January 7, 2005

Idiopathic Pleuroparenchymal Fibroelastosis*: Description of a Novel Clinicopathologic Entity

Between 1996 and 2001, we identified five cases of a unique idiopathic pleuroparenchymal lung disease characterized by a clinical presentation suggestive of a chronic idiopathic interstitial pneumonia, marked pleural and parenchymal radiographic involvement with an upper lobe predominance, and surgical lung biopsy findings that did not fit with any of the currently defined interstitial pneumonias. The pathologic findings included the following: (1) intense fibrosis of the visceral pleura; (2) prominent, homogenous, subpleural fibroelastosis; (3) sparing of the parenchyma distant from the pleura; (4) mild, patchy lymphoplasmacytic infiltrates; and (5) small numbers of fibroblastic foci present at the leading edge of the fibrosis. In this report, we characterize the clinical, radiographic, physiologic, and pathologic findings of this entity, which we term idiopathic pleuroparenchymal fibroelastosis.

(CHEST 2004; 126:2007-2013)

Key words: idiopathic; interstitial lung disease; pathology; pleural fibrosis; pulmonary fibrosis

Abbreviations: CMF = cyclophosphamide, methotrexate, and fluorouracil; HLA = human leukocyte antigen; HRCT = high-resolution CT; IIP = idiopathic interstitial pneumonia; UIP = usual interstitial pneumonitis

Between 1996 and 2001, we identified five patients with a cryptogenic syndrome of clinically significant chest symptoms, radiographic pleuroparenchymal abnormalities, and fibroelastotic changes seen on surgical lung biopsy specimens. Moreover, the pathologic findings in these five cases were distinctive and could not be classified within any of the currently defined idiopathic interstitial pneumonias (IIPs). None of the patients had evidence of a characterized connective tissue disease, sarcoidosis, human leukocyte antigen (HLA)-B27-related disease, hypersensitivity pneumonitis, infection, asbestosis, or other pneumoconiosis. Thus, we report five cases of an idiopathic pleuroparenchymal fibroelastotic syndrome with unique pathology.


The clinical database of the Interstitial Lung Disease Program at National Jewish Medical and Research Center was reviewed for cases of combined pleural and lung parenchymal fibrosis for visit dates between 1996 and 2001. All living study subjects had been prospectively enrolled in our specialized center of research longitudinal study of interstitial lung disease that was approved by our institutional review board and supported by the National Institutes of Health. Case records were abstracted for all clinical data. Radiographic studies were reviewed by an expert thoracic radiologist (D.A.L.). Surgical lung biopsy specimens were reviewed by an expert pulmonary pathologist (C.D.C.).


Clinical Features

Patient 1 was a 65-year-old woman with "incidental" pleural thickening seen on a chest radiograph 10 years prior to referral. Four years prior to referral, she underwent a modified radical mastectomy for adenocarcinoma of the breast and was treated with adjuvant chemotherapy of cyclophosphamide, methotrexate, and fluorouracil (CMF) without radiation therapy. The patient was treated with daily doses of tamoxifen, and she returned to her baseline function of aerobic exercise 60 min daily. Eight months prior to referral, dyspnea on exertion and a nonproductive cough developed. Chest radiography revealed a new right pleural effusion and progressive, pleural thickening (greater in the right lung than in the left) when compared to prior radiographs. Pleural fluid was negative for malignancy. A diagnostic video-assisted thorascopic lung biopsy was performed, and at surgery a complex pleural process with extensive fibrosis requiring decortication was found. Physical examination findings were significant for tachypnea, tachycardia, diffusely decreased breath sounds, and decreased diaphragmatic excursion. Extensive evaluation was negative for pneumoconiosis, autoimmune disease, and HLA-B27-related disease.

Patient 2 was a 52-year-old man in whom exertional breathlessness developed following an upper respiratory tract infection. A chest radiograph revealed bilateral pleural thickening. One year later, he underwent right-sided pleural decortication with symptomatic improvement. However, several months later, progressive dyspnea again developed. Ultimately, the patient underwent left pleural decortication. The patient returned to work but remained dyspneic with a productive cough. He was then referred to our institution. His medical history was significant for Charcot-Marie-Tooth disease (hereditary motor sensory neuropathy), gastroesophageal reflux, and narcolepsy. A sister had sarcoidosis, and he had previously worked in both construction and agriculture, although a direct exposure to asbestos was absent. On examination, he was mildly tachycardic and tachypneic. Fine mid-late inspiratory rales and distant breath sounds were noted. Autoimmune serology findings were negative.

Table 1-Clinical Characteristics*

Patient 3 was a 61-year-old woman who presented with chronic cough. Diagnosed with asthma in her 20s, she had experienced multiple episodes of "bronchitis" and "pneumonia" over her lifetime. At the time of referral, the cough was accompanied by wheezing, dyspnea, and chest tightness that occurred on a daily basis. Her medical history was significant for breast cancer that had been diagnosed and treated 10 years previously with a left modified radical mastectomy, chemotherapy with CMF, and radiation therapy. She had experienced no significant environmental or occupational exposures. Examination findings noted mild tachypnea and tachycardia with fine mid-late inspiratory rales at the left base, and mild- moderate kyphoscoliosis, and a mid-systolic click found during her cardiologic examination that was consistent with mitral valve prolapse. Bronchoscopy, routine laboratory examination findings, autoimmune serology results, cystic fibrosis genotyping results, and α^sub 1^-antitrypsin levels were all unrevealing. Prior chest radiographs and chest CT scans had revealed biapical pleural thickening 5 years earlier.

Patient 4 reported reduced exercise tolerance as a teenager. At age 32 years, she underwent a pulmonary evaluation following a diagnosis of pulmonary fibrosis in her twin sister. Her pulmonary physiology was restrictive, but as she was asymptomatic no further evaluation was performed. Seven years later, cough and pleuritic chest pain developed. An examination revealed a loud pleural rub, and she was treated with antibiotics. Over the next year, recurrent pneumonias developed and she was referred to our institution. The patient was a life-long nonsmoker without occupational or environmental exposures. Family history was significant for a twin sister who died of progressive pleuroparenchymal fibrosis (ie, patient 5) and a grandfather with rheumatoid arthritis. An examination revealed mild tachypnea and tachycardia, a pleural rub at the right base, and rales at the left base. Laboratory examination findings were notable for an erythrocyte sedimentation rate of 47 mm/h but negative autoimmune serology results.

Patient 5, the twin sister of patient 4, presented in 1987 at age 32 years with right upper lobe pneumonia. Chest radiographs revealed progressive upper lobe volume loss and bilateral pleural thickening. Her pulmonary physiology was restrictive. The patient was a nonsmoker and worked as a nurse. Her anti-nuclear antibody titer was 1:80, and rheumatoid factor titer was 1:160 without other evidence of a connective tissue disease. An evaluation for HLA-B27- associated disease was negative. The patient underwent surgical lung biopsy that showed pleural fibrosis and patchy interstitial fibrosis. The patient was treated with steroids without improvement. She died of progressive respiratory failure 5 years after undergoing surgical lung biopsy. An autopsy revealed marked pleural and interstitial fibrosis that was identical to that found in her twin sister.

A summary of the clinical data from all five patients may be found in Table 1. A summary of the physiologic data may likewise be found in Table 2.

Imaging Features

Chest radiographs in all cases showed marked apical pleural thickening, which was associated with superior hilar retraction (Fig 1). High-resolution CT (HRCT) scans were available in four patients (Fig 2, Table 3). The salient HRCT scan feature was intense pleural thickening associated with evidence of fibrosis. Associated features included upper lobe volume loss, architectural distortion, traction bronchiectasis, reticular abnormalities, and honeycombing. The upper lobes were always more severely involved, with involvement of the lower lobes being absent or less marked.

Pathologic Features

The pathologic features include a markedly thickened visceral pleura and prominent subpleural fibrosis characterized by a homogeneous mixture of elastic tissue and dense collagen (Fig 3, 4). The border between the fibroelastosis and the underlying normal lung parenchyma is relatively abrupt, and the parenchyma distant from the pleura is spared. Rare fibroblastic foci are noted at the leading edge of the fihrosis (Fig. 5). Inflammation is variable and primarily consists of small aggregates of lymphocytes. Asbestos bodies are absent.

Table 2-Pulmonary Physiology Findings*

FIGURE 1. A chest radiograph showsvery marked bilateral upper lobe volume loss, with hilar retraction, and marked apical pleural thickening.

FIGURE 2. Retargeted HRCT images through the upper lung shows marked visceral pleural thickening extending into the major fissures, with subpleural reticular abnormalities. There is architectural distortion with traction bronchiectasis. Findings were bilateral.

Table 3-Radiologic Findings*


We report herein on five cases of a rare clinicopathologic syndrome with clinical features that overlap those of a chronic IIP. The most characteristic features of this disorder are the radiographic evidence of mid-lung zone and upper lung zone pleural and parenehymal abnormalities, and distinctive histopathologic findings on surgical lung biopsy specimens. In all five cases, the pathology was identical and was characterized by a combination of pleural and parenchymal fibroelastosis.

FIGURE 3. Top, A: low-power view of a surgical lung biopsy specimen (hematoxylin-eosin, original 20). Note pleural and subpleural fihrosis with large areas of normal lung. Inset, B: abrupt transition between fibrotic and near-normal lung (hematoxylin- eosin, original 40).

This distinctive pathologic pattern does not fall within any of the previously described UPs or that described in asbestos-related, connective tissue disease-associated, or drug-related pleuroparenchymal disease. While some of the histologic features overlap with those of nonspecific interstitial pneumonia and usual interstitial pneumonia (UIP), the intense pleural fibrosis, pronounced parenchymal fibroelastosis, upper lobe predominance, and sparing of the lung away from the pleura marks this entity as distinct. Although UIP is also a subpleural-predominant interstitial fibrosis, it is temporally heterogeneous in its fibrosing patten, often showing honeycomb changes, dense fibrosis, fibroblastic foci, and normal alveolated lung parenchyma in the same field. Nonspecific interstitial pneumonia can have a bronchiolocentric/subpleural distribution pattern that is temporally homogeneous, but it lacks the fibroelastotic component that is so prominent in these cases. The pathologic findings of visceral pleural fibrosis secondary to asbestos exposure are nonspecific, and while the visceral pleura is thickened by fibrous tissue with relatively little inflammation and the fibrosis may extend a short distance into the underlying lung parenchyma, there is not an admixture of elastotic and fibrotic tissue, as was seen in these cases. Pulmonary apical caps histologically reveal visceral pleural fibrosis with subpleural, parenchymal collagen deposition and elastic fibers; however, pulmonary apical caps are typically asymptomatic and nonprogressive.1

FIGURE 4. Surgical lung biopsy specimen at low power (Movat pentachrome, original 40) [top, A] and high power (Movat pentachrome, original 200) [inset, B] demonstrating the dense collagen (yellow) of the pleura and the underlying fibroelastic tissue in the parenchyma. The inset demonstrates the amorphous and irregular features of the elastic fibers (black). The intervening matrix is a mix of collagen (yellow) and mucopolysaccharide (blue).

The simultaneous occurrence of both pleural and parenchymal fibrosis is a rare event and is largely limited to asbestos-related disease, connective tissue-associated disease, radiation-induced lung injury, or drugs.2-9 None of the patients offered convincing evidence of asbestos exposure, and the biopsy specimens were universally negative for the presence of ferruginous bodies. None of our patients had a characterized autoimmune disease. The chemotherapy received by two of our patients may offer one explanation; however, while methotrexate has been shown to produce acute pleuritis, pleural thickening, and, rarely, parenchymal fibrosis, frank pleural fibrosis has not previously been described.10 Cyclophosphamide-induced injury occurs in

External beam radiation, on the other hand, is associated with both pleural fibrosis and parenchymal disease characterized either by an acute pneunionitis weeks to months following therapy or by late fibrosis months to years following therapy along with UIP on histopathologic examination. While radiation-induced injury is commonly seen in the irradiated lung fields, radiation fibrosis need not be limited to the areas within the radiation ports. Patient 3 received radiation therapy in conjunction with her chemotherapy, and we considered the possibility that pleuroparenchymal fibroelastosis may be a manifestation of radiation-induced lung injury in this patient. Still, the finding of elastosis and the distribution of disease would make this case unique even within this setting.

FIGURE 5. Section reveals the dense flbrosis of the pleural and subpleural areas, with abrupt transition to normal lung. Encircled area identifies a fibroblastic focus in a transition zone between densely fibrotic and more normal lung parenchyma (hematoxylin- eosin, original 20.

Previous case reports of idiopathic, upper lobe-predominant fibrosis appear in both the English and non-English language literature.14-22 In the 1960s, The Postgraduate Medical School of London published two separate case reports of idiopathic upper lobe fibrosis, "Undiagnosable Lung Disease"15 and "A Case of Idiopathic Cavitation of the Lung."14 The pathologic description of the latter case is particularly suggestive as the findings included dense pleural fibrosis and the deposition of large quantities of elastin. In 1975, Davies et al16 described five patients with progressive upper lobe fibrosis of unclear etiology that was not dissimilar from those described in this report. Two case reports of what we believe to be the same entity are also described in the French-language literature.17 The largest series of patients with idiopathic upper lobe fibrosis (seven patients) has come from Osaka, Japan.21 The salient features in these cases included subpleural, upper lobe fibrosis without honeycombing; a slow, progressive clinical course similar to that of a chronic IIP; and a high incidence of pneumothoraces. While there appear to be clinical, radiologic, and pathologic differences among the Osaka patients and our series, it may well be that these cases represent the same spectrum of disease (R. Amitani, MD; personal communication; July 2003).

Patients 4 and 5 in our series were believed to have familial/ genetic lung disease. Case reports of other familial interstitial lung diseases included lymphoid interstitial pneumonias, desquamative interstitial pneumonitis, and sarcoidosis.23-26 There are also several reports3,4 in the literature of idiopathic bilateral pleural fibrosis. Of greatest interest is the case series of idiopathic pleural fibrosis reported by Azoulay et al,4 which described the cases of three sisters. Two of the sisters died, and the third underwent successful lung transplantation. Each disease process started with apical-predominant pleural thickening and progressed to more diffuse pleural involvement. The examination of specimens obtained during surgical lung biopsy from two of these patients revealed that the parenchyma immediately beneath the pleura was clearly abnormal while the parenchyma distant from the pleura was spared, which is similar to the condition of the patients in this report. Moreover, the twin sisters (patients 4 and 5) in this report, in contrast to the other patients in this series, had aggressive disease courses resulting in the death of both patients at ages 41 and 37, respectively. We hypothesize that patients 4 and 5 in this report had the same clinicopathologic entity as those described by Azoulay et al.4

In summary, we have reported five cases of a unique idiopathic pleuroparenchymal lung disease that is characterized by upper lobe radiographic predominance and pathologic findings that do not fit with any of the currently defined interstitial pneumonias. We term this disorder idiopathic pleuroparenchymal fibroelastosis.

* From the Interstitial Lung Disease Program, National Jewish Medical and Research Center, Denver, CO.


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Stephen K. Frankel, MD, FCCP; Carlyne D. Cool, MD; David A. Lynch, MD; and Kevin K. Brown, MD, FCCP

Manuscript received September 12, 2003; revision accepted July 26, 2004.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]).

Correspondence to: Kevin K. Brown, MD, FCCP, National Jewish Medical and Research Center, 1400 Jackson St, Denver, CO 80206; e- mail [email protected]

Copyright American College of Chest Physicians Dec 2004