Lung Biopsy Interpretation
Case 7 -
Anna-Luise A. Katzenstein & Jeffrey L. Myers
This 64 year old woman presented with a 5 month history of nonproductive cough and weight loss. Chest
x-ray and CT showed two right upper lobe nodules, one of which was cavitating. A right upper lobectomy
was performed because of the clinical suspicion of malignancy. Grossly, the lesions were well
circumscribed, rubbery, pink to tan, and focally necrotic. They measured 8 and 4 cm in diameter each.
The patient had no history of sinus or renal disease. An ANCA test was negative.
Case 7 - Figure 1 - Low magnification showing haphazardly arranged, basophilic appearing necrotic zone within background fibrosis and chronic inflammation.
Case 7 - Figure 2 - Higher magnification of necrotic zone showing karyorrhectic nuclear debris and surrounding rim of palisading epithelioid histiocytes and multinucleated giant cells.
Case 7 - Figure 3 - Necrotizing vasculitis involving a portion of the wall of a medium sized pulmonary artery.
Case 7 - Figure 4 - Necrotizing acute capillaritis in lung tissue adjacent to an area of necrotizing granulomatous inflammation. Note the acute inflammation and histiocytes that infiltrate, expand and destroy the alveolar septum.
This biopsy contains a widespread necrotizing inflammatory reaction with extensive suppuration.
Small, haphazardly arranged necrotic foci bounded by palisading epithelioid histiocytes are numerous and
are present within a background of fibrosis and chronic inflammation. The necrotic zones have a deeply
basophilic appearance due to the presence of abundant nuclear debris. This type of necrotizing
granulomatous inflammation with "geographic" shapes and "dirty" necrosis is characteristic of Wegener's
granulomatosis. Another typical feature is the presence of abundant acute inflammation with microabscess
formation. Many of the microabscesses are surrounded by a rim of epithelioid histiocytes and thus
represent small suppurative granulomas. Multinucleated giant cells are numerous in the surrounding
cellular infiltrate and they stand out at low magnification because of darkly staining, eosinophilic
cytoplasm and dense nuclear chromatin. The final feature, and one that is necessary for the histologic
diagnosis of Wegener's, is a necrotizing vasculitis. In this case medium sized arteries contain an acute
and chronic inflammatory cell infiltrate in their walls with associated necrosis of portions of the
walls. The inflammatory cell infiltrate is patchy, often involving only small segments of the wall.
Both arteries and veins are involved by the necrotizing process.
Wegener's granulomatosis is the most common primary pulmonary vasculitis. Lung involvement occurs in
90% of cases, and is often the principle manifestation of the disease. In the classically described
generalized form of the disease there is a triad of upper respiratory tract involvement, lung lesions and
glomerulonephritis. Multiple other sites can be involved as well, including skin, middle ear, eyes,
joints and nervous system, for example. Occasionally the disease is confined to a single organ. When
the lung is the only site of involvement, as in this case, the disease is termed limited or localized Wegener's.
Wegener's granulomatosis occurs most often in middle-aged adults, although there is a wide age range
that includes young children and the elderly. The most common presenting complaints include fever,
malaise, weight loss, cough, chest pain, and hemoptysis. There may also be signs and symptoms related to
extrapulmonary involvement, such as rhinorrhea, nasal ulceration, or sinus pain, for example. Less
often, patients present with hematuria or renal failure, while otitis media, skin lesions, arthralgias,
myalgias, arthritis, neurologic abnormalities or eye changes may be present in a few. Radiographically,
multiple, often cavitary, nodular densities are the most characteristic findings, although localized
areas of consolidation and rarely solitary nodules may occur. A combination of cyclophosphamide and
corticosteroids is used for treatment. Ninety percent of patients improve with this regimen, and
complete remission is induced in 75%.
The diagnosis of Wegener's requires tissue biopsy in most cases, and lung is the most frequent biopsy
site. The use of the anti-neutrophil cytoplasmic antibody (ANCA) test can
help establish the diagnosis in difficult cases. ANCA are autoantibodies that react with components of
neutrophil granules and monocyte lysosomes. They can be detected by indirect immunofluorescence
techniques which have been the gold standard of ANCA testing, and by enzyme linked immunosorbent assay
(ELISA). They are divided into C (for cytoplasmic) and P (for perinuclear) types according to the immunofluorescent staining pattern. By
ELISA techniques most C-ANCA react with proteinase-3 (PR-3), a 29 kilodalton neutral serine protease and
they are also termed PR3-ANCA. Most P-ANCA
react against myeloperoxidase (MPO) and they are also termed MPO-ANCA. A variety of other substrates have been identified less commonly for some
P-ANCA, including enolase, catalase, cathepsin G, elastase, lactoferrin, and lysozyme, for example. ANCA
are present in about 95% of generalized and about 60% of localized Wegener's patients, and most, but not
all, are C-ANCA. P-ANCA are less specific than C-ANCA and are found more often in other diseases such as
microscopic polyarteritis, Churg-Strauss disease, and crescentic glomerulonephritis, for example. Since
ANCA may be negative in otherwise typical vasculitides, they are helpful diagnostically only when
present. A negative result, therefore, as in the current case, should not detract from the diagnosis if
the pathologic features are characteristic.
The pathologic findings in Wegener's are variable, but generally can be fit into three main categories
which greatly facilitate diagnosis (Table 1). The classical variant is the
most common, and is exemplified by the current case. It is characterized by large areas of parenchymal
necrosis which typically are irregularly, haphazardly or "geographically" shaped. The necrotic zones
usually appear basophilic or "dirty" and contain remnants of nuclear debris. They are bounded by
epithelioid histiocytes often arranged in a palisading configuration, and darkly staining multinucleated
giant cells may be numerous. Fibrosis and non-specific chronic inflammation usually surround the
necrotizing granulomatous foci, and neutrophils are generally numerous as well. The changes are
accompanied by a necrotizing vasculitis that usually involves small to medium-sized arteries and veins,
but sometimes affects capillaries as well. Occasionally the necrotizing granulomatous inflammation
centers upon and destroys bronchioles, and this finding constitutes the bronchocentric variant. The only reason to recognize this variant is to
facilitate its distinction from bronchocentric granulomatosis, an extremely rare disease that is usually
associated with eosinophilia, asthma and fungal hypersensitivity. The presence of a necrotizing
vasculitis in Wegener's is the single most important histologic feature that separates these two
entities. Eosinophils are present in large numbers in the eosinophil variant
of Wegener's, and Churg-Strauss syndrome may enter the differential diagnosis of such cases. The
presence of asthma and blood eosinophilia clinically and eosinophilic pneumonia-like areas histologically
is characteristic of Churg-Strauss syndrome and not seen in Wegener's.
The BOOP-like variant of Wegener's, as the name implies, is characterized
by extensive intraluminal organization resembling bronchiolitis obliterans-organizing pneumonia (BOOP).
Large areas of necrotizing granulomatous inflammation are not present, although tiny foci of "dirty"
necrosis are seen as are small suppurative granulomas and microabscesses. Acute inflammatory cells are
usually numerous, and necrotizing vasculitis is not difficult to identify. In the hemorrhage and capillaritis variant the main finding is extensive intraalveolar
hemorrhage accompanied by a necrotizing capillaritis. The latter is often subtle and is characterized by
a necrotic neutrophil infiltrate that expands and destroys alveolar septa. Granulomatous inflammation is
not a feature. Other conditions besides Wegener's can cause similar capillaritis and hemorrhage,
including most often microscopic polyangiitis and lupus, and clinical and laboratory findings are needed
to separate them.
There has been controversy in the literature whether identification of vasculitis is necessary to
diagnose Wegener's granulomatosis. For a clinical diagnosis, that is based
on pattern of organ involvement and confirmatory laboratory studies (positive C-ANCA), vasculitis may be
absent. Biopsies from the upper respiratory tract are especially notorious for lacking vasculitis, but
when there is renal and lung involvement and a positive C-ANCA, vasculitis is not necessary for
diagnosis. For a pathologic diagnosis on a lung biopsy specimen, however,
evidence of necrotizing vasculitis must be present.
Churg-Strauss syndrome and microscopic polyangiitis are the two most common vasculitides in the
differential diagnosis of Wegener's, and their distinguishing features are listed in Table 2.
Lymphomatoid granulomatosis enters the histologic differential diagnosis because of parenchymal necrosis
and vascular infiltration, and it is also
included in the table for comparison.
Table 1. Histologic Variants of Wegener's Granulomatosis
|• Necrotizing granulomatous inflammation|
|• Large areas of parenchymal necrosis|
|- May be bronchocentric (bronchocentric variant)|
|- Eosinophils may be prominent (eosinophilic variant)|
|• Necrotizing vasculitis|
|• Intraluminal organization (BOOP)|
|• Small necrotic foci, microabscesses, suppurative granulomas|
|• Necrotizing vasculitis|
|• Absent large foci of necrosis|
|Alveolar hemorrhage and capillaritis|
|• Fresh blood and hemosiderin in alveolar spaces|
|• Acute inflammation and necrosis of alveolar septa (capillaritis)|
|• Absent granulomatous inflammation|
|• Absent vasculitis of medium sized arteries and veins|
Table 2. Contrasting Features of Wegener's Granulomatosis (WG), Churg-Strauss Syndrome (CSS),
Microscopic Polyangiitis (MPA), and Lymphomatoid Granulomatosis (LYG)
| ||WG ||CSS ||MPA ||LYG|
|Asthma ||No ||Yes ||No ||No|
|Eosinophilia ||Usually not ||Yes, high ||No ||No|
|ANCA ||60-95%, usually C-ANCA ||70%, usually P-ANCA ||80%, usually P-ANCA ||No|
|Glomerulo-nephritis ||Frequent ||Occasional, mild ||Usual ||No|
|Necrotizing URT lesions ||Occasional ||No ||No ||Rare|
|Necrotizing granulomatous inflammation ||Yes ||Yes ||No ||No|
|Necrotizing vasculitis ||Yes ||Yes ||Yes ||No|
|Tissue eosinophilia ||Rare ||Yes ||No ||No|
|Atypical lymphoid infiltrate ||No ||No ||No ||Yes|
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