Vasculitides and Other Causes of Pulmonary Hemorrhage

Pathologic Features

The histologic manifestations of GPA are varied but are composed of three main elements that are very helpful in the histologic diagnosis of this entity. They include vasculitis, necrosis, and inflammatory background.

The vasculitis involves medium-sized and small veins and arteries. Capillaritis is also frequently present and an important diagnostic feature. In general, vasculitis is best appreciated in the parenchyma away from the other inflammatory lesions. The vasculitis is often focal with eccentric involvement of the vessel wall ( Fig. 8.1 ), or it can be limited to the endothelium and subendothelial spaces ( Fig. 8.2 ). The inflammatory cells that produce the vasculitis often include lymphocytes, macrophages, plasma cells, and occasionally eosinophils. A granulomatous reaction is often present within the vessel wall, and in some cases it can obscure and destroy the vessel. An elastic stain can be helpful for identification of the vessel wall within the granulomatous inflammation ( Fig. 8.3 ).

In GPA, granulomas are generally poorly formed or may show palisading histiocytes ( Fig. 8.4 ). Well-formed sarcoidlike granulomas are uncommon in GPA, and their presence should stimulate consideration of other diagnoses. In these cases, an infectious process or necrotizing sarcoidosis should be considered in the differential diagnosis. In contrast to an infectious or sarcoid granuloma, the lesions in GPA do not have a clear demarcation from the adjacent uninvolved pulmonary parenchyma, which is an important criterion for the differential diagnosis of these pathologic entities. In GPA, an inflammatory overflow always extends beyond the area of granuloma ( Fig. 8.5 ).

The necrosis in GPA is very often described as geographic and basophilic ( Figs. 8.5 and 8.6 , [CR] ). It is considered geographic due to its irregular border. The necrosis is thought to represent progressive collagenous necrosis and not infarctlike necrosis. It is considered basophilic because, contrary to the caseating necrosis of infectious granulomatous diseases, the area of necrosis in GPA is rich in cellular debris and neutrophils, which imparts a “dirty” appearance.

Small foci of collagen necrosis can be seen around involved blood vessels or within the pulmonary parenchyma. The necrosis is characterized by a small collection of neutrophils (microabscess) around an area of dense eosinophilic collagen fibers ( Fig. 8.7 ).

Another helpful characteristic of the inflammatory infiltrate in GPA is the presence of scattered multinucleated giant cells ( Fig. 8.8 ). They can be seen within the vasculitic process or within the background inflammatory infiltrate.

Within the inflammatory background, areas of organizing pneumonia and hemosiderin-laden macrophages can also be found. The latter is an indication of chronic hemorrhage due to the vasculitic process ( Fig. 8.9 ). Bronchitis, bronchiolitis, and endogenous lipoid pneumonia can be observed.

The lung biopsy findings from patients with GPA may not show the classical histologic findings, especially if the biopsy is taken very early in the course of the disease or after treatment. The presence of capillaritis with microabscess formation in a small biopsy should raise the possibility of vasculitis, including GPA. Interstitial fibrosis, sometimes with scattered giant cells, or bronchial and bronchiolar scarring or cicatricial vascular changes, can be seen in biopsies of patients who received treatment.

Differential Diagnosis

Lymphomatoid granulomatosis (LYG) is an important consideration in the differential diagnosis of GPA. The two entities have similar clinical and demographic features. Histologically, LYG is a form of diffuse large B-cell lymphoma characterized by a polymorphic lymphoid population with a T-cell–rich lymphocytic vasculitis, which is secondary. Granulomatous inflammation is characteristically absent. The difference between LYG and GPA is in the cellular composition of the infiltrate. The former is composed of a mixture of small and large atypical lymphocytes, whereas in GPA the infiltrate is composed of a mixture of granulomatous and acute and chronic inflammatory cells with neutrophil microabscesses. Also, in GPA, the inflammation causes necrosis of the vascular wall, whereas in LYG, the lymphocytes infiltrate the walls of the blood vessels. Immunohistochemical stains for lymphoid markers usually reveal a B-cell lymphoma phenotype in LYG with a reactive T-cell–rich infiltrate and vasculitis, discussed more extensively in another chapter.

EGPA (Churg-Strauss syndrome) and MPA are two ANCA-related diseases where the vasculitic component is almost impossible to distinguish from GPA in small biopsies. The two diseases, however, differ from GPA in their clinical and laboratory features, as well as their histology. These disorders are discussed later in this chapter. Bronchocentric granulomatosis (BCG) also enters into the differential diagnosis of GPA, because the latter may have a bronchocentric pattern of lung involvement, and BCG may show secondary involvement of blood vessels. However, systemic involvement and positive ANCA tests are seen in GPA but not BCG.

Necrotizing sarcoid granulomatosis (NSG) is characterized by confluent areas of nonnecrotizing granulomatous inflammation with extensive coagulative necrosis. Contrary to GPA, the granulomas in this disease are well formed (sarcoidlike), there is a clear demarcation between granulomatous and normal pulmonary parenchyma, and the ANCA test is negative.

The differential diagnosis of GPA and infectious granulomatous inflammation has been already discussed. An important point to keep in mind, however, is that whenever a granulomatous inflammatory process is identified in a biopsy, special stains to rule out the presence of microorganisms must be performed, even if GPA is considered clinically and histologically.

Rheumatoid nodules also form part of the differential diagnosis but usually occur in patients with a known diagnosis of rheumatoid arthritis and lack the geographic necrosis and microabscess formation seen in Wegener’s granulomatosis.

Other causes of diffuse pulmonary hemorrhage with small-vessel vasculitis (capillaritis) may also be considered in the differential diagnosis. These include drug-induced vasculitis, collagen vascular disease–associated vasculitis, cryoglobulinemia, and antiphospholipid antibody syndrome. These processes lack the inflammatory lesions of GPA and often have other associated laboratory abnormalities that can help suggest the correct etiology.

Pathologic Features

The histopathologic findings in biopsies of patients with EGPA depend on the phase of the disease. In the prodromic/eosinophilic phase, eosinophilic pneumonia is the most common finding ( Fig. 8.10 ). Extravasation of eosinophils in other anatomic sites or eosinophilic bronchitis can also be seen.

In the vasculitic phase, besides eosinophilic pneumonia, eosinophilic granulomas (allergic granulomas) and eosinophilic vasculitis can be seen. The granulomas are extravascular and consist of a necrotic center with eosinophils surrounded by palisading histiocytes ( Fig. 8.11 ). Multinucleated giant cells can be present. The vasculitis involves arteries, veins, and capillaries ( Fig. 8.12 ). The inflammatory infiltrate includes lymphocytes, neutrophils, plasma cells, and epithelioid macrophages in addition to eosinophils. Diffuse pulmonary hemorrhage can occur in association with eosinophilic capillaritis.

Eosinophils are very sensitive to corticosteroid therapy. Therefore in patients who have been treated with corticosteroids, the characteristic eosinophils can be absent or reduced in numbers and may appear fragmented. These degenerative changes can make histologic interpretation more difficult, and it is possible to be misled into interpreting degenerated eosinophils as neutrophils. However, the larger size of the nuclear lobes in eosinophils compared with neutrophils is a helpful clue, as well as the more eosinophilic appearance of the background compared with the more basophilic appearance of the necrotic/inflammatory background with degenerating neutrophils.

Differential Diagnosis

The differential diagnosis of EGPA includes other vasculitides and other pathologic entities characterized by the presence of eosinophils.

EGPA is distinguished from GPA by the clinical presentation, histopathology, and usual presence of c-ANCA (as opposed to p-ANCA in most patients with EGPA). Although eosinophils can be seen in GPA, they are not the predominant cells of the inflammatory infiltrate, and the range of histologic findings differs, as discussed earlier. The ANCA test, although not specific, can be helpful in the differentiation between the two entities. Clinically, EGPA is characterized by a spectrum of manifestations that differ from those of GPA, and most patients have peripheral blood eosinophilia. In contrast, renal involvement is much more common in GPA.

Eosinophilic pneumonia caused by other entities such as parasitic infections or drugs must be differentiated from EGPA. Clinical information indicating a systemic process (prodromic phase–asthma and allergic rhinitis) is helpful for making the correct diagnosis. Eosinophilic pneumonia can be an early manifestation of EGPA (eosinophilic phase). Observation of vasculitis is also helpful for supporting a diagnosis.

Allergic bronchopulmonary fungal disease (ABPFD) can show eosinophilic pneumonia and bronchocentric granulomas. Unlike EGPA, in ABPFD signs and symptoms of systemic vasculitis are absent.