The diagnose of sarcoidosis should followed three basic criteria which contained clinical features, radiography and histopathological evidence. Patients with pulmonary sarcoidosis usually presented as non-specific constitutional complaints (e.g. fever, weight loss, fatigue, anorexia, malaise) and/or symptoms directly related to the respiratory (e.g. cough, dyspnoea, particularly with exertion, chest pain and, occasionally, haemoptysis). Early in the disease, the physical findings in the chest are usually limited to dry, crackling rales, most commonly heard at the posterior base of the lung. In histopathology evidence, the biopsy sample of sarcoidosis usually contained non-caseating epithelioid granulomas.
In radiography of sarcoidosis patients, according to ATS/ERS/WASOG statement on sarcoidosis, the typical HRCT manifestations which have been seen in 90% of patients including both hilar-mediastinal lymphadenopathy and micronodules with a perilymphatic and fissural distribution in both lungs, upper and posterior predominantly. The clinical classification of sarcoidosis based on Scadding radiographic staging: Stage 0: Corresponds to the normal sign of radiology of lymph nodes and lungs; Stage I: Bilateral hilar and mediastinum lymph node enlargement with or without paratracheal lymphadenopathy, not associated with visible lung disease; Stage II: Bilateral hilar lymph node enlargement associated with visible lung disease; Stage III: Diffuse lung disease without lymph node enlargement; Stage IV: Lung and bronchial variation (e.g. lung fibrosis with honeycombing pattern)[12, 13].
However, The atypical patterns contained large nodules and masses, alone or associated with enlarged lymph nodes (1-4 cm in diameter, large ill-defined opacities on CT), distribution could be variable in different patterns, and small satellite nodules could also be visible at the periphery of these masses, leading to the “galaxy sign” appearance. Diletta Cozzi summarized the previous studies and concluded that 25-30% of patients develop unusual sarcoidosis with non-specific radiological patterns, which are various and in different frequencies.
The atypical lesion patterns in lung parenchymal included large pulmonary nodules and masses, patchy air space consolidations, patchy ground glass opacities and areas of air trapping and mosaic attenuation. Opacities represent confluent and coalescing nodules in the interstitium or the acini of the lung parenchyma and often superimposed on the background of the interstitial nodules. Mosaic attenuation occurred in the patients with small airway involvement. Ma J et.al. concluded 190 patients’ chest CT manifestations and clinical characteristics from 2000 to 2015 in their hospital. The result showed that the atypical chest CT manifestations of sarcoidosis mainly included unilateral hilar lymphadenopathy with or without mediastinal lymphadenopathy (n=12, 6.3%), mediastinal lymphadenopathy without hilar lymphadenopathy (n=9, 4.7%), patchy consolidation (n=23, 12.1%), sarcoid galaxy sign (n=22, 11.6%), reversed halo sign (n=1, 0.5%), ground glass opacities (n=52, 27.4%). And 8 out of 10 patients who underwent inspiratory and expiratory CT showed air-trapping phenomenon. They re-evaluated CT images of these patients after treatment, and the majority of atypical chest CT manifestation of sarcoidosis patients showed an improvement of lesions.
When the radiology showed atypical findings, clinicians should consider clinical presentation as well as histopathological testing for achieving diagnose.
- Pulmonary nodules or Mass-like opacities
Mass-like opacities is one of the atypical manifestations in sarcoidosis patients’ imaging performance, the differential diagnosis of which based on imaging findings contained lymphoma, vasculitis, and atypical pulmonary infection. The lung consolidation that influenced alveoli and airspaces distributed in the peribronchovascular areas of the upper and middle lungs. It was reported that pulmonary nodules and masses occurred in 15%-25% of sarcoidosis patients with parenchymal opacities which usually presented in 1-4 cm in diameter that represent coalescent interstitial granulomas distributed in perihilar and bilateral, perihilar or peripheral regions commonly[18-20]. Clinicians should aware of the metastatic possibility if multiple rounded macronodules scaled out 5 mm in diameter occurred in radiographs.
Marie Tominna et.al. reported a 30 years old African American woman diagnosed with sarcoidosis who manifested in distributed, sharply demarcated, mass like ground glass opacities in both lungs. And CT showed right paratracheal, bilateral hilar, para-aortic, subcarinal and perivascular lymphadenopathy. Histopathology findings revealed noncaseating granulomas, consistent with sarcoidosis diagnosis. And treatment of corticosteroids to this patient showed a good response.
A. Atig et.al reported a 62 years old woman who manifested in dyspnea came into clinic and chest CT exams showed a mass consolidation in right lower lobe, coexistent with bronchovascular bundles thickening and mediastinal lymphadenopathy. However, after transbronchial lung biopsy, the histopathology result turned out to be neither malignancy disease nor granulomatous. The bronchoalveolar lavage fluid tests showed neither alveolitis nor tumor cells. They decided to give the patient diagnose of systemic sarocidosis with pseudo-tumor pulmonary affection. After treatment with corticosteroids for 3 years, the repeat radiology image showed an improvement of lesions, which suggested previous diagnose of sarcoidosis.
Dylan W.Kelleher et.al. reported a 44-year-old African woman with a history of childhood asthma and type 2 diabetes mellitus presented with shortness of breath. Her chest radiograph revealed a mass-like opacity in the left lower lobe, and her chest CT scan showed a large, 6.7×5.4×9.9-cm left lower lobe mass and hilar lymphadenopathy. Thus, according to the existing evidence, the patient was suspected to pulmonary malignancy firstly. In order to ascertain diagnose, the patient underwent computed tomography-guided biopsy of the lung mass, and the result revealed a multifocal non-necrotizing granuloma with multinucleated giant cells. Biopsy of bronchoscopy and mediastinoscopy revealed granulomatous inflammation without evidence of malignancy or infection. According to the histopathology result, she was confirmed diagnose of sarcoidosis. Then she was treated with high-dose prednisone, and repeat imaging showed a significantly shrinking of lung mass and lymphadenopathy.
Kwas Hamida et.al reported a 37-year-old woman, who manifested in chest pain, cough, fever, anorexia and weight loss within the past 15 days. Chest X-ray showed diffuse and bilateral alveolar opacities with air bronchograms. Chest CT scan showed diffuse and bilateral alveolar consolidation, perilymphatic distribution of micronodules and mediastinal lymphadenopthy. Laboratory examination showed elevated serum angiotensin converting enzyme (ACE) level (140 UI/ml). BALF represented lymphocytic alveolitis but CD4+/CD8+ ratio didn’t higher than normal. The histopathology of bronchial biopsy showed non-caseous epithelioid cell granuloma. Thus, diagnose of sarcoidosis could be generated. After 5 months of oral corticosteroid treatment, the patient declared a relief of her syndrome.
When sarcoidosis patient manifested in solitary pulmonary nodule, the clinicians ought to pay attention to the differential diagnosis of malignant disease. Han Na Lee et.al reported a 52-year-old woman who presented with uveitis, fever of unknown origin and atypical manifestation of sarcoidosis. Her chest computed tomography showed solitary pulmonary nodule, which enlarged 0.4 cm over 18 months. And the serum angiotensin converting enzyme (ACE) was 71.6U/L, higher than normal. However, the histopathology of thoracoscopic wedge resection for a nodule and excisional biopsy for a lymph node showed several small non-caseating granulomas adjacent to the bronchiolar epithelium, which confirmed the diagnosis of sarcoidosis.
Haykel Abdelhedi et.al reported a case of a 56 years old woman whose chest CT showed asymmetric mediastinal and bilateral hilar compressive lymphadenopathy. The chest radiography showed bilateral hilar enlargement, and pulmonary nodules, size in 5 to 10 mm diameter, were scattered in right upper lobe, right middle lobe medial segment, lateral basal segment and sub-pleural. However, these micronodules predominantly diffused in right mid-lobe and formed as tree-bud pattern in some area. FOB (Fronchofiberscope) showed granulomatous diffused along the bronchial. The histopathology of TBLB presented as ephithelial and giant cell inflammation without caseous necrosis. BALF showed CD4+ T cell proliferation, and CD4+/CD8+ ratio was 4.5, higher than normal. This case indicated that when chest image manifested in multiple nodules dissemination, the differentiation diagnose of sarcoidosis should consider tumor (e.g., metastasis, lymphoma) firstly and infections (e.g., tuberculosis) secondly. When it occurred, the histological biopsy tests could be beneficial to figure out.
- Ground glass opacities
Chunmei Ma et.al reported a case of a 40-year-old Chinese woman presented to the hospital with cough and a history of recurrent rash on the skin of the wrist and knee which resolved spontaneously. The chest CT revealed the presence of diffused ground glass opacity with minor lymphadenopathy. The histopathology of transbronchial biopsy indicated the epithelial granulomas with no caseous necrosis. Patient confirmed diagnose of sarcoidosis.
3. Sarcoid cluster sign
I. Herráez Ortega et.al reported a new atypical appearance in HRCT with the description of the presence of clusters of multiple small micronodules distributed in the non-subpleural peripheral regions of the upper and middle fields of the lungs, sometimes along the lymph vessels on HRCT, and given the name “sarcoid cluster sign” (SCS).
4．Sarcoid galaxy sign
Masashi Nakatsu et.al firstly defined the “Sarcoid Galaxy” sign as an atypical manifestation of pulmonary sarcoidosis chest CT appearance. The appearance of characteristic CT pattern is that the large parenchymal nodules in pulmonary sarcoidosis appeared with some noncaseating small granulomas surrounding nearby loosely which are similar to a “galaxy”, tending to coalesce into a large nodule and usually accompany with mediastinal and hilar lymphadenopathy. Nodules in sarcoidosis mostly distributed along lymphatics in bronchovascular bundles.
Alveolar or pseudoalveolar sarcoidosis present in reversible consolidations with peripheral distribution as its typical presentation in “galaxy” sign. Paul McCabe reported a case that a 27-year-old woman’s HRCT presented in atypical opacities with galaxy sign with mediastinal lymphadenopathy.
- Reversed halo sign (RHS)
Edson Marchiori et.al reported that reversed halo sign, ground-glass attenuation surrounded by a partial or complete rim of consolidation, is an atypical tomographic feature of sarcoidosis. However, this description was often used to describe cryptogenic organizing pneumonia and some other diseases, including infectious (aspergillosis, blastomycosis, tuberculosis) and non-infectious conditions (drugs, hematological malignancy, granulomatosis with polyangiitis, hypersensitivity pneumonitis, inflammatory bowel disease, inhalation injury, irradiation injury, and transplantation)[32, 33]. Thus, in this circumstance, the clinical manifestations and histopathology tests counting more. Ajmal Nazir Neelambra et.al reported a 32 years old female presented with dry cough and progressive dyspnea for 3 weeks, her chest HRCT showed peripherally based patchy, subsegmental lesions of the upper lobe and left lower lobe. After systemic treatment of steroids for 3 months and gradually tapered to stop, the lesions on chest HRCT disappeared accompanied with the relief of her syndrome, which demonstrated the good responds to steroids therapy. In this case, the patient was diagnosed with cryptogenic organizing pneumonia and sarcoidosis, in that neither single diagnose could explain her syndrome or other tests results.
- Pulmonary cavitary
A cavitary lesion was defined as an air-containing lesion of more than 1-cm diameter with either thin walls (≤4mm) or thick walls (＞4 mm or located within an infiltrate or a mass). These lesions differed from the honeycombing feature occasionally observed in fibrotic sarcoidosis based on the heterogeneity of the size of the cysts and based on the presence of normal lung seperated rows of clustered cysts. Sandrine Hours et.al retrospectively reviewed the chest HRCT characteristics of 23 sarcoidosis patients with pulmonary cavitary lesions extracted from a large cohort of patients with pulmonary sarcoidosis in their hospital from 1988 to 2005. They concluded that about 82.6% of patients with cavitary, accompanied with granulomatous lesions around the cavitary, had high levels of SACE that suggested the active disease status. Complications of cavitary lesions including hemoptysis, aspergilloma, pneumothorax, and other infections were seen in these patients.
- Atypical pattern of Lymphadenopathy
Intrathoracic lymphadenopathy is the most common findings in sarcoidosis with bilateral hilar lymphadenopathy (BHL) alone or with mediastinal lymphadenopathy, occurs in 95% of patients. Whereas, unilateral or asymmetric lymphadenopathy and “egg-shell-like” calcifications in lymph nodes are atypical patterns of sarcoidosis. M.E. BEIN et.al reported that they analyzed 62 sarcoidosis patients’ chest radiographs, and the result turned out that approximately 95% patients had lymph nodes enlargement, 75% in the right paratracheal or aortopulmonic window regions and about 20% in the subcarinal or anterior mediastinal regions. And the most common lymphadenopathy combination features included aortopulmonic window, bilateral hilar, and right paratracheal regions .
Dylan W.Kelleher et.al reported a 44-year-old African woman with a mass-like opacity in the left lower lobe, and her chest CT scan showed a large, 6.7×5.4×9.9-cm left lower lobe mass and hilar lymphadenopathy. Thus, according to the existing evidence, the patient was suspected to pulmonary malignancy firstly. In order to ascertain diagnose, the patient underwent computed tomography-guided biopsy of the lung mass, and the result revealed a multifocal non-necrotizing granuloma with multinucleated giant cells. Then she was treated with high-dose prednisone, and repeat imaging showed a significantly shrinking of lung mass and lymphadenopathy.
Andrew Meillier et.al reported a case that a 38-year-old Caucasian female, manifested in chronic cough, fatigue and a loss of appetite for 6 weeks, physic exam showed right facial droop which indicated Bell’s palsy syndrome. The chest CT showed unilateral lymph node enlargement in aorto-pulmonic window. PET/CT showed multiple active lymph nodes in the mediastium. EBUS showed a mediastinal mass. The histopathology of mediastinal mass and lymph node indicated non-caseating lymphadenophathy with focal necrosis. The pathology denied malignancy. However, the clinical, radiological and pathological results suggested diagnose of sarcoidosis.
- Pleura involvement of sarcoidosis
Involvement of pleura by sarcoidosis remains a rare manifestation and varies from pleural effusion, pneumothorax, pleural thickening, hydropneumothorax, trapped lung, hemothorax, or chylothorax. Onkar Jha et.al reported a case of a 65-year-old male, presented as 4 months history of dry cough, dyspnea and intermittent fever. His chest X radiation showed right lower zone nonhomogeneous opacity. However, his sputum smear was negative for acid-fast Bacilli (AFB). Contrast enhanced computed tomography (CECT) chest showed multiple discrete and conglomerating heterogeneous mediastinal and bilateral hilar lymphadenopathy with few showing calcification and nonhomogeneous attenuation. Moreover, ill-defined right lower lobe ground glass opacities with minimal pleural effusion also presented on the image. PET/CT showed multiple fludeoxyglucouse (FDG) avid lymph node revealed in prevascular, aortopulmonary window, bilateral paratracheal, sub-carinal, para-esophageal and bilateral hilar regions with FDG avid inter- and intra-lobular nodular septal thickening with multiple small nodules in perilymphatic distribution along the fissures and subpleural locations involving both lungs. EBUS showed large heterogeneous lymph nodes at stations 7, 4R, 4L, 10R and 10L. TBLB showed non-necrotizing granulomatous inflammation in the interstitium and sub-bronchial mucosal granulomas. Thus, diagnose of sarcoidosis could be made. Remi Trien et.al reported a case of a 43-year-old woman who diagnosed with sarcoidosis and probably induced by interferon-alpha-2b, which was used to treat her history disease hepatitis C. The chest radiograph showed bilateral diffuse prominence of bronchovascular markings. Chest computed tomography showed centrilobular nodules in bilateral lung parenchymal with intralobular septal thickening. Moreover, the other accompanied characteristics included central peribronchovascular interstitium, nodularity of major fissures, mediastinal lymphadenopathy. The histopathology of enlarged lymph nodes in mediastinal appeared non-caseating granulomatous inflammation, which consistent with diagnose of sarcoidosis.
Massive hemoptysis occurred approximately less than 0.5% of the patients. Wang'ondu RW et.al reported a 45-year-old male with a history of stage IV pulmonary sarcoidosis with cardiac involvement, presented as a two months history of cough and acute non-massive hemoptysis with hypoxia. The chest CT showed ground-glass consolidation and interlobular septal thickening. The clinical manifestation and image characteristic suggested diagnose of diffuse alveolar hemorrhage (DAH). Masoud Nazemiyeh et.al reported a rare presentation of pulmonary sarcoidosis with massive hemoptysis in early course of disease rather than lung parenchymal involvement.
- SLS-Sarcoidosis lymphoma syndrome
Assad Oskuei et.al reported a patient had both sarcoidosis and a B-cell lymphoma with features of splenic marginal zone lymphoma (SMZL). Chest CT showed lymphadenopathy in mediastinum, hilar regions and in both axillae; in the lung parenchyma there were multiple areas of consolidation scattered diffusely, bilaterally, worse at the lung bases. The radiology manifestation was consistent with the suspicion of malignancy disease (lymphoma or bronchoalveolar cell carcinoma) or cryptogenic organizing pneumonia. After bronchoscopy and bronchoalveolar lavage result showed negative, which contained cytology, tuberculosis smear, bacterial and fungal cultures. Left axillary lymph node biopsy showed necrosis. After prednisone tapering therapy, the patient admitted an improvement of syndrome and the repeat CT image showed attenuation of opacities. The right upper, middle and lower lobes histopathological evaluation revealed multifocal well-formed non-necrotising granulomatous. SACE and hypercalcaemia levels showed elevated which supported sarcoidosis diagnose. After treatment for a year, the patient complaint left upper abdominal pain, and physic exam presented with massive splenomegaly. Then he was treated with splenomegaly and histopathological assessment showed a low-grade B-cell lymphoma consistent with marginal zone lymphoma with extensive plasmacytic differentiation reflected by the presence of component of lambda restricted plasma cells involving the spleen and perisplenic lymph nodes. Thus, the clinical features and pathology characteristic supported diagnose of sarcoidosis and lymphoma.
- Necrotizing sarcoid granulomatosis (NSG)
Te-Chih Hsiung et.al reported a case of 35-year old man who manifested in fever and night sweating with a history of pulmonary tuberculosis exposure history. His chest CT showed a 3×4 cm left paratracheal lymphadenopathy. The histopathology of EBUS guided TBNA presented as granulomatous inflammation with focal necrosis and perivascular involvement. The tests of microbiology study, septum acid-fast stain and mycobacterial cultures for tuberculosis showed negative results. Tuberculin skin test with purified protein derivative showed a positive result (induration greater than 15mm). However, after anti-tuberculosis treatment for 2 months, the repeat chest CT scan showed progression of mediastinal lesions and newly developed pulmonary infiltration in the left upper lung. In BALF, the lymphocyte ratio had increased (30%), the CD4/CD8 ratio had increased 8 times than normal. A diagnose of necrotizing subtype sarcoidosis with potential tuberculosis infection was formulated. After oral prednisone treatment for 1 month, the patient's clincal and radiological aspects showed improvement.
- Pleural plaquelike opacities
Pathces of subpleural micronodules which usually occurred on the visceral pleural that referred to “pseudoplaques”, which are formed by multiple coalescent micronodules (granulomas) with well-defined irregular margins and usually detected in upper and middle zones of both lungs.
- Airway involvement
Airway involvement could be atypical manifestations in HRCT of patients with sarcoidosis. The most common appearances included mosaic attenuation pattern, air trapping, tracheobronchial abnormalities and atelectasis. Due to the small airways involvement, which may be secondary to peribronchiolar granulomas or fibrosis that could generate obstruction, air trapping and mosaic attenuation patterns on expiratory CT are common radiological features of pulmonary sarcoidosis[45, 46].
A comparison between atypical and typical sarcoidosis in progression, recurrence, prognosis, treatment underwent by Roberta Polverosi et.al. In this research, they concluded 56 patients with pulmonary involvement of sarcoidosis. However, 39 of them showed typical patterns and the other 17 appearanced with atypical patterns in chest HRCT. However, they figured out that in these untreated sarcoidosis patients, people with typical patterns showed more stable in radiologic findings than patietns with atypical appearance. Recurrences occurred more often in patients with typical patterns than atypical groups.
Detecting atypical sarcoidosis is still a difficulty in sarcoidosis diagnosis. We here concluded three atypical manifestations in chest HRCT images of sarcoidosis patients and reviewed articles on “pubmed” database that including ‘atypical’ and ‘sarcoidosis’ key words, and reviewed the articles of lung involvement, intending to remind clinicians to notice unfamiliar appearances of sarcoidosis. Moreover, atypical manifestations in chest radiology images of sarcoidosis sometimes resemble to the differential diagnoses, including granulomatous disorders (tuberculosis, leishmaniosis, tularaemia, fungal disease, sarcoidosis-lymphoma-syndrome), infectious disease (myobaterial, fungal), non-infectious disease (hodgkin and non-hodgkin lymphomas, sarcomas, silicosis, berylliosis). There is a metaphor that sarcoidosis could be described as “the great pretender” since its manifestations can present as different disease manifestation. The combination of clinical history, histopathology evidence and HRCT could help to differentiate sarcoidosis.