British Journal of Radiology (2007) 80, e162-e166
© 2007 British Institute of Radiology
doi: 10.1259/bjr/46361210
Reversed halo sign in lymphomatoid granulomatosis
R E Benamore, MB BChir, MRCP, FRCR
1
G L Weisbrod, MD, FRCPC
1
D M Hwang, MD, PhD, FRCPC
2
D J Bailey, MD, FRCPC
2
A F Pierre, MD, MSc, FRCSC
3
N M Lazar, MD, FRCPC
4 and
N Maimon, MD
4
Departments of 1 Medical Imaging, 2 Pathology, 3 Thoracic Surgery and 4 Respirology, Toronto General Hospital, NCSB, 1C- 571, 585 University Avenue, Toronto, Ontario, M5G 2N2, Canada
Correspondence: Dr Rachel E Benamore, Department of Medical Imaging, Toronto General Hospital, NCSB, 1C-571, Toronto, M5G 2N2, Canada. E-mail: rachelbenamore{at}doctors.org.uk
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Abstract
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Lymphomatoid granulomatosis is a rare lymphoproliferative disorder which affects extranodal sites, most commonly lung. Radiologically, it typically presents with multiple nodular opacities that may wax and wane. The reversed halo sign has previously been reported in cryptogenic organizing pneumonia and more recently in South American blastomycosis. We describe a case of histologically proven lymphomatoid granulomatosis in a patient who presented initially with the more typical nodular opacities, which subsequently progressed into the reversed halo sign. To the best of our knowledge, this association has not been previously described.
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Case report
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A 50-year-old woman was referred to our institution in April 2004 for consideration for open lung biopsy. She was an ex-smoker and had no significant past medical history or other environmental risk factors for respiratory disease. Prior to referral, she initially presented to her family doctor in August 2003 with cough, fevers and fatigue. Her initial chest radiograph (CXR) demonstrated bilateral ill-defined nodular air space opacities. She was treated with several courses of antibiotics, but neither her clinical symptoms nor her CXR appearances improved. A chest CT in November 2003 demonstrated multiple small nodules distributed throughout the lungs (Figure 1
). Bronchoscopy, transbronchial biopsy (TBB) and bronchoalveolar lavage (BAL) revealed an increased proportion of eosinophils in the lavage fluid (15%). She improved somewhat with no treatment and her CXR in December 2003 was normal. A repeat CXR and CT in February 2004 showed worsening, with multiple air space opacities in the mid and lower zones (Figure 2). At the time of initial referral to our institution in April 2004, she still described constitutional symptoms. Since her clinical status was stable, she received no treatment after initial consultation. Repeat CT in May 2004 showed significant improvement, with some residual nodular ground glass opacities in the lower zones (Figure 3). She was assessed clinically in June and was virtually asymptomatic. Physical examination revealed scattered bibasal crackles and pulmonary function tests were normal. In July 2005, she had recurrence of night sweats, but no respiratory symptoms. Clinical examination remained unchanged. A repeat bronchoscopy with BAL and TBB was non-diagnostic. CXR showed recurrence of multiple ill-defined nodular opacities throughout both lungs, which were more florid than on previous examinations. CT showed multiple nodules and the reversed halo sign (Figure 4).
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Figure 1. Unenhanced CT of the thorax on lung window settings, November 2003. There are multiple small(approximately 1 cm) nodules throughout the lungs, with no zonal predominance. Some have ill-defined borders and appear to represent air space disease. No significant lymphadenopathy was demonstrated on mediastinal window settings.
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Figure 2. Unenhanced CT thorax on lung window settings February 2004. The chest radiograph(CXR) from December 2003 was normal. Selected images are at the same anatomical levels as the previous scan. There has been enlargement of the small nodules in both upper lobes and right lower lobe in the posterior costophrenic recess. New nodules are also seen, some of which are coalescing into areas of consolidation in the middle lobe and anterobasal segment of the right lower lobe.
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Figure 3. Unenhanced CT of the chest, May 2004. There has been significant improvement in the nodules and consolidation, with residual nodular areas of ground glass opacity in the mid and lower zones.
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Figure 4. (a) Chest radiograph (CXR) July 2005. There are multiple, bilateral, ill-defined nodular air space opacities, with lower zone predominance. Some of these appear to be cavitating on this plain radiograph. (b) Unenhanced CT chest, July 2005. There are multiple opacities, with central areas of ground glass opacity surrounded by denser crescentic consolidation at least 2 mm in thickness. This is described as the reversed halo sign. These areas are admixed with poorly defined nodules. These abnormalities do not all clearly correspond to sites of previous disease involvement.
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Cryptogenic organizing pneumonia (COP) was considered most likely clinically and radiologically, but to confirm the diagnosis the patient underwent an open lung biopsy (Figure 5). This showed a patchy, angiocentric, intense lymphoid infiltrate composed predominantly of small lymphocytes admixed with histiocytes and occasional plasma cells, with focal areas of angioinvasion. There were only rare, large, transformed lymphocytes present. No necrosis was detected. Immunohistochemistry revealed a T cell-predominant infiltrate, with only occasional small B cells identified. The large majority of the T cells were of the CD4-positive (helper-inducer) subset. No aberrant T cell phenotype was identified. No staining was detected for Epstein–Barr virus (EBV) by EBER in situ hybridization. Features were in keeping with grade 1 lymphomatoid granulomatosis.
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Figure 5. (a) Low-power view shows central areas of air space filling (A) with oedema fluid and foamy histiocytes, surrounded by a denser rim of lymphocytic infiltration (L). (b) High-power views show areas of angioinvasion (I). (c) The inset image shows CD3-positive T cells (darkly staining) completely infiltrating (I) a vessel. The outline of the vessel wall is accentuated by the lack of staining.
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Discussion
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Voloudaki et al [1] described the CT findings of two patients with COP (formerly bronchiolitis obliterans organizing pneumonia or BOOP) who demonstrated crescentic and ring-shaped opacities that surrounded areas of ground glass attenuation. The central areas of ground glass attenuation correlated with alveolar septal inflammation and cellular debris in alveolar spaces, whereas the denser peripheral areas corresponded to granulomatous tissue in peripheral air spaces. Kim et al [2] were the first group to describe this particular CT feature as the "reversed halo sign", which is defined as central ground glass opacity surrounded by denser consolidation shaped like a crescent (forming more than three-quarters of a circle) or ring (forming a complete circle) that is at least 2 mm in thickness. The authors suggested the sign may be specific for the diagnosis of COP. Gasparetto et al [3] found the reversed halo sign to be present in 10% of patients infected with South American blastomycosis (paracoccidioidomycosis). Pathologically, the central area of ground glass consisted of an inflammatory infiltrate in the alveolar septa, composed of macrophages, lymphocytes, plasma cells and giant cells, with relative preservation of the alveolar spaces. The peripheral areas of consolidation corresponded to dense and homogeneous intra-alveolar inflammatory infiltrates, with no evidence of organizing pneumonia.
Lymphomatoid granulomatosis (LG) is a rare disease, first described by Liebow et al in 1972 [4]. It most commonly involves the lung, but other sites include brain, kidney, liver and skin. Pathologically, pulmonary lesions contain polymorphous and atypical lymphohistiocytic infiltrates that characteristically surround and invade into vessels. Immunohistochemistry typically demonstrates EBV-positive B cells, with an exuberant T cell reaction, and EBV has been implicated in pathogenesis [5], although a proportion of cases are EBV negative [6]. In the current WHO classification [7], LG is grouped among the non-Hodgkin's lymphomas as a neoplasm of mature B cells. LG is graded from 1 to 3 based on the proportion of large transformed B cells present, with grade 1 containing the lowest proportion. Grade 2 contains increased large transformed cells but still retains an inflammatory cell background, whereas grade 3 consists almost entirely of large transformed cells and is considered to be a subtype of diffuse large B cell lymphoma. In some cases, however, large transformed B cells may not be detected at all, and it has been proposed that some of these may represent peripheral T cell lymphomas [6]. Clinically, the majority of patients are symptomatic at diagnosis. Common symptoms include cough, dyspnoea, fever, sweats and weight loss. Patients may be hypoxic and pulmonary function tests are variable. The natural course of LG is variable with spontaneous remissions being reported, but death occurs in over half of patients despite combination chemotherapy [8]. Improved survival is seen in patients without symptoms or extrapulmonary involvement and in those who enter a complete remission. The relationship of histological grade with prognosis is not clear. Although an increased proportion of large transformed B cells and necrosis may be important [9], more recent studies have shown no association between histological grade and survival [6]. Although there is no consensus on treatment, steroids are usually administered and may be combined with cyclophosphamide or combination chemotherapy. Radiologically, LG presents most commonly as multiple bilateral pulmonary nodules in about 80% of cases, the majority being less than 1 cm in size. They are round in shape and usually have ill-defined margins and tend to have a mid and lower zone predominance. Nodules may be solitary and have been reported to be as large as 10 cm. Nodules typically are located along bronchovascular structures and may coalesce to form areas of consolidation; they may cavitate or demonstrate air bronchograms. Less common radiological appearances include coarse linear patterns along the bronchovascular bundles or thin-walled cysts. Nodules can disappear or migrate spontaneously [10–13]. Nodular opacities are felt to correlate pathologically with angiocentric granulomatous inflammation, whereas larger mass-like opacities represent pulmonary infarcts, although necrosis has also been described in nodules less than 2 cm in size [9, 13]. Although in this case it was not possible to correlate histological findings definitively with the radiological reversed halo appearance, some areas within the biopsy appeared to show a central area of air space filling with oedema fluid and foamy histiocytes, surrounded by a denser rim of lymphocytic infiltration (Figure 5a
).
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Conclusion
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We describe a new cause of the reversed halo sign in a patient with histologically proven LG. This can be added to the known causes of the reversed halo sign, including COP and South American blastomycosis.
Received for publication January 3, 2006.
Revision received April 25, 2006.
Accepted for publication May 19, 2006.
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References
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- Kim SJ, Lee KS, Ryu YH, Yoon YC, Choe KO, Kim TS, et al. Reversed halo sign on high-resolution CT of cryptogenic organising pneumonia: diagnostic implications. AJR Am J Roentgenol 2003;180:1251–4.[Abstract/Free Full Text]
- Gasparetto EL, Escuissato DL, Davaus T, de Cerqueira EMFP, Souza AS, Marchiori E, et al. Reversed halo sign in pulmonary paracoccidioidomycosis. AJR Am J Roentgenol 2005;184:1932–4.[Abstract/Free Full Text]
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Abstract
Case report
