Lung
Noninfectious granulomatous inflammation
Granulomatosis with polyangiitis (GPA)
Last staff update: 19 February 2024 (update in progress)
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PubMed search: Granulomatosis with polyangiitis
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Laboratory | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Frozen section description | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Positive stains | Negative stains | Videos | Sample pathology report | Differential diagnosis | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Cima L, Lin S, Cecchini M. Granulomatosis with polyangiitis (GPA). PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lungnontumorgranulomatosiswithpolyangiitis.html. Accessed April 19th, 2024.
Definition / general
- Granulomatosis with polyangiitis (GPA) is a systemic autoimmune vasculitis syndrome commonly involving the lower respiratory tract, the upper respiratory tract and the kidney
- Characterized by a necrotizing vasculitis and a systemic granulomatous inflammatory process which replaces the involved tissues
Essential features
- Classic GPA clinicopathological triad
- Vascular, respiratory and renal involvement
- Histopathological features
- Necrotizing vasculitis of small to medium sized arteries and veins
- Eosinophilic palisading granulomas
- Glomerulonephritis
- Association with antineutrophil cytoplasmic antibodies (ANCA) positivity
- C-ANCA is more specific for GPA
Terminology
- Obsolete term (not recommended): Wegener granulomatosis (WG), name changed due to Wegener's Nazi association in the 1930s (Lancet 2006;367:1362)
ICD coding
- ICD-11: 4A44.A1 - granulomatosis with polyangiitis
Epidemiology
- Incidence
- M = F (slight male predominance)
- Mean age: 50 years (Int J Immunopathol Pharmacol 2016;29:151)
- Rare in children and young adults
- Caucasian population of European descent is most commonly affected
- Risk factors
- Infectious, environmental and drug induced triggers
- First degree relatives with GPA
- HLA-DPB1*0401 variant as genetic risk factor (Ann Rheum Dis 2011;70:707)
- Thyroid disease: Graves disease and Hashimoto thyroiditis (Arthritis Rheum 2003;48:2299)
Sites
- Systemic vasculitis may manifest in a classic triad involving
- Head and neck region (upper respiratory tract)
- Lower respiratory tract
- Kidney
- Can also occur in a combination of 1 or 2 of the classic sites, along with additional sites
- Skin, joints, middle ear, eye and nervous system
- Solitary lung involvement can occur and is difficult to diagnose for the pathologist
- Reference: Autoimmun Rev 2014;13:1121
Pathophysiology
- Exact pathophysiology is unclear and pathogenesis is likely multifactorial
Etiology
- Exact mechanism is unclear
- Thought to be a result of exposure to infectious, environmental or drug induced triggers in patients with predisposing genetic background
- Recent discoveries suggest excessive activation of neutrophils that form neutrophil extracellular traps (NETs) (Front Immunol 2019;10:2617)
- Excessive NET formation is involved in ANCA mediated vascular injury and production of ANCA themselves
- Viscous cycle of NET formation and ANCA production is thought to drive GPA pathogenesis
Clinical features
- Typically manifest in upper / lower respiratory tract and kidney; pulmonary symptoms / signs in the absence of upper respiratory symptoms / signs are unusual
- Most common presenting symptoms / signs (local): rhinorrhea, purulent / bloody nasal discharge, oral or nasal ulcers, sinus pain, cough, hemoptysis and chest pain
- Most common presenting symptoms / signs (systemic): polyarthralgias, myalgias, fever, malaise, weight loss
- Reference: Arthritis Rheum 1990;33:1101
Diagnosis
- Clinical setting: corresponding sites of pathology, symptoms, radiological findings and patient demographics
- Positive ELISA serum C-ANCA test or less commonly P-ANCA test
- Biopsy or resection shows characteristic histologic findings consistent with GPA
- Special stains and cultures exclude infections
- Reference: Arthritis Rheum 1990;33:1101
Laboratory
- ELISA test for serum antineutrophil cytoplasmic antibodies (ANCA) serotypes
- Cytoplasmic (C) [PR3]-ANCA (proteinase 3); highly specific for GPA
- Perinuclear (P) [MPO]-ANCA (myeloperoxidase); less specific for GPA
- C-ANCA found in 90% with active generalized disease and 60% with limited disease
- Positive test in an appropriate clinical setting supports GPA diagnosis
- Negative test does not exclude the diagnosis, especially with characteristic histopathology
- ANCA positivity strongly related to relapse in GPA with renal involvement (J Am Soc Nephrol 2015;26:537)
Radiology description
- Upper respiratory tract involvement: sinonasal mucosal thickening with bony / cartilaginous erosion
- Lower respiratory tract involvement: 4 patterns of involvement (Chest 1990;97:906, J Thorac Imaging 1988;3:33, Clin Radiol 1982;33:545)
- Nodules with or without cavitation, often around bronchovascular bundles or in a subpleural distribution
- Pulmonary hemorrhage, which can occur with nodules but in some cases the consolidation associated with the hemorrhage predominates
- Reticulonodular pattern can be the first pattern and is often asymptomatic
- Peripheral wedge-like consolidation
- Renal involvement: typically a hypovascular mass with unclear margins; in some cases, opacity of the perirenal fat and para-aortic lymph nodes can be seen
Radiology images
Images hosted on other servers:
Multiple nodules and ground glass opacities
Large bilateral pulmonary cavities
Prognostic factors
- Can be fatal without treatment
- Excellent prognosis with treatment; 5 year survival is > 80%
- Increased incidence of infection with higher disease burden, long term exposure to glucocorticoids and kidney involvement
- Reference: Nat Rev Dis Primers 2020;6:71
Case reports
- 15 year old girl with granulomatosis with polyangiitis with cardiac involvement (AME Case Rep 2022;7:8)
- 16 year old girl with granulomatosis with polyangiitis masquerading as tuberculosis (Pan Afr Med 2021;38:285)
- 25 year old man with granulomatosis with polyangiitis presented with pulmonary, cutaneous and neurological manifestations (Cureus 2022;14:e31753)
- 25 year old woman with granulomatosis with polyangiitis diagnosed during the postpartum period (Matern Health Neonatol Perinatol 2023;9:2)
- 25 year old woman with granulomatosis with polyangiitis presented with thrombotic vasculopathy (Cureus 2023;15:e34479)
- 32 year old woman with granulomatosis with polyangiitis related pancolitis and stricturing small bowel disease (Case Rep Gastroenterol 2023;17:155)
- 36 year old man with granulomatosis with polyangiitis presented with recurrent myocardial infarction (Clin Exp Emerg Med 2023;10:246)
- 44 year old woman with granulomatosis with polyangiitis presented with oral involvement (J Dent Sci 2023;18:451)
- 48 year old woman with granulomatosis with polyangiitis presented with acute pancreatitis (ACG Case Rep J 2023;10:e00986)
- Man in his 60s with granulomatosis with polyangiitis presented with multiple renal masses (Radiol Case Rep 2023;18:1292)
- 65 year old man with obstructive pneumonia progressing to hypertrophic pachymeningitis (Medicine (Baltimore) 2021;100:e24028)
- 66 year old woman with rare initial presentation of pancreatic disease (BMJ Case Rep 2021;14:e241033)
- 71 year old woman with spontaneously regressed granulomatosis with polyangiitis (Respir Investig 2021;59:372)
- 72 year old woman with ANCA negative granulomatosis with polyangiitis, complicated with peripheral neuropathy; the patient underwent remission induction with mepolizumab monotherapy (Intern Med 2023 Feb 1 [Epub ahead of print])
- 75 year old woman with refractory granulomatosis with polyangiitis complicated with IgG4 related disease (Intern Med 2023 Feb 22 [Epub ahead of print])
- 77 year old woman with ANCA negative granulomatosis with polyangiitis with multiple brain infarctions and endomyocarditis (Heliyon 2023;9:e12881)
Treatment
- Usually treated with corticosteroids and cyclophosphamide with excellent prognosis
- Recent addition of rituximab (monoclonal antibody) for poorly responding cases or relapses suggested (N Engl J Med 2010;363:221)
- Methotrexate serves as effective maintenance therapy for mild / limited GPA (Am J Med 2003;114:463)
Gross description
- Multiple bilateral pulmonary nodules with frequent cavitation; rarely manifests as solitary lung lesion
Gross images
Contributed by Yale Rosen, M.D. and Philip Kane, M.D.
Nodules with central cavitation
Solid nodule
Solid nodule with areas of cavitation
Frozen section description
- Necrotizing granulomatous inflammation, reactive changes in the background lung should not be interpreted as malignancy
Microscopic (histologic) description
- Necrotizing granulomatous inflammation
- Deeply basophilic necrosis due to the presence of nuclear debris derived from necrosis and karyorrhexis; this type of blue necrosis is referred to as dirty necrosis
- Necrosis is often described as suppurative given the large number of neutrophils that are often present
- Necrosis is often described as geographic, which is best appreciated at low magnification and refers to the irregular contours of the necrosis that resemble the outlines of countries on a map (Am J Surg Pathol 1991;15:315)
- Multinucleated giant cells in the granulomatous inflammation often have strikingly hyperchromatic nuclei
- Medium to small arteries and veins are heavily inflamed in GPA, the inflammatory cells being neutrophils, histiocytes and lymphocytes
- Necrotizing vasculitis is one of the diagnostic features and consists of necrosis of the vessel wall by an inflammatory infiltrate; this is best recognized when the vasculitis focally involves the vessel and the remainder of the vessel is intact (Hum Pathol 1988;19:1065)
- Elastic stains can help identify blood vessels; however, this may present a pitfall since completely necrotic blood vessels within zones of necrosis can be present that do not qualify for true necrotizing vasculitis
- GPA can also present as diffuse alveolar hemorrhage due to the destruction of capillaries in the alveolar septa
- This produces an inflammatory infiltrate that is rich in neutrophils and karyorrhectic debris that produces a histologic picture similar to leukocytoclastic vasculitis of the skin
- This histologic finding is typically classified as capillaritis (Semin Respir Crit Care Med 2004;25:475)
- In these cases, the adjacent alveoli are filled with hemosiderin laden macrophages, red blood cells and neutrophils
Microscopic (histologic) images
Contributed by Matthew J. Cecchini, M.D., Ph.D.
Blue (dirty) necrosis
Geographic necrosis
Blue (dirty) necrosis in core needle biopsy
Granulomatous inflammation
Vasculitis
Focal vasculitis
Small vessel vasculitis
Hyperchromatic giant cells
Capillaritis
Virtual slides
Images hosted on other servers:
GPA with necrotic mass lesion
Granulomatosis with polyangiitis
Positive stains
- Elastic stains can aid in the identification of areas of vasculitis
Negative stains
- Fungal stains (GMS and PASD) are negative for fungal organisms
- Acid fast stains (ZN) are negative for acid fast organisms
Videos
Granulomatosis with polyangiitis (pathophysiology, symptoms, treatment)
GPA symptoms, diagnosis, treatment
GPA review
GPA discussion at 5:01
Sample pathology report
- Lung, right, lower lobe, wedge biopsy:
- Necrotizing granulomatous inflammation and vasculitis, most consistent with granulomatosis with polyangiitis (GPA) (see comment)
- Comment: In this specimen, there is prominent granulomatous inflammation and vasculitis. Histochemical stains for fungal and acid fast organisms are negative. The features are most consistent with a diagnosis of granulomatosis with polyangiitis (GPA). Correlation with the clinical findings and serology is recommended for definitive classification.
Differential diagnosis
- Granulomatous infection:
- Cultures or special stains are positive
- Eosinophilic granulomatosis with polyangiitis:
- P-ANCA positive
- Eosinophil rich inflammation
- Microscopic polyangiitis:
- Absence of granulomatous inflammation
- Acute lupus pneumonitis:
- Nonspecific findings with alveolar wall damage, inflammation, edema and features of acute lung injury including hyaline membranes
- Idiopathic pulmonary hemosiderosis:
- Absence of vasculitis and granulomatous inflammation
Board review style question #1
Which of the following serology tests is the most specific for granulomatosis with polyangiitis?
- ANA
- C-ANCA
- CRP
- ESR
- P-ANCA
Board review style answer #1
B. C-ANCA. Cytoplasmic (C) [PR3]-ANCA (proteinase 3) is highly specific for GPA and found in 90% of cases with generalized disease. Answer A is incorrect because ANA detects antinuclear antibodies and is seen in systemic autoimmune disorders such as systemic lupus erythematosus. Answer C is incorrect because CRP stands for C reactive protein and is a test that measure general inflammation in the body and is not specific. Answer D is similarly incorrect because erythrocyte sedimentation rate (ESR) is a general nonspecific marker of inflammation. Answer E is incorrect because P-ANCA is more commonly seen in eosinophilic granulomatosis with polyangiitis.
Comment Here
Reference: Granulomatosis with polyangiitis (GPA)
Comment Here
Reference: Granulomatosis with polyangiitis (GPA)
Board review style question #2
What histologic finding is seen in this image with septal expansion by neutrophils and karyorrhectic debris?
- Acute bronchopneumonia
- Acute lung injury
- Capillaritis
- Granulomatous inflammation
- Organizing pneumonia
Board review style answer #2
C. Capillaritis. Neutrophils and karyorrhectic debris is best classified as capillaritis. Answers A, B, D and E are incorrect because they should not have neutrophils or karyorrhectic debris in the interstitium.
Comment Here
Reference: Granulomatosis with polyangiitis (GPA)
Comment Here
Reference: Granulomatosis with polyangiitis (GPA)
