Pulmonary ossification: a review
Review Article

Pulmonary ossification: a review

Ana Casal1, Lucía Ferreiro2,3, María Elena Toubes2, Luis Valdés2,3,4

1Pulmonary Department, Álvaro Cunqueiro’s Hospital, Integrated Management Organisation Structure Vigo, Pneumovigo I+I Research Group, Health Research Institute Galicia Sur (IIS Galicia Sur), Vigo, Spain; 2Pulmonary Department, Santiago de Compostela University Hospital Complex, Santiago de Compostela, Spain; 3Santiago de Compostela Health Research Institute (IDIS), Santiago de Compostela, Spain; 4Medicine Department, Faculty of Medicine, University of Medicine of Santiago de Compostela, Santiago de Compostela, Spain

Contributions: (I) Conception and design: A Casal, L Valdés; (II) Administrative support: L Ferreiro; (III) Provision of study materials or patients: L Ferreiro; (IV) Collection and assembly of data: ME Toubes; (V) Data analysis and interpretation: A Casal; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Ana Casal, PhD. Pulmonary Department, Álvaro Cunqueiro’s Hospital, Integrated Management Organisation Structure Vigo, Pneumovigo I+I Research Group, Health Research Institute Galicia Sur (IIS Galicia Sur), Clara Campoamor Street, 341, 36312 Vigo, Spain. Email: ana.casal.mourino@sergas.es.

Abstract: Pulmonary ossification (PO) is a rare disease, especially in patients without a previous history of lung disease. PO has an indolent course that may progressively cause lung function impairment. It is characterized by the presence of ectopic metaplastic bone in the lungs. Although it is generally idiopathic, it may be associated with other diseases, such as interstitial lung diseases. High resolution computed tomography (HRCT) of the chest is the technology of choice for diagnosis, as it allows differential diagnosis with other diseases and spares the use of more aggressive diagnostic techniques. Distinctive radiological findings include two ossification patterns: dendriform and nodular (the most frequent). Each pattern is associated with specific histological findings and can be related to different entities or otherwise be idiopathic forms. This review provides an updated overview of the pathogenesis, diagnostic and histopathological criteria and prognostic factors. As specific treatment is not currently available, the objective is to prevent fibrotic interstitial progression. For a correct management of the disease, it is necessary to consider the associated comorbidities and closely monitor cases. The purpose of this approach is to prevent progression, in case it is associated with diffuse interstitial lung disease. Further research and long-term follow-up are necessary for a better understanding of the pathogenesis and prognosis of PO.

Keywords: Pulmonary ossification (PO); dendriform; nodular; interstitial lung disease

Submitted Nov 30, 2024. Accepted for publication Mar 05, 2025. Published online May 26, 2025.

doi: 10.21037/jtd-2024-2083

Introduction

Pulmonary ossification (PO) is a very rare respiratory disease that was first described by Luschka. Manifestations include pulmonary calcification and ossification (1,2). This condition is characterized by formation of ectopic bone tissue with or without marrow elements in the lung parenchyma.

In the past, PO used to be an incidental finding during the autopsy of patients with other respiratory diseases (3,4). However, PO is increasingly found on high-resolution computed tomography (HRCT) scans of the chest. This entity is prevailingly observed in patients with fibrotic lung disease, more specifically in idiopathic pulmonary fibrosis (5,6) (Figure 1).

Figure 1 Thoracic CT images of a case with dendriform pulmonary ossification. Thoracic CT images showing interstitial lung disease consisting almost predominantly of bilateral diffuse subpleural reticulation with foci of dendriform ossification (indeterminate pattern for UIP—early UIP). No significant bronchiectasis or honeycombing. White arrows indicate sites of pulmonary ossification. CT, computed tomography; UIP, usual interstitial pneumonia.

Clinical characteristics

Nishioka et al. recently carried out a national survey study in Japan to assess the clinical, functional, radiological and histopathological characteristics of patients diagnosed with idiopathic dendriform pulmonary ossification (DPO). Follow-up was performed of 22 cases over a period of 20 years. Most patients were male (82%) with an age at diagnosis of 22 to 56 years [mean 37.9, standard deviation (SD) 9.1]. Around 80% were asymptomatic and disease was discovered during an elective medical visit (7). In a review of 43 patients, the male to female ratio was 6:1 (8). Early symptoms include spontaneous pneumothorax of unclear etiology, although occupation of the visceral pleura by the PO has been suggested as a causative factor (9). Notwithstanding that most patients are asymptomatic at diagnosis, 36% presented with a reduced forced vital capacity (FVC). In addition, over 50% of cases demonstrated a lung function decline as assessed by a reduction in FVC and diffusing capacity for carbon monoxide during follow-up (7,10). Table 1 summarizes the most common clinical features of the disease.

Table 1

Characteristics observed in patients with idiopathic dendriform pulmonary ossification (7)

Characteristics Values
Males 82%
Smoking status
   Never smokers 80%
Previous lung disease
   Pneumothorax 5%
   Asthma 5%
Family history 9%
Age at diagnosis (years old), mean 38
Diagnosis
   Medical check-up 77%
   Symptomatic case 18%
   Incidental in HRCT 5%
KL-6 >500 U/mL 17%
Lung function at diagnosis
   FEV1/FVC <70% 9%
   FVC <80% 36%
   DLCO <80% 63%
Lung function decline
   FVC ≥100 mL/year 24%
   FVC ≥5%/year 12%
   FEV1 ≥100 mL/year 24%
   DLCO ≥15%/year 0%
Worsening of symptoms 14%
Follow-up HRCT
   Stable 12%
   Progression 88%
Overall survival >90%

DLCO, diffusing capacity of the lungs for carbon monoxide; FEV1, forced expiratory volume in the first second; FVC, forced vital capacity; HRCT, high-resolution computed tomography; KL-6, Krebs von den Lungen-6.

Incidence and prevalence

According to the case series available, the incidence of PO ranges from 0.16% to 0.4%. PO is very rarely idiopathic, being most frequently secondary or associated with other diseases. In a series of 1,393 adult autopsies, DPO was identified in 8 cases. Prevalence was 0.5% and incidence was 0.28 cases/year (3). In another series of 10,426 autopsies, a total of 17 cases of DPO were confirmed, thereby accounting for an incidence of 1.63 cases/1,000 autopsies (4). Cases have also been reported within the same family. Such is the case of a 29-year-old male patient and his father, who both developed spontaneous pneumothorax (11). In patients with usual interstitial pneumonia (UIP), the incidence of PO may reach 6.7% following an HRCT or an open pulmonary biopsy (12).

Patterns of PO

There are two PO patterns: dendriform and nodular. DPO may be idiopathic (4,13) or, most frequently, be associated with primary lung disease. Associated lung diseases include diffuse interstitial lung disease (especially idiopathic pulmonary fibrosis), emphysema; chronic obstructive pulmonary disease; pneumoconiosis; aspiration pneumonia; tuberculosis; inhalation of foreign bodies; sarcoidosis or malignant diseases; among others (3).

Likewise, the nodular pulmonary ossification (NPO) form, the most frequent type of PO, can be idiopathic or secondary. Unlike DPO, secondary NPO forms have been associated with passive venous congestion caused by chronic heart failure, mitral stenosis and hypertrophic subaortic stenosis, to name a few (14). Figure 2 shows the most frequent causes of PO described in literature.

Figure 2 Types and causes of lung ossification. ARDS, acute respiratory distress syndrome; COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus; ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis; OP, organizing pneumonia.

Pathogeny

The pathogenesis of PO is not fully understood, and several hypotheses have been suggested to account for its etiology. The most widely studied hypothesis is that PO develops by organization of an alveolar exudate in response to chronic insults, which leads to the development of fibro-osseus metaplasia. Another theory is that angiogenesis and subsequent anoxia and fibrotic lung repair generate an acidic ambient that ultimately stimulates the proliferation of fibroblasts and bone formation (5,15). One of the main differences in the pathogenesis of DPO and NPO is that the ectopic bone tissue of the former contains a marrow component. Thus, the formation of bone marrow tissue is not secondary to the precipitation of calcium and phosphate in lung tissue or hypercalcemia, but it is a metaplastic bone formation in the lung interstitium (13).

Likewise, DPO is associated with a dendriform pattern characterized by a branched form resembling a tree that expands throughout the interstitium and alveolar septa. Bone spicules show a regular dichotomous pattern that branches at angles of 60° to 70° roughly every 2.0 cm (3). Hence, DPO may progress to interstitial fibrosis and has been considered a radiological and histological marker included in the phenotype of progressive pulmonary fibrosis (16).

Other predisposing agents have been associated with the pathogenesis of PO, including the transforming growth factor beta (TGF-β). This post-inflammatory mediator stimulates the proliferation of osteoblasts and chrondrocytes (17). Serum levels of Krebs von den Lungen-6 (KL-6), a glycoprotein produced by type II pneumocytes in response to cell insults, have been suggested as a predictive factor of progression. In the light that disease progression in PO is associated with an increase in the number of ossified lesions and surrounding reactive fibrosis, it could cause an increase in the levels of KL-6 in serum, a known marker of interstitial lung disease. Hence, KL-6 emerges as a potential predictor of progression (18). On another note, cases have been reported of ectopic bone formation in vitro induced by other mediators, including bone morphogenic protein or interleukin-1 and interleukin-4 (19).

Azuma et al. have first described a familial clustering of DPO (11). There are many molecular biological hypotheses that lead to the formation of ectopic bone in the lungs. The bone morphogenetic protein (BMP) genes and TGF-β gene families have been hypothesized as a conceivable pathogenesis of DPO, because they regulate ectopic bone formation (20). These genes are associated with the embryonic molecular regulation of limb growth. BMP signaling molecules regulate the morphogenesis of the limbs together with other signaling molecules, including fibroblast growth factors (21). There might be a relationship between ectopic bone formation in the lung and bone hypoplasia but further studies are needed to better elucidate these mechanisms.

Histological diagnostic approach

Diffuse PO is a rare disease increasingly diagnosed in vivo, although it is most frequently found post-mortem. Although PO is commonly an incidental finding on an HRCT performed for other cause, it is also found by surgical biopsy, a lung tissue sample obtained for other purposes. Other types of less-invasive lung biopsies, including transbronchial lung biopsy (TBLB) are not suitable for correct diagnosis as the sample of pulmonary interstitium obtained is too small. A valid and acceptable alternative is transbronchial lung cryobiopsy. This new procedure has been proven to have a superior diagnostic performance for interstitial lung disease, as compared to TBLB. However, this procedure is associated with a slightly higher risk for secondary pneumothorax and lung hemorrhages, as compared to TBLB. Conversely, the risk for these events is lower in cryobiopsy than in surgical lung biopsy (22,23).

Dendriform lung ossification as a phenotype of interstitial lung abnormality (ILA)

ILAs are defined as incidental radiological findings on HRCT, including ground-glass opacities; reticular abnormalities; lung architectural distortion; bronchiectasis; and honeycomb pattern or cysts involving over 5% of the lung surface (24). ILA is considered an early stage of radiological involvement that may progress to defined interstitial lung disease over time. However, the pathogenesis and course of ILA are still poorly understood (25).

The typical radiological findings of DPO on HRCT are calcified branching structures predominantly distributed in the lower lobes, without any other remarkable finding (7,8). However, recent studies suggest that the idiopathic form could be included in the group of disorders associated with ILA (25,26). A retrospective cohort study of 16 patients conducted by Ueno et al. revealed that all radiological lesions of patients with DPO were associated with a histological finding of dendriform ossification, cicatricial PO and/or fibrosis. In these cases, lesions had a lower lobe distribution and a linear branching pattern, which is consistent with the distribution described in ILAs. It is worth noting that some of the POs in these series did not exhibit high attenuation in the HRCT bone window level. This could be explained by the small size of abnormalities and the reduced fat fraction of bone marrow (26).

Considering defined interstitial lung disease, the UIP pattern also shows radiological and histological PO, which is one of the most common forms of ILA. Therefore, bone formation in ILA may resemble that associated with the UIP pattern. In the light of their shared features, DPO, as an ILA phenotype, has been suggested to be an early stage of disease that may ultimately progress to interstitial lung disease (12).

On this line, in their study of patients with interstitial lung disease, Kim et al. found that DPO was found in 5 of 75 patients with pathologically proven UIP (12). The presence of DPO can help the diagnose of UIP pattern and it can be considered as an ancillary finding of fibrosis. In the study published by Egashira et al., DPO was found to have a much higher prevalence in UIP patients than in other non-idiopathic pulmonary fibrosis fibrotic interstitial lung diseases (5). Many studies have shown the relationship between IPF and DPO, helping the differentiation of idiopathic pulmonary fibrosis from other interstitial lung diseases; they have also demonstrated that DPO is highly associated with a higher grade of fibrosis and to poor survival. Thus, DPO could reflect the severity of fibrosis (27,28).

Conclusions

PO is a low-prevalence entity more frequent in men than in women that occurs in early stages of life. This disease has an indolent course that may progressively cause lung function impairment. Although it is generally idiopathic, it may be associated with other diseases, prevailingly lung interstitial diseases. An association has been observed with the UIP radiological pattern. HRCT is the technology of choice for diagnosis, as it allows for differential diagnosis with other diseases and spares the use of more aggressive diagnostic techniques. As a specific treatment is not currently available, treatment is aimed at preventing progression to fibrosing interstitial lung disease. For such reason, early diagnosis and appropriate management of associated comorbidities are crucial. Further research and long-term follow-up are necessary for a better understanding of the pathogenesis and prognosis of this disease.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2083/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2083/coif). The authors have no conflicts of interest to declare.

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Cite this article as: Casal A, Ferreiro L, Toubes ME, Valdés L. Pulmonary ossification: a review. J Thorac Dis 2025;17(5):3450-3455. doi: 10.21037/jtd-2024-2083

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