculated pericardial effusion (straight arrows) surrounding the heart. (b) Short axis STIR image in the same patient shows heterogeneous high signal in the pericardial fluid (straight arrow). There is also myocardial edema (arrowheads) in the ventricle indicating myocardial involvement
Cardiac tamponade Inoue et al.[36] describe, a 42-year old Japanese woman with mixed connective tissue disease who developed fulminant hepatic failure and hepatic encephalopathy. Echocardiography revealed a massive pericardial effusion associated with cardiac 197
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tamponade. Bezerra et al.[37] also described a case of fulminant hepatic failure due to cardiac tamponade associated with mixed connective tissue disease. An extremely rare case of cardiac tamponade as an initial manifestation of undifferentiated connective tissue diseases has been reported.[38] The report described a case of a middle-aged man who presented with symptoms of fatigue, exertional dyspnea and orthopnea. His physical exam was significant for anasarca, elevated JVP and pulsus paradoxus. Chest X-ray showed pleural effusions and cardiomegaly the EKG revealed pulses alternans and a transthoracic echocardiography showed a large pericardial effusion associated with circulatory compromise.[36] Right heart catheter study revealed features of cardiac tamponade. Once diagnosed these patients carry the risk developing CDT within 5 years of disease onset and should be followed up in clinic periodically.[36] Briasoulis and associates,[39] report a case of a 24-year old woman admitted with a new onset heart failure and features of cardiac tamponade. Further investigations revealed progressive mixed connective tissue disease associated with severe hypothyroidism. Despite early recognition prompt recognition and prompt treatment with glucocorticoids, thyroxin, metoprolol, lisinopril, furosemide, and milrinone, the patient deteriorated and died within 4 weeks. Pleural disease Pleuritis/pleural effusion/thickening is a general finding in PSS. Pleuritic chest pain occurs in 40% patients. This is common, with pleuritic chest pain in 40%, but radiographic signs of thickening and effusions are less common.[13,14] Diffuse pleural thickening is seen in 20% on HRCT significant effusions are uncommon.[11,12,14,21] There is no pattern to the pleural thickening in mixed connective tissue disease [Figures 10 and 11]. Pleural effusions Taormina and associates [21] analyzed the chest film manifestations of 73 PSS patients which were sub-grouped on the basis of previously described criteria. Radiographic abnormalities, either interstitial lung disease or pleural effusion, were present as follows: Pleural effusions were found in 18% (8/44); CRST/CREST, 0% (0/9); and PSS-overlap syndromes, 75% (15/20). Pericardial effusion associated with scleroderma is usually asymptomatic. The incidence of pericardial involvement in scleroderma is about 50% on autopsy series. Asymptomatic pericarditis occurs in 16% of patients with diffuse disease and 30% of patients with limited scleroderma. A case of scleroderma associated large pericardial effusion, which antedated the other clinical and serologic features of scleroderma.[34] Pleuropulmonary disease and pleural effusions is a common feature of several connective tissue diseases. Pleural effusions in connective tissue disease are non-specific and require exclusion of other causes such as infection. In particular, rheumatoid nodules may mimic infectious and neoplastic lung diseases. In rheumatoid pleural effusions, a needle biopsy may reduce the likelihood of infection or malignancy. Pleural effusions caused in SLE and rheumatoid arthritis (RA) has characteristics on pleural fluid analysis that aid in diagnosis,[40,41] but other causes of effusion may complicate the issue and must be excluded. Moreover, drugs used in connective tissue disease may cause interstitial disease, increase susceptibility to infection, or both. This complicates differential diagnosis. Acute lupus pneumonitis and SLErelated alveolar hemorrhage are usually fulminant processes, 198
often associated with fever.[40,41] Highland, Heffner[42] reviewed the association of pleural effusions and interstitial parenchymal lung disease and the recent reports of occurrence of effusions to include systemic sclerosis, polymyositis-dermatomyositis, several drugs, and several miscellaneous causes of interstitial lung disease.[42] The effusions require a clinical evaluation to exclude complications of therapy and coexisting conditions unrelated to the underlying interstitial lung disease. Pulmonary hypertension is an independent risk factor for pleural effusion irrespective of connective tissue disease. Pleural effusions frequently occur with pulmonary hypertension. A study by Luo et al.[43] in patients with idiopathic and heritable PH demonstrated that pleural effusions frequently occur in patients with isolated right-sided heart failure.[43] The authors found 39.3% patients with PAH associated with CTD had pleural effusions, 45.1% with scleroderma and 27.8% with mixed connective tissue disease. The elevation of tumor markers in SLE, RA, or diabetes mellitus has been reported recently. Kimura and associates[41] report a female patient with PSS and pleuritis that demonstrated a high level of CA125 in her pleural effusion and blood serum. The authors measured the serum levels of CA125 and CA19-9 in 27 female patients with collagen diseases including SLE, PSS, dermatomyositis and Sjögren syndrome, and 11 healthy females as controls. All 27 patients showed no elevation CA125 and CA19-9 as compared with the healthy controls, there was any evident elevation of CA19-9 or CA125 levels in collagen diseases except in the reported case. Elevated serum CA125 may be one of the indicators of pleural effusion in collagen disease. Diffuse alveolar hemorrhage Diffuse alveolar haemorrhage is a rare but potentially serious complication of PSS and may occur with a systemic vasculitis or rarely with isolated pulmonary capillaritis.[44-47] Griffin and co-workers,[44] have described a case of a 41-year-old man with PSS that developed severe diffuse alveolar haemorrhage and died. The authors emphasize the importance of diffuse alveolar haemorrhage as a rare but potentially serious complication of connective tissue disease that should not be overlooked. Chaer and co-workers[45] report a 38-year-old woman with limited cutaneous systemic sclerosis and pulmonary fibrosis with diffuse alveolar hemorrhage during the course of her disease. The patient responded to steroids. Pulmonary thromboemboli in systemic sclerosis Mizoguchi et al. [48] employed ELISA and VDRL tests in order to detect Anticardiolipin antibodies (ACL) antibodies in sera samples obtained from 105 patients with SLE, RA, scleroderma, dermatomyositis, primary Sjögren’s syndrome, vasculitis and pulmonary thromboemboli. ACL antibodies were detected in 4 patients out of 11 scleroderma, 1 patient out of 7 vasculitis, 2 patients out of 5 primary Sjögren’s syndrome, and 3 patients out of 6 pulmonary thromboemboli. Mizoguchi and co-workers[49] have reported a case of recurrent pulmonary embolism due to intracardiac thrombi in systemic sclerosis. Pulmonary endothelium plays an important role in the mechanism of PAH. A study by Peled and co-workers[50] postulates that a systemic component of endothelial dysfunction might be involved in idiopathic, scleroderma-associated and chronic Annals of Thoracic Medicine - Vol 9, Issue 4, October-December 2014
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thromboembolic PAH that is correlated with disease severity [Figure 18]. Lung neoplasms Houser and Jonsson SM(50) reported a case of lung cancer associated with PSS and conducted a brief review. Richards RL & Miline JA[51] reported two cases in which cancer was associated with PSS. The authors reviewed 4 other cases previously reported. They found no evidence of an intimate association between malignant disease in general and PSS such as found dermatomyositis. In only one of the six patients, a bronchial carcinoma and the cutaneous and vascular changes of PSS develop together in a patient with previously normal lungs. In the other 5 patients, the lung manifestations of PSS preceded the lung cancer by a number of years, and in these pathological changes of the primary disease were present in parts of the lungs unaffected by tumour. The authors concluded that there was good evidence that PSS may predispose to the development of cancer of the lung. Adzić et al.[52] reviewed 375 patients; with CTD six of these (25%) had PSS. The authors analysed lung cancer (LC) stage, clinical presentation, histological type, patients’ smoking status, method of diagnosis, treatment applied, and disease outcome. The majority of CTD patients who developed lung cancer were diagnosed at an advanced stage and had poor survival. Efforts for early detection of LC in CTD patients’ group are warranted. Lung cancer is the most frequent cancer seen in patients with PSS, followed by breast cancer. Cancer is associated with PSS in between 3.6 and 10.7% of patients.[53] The diagnosis of PSS may occur before, concurrent with, or after the diagnosis of malignancy. Risk factors for the development of malignancy in patients with PSS are female gender, increased age, and diffuse systemic sclerosis. There is no consistent relationship with autoantibodies such as anticentromere and antitopoisomerase and the risk of developing cancer in PSS.[54] In a study by Colaci et al.[55] in which two thousand and 40 patients with PSS were reviewed and concluded that systemic sclerosis is a risk factor for cancer, particularly smoking- and alcohol-related cancers. Men with systemic sclerosis is at a higher cancer risk than women. Both primary and secondary cancer preventive measures are needed in the care of patients with systemic sclerosis. In their study results from an Italian rheumatologic center and review of the literature Colaci et al.[56] confirmed the higher frequency of lung cancer among PSS patients compared to the general population, particularly within patients’ subset with serum anti-Scl70 antibodies and lung involvement. [Figures 12,19,20,21-25] Neuromuscular respiratory failure in PSS Peripheral neuropathy may be a cause of ventilatory muscle weakness found in MCTD and systemic lupus. Martyn and co-workers[57] reported a 34-year-old female patient with MCTD who developed severe pulmonary and neuromuscular complications. She presented initially with myasthenia gravis and then polymyositis, profound peripheral neuropathy, and respiratory muscle failure. Eventually she died despite aggressive immunosuppressive therapy and plasmapheresis. Autopsy revealed spinal cord changes secondary to a peripheral neuropathy and signs of neurogenic atrophy confined to the respiratory muscles.[57] [Figure 26]. Annals of Thoracic Medicine - Vol 9, Issue 4, October-December 2014
a
b
c
d
Figure 18: CT images showing major but non-occlusive pulmonary embolism in a patient with known PSS. Figure a and b are axial and coronal CT scans showing multiple pulmonary emboli (red arrows). Figures c and d are from the same patient showing pulmonary emboli associated with pulmonary fibrosis
a
b
Figure 19: (a) PA chest radiographs of a patient with known PSS that presented with a weight loss of 3.2 kg and left shoulder pain. The two radiographs are 6 months apart. Figure b show a suggestion of a mass lesion at the right cardiophrenic angle (red arrow)
a
b Figure 20: a and b are from the same patient as in the previous two figures confirming a mass at the right cardiophrenic angle associated with pulmonary fibrosis and destruction of the left scapular blade (red arrow) highly suggestive of a metastatic deposit. The patient is awaiting a biopsy for tissue typing
Bronchiectasis and bronchiolitis obliterans organizing pneumonia (BOOP) Bronchiectasis has been reported in 14% in, association with MCTD on HRCT usually secondary to traction of the airway secondary to from fibrosis or due to recurrent aspiration and infection[58] [Figures 2-5]. 199
Al-Jahdali, et al.: Thoracic manifestations of progressive systemic sclerosis
Figure 21: Coronal images of a patient with MCTD and peripheral neuropathy. This patient had paradoxical movement of the diaphragm on fluoroscopy and non-existent thoracic excursion in keeping with neuropathy. Note the extensive pulmonary fibrosis, multiple cysts/bullae, pleural thickening and the elevated right hemidiaphragm
Figure 23: Pre and post contrast axial CT scans showing the right posterior gutter mass and mediastinal lymphadenopathy. Note the dilated esophagus (the same patient as in the previous figure). Also see the following three figures showing PET/CT images
Figure 25: PET/CT coronal and axial images showing biopsy proved, adenocarcinoma, associated with PSS. Note the intense radionuclide uptake within the tumor and mediastinal lymph nodes and a tiny metastatic deposit within segment 2 of the liver. The images are from the same patient as in the previous three figures. Also note the dilated and thickened lower esophagus 200
a
b
c
d
Figure 22: (a) Axial CT scan shows basal fibrotic changes (curved arrows) and a welldefined mass in the anterior aspect of the left upper lobe (straight arrow). (b) FDG-PET image shows high uptake in the lesion in the left upper lobe (straight arrow), indicative of malignancy. There is also high uptake in left hilar lymph node (curved arrow), indicative of metastasis. (c) Fused PET-CT image shows high uptake in the tumor and left hilar lymph node. (d) Fused PET-CT image shows high uptake in the lymph node. The tumor was biopsy proven to be moderately differentiated adenocarcinoma
Figure 24: PET/CT showing biopsy proved, adenocarcinoma, associated with PSS. Note the intense radionuclide uptake within the tumor and mediastinal lymph nodes and a tiny metastatic deposit within segment 2 of the liver. The images are from the same patient as in the previous two figures. Also note the dilated and thickened lower esophagus
Figure 26: PET/CT axial images showing biopsy proved adenocarcinoma, associated with PSS. Note the intense radionuclide uptake within metastatic mediastinal lymph nodes. The images are from the same patient as in the previous four figures Annals of Thoracic Medicine - Vol 9, Issue 4, October-December 2014
Al-Jahdali, et al.: Thoracic manifestations of progressive systemic sclerosis
There is an ever growing list of pathologies associated with BOOP. Bridges and co-workers[58] described two cases associated with PSS with rapidly evolving pulmonary infiltrates, which upon biopsy showed histologic findings of BOOP. As BOOP responds to steroid therapy it is important to differentiate BOOP from SSC and other connective tissue disorders.[58,59] Taylor JG and Bolster MB[59] presented three cases of biopsy-proven BOOP in patients with PSS and MCTD. BOOP and PSS alveolitis have similar findings on spirometry, radiographs, and BAL; the definitive diagnosis of BOOP was made by open lung biopsy. As PSS alveolitis and BOOP are treated differently, histological diagnosis of BOOP is required.
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Summary Intra-thoracic manifestations of PSS are not well known. Imaging features are the key to diagnosis and the basis of accurate and timely intervention. The study illustrates the whole spectrum of intrathoracic manifestations of PSS and aims to familiarize the physician and radiologist with these features.
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How to cite this article: AL-Jahdali H, Rajiah P, Allen C, Koteyar SS, Khan AN. Pictorial review of intrathoracic manifestations of progressive systemic sclerosis. Ann Thorac Med 2014;9:193-202. Source of Support: Nil, Conflict of Interest: None declared.
Annals of Thoracic Medicine - Vol 9, Issue 4, October-December 2014
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