Pathology of Usual Interstitial Pneumonia

Usual interstitial pneumonia (UIP) refers to a morphologic entity defined by a combination of (1) patchy interstitial fibrosis with alternating areas of normal lung, (2) temporal heterogeneity of fibrosis characterized by scattered fibroblastic foci in the background of dense acellular collagen, and (3) architectural alteration due to chronic scarring or honeycomb change. ^[1]

The term UIP is often used interchangeably with idiopathic pulmonary fibrosis (IPF), but other clinical conditions are associated with UIP, although less commonly, including collagen vascular disease, drug toxicity, chronic hypersensitivity pneumonitis, asbestosis, familial IPF, and Hermansky-Pudlak syndrome. ^[1] Thus, UIP is not entirely synonymous with IPF, and diagnosis of IPF requires an exclusion of possible underlying clinical conditions, as mentioned above.

According to the 2002 American Thoracic Society (ATS)/European Respiratory Society (ERS) consensus statement, IPF is defined as a distinctive type of chronic fibrosing interstitial pneumonia of unknown cause limited to the lungs and with histologic features of UIP on surgical lung biopsy or certain clinical, radiologic, and pulmonary function test findings in the absence of surgical lung biopsy. ^[1]

The most recent consensus statement published in 2013 reaffirms the 2002 statement on IPF for the most part. ^[2] An official clinical practice guideline for the diagnosis of IPF was published in 2018; these guidelines have been endorsed by the ATS, the ERS, the Japanese Respiratory Society (JRS), and the Latin American Thoracic Society (ALAT). ^[3]

Usual interstitial pneumonia (UIP) is more common in men than in women.

The reported overall prevalence of interstitial lung disease in New Mexico is 80.9 per 100,000 males and 67.2 per 100,000 females, corresponding with annual incidence rates of 31.5 per 100,000 per year in males and 26.1 per 100,000 per year in females. ^[4]

The prevalence of IPF in different series ranges from 6-14.6 per 100,000 persons, but in those older than 75 years, the prevalence may exceed 175 per 100,000. ^[4]

The cause of usual interstitial pneumonia (UIP) in patients with idiopathic pulmonary fibrosis (IPF) is unknown by definition (ie, IPF is defined as idiopathic UIP).

Several associations have been identified, including cigarette smoking, gastroesophageal reflux disease, occupational exposure to wood and various other occupation-related dusts, Epstein-Barr virus, and hepatitis C virus. It has been postulated that no single etiologic agent serves as a common inciting event but rather that affected patients might have common defects in reparative pathways (ie, abnormal wound healing).

A growing body of evidence has shown that genetic factors contribute to disease risk. Recent studies have identified common and rare genetic variants associated with both sporadic and familial forms of pulmonary fibrosis. ^[5] Genome-wide association studies have reported IPF-associated genetic loci that are implicated in diverse biological processes including alveolar cell stability, host defense, cell-cell barrier function, and cell senescence. ^[6] A recent resequencing study confirms that host defense and cell senescence gene variants contribute to the risk of IPF. ^[7] The strongest risk variant is the MUC5B promoter variant rs35705950, with an odds ratio of 5.45 (95% confidence interval, 4.91-6.06) for 1 copy of the risk allele and 18.68 (95% confidence interval, 13.34-26.17) for 2 copies of the risk allele (P = 9.60 x 10^-295). The role of rare variation in FAM13A,TERT and RTEL1 gene regions was implicated in the risk of IPF. ^[7]

Usual interstitial pneumonia (UIP) is more common in men than in women. Patients with UIP usually present in the sixth or seventh decade of life with slowly progressive dyspnea and nonproductive cough refractory to antitussive agents. Patients with IPF who are younger than 50 years of age are rare; such patients may subsequently manifest features of an underlying connective tissue disease that was subclinical at the time of the IPF diagnosis or may be familial IPF. ^[5] Most UIP patients are current or past smokers. Constitutional symptoms are unusual, and digital clubbing develops in 25%-50% of patients. Although not specific, velcro-type fine end-inspiratory crackles on chest auscultation are characteristic physical finding in nearly all patients. Features of right heart failure (cor pulmonale) and peripheral edema may develop usually in later stage of disease.

Most patients display restrictive pulmonary function abnormalities, including reduced lung volumes with relative preservation of airflow, a reduction in the diffusion capacity for carbon monoxide (DLCO) with hypoxemia at rest and/or with exercise.

Some patients present with a more acute onset of respiratory symptoms that may mimic the clinical presentation of acute interstitial pneumonia (AIP). This syndrome has been termed acute exacerbation of idiopathic pulmonary fibrosis (IPF) or accelerated UIP and occurs in as many as 14% of untreated patients observed for 2 years. ^[8]

Most patients are known to have UIP at the time of acute worsening, but some patients present with acute exacerbation without a previously established diagnosis of UIP or IPF. The prognosis is grim, with short-term mortality rates in excess of 50% in most reported series. ^{[9, 10]}

A recent autopsy study suggested that acute exacerbation is a common cause of death in individuals with UIP. ^[11] Acute exacerbation of UIP or IPF is first described and is defined as the sudden onset of rapid clinical deterioration without an identifiable cause. ^[12] Proposed diagnostic criteria include (1) subjective worsening over 30 days or less, (2) new bilateral radiographic opacities, and (3) the absence of infection or another identifiable etiology.

Again, a diagnosis of acute exacerbation hinges on exclusion of other known and potentially treatable causes of clinical worsening, such as cardiac disease, pulmonary embolism, infection, and drug reaction. ^{[9, 10]}

Several biomarkers have been identified in IPF, including MMP7, SP-D, CCL-18, and KL-6, usually in small cohorts and without independent validation. Thus, the current ATS/ERS/JRS/ALAT guideline does not recommend the testing of these serum biomarkers in patients who are clinically suspected of having IPF. ^[3]

Imaging

The relative role of imaging studies and surgical lung biopsies in patients with UIP has changed over the last decade. High-resolution computed tomography (HRCT) has greatly improved diagnostic accuracy over conventional chest radiography and has therefore revolutionized the role of radiology in managing patients with UIP, as well as with diffuse interstitial lung diseases in general.

Experienced radiologists can make a specific diagnosis of UIP with a high degree of accuracy in patients with typical radiologic findings, which resulted in reserving surgical lung biopsy for patients with atypical radiologic findings. In this context, the bulk of the evidence indicates that a histopathologic diagnosis of UIP remains the single most important predictor of outcome at the time of diagnosis and thus remains the criterion standard for diagnosis. ^[13]

The most common chest radiographic abnormality in patients with IPF is peripheral reticular opacity, most marked at the bases, and often associated with honeycombing and lower-lobe volume loss (see the images below).

In patients with upper-lobe emphysema, the radiographic lung volumes may be normal or even increased. Chest radiographic findings are occasionally normal in patients with IPF.

Ground-glass attenuation is common but usually less extensive than reticular abnormality. Architectural distortion reflecting lung fibrosis is often prominent. Lobar volume loss is seen with more advanced fibrosis. On serial scans, the areas of ground-glass attenuation may regress but more commonly progress to fibrosis with honeycombing. Honeycomb cysts usually enlarge slowly over time.

HRCT in about half of patients shows a characteristic combination of peripheral, subpleural, irregular linear, or reticular opacities involving predominantly the lower lung zones with associated architectural distortions in the form of traction bronchiectasis and bibasilar honeycomb change.

Radiologically, cases associated with asbestosis or collagen vascular disease may show the lung parenchymal CT pattern of UIP indistinguishable from that caused by IPF. However, the presence of pleural plaques or diffuse pleural thickening could help to distinguish asbestosis from IPF.

In rare cases, patients with chronic hypersensitivity pneumonitis (HP) or with end-stage sarcoidosis develop a CT pattern similar to that of UIP. The presence of poorly defined fine micronodules or sparing of the lung bases would favor the diagnosis of HP. A possibility of sarcoidosis should be suspected if the cysts are large or if peribronchovascular nodules are present.

The use of diagnostic category is recommended for HRCT scanning patterns: 1) UIP pattern, 2) probable UIP pattern, 3) indeterminate for UIP pattern, and 4) alternative diagnosis, depending on the presence or absence of the classic features for UIP. ^[3] The degree of prominence as well as the presence of atypical radiologic features for UIP used in this categorization include ground glass opacities, cystic changes, mosaic attenuation, micro nodules formation, consolidation, peribroncovascular, perilymphatic and upper or middle lung predominant distribution, plural plaques, dilated esophagus, distal clavicle erosions, extensive lymphadenopathy, and plural effusion/plural thickening. ^[3]

Treatment options

No single pharmacological agent or combination of drugs has shown consistent efficacy in patients with UIP, although a number of novel therapies are being investigated in clinical trials. Potential therapeutic agents aim at promoting epithelial restoration (eg, stem cell progenitors); boosting host defense (eg, interferon-gamma); and decreasing inflammation (eg, antioxidants, cytokines), fibroproliferation (eg, growth factor inhibitors) or aberrant vascular remodeling (eg, angiostatic molecules). ^[14]

Lung transplantation is used in some cases, but its application is limited owing to the older age and frequent comorbidities in affected patients. In most patients, UIP follows a progressive course, with median survivals from the time of diagnosis of about 3 years.

In October 2014, two antifibrotic medications, pirfenidone and nintedanib, were concurrently approved by the FDA following the phase III trials (ASCEND and INPULSIS 1 and 2) that demonstrated the slowing of the decline in lung function in IPF patients by the medications. Since the FDA approval of these drugs, several systematic reviews and pooled data analyses have largely confirmed the outcomes of the trials. ^[15]

Whole lungs demonstrate honeycomb change affecting predominantly peripheral and lower lung zones (see the image below). The pleural surface shows a cobblestone appearance due to the retraction of interlobular septa-associated paraseptal scarring.

The histopathologic hallmark of usual interstitial pneumonia (UIP) is a low magnification appearance of the patchy dense fibrosis causing remodeling of lung architecture, often resulting in honeycomb change and alternates with areas of less affected parenchyma (see the image below).

This distinctive appearance due to alternating areas of qualitatively different abnormalities is the key to the diagnosis of UIP. As is in imaging studies, the distribution of fibrosis is more prominent at the periphery and bases of the lung.

Fibrosis predominates over inflammation in typical UIP and comprises mainly dense eosinophilic collagen deposition. In this background of chronic fibrosis, there are fibroblast foci in which fibroblasts and myofibroblasts are arranged in a linear fashion within a pale staining matrix (see the image below).

Overlying epithelium consists of hyperplastic type II pneumocytes or columnar nonciliated bronchiolar cells. Fibroblast foci are not specific for UIP but are a characteristic and important feature in establishing the diagnosis.

Honeycomb change is present in most surgical lung biopsy specimens and is another important diagnostic feature. Honeycomb change is defined by cystically dilated airspaces frequently lined by columnar respiratory type epithelium in scarred fibrotic lung tissue (see the image below).

Fibrotic scars that obscure the underlying lung architecture without associated honeycomb change are another form of architectural distortion characteristic of UIP. Smooth muscle hyperplasia is commonly seen in the areas of fibrosis and honeycomb change and can be quite striking in some areas. Liebow has described those findings as "muscular cirrhosis" of the lung.

A definitive pathologic diagnosis of the UIP pattern can be made when all of the above features are present, particularly when honeycombing is present. However, even in the absence of honeycomb change, a definite diagnosis of UIP can still be made if all of the other typical features are present. It was also recommended to categorize the histopathologic findings of biopsies into UIP, probable UIP, indeterminate for UIP, and alternative diagnosis as recommended for HRCT patterns.

Biopsy specimens from patients with acute exacerbation usually show a combination of UIP and superimposed diffuse alveolar damage (DAD) or, less often, organizing pneumonia (OP). ^[9] DAD has been described in nearly three-quarters of the lung specimens reported in the literature in this setting. ^[9] The feature of DAD may be patchy and typically include some combination of confluent alveolar septal thickening, minimal associated inflammatory cells, marked type II pneumocytes hyperplasia with cytological atypia, hyaline membranes, fibrin thrombi in small vessels, and squamous metaplasia of bronchiolar epithelium. In other patients, the superimposed pattern of acute lung injury more closely resembles OP without the features of DAD. ^[9]

The prognosis of interstitial pneumonia (UIP) is grim, with short-term mortality rates in excess of 50% in most reported series. ^{[9, 10]} In most patients, UIP follows a progressive course, with median survivals from the time of diagnosis of about 3 years.

No single histologic finding consistently predicts prognosis in individual patients with UIP. Patients with more extensive fibroblast foci have experienced shorter mean survival in some studies while other investigators have failed to demonstrate the same relationship to survival. ^{[16, 17]}

The natural history of idiopathic pulmonary fibrosis (IPF) has been known as a steady decline in lung function over time without a response to medical therapy. However, the clinical course of IPF is not always predictable despite its generally poor prognosis.

Some common genetic variants have also been associated with distinct clinical phenotypes. Clinical studies should be designed controlling for the genetic backgrounds of subjects, since clinical outcomes and therapeutic responses may differ by genotypes. Further understanding of these differences will allow the development of personalized approaches to IPF management. ^[5]

Pulmonary hypertension as a complicating factor

Pulmonary hypertension (PH) has been postulated to be a factor that complicates and affects the prognosis of IPF. ^{[18, 19]} Therapeutic agents for PH might be effective for those who have PH with IPF. Early diagnosis of PH in patients with IPF is difficult; lack of specific clinical symptoms often leads to delayed diagnosis of PH in patients with IPF. The reported prevalence of PH in patients with IPF ranges from 20%-84% when evaluated by pulmonary arterial enlargement on chest radiography, right ventricular systolic pressure using transthoracic echocardiography, or mean pulmonary artery pressure using right-heart catheterization. ^[14]

Biomarkers such as B-type natriuretic peptide (BNP) and N-terminal prohormone BNP are potentially helpful tools in identifying PH. ^{[19, 20]} One study has shown that iron deposition and increased alveolar septal capillary density in nonfibrotic areas of the UIP lung tissue are associated with right ventricular systolic pressure, seemingly independent of the degree of fibrosis, suggesting that these features are possible morphologic predictors of PH in UIP. ^[19]

Differential Diagnoses

Differential diagnoses of usual interstitial pneumonia (UIP) must be approached in two ways: histologically and clinically. In interpreting lung biopsies histologically, pathologists must address the differential diagnoses based on the histologic pattern. Histologic clues should be sought to a potential underlying condition such as asbestos bodies, infectious agents, or other exogenous agents. For clinical aspects, clinicians must address the etiologic possibilities and ultimately determine whether the process is idiopathic.

Histologic differential diagnoses of UIP include other patterns of interstitial pneumonias, including fibrosing nonspecific interstitial pneumonia (NSIP), desquamative interstitial pneumonia (DIP), and AIP. Distinguishing UIP from these conditions depends mainly on recognition of characteristic patchy distribution of fibrosis, fibroblastic foci, and honeycomb change typical of UIP.

Differentiating fibrosing NSIP from UIP is perhaps the greatest challenge. Areas indistinguishable from DIP may occur focally in otherwise typical UIP, and correlation with the findings on HRCT would be very helpful in that setting. It has been noted that areas typical of NSIP can occur focally in other conditions, making sampling bias a potential barrier to accurate diagnosis. In a review of 20 explanted lungs with UIP, all but 3 showed isolated areas that were indistinguishable from NSIP.

Other studies have shown that the presence of UIP in even a single piece of tissue defined a survival curve typical of idiopathic pulmonary fibrosis (IPF) in patients from whom surgical lung biopsy specimens taken from more than one site demonstrated both UIP and NSIP (discordant UIP). Therefore, it is very important to consider the sampling bias and clinical radiological correlation.

Occasionally, OP and DAD mimic UIP and also could be superimposed on underlying UIP with clinical manifestation of acute exacerbation. OP does not have significant interstitial fibrosis, which would be an important feature in distinguishing bronchiolitis obliterans organizing pneumonia (BOOP) from UIP. Finally, AIP (mainly showing features of organizing DAD and some scarring) can be difficult to distinguish from UIP, but the clinical and radiologic findings would be of great help.

With the current definition of UIP, only a few clinical conditions may cause an identical histologic pattern of UIP: collagen vascular disease, drug toxicity (especially nitrofurantoin), chronic HP, asbestosis, familial IPF, Hermansky-Pudlak syndrome. Distinguishing UIP in patients with other underlying or associated conditions is largely a matter of correlation with clinical information.

The presence of asbestos bodies in a background of UIP is diagnostic of asbestosis in a patient with a well-documented exposure history. Cytoplasmic vacuolization in hyperplastic pneumocytes with pigmented alveolar histiocytes is a helpful histopathologic clue to the diagnosis of Hermansky-Pudlak syndrome, a condition seen in patients with oculocutaneous albinism. Chronic HP can mimic UIP and may be indistinguishable from UIP. HP tends to be more cellular and bronchiolocentric. Peribronchiolar infiltrates in HP demonstrate varying degrees of granulomatous inflammation in most cases, usually in the form of isolated multinucleated giant cells or ill-defined clusters of epithelioid histiocytes. Honeycomb change can occur in HP but typically is not associated with the peripheral subpleural distribution as would be seen in UIP.

Langerhans cell histiocytosis (LCH) also tends to have a distinctly bronchiolocentric distribution. These bronchiolocentric nodules of LCH have stellate configuration and show variable degrees of cellularity and fibrosis. The cases in which fibrotic nodules predominate may be difficult to distinguish from UIP. Again, the key features are stellate configuration and bronchiolocentric distribution of the nodules in LCH, coupled with often striking paracicatricial airspace enlargement. Fibroblast foci are also uncommon in purely fibrotic nodules in LCH. HRCT scans can be very useful in distinguishing LCH from UIP in diagnostically challenging cases, as well.