What to do with all of these lung nodules?

1Division of Respiratory Medicine; 2Department of Medicine, University of Toronto, Toronto General Hospital, Toronto, Ontario Correspondence: Dr Dmitry Rozenberg, 9N 971 – 585 University Avenue, Toronto, Ontario M5G 2N2. Telephone 416-340-4800, fax 416-340-3254, e-mail dmitry.rozenberg@uhn.ca Learning objectives • To recognize that Caplan syndrome is a rare pulmonary manifestation of rheumatoid arthritis (RA) found in patients with occupational dust exposure. • To be aware of the differential diagnosis and management of cavitary pulmonary nodules in Caplan syndrome.


Learning objectives
• To recognize that Caplan syndrome is a rare pulmonary manifestation of rheumatoid arthritis (RA) found in patients with occupational dust exposure.• To be aware of the differential diagnosis and management of cavitary pulmonary nodules in Caplan syndrome.

CAN MEDS Competency: Medical Expert Pretest
• What is the classic clinical and radiological presentation of Caplan syndrome?• What is the differential diagnosis of cavitary pulmonary nodules in RA? • How do you treat Caplan syndrome?

CASE PrESENtAtioN
A 71-year-old man was referred to the authors' facility with a five-year history of multiple, bilateral cavitary lung nodules.He was asymptomatic from a respiratory standpoint, with only mild dyspnea on exertion over the past six months, with no weight loss, cough or hemoptysis.The patient described a 10-year history of polyarthritis consistent with his known diagnosis of seropositive rheumatoid arthritis (RA).His RA was previously well controlled with methotrexate and leflunomide for several years.Four years before presenting to the authors' centre, his medications were changed to azathioprine and prednisone, given the concern of multiple lung nodules (Figure 1A).He also had ischemic cardiomyopathy, atrial fibrillation, type 2 diabetes and gastroesophageal reflux disease.
He was a retired construction worker who had significant exposure to rock dust as a result of rock drilling for 10 years and rock mining in graphite mines in the latter part of his career.He had no asbestos or sandblasting exposure.He was an ex-smoker (30 pack-year history) with no alcohol or recreational drug use.He described no tuberculosis exposures.His family history was noncontributory.
On examination, the patient appeared comfortable and in no respiratory distress.His cardiorespiratory examination was unremarkable aside from an oxygen saturation of 92% on room air.He had hand changes consistent with a diagnosis of RA with no digital clubbing.He had no subcutaneous nodules, rashes or joint swelling.
Chest imaging demonstrated stable calcified mediastinal and hilar lymphadenopathy with numerous parenchymal nodules and cavities, which had waxed and waned over the past five years (Figures 1A to  1C).Cultures from a spontaneous sputum sample (culture and sensitivity, acid-fast bacilli and fungal) were negative six months before presentation at the authors' centre.Subsequently, bronchoscopy demonstrated normal anatomy, cytology and a second set of negative cultures (culture and sensitivity, acid-fast bacilli and fungal).A left-sided video-assisted thoracic surgical biopsy revealed multiple nodules with necrosis surrounded by dust, with areas of surrounding inflammation and fibroblastic response (Figures 2A and 2B).A diagnosis of Caplan syndrome was made.
Caplan syndrome is a rare entity that is specific to rheumatoid arthritis and presents with multiple, well-defined necrotic nodules in patients with occupational dust exposure.The present report describes a case of Caplan syndrome involving a 71-year-old man with a known diagnosis of seropositive rheumatoid arthritis who presented to the authors' centre with a fiveyear history of multiple, bilateral cavitary lung nodules with mild dyspnea on exertion.He was an ex-smoker (30 pack-years) and had previously worked with silica.The case highlights the clinical, radiological and pathological features of this syndrome and outlines the importance of considering a broad differential in the management of pulmonary nodules, especially in patients with rheumatoid arthritis.
What to do with all of these lung nodules?
Can Respir J Vol 21 No 3 May/June 2014 e53 The prevalence of nodules in RA is difficult to estimate.In two older case series of RA patients with 253 and 702 patients screened using chest x-ray, no nodules were identified (4,5).However, one study demonstrated pulmonary nodules to be quite common, found in 13 of 40 (32%) patients who underwent biopsy for suspected lung involvement (6).Multiple cavitary pulmonary nodules can have malignant and benign etiologies, as outlined in Table 1.
In the present case, malignancy and infection (including mycobacterium) was believed to be unlikely given the indolent course, normal sputum cultures, negative bronchoscopy and video-assisted thoracic surgical biopsy.A diagnosis of Caplan syndrome was made based on the diagnostic criteria of multiple, well-defined pulmonary nodules and inorganic dust exposure in a patient with RA (7).An open-lung biopsy was not absolutely necessary, but was helpful to confirm this rare entity and exclude alternative diagnoses.Histopathology can be useful in patients without a diagnosis of RA because the nodules can precede the onset of RA symptoms.
Caplan (8) originally described this entity in 1953, having observed an increased prevalence of pulmonary manifestations in coal miners with RA who were exposed to mineral coal or silica dust.He observed well-defined rounded opacities 0.5 cm to 5 cm in size that were bilateral and predominantly peripheral on chest x-ray, a pattern different from progressive massive fibrosis (PMF), associated with coal worker's pneumoconiosis.Although most cases of Caplan syndrome have been reported in coal workers, some have been in patients exposed to asbestos or free silica (9,10), as in our case.
The majority of the literature regarding Caplan syndrome was published before the advent of chest computed tomography (CT), with reliance entirely on chest x-rays.Although a few case reports have described using chest CT, it has not been helpful in distinguishing Caplan syndrome from simple silicotic nodules (11,12).However, CT imaging can be useful in recognizing other forms of RA-associated lung disease.Typically, radiological findings of Caplan syndrome include benign-appearing nodules that can coalesce, cavitate or calcify in the periphery of the lung (7).Although uncommon, pulmonary complications can include pneumothorax, pleural effusions, hemoptysis and, most importantly, an increased prevalence of tuberculosis compared with other pneumoconioses (5).A more comprehensive overview of the clinical and radiological presentations can be found in a review article by Schreiber et al (7).

Rozenberg and Shapera
Can Respir J Vol 21 No 3 May/June 2014 e54 A few case reports have described pulmonary function tests in Caplan syndrome, which typically have shown mild airway obstruction (7,12).In the largest study to date, however, Constantinidis et al (13) retrospectively compared 24 patients with Caplan syndrome and 36 patients with PMF suggesting overlap in pulmonary function tests.When adjusted for age, smoking and mining exposure, patients with Caplan syndrome had less airflow obstruction than patients with PMF, but no other differences with respect to lung volumes and diffusion capacity were identified.In the present case, we speculate the reduced VC and DLCO could be due to the patient's upper lobe cavitary fibrotic changes producing a physiological pattern of lung restriction that resembles mild PMF.There were no signs of diffuse interstitial lung disease, pulmonary vascular disease or history of diaphragmatic dysfunction.
There have been two pathologies described in Caplan syndrome, both illustrated in our case.The classic pattern initially described in 1955 has an area of central necrosis of the RA nodules surrounded by dust particles.This area is further surrounded by multiple inflammatory cells: neutrophils, macrophages and several giant cells (Figure 2A) (14).The second pattern is the silicotic type, in which the nodules are smaller and contain the same features of a silicotic nodule, but maintain an outer ring of inflammatory cells that is different from a simple silicotic nodule (Figure 2B) (10).The differential for these pathological findings includes RA nodules, silicotic nodules and coal worker's pneumoconiosis (7).
Despite numerous descriptions of the clinical features of Caplan syndrome, the pathogenesis and detailed understanding of the interactions between inhaled inorganic dusts and the immune response in patients with RA have not been defined.There is increasing evidence that silica inhalation can be associated with the development of autoimmune diseases such as RA, systemic sclerosis, systemic lupus erythematosus and antineutrophil cytoplasmic antibody vasculitis but its pathogenesis requires further study (7).
The pulmonary manifestations of Caplan syndrome do not require any specific therapy unless rare complications develop such as infection or bronchopleural fistula (15).In a few cases, the use of corticosteroids has been described in slowing the progression of rapidly growing nodules (16).The role of tumour necrosis factor inhibitors in the treatment of Caplan syndrome is unknown, but worsening of RA nodules has been reported with tumour necrosis factor use (17).Treatment should be focused on smoking cessation, limiting occupational exposure and controlling the extrapulmonary manifestations of the underlying RA.

SuMMAry
The present case demonstrates the classic historical, radiological and pathological features of Caplan syndrome, a rare entity.The case outlines the importance of considering a broad differential in the management of cavitary pulmonary nodules, especially in patients with RA.Given there is no specific therapy for Caplan syndrome, the focus should be on management of extrapulmonary RA.

Post-test:
• What is the classic clinical and radiological presentation of Caplan syndrome?Caplan syndrome can present in patients with RA and occupational dust exposure (usually coal) with minimal respiratory symptoms.Radiology demonstrates well-defined rounded opacities that are 0.5 cm to 5 cm in size that are bilateral and predominantly peripheral, and can cavitate and fluctuate over the years.
• What is the differential diagnosis of cavitary pulmonary nodules in RA?It is important to consider a broad differential in the work-up of cavitary pulmonary nodules (see Table 1) ensuring that malignancy and tuberculosis are excluded.
• How do you treat Caplan syndrome?Caplan syndrome does not require any particular treatment.The management should be focused on treating the extrapulmonary manifestations of RA.

DiSCLoSurES:
The authors have no financial disclosures or conflicts of interest to declare.