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Intermittent Cough and Hemoptysis With Tree-in-Bud Opacities on Imaging

      Case Presentation

      A 44-year-old man with hyperthyroidism and no smoking history presented to his internist with 5 months of intermittent cough and hemoptysis. The patient’s family history was remarkable only for non-Hodgkin’s lymphoma in his father. He had a history of a 25-day exposure to a home renovation at work 2 years prior to presentation. He was treated with oral clarithromycin with no improvement in his symptoms. A chest radiograph showed bilateral nodular opacities with a left lower lobar consolidative opacity (Fig 1A, 1B); the patient underwent CT scanning of the chest, which showed areas of nodular infiltration in the lower lobes with tree-in-bud-like opacities. He was referred to a pulmonologist.
      BAL results were positive for Haemophilus haemolyticus and negative for malignant cells. He had brief improvement after two courses of levofloxacin, but symptoms recurred. Three months later, repeat chest radiography revealed worsening of the bilateral lower lobe nodular opacities (Fig 1C, 1D). A CT scan of the chest was performed that showed dense, branching, nodular opacities with a tree-in-bud pattern bilaterally with a lower lobe predominance (Fig 2). Given prolonged symptoms and lack of response to antibiotics and worsening imaging findings, a broader differential diagnosis was considered, which included granulomatous disease (such as histoplasmosis, sarcoidosis, pneumoconiosis, and TB) and interstitial pneumonitis and other diseases that can present similarly on CT scanning with reticulonodular opacifications, such as amyloidosis, pulmonary alveolar microlithiasis, and pneumonitis secondary to asbestosis, pulmonary fibrosis, and metastatic disease (Table 1). Of note, pulmonary fibrosis and asbestosis typically present with reticular abnormalities; interstitial pneumonitis usually presents with a nodular pattern. Infectious causes seemed less likely. The patient underwent elective video-assisted thoracoscopic surgery (VATS) with right lower lobe wedge resection and biopsy. Histologic analysis of the biopsied tissue revealed normal lung parenchyma admixed with numerous foci of osseous metaplasia, bone marrow elements, and alveolar hemorrhage with reactive changes in adjacent lung tissue (Fig 3). There were areas of intraalveolar blood and hemosiderin deposits, although the former can be seen as an artifact of the biopsy specimen (Fig 3D, 3E). There was no fibrosis seen on histologic evaluation.
      Figure thumbnail gr1
      Figure 1A, Initial posteroanterior chest radiograph shows abnormal nodular opacities bilaterally, greatest in the lower lung zones with a consolidative opacity in the left lower lobe. B, Initial lateral chest radiograph shows abnormal nodular opacities bilaterally, greatest in the lower lung zones with a consolidative opacity in the left lower lobe. C, Posteroanterior chest radiograph that was obtained 3 months later shows nodular opacities bilaterally, greatest in the lower lung zones. D, Lateral chest radiograph that was obtained 3 months later shows nodular opacities bilaterally, greatest in the lower lung zones.
      Figure thumbnail gr2
      Figure 2A, Axial CT images with 1-mm collimation of the lower lungs with the use of an edge-enhanced algorithm and lung windows. There are branching nodular opacities most numerous in the periphery of the lower lobes bilaterally that include several subpleural nodules. Some of the nodular opacities are hyperattenuating; no honeycombing, traction bronchiectasis, or architectural distortion is found. B, Coronal image of the chest with 2-mm collimation with the use of a standard algorithm and lung windows. The branching nature of the dense nodular opacities and their lower lobe predominance are evident. The opacities produce a lattice-like appearance. C, Axial maximum-intensity projection images with 10-mm thickness with the use of a standard reconstruction algorithm and mediastinal windows allow better visualization of the hyperattenuating nature of the branching opacities.
      Table 1Differential Diagnosis for Calcification/Ossification on CT Imaging
      Differential DiagnosisClinical PresentationRadiologic Finding
      Viral infectionsChronic symptoms, hemoptysisChest radiograph: varies (eg, scattered punctate calcifications in prior varicella infection)
      Interstitial pneumonitis (eg, usual interstitial fibrosis, nonspecific interstitial pneumonia)Male predilection; chronic symptoms, exertional dyspnea, nonproductive coughCT scan: small, high-attenuating nodules in peripheral interstitium, with dendriform appearance (dendriform diffuse pulmonary ossification)
      Chronic gastric acid aspirationMale, history of coughing in supine position, OSA, cleft lip or palateCT scan: small high-attenuating nodules in peripheral interstitium, with dendriform appearance (dendriform diffuse pulmonary ossification)
      Chronically elevated pulmonary venous pressureChronic mitral valve stenosis or left heart failureCT scan: small centrilobular nodules of high attenuation with lower lobe predominance that may coalesce (nodular diffuse pulmonary ossification)
      Granulomatous diseaseFeatures typical of histoplasmosis, coccidiomycosis, TB, pneumoconiosis (including silicosis), or sarcoidosisDisease dependent (eg, histoplasmosis, epithelioid granulomas in sarcoid, cavitary tuberculous lesions, perilymphatic or centrilobular calcifications in silicosis)
      AmyloidosisLocalized or diffuse lung disease, restrictive patternCT scan: interstitial opacities with calcification, favor subpleural and lower lung fields
      Pulmonary alveolar microlithiasisUsually found incidentallyCT scan: many bilateral, calcified micronodules measuring <1 mm
      Calcified tumorsFeatures typical of pulmonary chondromas, some metastatic diseases (eg, osteosarcomas, chrondrosarcomas, thyroid cancers, mucinous type carcinomas)CT scan: varied sizes from small nodules <10 mm to large calcified nodules measuring 10-30 mm to calcified masses >30 mm with focal or diffuse calcification; random distribution common in metastatic disease
      Diffuse pulmonary ossification
       PrimaryIdiopathicCT scan: nodular or dendriform ossifications
       SecondaryUsually found incidentally, can present with chronic cough; often in association with other conditions such as chronic lung disease, mitral valve stenosis, chronic cardiac diseaseCT scan: nodular or dendriform ossifications
      Figure thumbnail gr3
      Figure 3A-F, Hematoxylin-eosin stained view of A, the biopsy specimen with mature bone trabeculae surrounded by lung parenchyma (10x); B, the lung biopsy specimen that contains parenchyma (blue arrow) and mature bone trabeculae (yellow arrow) (10x); C, multiple foci of osseous metaplasia (10x); D, lung parenchyma with areas of hemorrhage (blue arrow) (10x); E, background lung parenchyma with hemosiderin (blue arrow) (100x); F, the lung biopsy specimen with mature bone trabeculae and bone marrow elements (100x).
      What is the diagnosis?
      Answer: Idiopathic diffuse pulmonary ossification

      Clinical Discussion

      Diffuse pulmonary ossification (DPO) is a rare disease wherein native pulmonary cells undergo metaplastic bone formation in the interstitium and alveolar spaces of the lungs as a nonspecific reaction to injury.
      • Kanne J.P.
      • Godwin J.D.
      • Takasugi J.E.
      • Schmidt R.A.
      • Stern E.J.
      Diffuse pulmonary ossification.
      In general, the disease is believed to be indolent and slowly progressive.
      • Lara J.F.
      • Catroppo J.F.
      • Kim D.U.
      • da Costa D.
      Dendriform pulmonary ossification, a form of diffuse pulmonary ossification: report of a 26-year autopsy experience.
      DPO is most often described in male patients in the fifth or sixth decades of life
      • Kanne J.P.
      • Godwin J.D.
      • Takasugi J.E.
      • Schmidt R.A.
      • Stern E.J.
      Diffuse pulmonary ossification.
      and most commonly affects the bilateral lower lobes.
      • Fernandez-Bussy S.
      • Labarca G.
      • Pires Y.
      • Diaz J.C.
      • Caviedes I.
      Dendriform pulmonary ossification.
      DPO is a diagnosis that has traditionally been made postmortem. However, when patients are symptomatic, they generally present with nonspecific respiratory symptoms such as shortness of breath, dyspnea on exertion, cough,
      • Lara J.F.
      • Catroppo J.F.
      • Kim D.U.
      • da Costa D.
      Dendriform pulmonary ossification, a form of diffuse pulmonary ossification: report of a 26-year autopsy experience.
      or associated complications such as recurrent pneumothorax.
      • Tsai A.P.
      • English J.C.
      • Murphy D.
      • Sin D.D.
      Recurrent pneumothorax related to diffuse dendriform pulmonary ossification in genetically predisposed individual.
      ,
      • Jungmann H.
      • Godbert B.
      • Wissler M.
      • et al.
      Diffuse pulmonary ossification in a patient exposed to silica.
      The patient presented with cough and hemoptysis, the latter of which is described less commonly in the literature.
      Because of the rarity of DPO, the pathophysiologic condition is not understood fully. When DPO was first described in 1856, the leading theory regarding the development of this disease was chronic hypoxia and repetitive injury leading to free radical formation, fibroblast proliferation, and eventual metaplastic ossification.
      • Tsai A.P.
      • English J.C.
      • Murphy D.
      • Sin D.D.
      Recurrent pneumothorax related to diffuse dendriform pulmonary ossification in genetically predisposed individual.
      Chemical factors (such as fibrin and transforming growth factor-beta) and mechanical stress have also been implicated as responses to inflammation.
      • Kanne J.P.
      • Godwin J.D.
      • Takasugi J.E.
      • Schmidt R.A.
      • Stern E.J.
      Diffuse pulmonary ossification.
      Roles for bone morphogenetic protein gene families
      • Burkett A.
      • Coffey N.
      • Voduc N.
      Diffuse pulmonary ossification as a rare cause of interstitial lung disease.
      and epithelial mesenchymal transition
      • Mizushina Y.
      • Bando M.
      • Hosono T.
      • et al.
      A rare case of asymptomatic diffuse pulmonary ossification detected during a routine health examination.
      have also been suggested.
      DPO can be subtyped as nodular or dendriform. Dendriform DPO has been reported in association with chronic lung disease, recurrent aspiration pneumonia, cardiac disease, autoimmune diseases, or other systemic diseases. Nodular DPO, the more common subtype, has been associated with passive congestive processes that lead to persistent pulmonary edema or pulmonary hypertension, including mitral valve stenosis.
      • Kanne J.P.
      • Godwin J.D.
      • Takasugi J.E.
      • Schmidt R.A.
      • Stern E.J.
      Diffuse pulmonary ossification.
      ,
      • Roriz D.
      • Abreu I.
      • Marques C.
      • Teizeira L.
      • Soares P.B.
      • Alves F.C.
      Diffuse pulmonary ossification: a case report.
      Given the paucity of reported cases, it is difficult to determine whether these reported associations are significant.
      Though CT scan can be used to diagnose DPO, tissue biopsy and histologic confirmation of the pulmonary ossification remains the gold standard. Small dense nodules can suggest calcification if seen on imaging. The patient has been seen most recently 15 months after VATS and is asymptomatic.

      Imaging Discussion

      Chest radiographs are nonspecific and usually do not yield a diagnosis in DPO due to the small size of the abnormalities. If noticed, the disease may appear as subtle nodular opacities at the lung bases. Idiopathic DPO can be diagnosed with CT scans that show extensive ossification with nodular and branching appearance, without associated ground glass or honeycombing and with preservation of native architecture.
      • Burkett A.
      • Coffey N.
      • Voduc N.
      Diffuse pulmonary ossification as a rare cause of interstitial lung disease.
      DPO tends to affect the lower lobes predominantly, as was seen in the patient. More specifically, CT scans of nodular pulmonary ossification present with centrilobular nodules, often of high attenuation, with a lower lobe predominance that may coalesce. Dendriform pulmonary ossification presents with CT scans that show linear branching opacities. The presence of reticulation may raise suspicion for pulmonary fibrosis.
      • Kanne J.P.
      • Godwin J.D.
      • Takasugi J.E.
      • Schmidt R.A.
      • Stern E.J.
      Diffuse pulmonary ossification.
      Small nodules, 1 to 5 mm in diameter, are present in the peripheral interstitium (interlobular septa and subpleural and perifissural spaces), and form contiguous, branching structures that produce a lattice-like appearance. In the idiopathic setting, signs of fibrosis, which include lobular distortion, traction bronchiectasis, and honeycombing, are absent. However, secondary DPO can present with signs of other associated interstitial lung diseases, such as nonspecific interstitial pneumonia or usual interstitial fibrosis. In secondary DPO, CT imaging findings may reflect findings that are consistent with these diseases in addition to the reticulonodular pattern suggestive of DPO.
      Identification of high-attenuation foci in some of the nodules, which reflect the underlying ossification, is often best accomplished on thin-section images with standard reconstruction algorithm and soft tissue windows and/or maximum-intensity-projection images and is a key to the diagnosis.
      • Kim T.S.
      • Han J.
      • Chung M.P.
      • Chung M.J.
      • Choi Y.S.
      Disseminated dendriform pulmonary ossification associated with usual interstitial pneumonia: incidence and thin-section CT-pathologic correlation.
      Diffuse, small, high-attenuation nodules may be caused by substances other than calcification and are of similar densities. These imaging modalities can allow better visualization of the branching of the nodules and calcification. Lymphangitic carcinomatosis, which can cause a similar pattern of nodular thickening of the peripheral interstitium, would not be expected to have these high-attenuation foci. Septal amyloidosis, which is considered the least common form of pulmonary amyloidosis, is in the differential diagnosis, but patients with this condition are often more symptomatic, with symptoms of cough and progressive dyspnea. Septal amyloidosis also can include diffuse homogenous alveolar opacities, which are not seen in DPO.
      There are many other causes of high-attenuation pulmonary abnormalities on CT images.
      • Marchiori E.
      • Souza A.
      • Franquet T.
      • Muller N.L.
      Diffuse high-attenuation pulmonary abnormalities: a pattern-oriented diagnostic approach on high-resolution CT.
      Diffuse small (<10 mm) calcified nodules may be caused by infections, pulmonary metastases, chronic hemorrhagic conditions, occupational diseases, deposition diseases, and idiopathic disorders, such as pulmonary alveolar microlithiasis. Pulmonary alveolar microlithiasis is characterized by innumerable bilateral calcified micronodules, usually <1 mm, and can be differentiated by the presence of calcium phosphate deposits on histologic staining. Diffuse small high-attenuation nodules not caused by calcification may be seen in talcosis, mercury, and acrylic cement embolism. Multiple large calcified nodules (10 to 30 mm) or masses (>30 mm) may be caused by calcified pulmonary metastases, amyloidosis, calcified hyalinizing granulomas, necrobiotic nodules, and progressive massive fibrosis. The differential diagnosis of high-attenuation consolidation includes amiodarone lung, iodinated oil embolism, and pulmonary alveolar microlithiasis. However, these conditions do not have the classic pattern of findings seen with dendriform pulmonary ossification.

      Pathologic Discussion

      Tissue biopsy during VATS or another direct approach that shows the ossification remains the gold standard for diagnosis of this disease.
      • Lara J.F.
      • Catroppo J.F.
      • Kim D.U.
      • da Costa D.
      Dendriform pulmonary ossification, a form of diffuse pulmonary ossification: report of a 26-year autopsy experience.
      Focal osseous metaplasia in the lung is not uncommon and can occur in response to chronic injury, but these findings usually do not represent DPO. In DPO, the histologic evidence shows nodular pulmonary ossification in the alveolar spaces, involves formation of mature lamellar bones, and does not typically present with bone marrow components.
      • Kanne J.P.
      • Godwin J.D.
      • Takasugi J.E.
      • Schmidt R.A.
      • Stern E.J.
      Diffuse pulmonary ossification.
      Dendriform pulmonary ossification is associated with septal fibrosis and branching deposition of heterotopic bone cells, contains bone marrow components, and involves some projection into the alveolar spaces of the lung.
      • Kanne J.P.
      • Godwin J.D.
      • Takasugi J.E.
      • Schmidt R.A.
      • Stern E.J.
      Diffuse pulmonary ossification.
      In this patient, the wedge biopsy showed mature bone trabeculae and bone marrow elements surrounded by typical lung parenchyma. Multiple foci of osseous metaplasia can also be seen, as can areas of hemorrhage and hemosiderin deposition in a background of lung parenchyma. The most common cause for osseous metaplasia on pathologic examination is usual interstitial pneumonia. However, the patient’s demographic and CT chest images were inconsistent with this diagnosis. Although DPO was the most likely cause of the patient’s presenting symptom of cough, an alternative cause for hemoptysis was not identified.

      Conclusions

      DPO is a rare and indolent disease that is characterized by osseous metaplasia in pulmonary tissue that is being increasingly recognized due to the advent of high resolution CT scanning.
      Idiopathic DPO can be diagnosed with a CT scan that shows extensive subpleural reticulations and ossifications, predominantly in the lower lobes, without associated ground glass or honeycombing and with preservation of native architecture.
      Tissue biopsy during VATS or other direct approach that shows the ossification on pathologic evaluation remains the gold standard for diagnosis of DPO, and underlying fibrosis, such as usual interstitial pneumonia, should be excluded prior to the diagnosis of DPO.
      There are no guidelines for the monitoring of DPO with imaging, but interval follow up is suggested to ensure stability of pulmonary symptoms

      Acknowledgments

      Financial/nonfinancial disclosures: None declared.

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