Idiopathic Interstitial Pneumonias

Pathologic Features

Gross Findings

The lungs tend to be small, and the visceral pleura shows retractions along the interlobular septa. The cut surfaces reveal patchy, dense, established fibrosis, more severe in the lower lobes ( Fig. 16.1 ). Central and upper portions of the lung may be relatively preserved. The fibrosis typically produces grossly observable fibrotic cysts. Because these fibrotic cysts tend to be back to back with little intervening normal lung, they resemble a honeycomb—hence the term honeycombing.

Microscopic Findings

Microscopically, UIP is characterized by its variegated appearance; areas of fibrosis alternate with areas of normal lung ( Fig. 16.2 , [CR] ). The fibrosis is subpleural and paraseptal in distribution and significantly disrupts the normal alveolar architecture. At the interface of the established scar and normal lung are areas of active fibrogenesis, termed fibroblast foci, composed of myofibroblasts and loose connective tissue underneath a degenerating and desquamating epithelium. Fibroblast foci need to be distinguished from areas of organizing pneumonia, which are more exuberant and fill airspaces and alveolar ducts, rather than line up along walls of alveoli. There should only be minimal inflammation in the lung in areas away from scar. No more than very rare granulomas are acceptable, and even then, they raise the possibility of an alternative diagnosis.

The lung is thus described as having both spatial (alternating areas of normal and fibrotic lung) and temporal (presence of normal, fibrosing, and fibrotic lung) heterogeneity. Scarring results in remodeling of the pulmonary architecture with formation of cystic spaces (so-called microscopic honeycombing ). The cysts may contain mucus and/or inflammatory cells. Inflammation and fibroblast foci found entirely within areas of honeycombing are considered nonspecific. Smooth muscle metaplasia may accompany scarring, thus resulting in the historic phrase “muscular cirrhosis of the lung” for this disease. Secondary vascular changes are common and consist of medial thickening and intimal fibrosis. These latter findings do not necessarily correlate with clinical pulmonary hypertension.

Similarly to the radiologic findings, biopsies should be categorized as definite UIP, probable UIP, possible UIP, and inconsistent with UIP. Biopsies are considered definite UIP if they show all of the findings of UIP as described earlier. Biopsies are considered probable UIP if they have honeycomb change only or absence of spatial or temporal heterogeneity. Biopsies are considered possible UIP if they show relatively mild fibrosis but with no other distinguishing feature. Biopsies with extensive organizing pneumonitis, marked inflammation including eosinophils or granulomas, or other inconsistent features (as described later) are considered inconsistent with UIP.

The histopathologic categories are combined with the radiology either to make final diagnoses or to form the basis of discussion at a multidisciplinary conference as described previously. For instance, given a definite or possible UIP radiologic diagnosis, most pathologic categories lead to a diagnosis of probable or definite IPF, whereas an inconsistent with UIP pathology pattern would refute the diagnosis. Radiology that is inconsistent with IPF, on the other hand, leads to a diagnosis other than IPF, regardless of histopathology, other than in those patients with a definite UIP histology pattern. Even then, these latter patients need to be reviewed at a multidisciplinary conference discussion before making the diagnosis. Furthermore, one caveat to the exclusion of hyaline membranes and organizing pneumonia in IPF/UIP is that biopsies from patients with the so-called accelerated decline or acute exacerbation of IPF may show a combination of UIP and diffuse alveolar damage (DAD) and/or organizing pneumonitis ( Fig. 16.3 ).

Differential Diagnosis

Differentiating UIP/IPF from other entities involves histologic and etiologic considerations. The histologic differential diagnoses include the fibrosing pattern of NSIP, organizing DAD, and diseases with airway-centered inflammation and fibrosis (eg, chronic hypersensitivity pneumonitis and chronic aspiration). In separating UIP from NSIP and DAD, the presence or absence of temporal heterogeneity is the most helpful histologic finding. The fibrosing pattern of NSIP is characterized by relatively uniform interstitial fibrosis, which may be accompanied by mild-to-moderate chronic inflammation. The hallmark of organizing DAD is diffuse interstitial fibroblast proliferation, which incorporates remnants of hyaline membranes into the alveolar septa. In contrast to NSIP and DAD, UIP has a variegated appearance with dense scars, scattered fibroblast foci, and areas of normal lung.

In patients with acute respiratory failure, the differential may include AIP vs. IPF/UIP with an acute exacerbation. Early in the disease, AIP will not show established fibrosis, whereas the presence of honeycombing with a superimposed pattern of organizing-phase DAD suggests IPF/UIP with an exacerbation. Later in the disease, there may be some degree of established fibrosis in both, at which time the distinction requires careful clinical correlation with previous clinical findings. If those are not available, the distinction may not be possible.

Sometimes, in a patient with multiple biopsies, UIP is seen in one lobe and an NSIP pattern is seen in another lobe. In such cases, the overall histologic diagnosis should be UIP. If the distinction between the two patterns cannot be made with certainty, the term unclassifiable fibrotic interstitial pneumonia can be used. If there are areas of honeycombing, however, the biopsy most likely represents UIP/IPF.

The fibrosis in UIP is centered under the pleura and along septa. A critical distinction is between this pattern and that where the fibrosis is centered on airways, so-called airway centric fibrosis (ACF). When there is a moderate amount of inflammation such as in subacute chronic hypersensitivity pneumonitis, this distinction is relatively easy. In the absence of inflammation, this distinction can be difficult. ACF will typically be centered in the lung parenchyma, radiating away from airways and can extend to the pleura, in a wedge shape. Mucus can accumulate in these fibrotic airways but this differs from the mucus accumulation of honeycomb lung.

By current classification, ACF is considered inconsistent with UIP/IPF and suggests an airway-based disease, such as chronic hypersensitivity pneumonitis or chronic aspiration. While some cases of bronchocentric fibrosis have been reported as a novel form of idiopathic ILD, it is difficult if not impossible to exclude occult antigen exposure or aspiration in these cases. Aspirated foreign material should be carefully sought. Scattered granulomas also suggest either chronic hypersensitivity pneumonitis or aspiration. As this process becomes more extensive, there will be overlap with honeycomb lung, and it may not be possible to recognize the initial pattern. In the past, this problem was not of major clinical significance given the limited therapeutic options available. However, given the recent availability of medications that are currently only approved for IPF (see below) and not for other entities, this has now become a problem area with no simple resolution.

Connective tissue diseases, many drug and radiation reactions, and familial fibrotic ILD with a UIP pattern usually cannot be separated from UIP/IPF without clinicopathologic correlation. However, some soft clues may be present. Although asbestosis (interstitial fibrosis due to asbestos) virtually always shows identifiable ferruginous bodies, pleural plaques also are associated with asbestosis, and their presence should prompt a search for asbestos bodies and an inquiry into asbestos exposure. The presence of prominent lymphoid aggregates, lymphoid follicles, and especially chronic pleuritis should raise the possibility of a connective tissue disease. The very rare Hermansky-Pudlak syndrome is an autosomal-recessive condition that is characterized by defects in platelet aggregation, oculocutaneous albinism, and accumulation of ceroid-filled histiocytes in many organs. Pulmonary involvement manifests as fibrotic ILD, typically with a nonspecific pattern of fibrosis, with foamy hyperplastic type II cells due to accumulation of phagolysosomes (see also Chapter 35 ).

Pathologic Features

Histologically, NSIP is divided into cellular and fibrosing patterns. The rarer cellular NSIP pattern is characterized by mild-to-moderate interstitial chronic inflammation with a mixture of lymphocytes and plasma cells ( Fig. 16.4 , [CR] ). Lymphoid aggregates are a common finding. Sometimes an organizing pneumonia pattern is also present, especially when seen in a patient with underlying collagen vascular disease ( [CR] ).

The hallmark of the more common fibrosing NSIP pattern is the presence of diffuse, temporally uniform interstitial fibrosis ( Fig. 16.5 , [CR] ). This may or may not be accompanied by mild-to-moderate chronic inflammation. The fibrous connective tissue may be dense or loose in character, but has the same appearance throughout the lung. Honeycomb change and organizing pneumonia are either absent or inconspicuous in pure forms Fig. 16.6 ).

Differential Diagnosis

Histologic differential diagnoses for the cellular NSIP pattern include the LIP pattern and organizing pneumonia. Although both cellular NSIP and LIP are characterized by the presence of chronic inflammatory cells in the alveolar septa, the extent of expansion is dramatically greater in LIP. Organizing pneumonia can be a minor component of cellular NSIP. In NSIP, the interstitial chronic inflammation is diffuse, whereas it is limited to areas of fibroblast proliferation in COP.

Histologic differential diagnoses of the fibrosing NSIP pattern include UIP and organizing DAD. Separation of fibrosing NSIP and UIP has been discussed earlier. Fibrosing NSIP and organizing DAD are similar in that they are both characterized by uniform interstitial thickening, but the septa in organizing DAD shows proliferating fibroplasia, whereas there is dense scarring in fibrosing NSIP. Organizing DAD can be distinguished by the presence of residual hyaline membranes and the clinical history.

Etiologic differential diagnoses that must be considered in patients with NSIP include hypersensitivity pneumonitis, connective tissue diseases, drug toxicity, infection, and immunodeficiency. Poorly formed granulomas associated with the NSIP pattern should raise the level of concern to exclude these possibilities.