Honeycomb Lung Pathology

Updated: Sep 20, 2017
  • Author: Brandon A Umphress, MD; Chief Editor: Philip T Cagle, MD  more...
  • Print


In pathology, honeycomb lung refers to the characteristic appearance of variably sized cysts in a background of densely scarred lung tissue. Microscopically, enlarged airspaces surrounded by fibrosis with hyperplastic or bronchiolar type epithelium are present. [1]  However, these changes are nonspecific and are often seen in numerous end-stage interstitial lung diseases (ILDs). [2]  Recognition of honeycomb change is imperative as its presence is associated with a poor prognosis.



Studies in the United States estimate the overall incidence of interstitial lung disease (ILD) to be approximately 30 per 100,000/year, with a slight male predominance and a higher prevalence in older adults. [3]  Once a patient is diagnosed with ILD, progression to end-stage disease with honeycomb changes is based largely on the underlying disease process.



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

Although a large and diverse list of ILDs have been described, the majority seen in clinical practice are idiopathic pulmonary fibrosis (IPF), chronic hypersensitivity pneumonitis (HP), collagen vascular disease (CVD)–associated ILD, and sarcoidosis. [4]  Idiopathic usual interstitial pneumonia (UIP) is the most common idiopathic interstitial pneumonia, and it is associated with a poor prognosis and eventual honeycomb changes. [5] Furthermore, nonspecific interstitial pneumonia (NSIP), although less common, can be associated with honeycomb changes. CVDs include systemic lupus erythematosusrheumatoid arthritis, progressive systemic sclerosis (diffuse scleroderma), Sjögren syndrome, and dermatomyositis/polymyositis. [6]

An increased frequency of bronchiolar histotypes in lung carcinomas appears to be associated with IPF, in which abnormal bronchiolar proliferation occurs in transformed small airways in honeycomb lung regions. [7]

Dozens of drugs have been linked to ILD; however, methotrexate and bleomycin are the two agents most strongly associated with fibrosing interstitial pneumonia and they are capable of producing UIP and/or NSIP patterns. [8]  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 interstitial lung disease (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 (see the image below).

Computed tomography scan depicting early bilateral Computed tomography scan depicting early bilateral honeycomb changes of the lower lobes of the lung.


The pattern of distribution may be quite variable. Thus, when surgical biopsies (wedge resections) are performed for diagnosis, at least two lobes should be sampled. Biopsy of one lobe is suboptimal, and transbronchial biopsies are usually insufficient for diagnosis as they tend to be smaller with significant crush artifact.

A potential alternative to traditional lung and transbronchial biopsy is the relatively recent advent of transbronchial cryobiopsy using flexible cryoprobes. This novel technique has been shown to provide a greater surface area of tissue for histologic analysis. [9]  Furthermore, validation studies have demonstrated cryobiopsy as a reliable diagnostic tool of ILD with lower complication rates compared with surgical lung biopsy. [7]   Although promising, further studies are likely needed for this diagnostic approach.


Clinical Features and Imaging

Characterization of interstitial lung disease (ILD) requires clinical, radiologic, and pathological correlation. Clinically, patients often note progressive dyspnea or nonproductive cough present over a period of months to years. Other symptoms may include hemoptysis, wheezing, and chest pain; however, ILD can occasionally occur in asymptomatic patients in which ILD is suspected only radiographically. In honeycomb lung secondary to idiopathic usual interstitial pneumonia (UIP), most patients are over age 50 years and have had symptoms for more than 6 months. Patients with collagen vascular disease (CVD) often have associated rheumatologic signs and symptoms, although lung disease may occasionally 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.

From the perspective of the pathologist, it is important to understand that high-resolution computed tomography (CT) scanning is a critical tool for the diagnosis of ILD as it creates detailed images of the lung parenchyma and airways.

Basic patterns of ILD on CT scans 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). [10] Based on the imaging, the radiologist is often able to provide a differential diagnosis for the pattern of ILD that can be correlated with pathologic impressions of the biopsy. Furthermore, radiographic findings help to guide the surgeon in appropriate sampling of the lung tissue.

When examining a biopsy specimen, the pathologist must review the patient history and radiologic impression to 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. Descriptive diagnoses, listing the major microscopic findings, commenting on the overall pathologic pattern, and listing a differential diagnosis for the pattern is a common approach to histologic analysis. Final determination of the etiology of the ILD  is made by the clinician.


Differential Diagnosis

The most important diagnostic consideration is correctly identifying patients with a usual interstitial pneumonia pattern, because the prognosis is much worse in comparison to other patterns of interstitial lung disease.


Gross Findings

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

In idiopathic usual interstitial pneumonia (UIP), the lungs are often small and contracted with a cobblestone appearance to the pleura (see the images below). 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 surface of a small end-stage lung showing a Gross surface of a small end-stage lung showing a firm "cobblestone" appearance of the pleural surface.
Cut section of a lung with prominent subpleural fi Cut section of a lung with prominent subpleural fibrosis.
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.
End-stage disease in a lung that is decreased in s End-stage disease in a lung that is decreased in size and fibrotic.


Fibrotic parenchyma surrounding the airways can retract, causing bronchiectasis, which can be seen grossly. In idiopathic nonspecific interstitial pneumonia (NSIP), the fibrosis appears more homogeneous and honeycomb changes may not be as prominent, except in the areas of severe fibrosis. Gross findings of interstitial lung disease secondary to drugs, collagen vascular disease, and chronic hypersensitivity pneumonitis may be indistinguishable from idiopathic UIP or NSIP, thereby requiring histology and clinical history for the diagnosis. End-stage pulmonary sarcoidosis can also mimic idiopathic UIP grossly; however, fibrosis and honeycombing is more dramatic in the upper lobes [11] and prominence of the hilar or mediastinal lymph nodes would favor pulmonary sarcoidosis. [12]


Microscopic Findings

Note that immunohistochemistry is not useful in the evaluation of honeycomb lung.

Usual interstitial pneumonia

Usual interstitial pneumonia (UIP) is best characterized as a pattern of lung injury that can result from idiopathic UIP or an 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 images below]). On computed tomographic images, mixed microcystic and macrocystic honeycombing can be seen. [2]

Low-power histology demonstrating subpleural and i Low-power histology demonstrating subpleural and interstitial fibrosis with temporal heterogeneity seen with a usual interstitial pneumonia (UIP) pattern.
Top image: Typical histologic finding of spatial h Top image: 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). Bottom image: 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 observed in UIP (see the top micrograph of the first 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, bronchiolar metaplasia, or bronchiolization (see below), and they are often filled with mucin and occasionally neutrophils (see below). [13]

Top image: Fibroblastic focus (x200). Bottom image Top image: Fibroblastic focus (x200). Bottom image: Honeycomb change with bronchiolization of airspaces (x200).
Dilated airspaces lined by bronchiolar-type epithe Dilated airspaces lined by bronchiolar-type epithelium and surrounding fibrosis consistent with microscopic honeycomb change.

Nonspecific interstitial pneumonia

Nonspecific interstitial pneumonia (NSIP), either idiopathic or secondary to other disease, is also best considered a pattern of lung injury, but differs from UIPs as the interstitial changes are relatively homogeneous. Three patterns of NSIP have been described: cellular, fibrotic, and mixed; however, more recent consensus has recommended the usage of cellular and fibrotic NSIP as the main subtypes. [14]  In cellular NSIP, mild to moderate lymphoplasmacytic inflammation is distributed evenly throughout the interstitium. The inflammation is usually not prominent and fibrosis is insignificant. In fibrotic NSIP, the interstitial fibrosis is temporally and spatially homogeneous, meaning it is evenly distributed throughout the interstitium with a uniformly mature appearance.

Fibroblastic foci are not a significant feature and honeycomb changes are relatively uncommon (however, they may be present in areas of severe fibrosis). Mixed NSIP is merely a combination of the fibrotic and cellular patterns. [13]

Acute interstitial pneumonia

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 interstitial lung diseases (ILDs), AIP may progress rapidly to interstitial fibrosis and honeycomb changes, within 3 weeks of onset. [15]

Interstitial lung disease–associated collagen vascular disease

Rheumatoid arthritis

ILD is common in collagen vascular disease (CVD), with the most frequent histopathologic pattern resembling NSIP with the exception of rheumatoid arthritis (RA) which can lead to a UIP picture. [16, 17, 18, 19, 20]

Systemic lupus erythematosus

Although uncommon, systemic lupus erythematosus can cause both acute and chronic lung disease. Acute lupus pneumonitis, characterized by acute onset of fever, dyspnea, and cough can lead to a DAD pattern and, eventually, ILD with NSIP as the most commonly observed histopathologic pattern (although UIP can also be observed). [21, 22]


ILD affects approximately 40% of patients with progressive systemic sclerosis (diffuse scleroderma), and it is the leading cause of mortality in these patients (see the following image of an explanted lung in a patient with scleroderma). [23] 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, NSIP (and, less commonly, UIP) can develop. [24]  Vascular intimal hyperplasia and medial hypertrophy may be present and is indicative of pulmonary hypertension.

Explanted lung with a firm, fibrotic surface in a Explanted lung with a firm, fibrotic surface in a patient with a history of scleroderma.



Up to 40% of patients with dermatomyositis/polymyositis are affected by ILD. [25] 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.

Sjögren syndrome

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. [26]


Sarcoidosis is a systemic disease of unknown etiology that is more common in young adults. Lung disease is usually mild; however, some patients (albeit few) develop fibrosis and honeycomb changes. Honeycombing usually involves the middle and upper lung zones and only rarely involves the lower lungs. [27, 28, 29, 30, 31]

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. [12] The granulomas are composed of epithelioid histiocytes, multinucleated giant cells and, occasionally, asteroid and Schaumann bodies seen in giant cells. The granulomas are usually distributed along the lymphatics of the pleura and along the bronchovascular bundle, and the peribronchial distribution of the granulomas enables use of transbronchial biopsy in the diagnosis of sarcoidosis.

In advanced disease, only rare giant cells may be present with fibrosis around the lymphatics, collagenous desposition around the bronchioles, and bronchiectasis of the upper lobes. [28]  Most importantly, pulmonary sarcoidosis is a diagnosis of exclusion, and special stains should be performed to exclude underlying infection, particularly fungal and mycobacterial.

Hypersensitivity pneumonitis

Chronic hypersensitivity pneumonitis (HP) is caused by a type IV hypersensitivity reaction to an inhaled antigen, often observed in patients with exposure to bird droppings, animal urine (specifically rats or gerbils), moldy hay (“farmer’s lung”), certain chemicals (paints, resins, plastics, pesticides, etc), and various bacteria and fungi. [32]  The inhaled antigen stimulates airway inflammation and, eventually, interstitial fibrosis that can have either an 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.


Molecular/Genetic Studies

Currently, molecular and genetic testing are not routinely used in the diagnosis of interstitial lung disease (ILD). however, there are a few inherited ILDs with associated genetic defects. The inherited ILDs can be subdivided into systemic disorders affecting multiple organs and those that primarily affect the lung. [33]

ILD systemic disorders include the following:

  • Dyskeratosis congenita
  • Neurofibromatosis I
  • Tuberous sclerosis (lymphangioleiomyomatosis)
  • Birt-Hogg-Dube Syndrome
  • Hyper Immunoglobulin E (IgE) syndrome
  • Hermansky-Pudlak syndrome
  • Gaucher disease, type I
  • Niemann-Pick Disease, type B
  • Lysinuric protein intolerance.

ILD primary lung disorders include the following:

  • Surfactant metabolism dysfunction
  • Surfactant metabolism dysfunction disorders 1-4
  • Familial pulmonary fibrosis
  • Pulmonary alveolar microlithiasis

Prognosis and Predictive Factors

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



There remains to be curative therapy for the causative entities of honeycomb lung; however, emerging modalities exist which can slow the progression of disease. Immunosuppresive or antifibrotic agents, depending on the etiology of the disease (ie, immunosuppressive therapy for collagen vascular disease (CVD)–related disease or anti-fibrotic agents in idiopathic pulmonary fibrosis [IPF]), may be appropriate.

In the treatment of IPF, nintedanib and pirfenidone are commercially available in certain countries, and they can help to slow the progression of disease. [34, 35, 36]  As cases progress, single or double lung transplantation can be performed, with patients having a median survival of 4.7 years, with survival benefit and an improved quality of life. [37]