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Honeycomb Lung Pathology 

  • Author: Brian M Nagao, MD; Chief Editor: Philip T Cagle, MD  more...
Updated: Jan 29, 2015


In pathology, honeycomb lung refers to the fibrotic cystic changes (honeycomb changes) seen in the lungs of those with certain end-stage interstitial lung diseases (ILDs). Honeycomb lung is a pathologic finding and not a specific disease entity. The importance of honeycomb lung is that its presence is associated with a poor prognosis.



Studies in the United States suggest the overall incidence of ILD to be approximately 30 per 100,000/year, with a slight male predominance, and a higher prevalence in older adults.[1] Once a patient is diagnosed with ILD, progression to end-stage disease with honeycomb changes is based largely on the underlying disease process.



ILD, also called diffuse parenchymal lung disease, is a broad classification encompassing mainly non-neoplastic, inflammatory lung diseases that cause alterations to lung parenchyma in a diffuse pattern.

Although over 20 distinct ILDs have been described, only a proportion of them are typically associated with honeycomb changes. Of the idiopathic interstitial pneumonias, idiopathic usual interstitial pneumonia (UIP) is the most common condition associated with honeycomb lung.[2] Honeycomb changes are occasionally seen in idiopathic nonspecific interstitial pneumonia (NSIP), another chronic fibrosing idiopathic interstitial pneumonia.

Collagen vascular diseases (CVDs) can be associated with ILD and fibrosis with honeycomb changes. These CVDs include systemic lupus erythematosus, rheumatoid arthritis, progressive systemic sclerosis (diffuse scleroderma), Sjögren syndrome, and dermatomyositis/polymyositis.[3]

Other causes of honeycomb lung include pulmonary sarcoidosis, chronic hypersensitivity pneumonitis(HP), and drug-induced ILD.

Dozens of drugs have been linked to ILD; however, methotrexate and bleomycin are the 2 agents most strongly associated with fibrosing interstitial pneumonia and are capable of producing UIP and/or NSIP patterns.[4] Regardless of the underlying disease process, the universal pathophysiology is believed to be acute injury to lung parenchyma leading to chronic interstitial inflammation, tissue destruction, fibroblastic activation and proliferation, pulmonary fibrosis, and eventually architectural remodeling with honeycomb changes. This process usually evolves over a period of months to years; however, it can be accelerated.



The location of honeycomb changes depends somewhat on the underlying disease; however, in most cases of ILD, the changes begin in the subpleural regions of the lung and are most severe in the lower lobes and lower portions of all lobes. The pattern of distribution may be quite variable. Thus, when surgical biopsies (wedge resections) are performed for diagnosis, at least 2 lobes should be sampled. Biopsy of one lobe is suboptimal, and even smaller transbronchial biopsies are usually insufficient for diagnosis.


Clinical Features and Imaging

Patients most often note progressive dyspnea or nonproductive cough present over a period a months to years. In honeycomb lung associated with idiopathic UIP, most patients are over 50 years old and have had symptoms for over 6 months. Other signs and symptoms can include hemoptysis, wheezing, and chest pain. Occasionally, ILD is identified in asymptomatic patients by chest radiography performed for alternate reasons. Age, gender, and smoking history are highly relevant to clinical presentation. ILD can result from CVDs. Such patients often have associated rheumatologic signs and symptoms, although occasionally lung disease may be the first manifestation of their CVD. The possibility of CVD should be explored in any patient with ILD, particularly young women in whom CVD is more common.

Characterization of ILD requires clinical, radiological, and pathological correlation. A complete review of the radiologic findings in ILD is beyond the scope of this article. From the perspective of the pathologist, understanding that high-resolution computed topography enables detailed images of lung parenchyma and airways and is an important tool in the diagnosis of ILD is important.

Basic patterns of ILD include reticular patterns (thickened interlobular and intralobular septa), nodular patterns (airspace and interstitial nodules), cystic patterns (bronchiectatic or honeycomb cysts), and altered attenuation (ground glass opacification or mosaic attenuation patterns).[5] Based on the imaging, the radiologist is often able to provide a diagnosis or differential diagnosis for the pattern of ILD that can be correlated with pathologic impressions of the biopsy. Radiology also has an important role in guiding the surgeon to appropriate sampling of the lung tissue.

Ideally, wedge biopsies from multiple lobes are obtained with attention to sampling areas that contain both abnormal lung parenchyma and adjacent normal lung tissue. Specimens showing only diffuse fibrosis and honeycomb changes are of limited diagnostic use because such findings are nonspecific. The role of transbronchial biopsy in ILD is generally limited to exclusion of pulmonary sarcoidosis or infection.

When examining a biopsy, the pathologist must review the patient history and radiologic impressions and ensure the pathologic impression is consistent with the entire clinical picture. Receiving enough clinical information to completely exclude all secondary causes of ILD is rare for pathologists. In our practice we prefer to be descriptive in the diagnosis, listing the major microscopic findings, commenting on the overall pathologic pattern, and listing a differential diagnosis for the pattern. Final determination of the etiology of the ILD is left to the clinician.


Gross Findings

Gross impressions serve not only to aid in the diagnosis but also guide appropriate sampling for histologic evaluation. In the explanted or autopsy lung specimen, appropriate sampling should include sections from all lobes with attention to transition areas between normal and abnormal lung, parenchyma surrounding the bronchovascular bundle, and the pleura with subpleural parenchyma.

In idiopathic UIP, the lungs are often small and contracted with a cobblestone appearance to the pleura. On cut section the lungs are firm with fibrosis and honeycomb changes that are more prominent in the subpleural regions and the lower portions of all the lung lobes with the most dramatic changes seen in the lower lobes (see the images below).

Gross photograph of typical lung findings in usual Gross photograph of typical lung findings in usual interstitial pneumonia (UIP). Fibrosis of both lobes can be seen with honeycomb change involving primarily the lower portions of the lobes.
A more severe case of usual interstitial pneumonia A more severe case of usual interstitial pneumonia (UIP) with virtually the entire lung involved by fibrosis with honeycomb change.

Fibrotic parenchyma surrounding the airways can retract, causing bronchiectasis, which can be seen grossly. In idiopathic NSIP, the fibrosis appears more homogenous and honeycomb changes may not be as prominent, except in the areas of severe fibrosis. Gross findings of ILD secondary to drugs, CVD, and chronic HP may be indistinguishable from idiopathic UIP or NSIP, and histology and clinical history are required for the diagnosis. End-stage pulmonary sarcoidosis can also mimic idiopathic UIP grossly; however, fibrosis and honeycombing that is more dramatic in the upper lobes[6] and prominence of the hilar lymph nodes would favor pulmonary sarcoidosis.


Microscopic Findings

UIP is best characterized as a pattern of lung injury that can result from idiopathic UIP or underlying disease. The cardinal finding in UIP is interstitial fibrosis and chronic inflammation that is temporally and spatially heterogeneous (the fibrosis is accentuated at the periphery of the lobules with abrupt transition to normal alveolar tissue [see the top part of the image below]).

A) Typical histologic finding of spatial heterogen A) Typical histologic finding of spatial heterogeneity in usual interstitial pneumonia (UIP) with an abrupt transition from honeycomb change (left) to normal lung (right; trichrome stain, x40) and B) spatially homogeneous pattern of fibrosis seen in nonspecific interstitial pneumonia (NSIP) (trichrome stain, x40).

The changes are temporally heterogeneous, with fresher areas of fibrosis showing edema and more significant interstitial lymphoplasmacytic inflammation and older areas with dense fibrosis and a paucity of inflammatory cells. Fibroblastic foci are oval-shaped plugs of edematous fibrous tissue that are often seen at the edges of the encroaching fibrosis and are commonly seen in UIP (see the top part of the image below). Dense fibrosis and honeycomb changes are typically located in the subpleural parenchyma, especially the lower lobes. The residual airspaces may show squamous metaplasia or bronchiolar metaplasia (bronchiolization) and are often filled with mucin and occasionally neutrophils (see the bottom part of the image below).

A) Fibroblastic focus (x200) and B) honeycomb chan A) Fibroblastic focus (x200) and B) honeycomb change with bronchiolization of airspaces (x200).

NSIP is also best considered a pattern of lung injury, but it differs from UIP because the interstitial changes of NSIP are relatively homogeneous. Three patterns of NSIP have been described: cellular, fibrotic, and mixed. In cellular NSIP, mild-to-moderate lymphoplasmacytic inflammation is distributed evenly throughout the interstitium. The inflammation is usually not prominent and should not demonstrate follicular hyperplasia. Fibrosis is not significant. In fibrotic NSIP, the interstitial fibrosis is temporally and spatially homogenous, meaning it is evenly distributed throughout the interstitium with a uniformly mature appearance (see the bottom part of the image below).

A) Typical histologic finding of spatial heterogen A) Typical histologic finding of spatial heterogeneity in usual interstitial pneumonia (UIP) with an abrupt transition from honeycomb change (left) to normal lung (right; trichrome stain, x40) and B) spatially homogeneous pattern of fibrosis seen in nonspecific interstitial pneumonia (NSIP) (trichrome stain, x40).

Fibroblastic foci may be seen but are usually inconspicuous. Honeycomb changes are uncommon but may be present in areas of severe fibrosis. Mixed NSIP is merely a combination of the fibrotic and cellular patterns. The NSIP pattern can be seen in idiopathic NSIP or be secondary to other disease.

Acute interstitial pneumonia (AIP), also called idiopathic acute respiratory distress syndrome, is a clinical diagnosis that correlates histologically with diffuse alveolar damage (DAD). In the exudative phase of DAD, mixed interstitial inflammation is present with interstitial edema, intraalveolar hemorrhage, and type II pneumocyte hyperplasia. Within several days, hyaline membranes form, and interstitial inflammation decreases. As the DAD progresses to the organizing/proliferative phase, the hyaline membranes are replaced by foci of organizing pneumonia. In contrast to other ILDs, AIP may progress rapidly to interstitial fibrosis and honeycomb changes, within 3 weeks of onset.[7]

ILD is common in CVD, and the fibrosis is generally UIP, NSIP, or mixed patterns. Occasionally, distinguishing idiopathic interstitial pneumonia from ILD secondary to CVD is difficult. However, some findings are more common in ILD secondary to CVD, such as pleural inflammation, interstitial lymphoplasmacytic infiltrates, follicular lymphoid hyperplasia, and vascular changes. ILD is seen in up to 20% of patients with rheumatoid arthritis.[8]

Rheumatoid arthritis ILD can resemble idiopathic NSIP or UIP. However, several distinguishing features exist. Pleuritis, with or without effusion, is often present in rheumatoid arthritis and is uncommon in idiopathic UIP. The chronic interstitial inflammation is more prominent and is associated with follicular bronchiolitis showing well-formed germinal centers. Rheumatoid nodules are subpleural nodular bodies consisting of a central core of necrotic tissue surrounded by palisading histiocytes. They are an infrequent but specific finding. The fibrosis tends to be NSIP-like; however, UIP-like fibrosis can also be seen.

Although uncommon, systemic lupus erythematosus can cause both acute and chronic lung disease. Acute lupus pneumonitis is characterized by diffuse alveolar damage with hyaline membranes, hemorrhage, and vasculitis. Pleuritis is common. In chronic lupus ILD, the fibrosis can be either UIP or NSIP pattern with or without honeycomb changes.

ILD affects approximately 40% of patients with progressive systemic sclerosis (diffuse scleroderma) and is the leading cause of mortality in these patients.[9] Early in the disease process the interstitial fibrosis has a distinctive appearance, with collagen deposition along the alveolar walls and preservation of the underlying lung architecture with sparse inflammation ("collagenization" of the alveoli). As the fibrosis progresses, a NSIP or UIP pattern can develop along with honeycomb changes. Vascular intimal hyperplasia and medial hypertrophy may be present and is indicative of pulmonary hypertension.

Up to 40% of patients with dermatomyositis/polymyositis are affected by ILD.[10] The most common appearance is cellular interstitial pneumonia with interstitial fibrosis, often indistinguishable from idiopathic NSIP. UIP-like fibrosis and honeycomb changes can be seen in a minority of cases.

In the lung, Sjögren syndrome manifests as follicular bronchiolitis with atrophy of the glands and fibrosis of the small airways. Often, conspicuous chronic interstitial inflammation can be found in a cellular NSIP pattern. The interstitial inflammation may be prominent and densely cellular with occasional small non-necrotizing granulomas (lymphoid interstitial pneumonia pattern). Interstitial fibrosis is uncommon, but, when present, may be in a fibrosing NSIP or UIP pattern.[11]

Sarcoidosis is a systemic disease of unknown etiology that is more common in young adults. Lung disease (pulmonary sarcoidosis) is usually mild; however, some patients develop fibrosis and honeycomb changes. Pulmonary sarcoidosis is characterized by areas of fibrosis that contain small, well-circumscribed, non-necrotizing granulomas that coalesce into larger nodular lesions that are rimmed by lymphocytes. The granulomas are composed of epithelioid histiocytes and multinucleated giant cells. The giant cells may have cytoplasmic inclusions, including asteroid bodies and Schaumann bodies. The granulomas are usually distributed along the lymphatics of the pleura and along the bronchovascular bundle. The peribronchial distribution of the granulomas enables use of transbronchial biopsy in the diagnosis of sarcoidosis.

In end-stage pulmonary sarcoidosis, severe interstitial fibrosis and/or confluent fibrosis with honeycomb changes can be found. Most importantly, pulmonary sarcoidosis is a diagnosis of exclusion, and special stains should be performed to exclude underlying infection, particularly fungal and mycobacterial.

Chronic HP is caused by a type IV hypersensitivity reaction to an inhaled antigen and is most commonly observed in patients who keep pet birds. The inhaled antigen stimulates airway inflammation and eventually interstitial fibrosis that can be either NSIP or UIP pattern with honeycomb changes. Microscopically, interstitial lymphoplasmacytic inflammation with scattered poorly formed granulomas can be seen. If the granulomas are abundant and well-formed, pulmonary sarcoidosis should be considered. If prominent necrotizing granulomatous inflammation is observed, an infectious process should be excluded.



Immunohistochemistry is not useful in the evaluation of honeycomb lung.



Currently, molecular and genetic testing are not used in the diagnosis of ILD. Although some cases of UIP are familial, genetic studies have not been clinically useful in predicting occurrence of honeycomb lung.


Prognosis and Predictive Factors

The prognosis in ILD varies with the underlying etiology, but when honeycomb changes are present, the prognosis is poor. Upon being diagnosed with UIP, most patients without lung transplant die within 3 years.


Differential Diagnosis

The most important diagnostic consideration is correctly identifying patients with a UIP pattern as the prognosis is much worse than with other patterns of interstitial lung disease.

Contributor Information and Disclosures

Brian M Nagao, MD Consulting Staff, Department of Pathology and Laboratory Medicine, University of California Davis Health System

Disclosure: Nothing to disclose.


Michael C Fishbein, MD Piansky Professor of Pathology and Medicine, University of California, Los Angeles, David Geffen School of Medicine

Michael C Fishbein, MD is a member of the following medical societies: American College of Cardiology, American Heart Association, International Academy of Pathology, International Society for Heart and Lung Transplantation, American Federation for Clinical Research, American College of Surgeons Oncology Group, American College of Surgeons Oncology Group, Society for Cardiovascular Pathology

Disclosure: Nothing to disclose.

Chief Editor

Philip T Cagle, MD Professor, Department of Pathology, Weill Medical College of Cornell University; Director, Pulmonary Pathology, The Methodist Hospital; Senior Member, The Methodist Hospital Research Institute

Philip T Cagle, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Chest Physicians, American Medical Association, American Society for Investigative Pathology, American Thoracic Society, College of American Pathologists, Federation of American Societies for Experimental Biology, Texas Medical Association, United States and Canadian Academy of Pathology, Harris County Medical Society, European Society of Pathology

Disclosure: Nothing to disclose.

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Gross photograph of typical lung findings in usual interstitial pneumonia (UIP). Fibrosis of both lobes can be seen with honeycomb change involving primarily the lower portions of the lobes.
A more severe case of usual interstitial pneumonia (UIP) with virtually the entire lung involved by fibrosis with honeycomb change.
A) Typical histologic finding of spatial heterogeneity in usual interstitial pneumonia (UIP) with an abrupt transition from honeycomb change (left) to normal lung (right; trichrome stain, x40) and B) spatially homogeneous pattern of fibrosis seen in nonspecific interstitial pneumonia (NSIP) (trichrome stain, x40).
A) Fibroblastic focus (x200) and B) honeycomb change with bronchiolization of airspaces (x200).
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