—  SHORT COURSE #26  —

Lung Biopsy Interpretation

Case 7 - Wegener's Granulomatosis

Anna-Luise A. Katzenstein & Jeffrey L. Myers


Clinical History
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.

Microscopic Description:


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.

Discussion:
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

Classical Wegener's
• Necrotizing granulomatous inflammation
• Large areas of parenchymal necrosis
- May be bronchocentric (bronchocentric variant)
- Eosinophils may be prominent (eosinophilic variant)
• Necrotizing vasculitis
BOOP-like variant
• 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

References

  1. Anderson G, Coles ET, Crane M, et al. Wegener's granuloma. A series of 265 British cases seen between 1975 and 1985. A report by a sub-committee of the British Thoracic Society research committee. Q J Med 302: 427-438, 1992.
  2. Bax, J., Gooszen, H., and Hoorntje, S.: Acute fulminating alveolar hemorrhage as presenting symptom in Wegener's granulomatosis. Anticytoplasmic antibodies as a diagnostic tool. Eur. J. Respir. Dis., 71:202, 1987
  3. Bosch X, Lopez-Soto A, Mirapeix E, et al. Antineutrophil cytoplasmic antibody-associated alveolar capillaritis in patients presenting with pulmonary hemorrhage. Arch Pathol Lab Med 118:517-22, 1994.
  4. Cordier J-F, Valeyre D, Guillevin L, Loire R and Brechot J-M: Pulmonary Wegener's granulomatosis: A clinical and imaging study of 77 cases. Chest 97:906,1990.
  5. Coulomb-L'Hermine A, Capron F, Zou W, et al. Expression of the chemokine RANTES in pulmonary Wegener's granulomatosis. Hum Pathol 2001; 32:320-326.
  6. Fienberg R, Mark EJ, Goodman M, et al. Correlation of antineutrophil cytoplasmic antibodies with the extrarenal histopathology of Wegener's (pathergic) granulomatosis and related forms of vasculitis. Hum Pathol 24:160-68, 1993.
  7. Gal AA, Salinas FF, Staton GW Jr. The clinical and pathological spectrum of antineutrophil cytoplasmic autoantibody-related pulmonary disease. A comparison between perinuclear and cytoplasmic antineutrophil cytoplasmic autoantibodies. Arch Pathol Lab Med 118:1209-14, 1994.
  8. Gal AA, Velasquez A. Antineutrophil cytoplasmic autoantibody in the absence of Wegener's granulomatosis or microscopic polyangiitis: Implications for the surgical pathologist. Mod Pathol 15:197-204, 2002.
  9. Gaudin PB, Askin FB, Falk RJ, Jennette JC. The pathologic spectrum of pulmonary lesions in patients with anti-neutrophil cytoplasmic autoantibodies specific for anti-proteinase 3 and anti-myeloperoxidase. Am J Clin Pathol 104:7-16, 1995.
  10. Gephardt GN, Shah LF, Tubbs RR and Ahmad M: Wegener's granulomatosis:
  11. Immunomicroscopic and ultrastructural study of four cases. Arch Pathol Lab Med 114:961,1990.
  12. Hoffman GS, Kerr Gs, Leavitt RY et al. Wegener granulomatosis: An analysis of 158 patients. Ann Intern Med 116:488-498, 1992.
  13. Hoffman GS and Specks U. Antineutrophil cytoplasmic antibodies. Arthritis Rheum 41: 1521-1537, 1998.
  14. Jayne DRW, Rasmussen N. Treatment of antineutrophil cytoplasm autoantibody-associated systemic vasculitis: Initiatives of the European Community systemic vasculitis clinical trials study group. Mayo Clin Proc 72: 737-747, 1997.
  15. Jennette JC, Falk, RJ. Small-vessel vasculitis. New Engl J Med 337:1512-1523, 1997.
  16. Katzenstein A. Diagnostic features and differential diagnosis of Churg-Strauss syndrome in the lung. Am J Clin Pathol 114:767-772, 2000.
  17. Katzenstein A-LA, Locke WK. Solitary lesions in Wegener's granulomatosis. A clinicopathologic study of 25 cases. Am J Surg Pathol, 19:545-552, 1995.
  18. Langford DA, Hoffman GS. Wenener's granulomatosis. Thorax 54:629-637, 1999.
  19. Lim LCL, Taylor JG III, Schmitz JL, et al. Diagnostic usefulness of antineutrophil cytoplasmic autoantibody serology. Comparative evaluation of commercial indirect fluorescent antibody kits and enzyme immunoassay kits. Am J Clin Pathol 111:363-369, 1999.
  20. Lombard CM, Duncan SR, Rizk NW and Colby TV: The diagnosis of Wegener's
  21. granulomatosis from transbronchial biopsy specimens. Hum Pathol 21:838,1990.
  22. Mark, E.J., Flieder, D.B., and Matsubara, O. Treated Wegener's granulomatosis: Distinctive pathological findings in the lungs of 20 patients and what they tell us about the natural history of the disease. Hum Pathol. 28:450-458, 1997.
  23. Mark, E. J., Matsubara, O., Tan-Liu, N. S., and Fienberg, R.: The pulmonary biopsy in the early diagnosis of Wegener's (pathergic) granulomatosis: A study based on 35 open lung biopsies. Hum. Pathol., 19:1065, 1988.
  24. Myers, J. L., and Katzenstein, A. A.: Wegener's granulomatosis presenting with massive pulmonary hemorrhage and capillaritis. Am. J. Surg. Pathol., 11:895, 1987.
  25. Nada AK, Torres VE, Ryu JH, Lie JT, Holley KE. Pulmonary fibrosis as an unusual clinical manifestation of a pulmonary-renal vasculitis in elderly patients. Mayo Clin Proc 65:847-856, 1990.
  26. Odeh M, Best L-A, Kerner H, et al. Localized Wegener's granulomatosis relapsing as diffuse massive intra-alveolar hemorrhage. Chest 104:955-56, 1993.
  27. Potter MB, Fincher RK, Finger DR. Eosinophilia in Wegener's granulomatosis. Chest 116:1480-83, 1999.
  28. Rao JK, Weinberger M, Oddone EZ, et al. The role of antineutrophil cytoplasmic antibody (c-ANCA) testing in the diagnosis of Wegener granulomatosis. A literature review and meta-analysis. Ann Intern Med 123:925-932, 1995.
  29. Savige J, Dimech W, Fritzler M et al. Addendum to the International Consensus Statement of testing and reporting of antineutrophil cytoplasmic antibodies. Am J Clin Pathol 120:312-318, 2003.
  30. Savige J, Gillis D, Benson E, et al. International consensus statement on testing and reporting of antineutrophil cytoplasmic antibodies (ANCA). Am J clin Pathol 111:507-513, 1999.
  31. Stegeman CA, Tervaert JWC, de Jong PE, et al. Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener's granulomatosis. New Engl J Med 335:16-20, 1996.
  32. Travis, W. D., Carpenter, H. A., and Lie, J. T.: Diffuse pulmonary hemorrhage. An uncommon manifestation of Wegener's granulomatosis. Am. J. Surg. Pathol., 11:702, 1987.
  33. Travis WD, Hoffman GS, Leavitt RY et al. Surgical pathology of the lung in Wegener's granulomatosis. Review of 87 open lung biopsies from 67 patients. Am J Surg Pathol 15:315-33, 1991.
  34. Ulbright, T., and Katzenstein, A.: Solitary necrotizing granulomas of the lung: differentiating features and etiology. Am. J. Surg. Pathol., 4:13, 1980.
  35. Uner AH, Rozum-Slota B, Katzenstein A-LA. BOOP-like variant of Wegener's granulomatosis. A clinicopathologic study of 16 cases. Am J Surg Pathol, 20:794-801,1996.
  36. Wong RCW, Silvestrini RA, Savige JA, Fulcher DA, Benson EM. Diagnostic value of classical and atypical antineutrophil cytoplasmic antibody (ANCA) immunofluorescence patterns. J Clin Pathol 52: 124-128, 1999.
  37. Yoshikawa, Y., and Watanabe, T.: Pulmonary lesions in Wegener's granulomatosis: A clinicopathologic study of 22 autopsy cases. Hum. Pathol., 17:401, 1986.
  38. Yousem S.A., Bronchocentric injury in Wegener's granulomatosis: A report of five cases. Hum Pathol 22: 535-540, 1991.
  39. Yousem, S., and Lombard, C.: Eosinophilic variant of Wegener's granulomatosis. Hum. Pathol., 19:682, 1988.