Percutaneous image-guided biopsy of lung nodules in the assessment of disease activity in Wegener's granulomatosis

D. M. Carruthers, S. Connor1, A. J. Howie2, A. R. Exley, K. Raza, P. A. Bacon and P. Guest1

Departments of Rheumatology,
1 Radiology and
2 Pathology, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TT, UK


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objective. In patients with known Wegener's granulomatosis (WG) and persistent chest radiographic abnormalities, assessment for disease activity is often difficult, prompting the need for histological diagnosis to determine appropriate treatment. Here we report the use of automated image-guided core needle biopsy of pulmonary lesions for the assessment of disease activity in WG, rather than for primary diagnosis.

Methods. Image-guided percutaneous core needle biopsy was performed on five occasions in four patients with thoracic WG and persistent radiographic abnormalities of the chest. Clinical features, indication for biopsy, radiographic abnormalities and pathological findings were recorded.

Results. Adequate pathological specimens were obtained, allowing exclusion of infection and tumour. Active chronic inflammation with or without vasculitis was demonstrated in each case, indicating the need for further immunosuppressive therapy. A small pneumothorax following biopsy in one case required no treatment. Follow-up chest imaging revealed a reduction in the extent of thoracic disease following therapy in all cases.

Conclusions. The safety and diagnostic accuracy of image-guided core biopsy of thoracic lesions makes it a useful tool in the assessment of disease activity in WG patients with persistent chest radiographic lesions.

KEY WORDS: Wegener's granulomatosis, Pulmonary nodule, Biopsy.


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Biopsy in Wegener's granulomatosis (WG) is the best confirmation of the diagnosis at presentation, demonstrating features such as granulomatous vasculitis. Here, we report an additional indication for biopsy in WG patients, where it was used to confirm disease activity and to direct therapy in chronic disease.

Prompt treatment of active WG with cyclophosphamide (CP) and corticosteroids has improved the prognosis of this disease considerably [1], but despite therapy 25% of patients have persistent disease activity and 50% will relapse [2]. Irreversible damage secondary to disease develops early during periods of disease activity while damage late in the disease is often therapy-related [3]. Early detection of relapse is therefore important, so that therapy can be instituted to reduce disease activity and consequent damage. However, it may be difficult to assess disease activity when chest radiograph abnormalities occur in isolation in WG. In these patients the differential diagnosis includes persistent or relapsed active disease, scars from healed disease, coincidental infection and tumour. Biopsy might be used to guide therapy, immunosuppression being recommenced only if there is active inflammation.

Biopsy techniques for pulmonary lesions require a balance between minimizing the invasive procedure and maximizing the amount of tissue available for histological analysis. The simplest approach is transbronchial biopsy, but the specimen is rarely informative in vasculitis. Open-lung biopsy has a high diagnostic accuracy in patients with WG [2, 4], but it is associated with appreciable morbidity. Image-guided fine needle aspiration is relatively safe, but cytological specimens from pulmonary nodules in WG give inadequate information for the assessment of disease activity [5]. However, automated image-guided core needle biopsy is now widely used for sampling a wide range of thoracic lesions [6].

Here we report four patients with WG in whom pulmonary lesions persisted on chest radiography despite the apparent induction of remission with standard treatment. Histological evidence of disease activity was confirmed in lung tissue obtained by image-guided automated core needle biopsy, thus allowing a decision on further therapy to be made.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
Four WG patients underwent transthoracic core needle biopsy of lung lesions between 1994 and 1998. A total of five biopsies were performed to assess disease activity within persistent radiographic pulmonary abnormalities. The clinical features, indication for biopsy, radiographic abnormalities and pathological features were reviewed.

Biopsy technique
We used a Bard Biopsy gun (Bard/Covington, CA, USA/Radioplast, Uppsala, Sweden), which consisted of a hand-held device that triggered rapid firing of an 18 gauge cutting needle that sheared off a core of tissue with minimal crushing of the specimen [7]. Each patient underwent a diagnostic computed tomgraphy (CT) scan (CT Prospeed, Milwaukee, WI, USA) with 10 mm contiguous slices to determine the most appropriate imaging modality for the biopsies (fluoroscopy or CT). Fluoroscopy benefited from being faster than CT and allowed sampling under direct visualization, although CT allowed better direction of the biopsy away from cavitation and necrotic tissue.

CT-guided biopsy (four occasions) commenced by determining the location and depth of the lesion and the most appropriate site of puncture. The patients were asked to suspend respiration during diagnostic CT sections and all needle manipulations. Three contiguous images were performed at the appropriate level, with the local anaesthetic needle left in place to aid in directing the biopsy needle. When further images demonstrated correct positioning, the biopsy gun was connected and fired. Fluoroscopy-guided biopsy, which required the lesion to be seen clearly on both frontal and lateral chest radiographs, was possible in only one patient. It was performed with biplanar screening after we had calculated the correct needle depth from the diagnostic CT scan.

A single core biopsy was performed on each patient and the specimen was fixed in formalin for routine pathological processing, sectioning and staining. Patients were all admitted for observation for at least 4 h after the procedure, and a chest radiograph was performed at the end of this period.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Four patients with WG had a total of five biopsies in order to determine whether pulmonary imaging abnormalities represented locally active WG. The case histories and indications for biopsy are shown in Table 1Go. In each case there was concern over the underlying diagnosis or the use of further CP therapy. C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and the titre of antineutrophil cytoplasmic antibodies (ANCA) at the time of biopsy are given, but proteinase 3 levels were not routinely available. The pre-biopsy thoracic CT appearances, the radiological features of the biopsied lesions and the details and complications of the procedure are shown in Table 2Go. A representative CT image is shown in Fig. 1Go. The pathological findings and their influence on management and imaging follow-up are given in Table 2Go and Fig. 3Go. The presence of active WG on biopsy supported the recommencement of immunosuppressive therapy in all cases.


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TABLE 1. Clinical features and indication for biopsy in four patients with WG

 

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TABLE 2. Radiographic features and outcome of image-guided biopsy

 


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FIG. 1. Prone axial CT scan imaged on mediastinal windows demonstrating the tip of the biopsy needle in a solid region of the posterior left lower lobe cavitating mass (patient 4).

 


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FIG. 3. Chest radiographs from patient 4 at (A) the time of his second biopsy and (B) after treatment with pulse cyclophosphamide. Reductions in size and number of lesions are shown.

 
Patient 1 is in remission at the 5-yr follow-up on methotrexate 20 mg weekly and prednisolone 10 mg daily. Patient 2 died 27 months after biopsy from marrow failure secondary to prolonged CP therapy. She had had no further relapses of her disease but there was no necropsy. Patient 3 had grumbling disease activity in the subglottic area which required a tracheostomy 4 months after lung biopsy. After 18 months of follow-up there were no further pulmonary symptoms. Patient 4 relapsed 14 months after the first biopsy when consolidation therapy with cyclosporin A was withdrawn. This relapse, for which a second lung biopsy was performed, required six pulses of CP to induce remission, which was maintained 7 months later with methotrexate 20 mg weekly and prednisolone 5 mg.



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FIG. 2. Florid necrotizing granulomatous inflammation with vasculitis, stained by elastin–haematoxylin–van Gieson, in keeping with active WG (patient 3). Magnification x200.

 


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Thorough assessment in systemic vasculitis to distinguish active disease from irreversible damage [8, 9] is critical for decisions on therapy. Active disease indicates the need for additional immunosuppression, whilst confirmation of remission should limit toxicity associated with the prolonged use of cytotoxic agents [10]. We have reported a series of patients with WG in whom disease activity was identified by percutaneous core needle biopsy of isolated pulmonary lesions. Pathological confirmation of active disease and exclusion of tumour and infection enabled informed decisions on therapy when speculative treatment was particularly undesirable because of previous high cumulative doses of CP.

The difficulty in assessing the presence of disease activity is illustrated by patients with Takayasu's arteritis. Active inflammatory infiltrates were seen in operative specimens in 44% of Takayasu's patients felt to have clinically inactive disease [11]. Hence histological evidence of disease activity may be required where the clinical picture is not clear. In the absence of histological evidence in our patients, inappropriate antimicrobial therapy may have been given for prolonged periods. This delay in the initiation of immunosuppressive therapy would have led to further local tissue scarring.

The lung is frequently affected in WG and may sometimes be the only organ involved [2]. Pulmonary nodules or focal infiltrates usually regress with therapy but it is not uncommon for local scarring or loss of lung volume to occur. Although persistent nodules may represent active disease, pulmonary cicatricial residues can have a similar appearance, and are present in 20% of patients with inactive disease [12]. In addition, the clinical and radiographic features of active WG may be mimicked by pulmonary infection, a common complication of tissue damage and immunosuppression. Patients will be compromised by immunosuppressive therapy if untreated infection underlies the current problem, hence biopsy evidence of active disease, with exclusion of infection and malignancy, will enable appropriate treatment decisions to be made.

Several methods have been used to obtain pulmonary tissue for histological examination. Image-guided transthoracic needle aspiration biopsy by fine needle aspiration in benign conditions provides a definitive diagnosis in under half of cases [13, 14] and may offer only suggestive findings for the diagnosis of WG [5]. Fluoroscopically guided transbronchial biopsy of gross parenchymal lesions offers a technique complementary to transthoracic needle biopsy in the presence of central masses [15], but may be impossible in WG because of upper airways stenosis. Blind transbronchial biopsy of alveolar tissue seldom gives a representative sample because of the focal distribution of the inflammatory lesions in WG [16]. However, the provision of a histological sample from a core needle biopsy, as opposed to a cytological specimen from aspiration, has increased the rate of diagnosis in benign disorders to over half without increased complications [6].

The purpose of the biopsy in our cases was to exclude more sinister causes of pulmonary nodules, such as infection and malignancy, and to provide the evidence of continuing disease activity necessary for the institution of further immunosuppression. Pathological features of WG include necrosis, chronic inflammation that may be granulomatous, and vasculitis [2], but the presence of only one of the histological findings may be diagnostically useful, as in our cases. The important point is that clinically significant information was gained from the histology on each occasion. The reduction in lesion number and size after treatment supports the fact that the correct therapeutic decisions were taken. In two cases, magnetic resonance imaging (MRI) was used as imaging follow-up; although the CT and MRI scans are not directly comparable, this is not important considering the dramatic change in lesion size.

Alternative, but less reliable approaches to the assessment of disease activity include non-invasive imaging and blood-test monitoring. Nodules, masses and areas of parenchymal opacification on high-resolution CT scanning are associated with active WG [12], and the presence of active disease in all our biopsy specimens supports this. However, CT features of active disease overlap with those of inactive disease and infection, although increased spiculation and thickening of cavity walls is seen more commonly in inactive WG [17]. CT can also record the reduction in nodule size and number which is generally associated with clinical improvement [18], but because of differences in the positioning of sections on serial CTs only large changes in size are relevant. Monitoring of ANCA titres may predict relapse [19] and distinguish relapse from infection [17], but up to 40% of WG patients may have persistently raised ANCA titres while in clinical remission [2]. Although ANCA titres were significantly raised at the time of biopsy in three out of our five cases, this provided insufficient evidence for disease activity, prompting the need for histological confirmation.

Though there were no serious biopsy-related complications in our patients, several factors may place these individuals at increased risk. The potential for pulmonary haemorrhage is increased, because of either increased vascular fragility or CP-induced thrombocytopenia. Percutaneous core needle biopsy of deep as opposed to subpleural nodules increases the risk of pneumothorax, and a fatal systemic air embolus after aspiration of a WG nodule has been reported in which the air embolism may have been introduced by coughing after puncture of a diseased pulmonary vessel [20].

Percutaneous core needle biopsy of focal lung lesions using an 18 gauge automated core biopsy gun has provided valuable histological evidence of disease activity and has helped guide therapy on five occasions in four patients with WG. Whilst the larger sample provided by an open lung biopsy [4] may be required to make a reliable initial diagnosis, the appreciable operative risk later in the disease course is best avoided. The safety and diagnostic accuracy of image-guided core biopsy makes it a useful tool in the assessment of WG patients with persistent focal lung lesions.


    Acknowledgments
 
P. A. B. is supported by the Arthritis Research Campaign.


    Notes
 
Correspondence to: D. M. Carruthers, Department of Rheumatology, Division of Immunity and Infection, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. Back


    References
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Submitted 11 October 1999; revised version accepted 24 January 2000.



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