Authors: Sun Cuihong, Li Min, Li Qiuyu, Liang Ying, Sun Yongchang, Zhu Xiang
Affiliation: Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Department of Pathology, Peking University Third Hospital
Cite this article: Sun Cuihong, Li Min, Li Qiuyu, et al. Neutrophil cytoplasmic antibody-negative granulomatosis with polyangiitis in a case[J] . Chinese Journal of Tuberculosis and Respiration, 2024, 47(3) : 240-244. DOI: 10.3760/cma.j.cn112147-20230813-00073.
summary
In this paper, we report an elderly male case characterized by multiple pulmonary nodules with cavitation. The patient was a 73-year-old male who was admitted to the hospital mainly due to "dry cough with shortness of breath for 3 months", chest CT showed multiple irregular masses, nodules, patches in both lungs, accompanied by cavitary formation, anemia, renal insufficiency, progression of lung nodules and enlargement of cavities after empirical anti-infection and anti-tuberculosis treatment. Multiple tests were negative for ANCA. Bronchoscopic mucosal biopsy of the lesion in the middle lobe of the right lung showed small patches of necrosis, focal granulomatous structure formation, and vasculitis findings, and elastic fiber staining showed residual vascular wall structures in necrotic lesions. ANCA-negative granulomatosis with polyangiitis was clinically diagnosed, and the lesions shrank after treatment with glucocorticoids and cyclophosphamide.
body
The patient, a 73-year-old male, was admitted to the hospital on 26 May 2022 with a "dry cough with shortness of breath for 3 months". The patient began to have a dry cough 3 months ago without obvious cause, accompanied by fatigue, decreased activity tolerance, no fever, no night sweats, no rash, and no joint and muscle aches. He was admitted to an external hospital, and chest CT showed multiple nodular opacities in both lungs and a posterior basal segment mass with cavitary opacities in the lower lobe of the right lung. 2 months ago, he visited the outpatient clinic of our department, and the re-examination of chest CT showed multiple nodules and mass shadows in both lungs, some of which were accompanied by cavitation (Figs. 1~3), and he was hospitalized and gave ultrasound-guided needle biopsy of the lesion in the right lung, and the pathology showed that the lung tissue was chronically inflammatory with large necrosis, and the molecular pathological results were PCR-TB(-). Special staining: acid-fast staining (-), PAS (-), PASM (-). Pulmonary tuberculosis is not excluded from clinical considerations, and anti-tuberculosis therapy is given for 3 weeks (isoniazid 0.3 g once daily; rifampicin 0.45 g once daily; ethambutol 0.75 g once daily). Chest CT scan showed that the lesions in both lungs had progressed compared with the previous ones (Figs. 4~10). The patient lost nearly 10 kg of weight in the past 3 months. Anamnesis: history of hypertension, diabetes mellitus, coronary heart disease, anemia found for 4 months, treated with oral ferrous succinate and roxadustat, renal insufficiency found for 3 months, untreated.
Fig.1~3 On March 27, 2022, chest CT showed multiple irregular masses, nodules, and patches in both lungs, and a mass in the lower lobe of the right lung, about 38 mm×27 mm, with internal cavities, marginal lobulations, and local pleural depressions
Fig. 4~10 On May 26, 2022, chest CT showed that the multiple nodular shadows in both lungs were larger than before, and newly seen cavities in some lesions, and the cavities became larger than before, and the mass shadow of the lower lobe of the right lung was about 48 mm×33 mm, and multiple cavitations were seen in the laboratory examination: hemoglobin 102 g/L. Urinalysis: urine glucose 3+, urine ketone body-, urine occult blood 3+, urine protein 2+. Blood biochemistry: urea 17.2 mmol/L, creatinine 266 μmol/L, albumin 28.2 g/L. The 24-hour urine protein was 1 252 mg. There were no abnormalities in tumor markers. The ESR was 36 mm/1 h, the spot type of antinuclear antibody was 1∶80, and the cytoplasmic type of antineutrophil cytoplasmic antibody (ANCA), perinuclear type of ANCA, antimyeloid peroxidase antibody and anti-protease 3 antibody were negative for two consecutive tests. Sputum acid-fast staining is negative, lymphocyte culture + interferon assay is positive. In order to further investigate neoplastic diseases, whole-body PET/CT showed multiple nodules and masses in both lungs, some with cavitation, and increased metabolism, active lesions around the sinuses, nasal septum, hilum, and paravertebral lesions, increased metabolism in the nasopharyngeal and parapharyngeal spaces, and granulomatosis with polyangitis (GPA) was not considered (Fig. 11). Bronchoscopy was performed, and the bronchial mucosa of the upper and middle lobes of the right lung was found to be diffusely congested and edema, and the cristae were thickened, resulting in the narrowing of the opening of the medial segment of the right middle lobe and close to occlusion. The pathological report showed small patchy necrosis, focal granulomatous structure formation, and inflammatory cell infiltration in the vascular wall, and no clear basis for tuberculosis and tumor, and Wegener's granuloma was considered (Fig. 13). Acid-fast staining (-), elastic fibers (+). Molecular pathology: fluorescent PCR-TB(-), in situ hybridization-EBV-EBER(-). So far, the GPA of clinical diagnosis has been basically established. In addition, in order to determine whether there is associated with GPA-related renal damage, a renal biopsy was performed, and the pathological report was focal segmental glomerulosclerosis (FSGS) with subacute tubulointerstitial nephropathy. After multidisciplinary consultation with the Department of Rheumatology and Immunology and the Department of Nephrology, granulomatosis with polyangiitis combined with focal segmental glomerulosclerosis was considered.
Fig.11 PET-CT on May 28, 2022 showed multiple nodules and masses in both lungs, some with cavitation, and the shadow of the mass in the lower lobe of the right lung, about 48 mm×33 mm, with multiple cavities and increased uptake, and SUVmax was 7.1
Fig.12 Bronchoscopy showed diffuse hyperemia and edema of the bronchial mucosa in the middle lobe of the right lung, thickening of the cristae (Fig. 12A), and stenosis of the medial segment of the right lobe (Fig. 12B)
FIGURE 13 The pathological results of bronchoscopic mucosal biopsy of the right lung showed chronic inflammation of the tracheal mucosa, infiltration of intramucosal inflammatory cells, and focal necrosis of the mucosal surface (Fig. 13A), infiltration of lymphmonocytes in the bronchial mucosa, and necrosis of the vascular wall in the foci, and lymphocytes and multinucleated histiocytes proliferation formed granulomatous structures (Fig. 13B), coagulation necrosis was seen in the focal area, and the surrounding lymphmonocytes and multinucleated histiocytes proliferated to form granulomatous structures, in which a small number of spindle cells were distributed in a ring and appeared to be a vascular wall structure (Fig. 13C), and granulomatous structures were shown in the center and surrounded by peripheral multinucleated cellsFig. 14 Chest CT (July 28, 2022, Fig. 14A~C) after 2 months of hormone and immunosuppressant treatment showed that the multiple nodular shadows in both lungs were smaller than before, and the mass shadows in the lower lobe of the right lung were smaller than before, about 33 mm×21 mm, and cavities were visible in the cavity and the wall of the cave was thinned. After 5 months of hormone and immunosuppressant treatment, chest CT (October 30, 2022, Fig. 14D~F) showed that multiple small nodules in both lungs basically disappeared, and the nodules and cavities in the lower lobe of the right lung were significantly reduced. After 2 months of treatment, the chest CT scan showed that the multiple nodular shadows in both lungs were smaller than before, the mass shadow of the lower lobe of the right lung was significantly reduced, and the cave wall was thinner (Fig. 14A~14C). After regular outpatient follow-up and treatment for 5 months, chest imaging showed that the lesions were obviously absorbed (Fig. 14D~14F).
discuss
Antineutrophil cytoplasmic antibody-associated vasculitis (ANCA) is a primary necrotizing small vessel vessel closely related to ANCA, characterized by oligo-or no immune complex deposition. The clinical manifestations are diverse, and there may be skin, ear, nose and throat, respiratory tract, kidney and nerve and other multi-system involvement, including the following three types: (1) Granulomatous polyangiitis (GPA) is a systemic, necrotizing granulomatous vasculitis, and the histopathological characteristics can be manifested as a triad of vasculitis, focal necrosis and granulomatous. Common clinical manifestations include destructive sinus lesions, pulmonary nodules, and oligoimmune glomerulonephritis, which can also involve other systems. Chest imaging is characterized by "three more and one hole", that is, polymorphism, multipleness, variability, and cavitation. The prevalence rate is (24~157)/1 million population[1]. Untreated GPA is expected to have a mean survival of 5 months and a 1-year survival rate of 20 percent [2]. Treatment is based on glucocorticoids combined with immunosuppressants, with remission in more than 80% of cases, and prognosis depends on organ involvement and severity. (2) The histological characteristics of microscopic polyangiitis (MPA) are systemic nongranulomatous necrotizing vasculitis, often manifesting rapidly progressive oligoimmune glomerulonephritis and alveolar hemorrhage, and multisystem lesions such as cutaneous purpura, congestive maculopapular rash, joint myalgia, and fever may occur. Chest imaging features patchy opacities and ground-glass opacities in both lungs. The prevalence rate is (0~66)/1 million people. (3) Eosinophilic granulomatosis with polyangiitis (EGPA) histological features also include eosinophilic tissue infiltration. Common clinical manifestations include asthma, peripheral eosinophilia and extravascular necrotizing granulomas, and peripheral neuropathy. Approximately 40% of patients develop detectable ANCA. The prevalence rate is (2~38)/1 million population[3]. ANCA is an autoantibody against the cytoplasmic proteins of neutrophils and monocytes, which are divided into three types: cytoplasmic ANCA (cANCA): the target antigen is protease 3 (PR3) which is most correlated with GPA (75%), and perinuclear ANCA (pANCA): the target antigen is myeloperoxidase, which is the same as MPA (60% ) or vasculitis confined to the kidneys (80%) is more relevant. In addition, the less common type of ANCA-negative oligoimmune complex vasculitis has both clinical and pathological manifestations consistent with AAV, but the ANCA test is negative. However, about 10%~20% of patients with GPA are ANCA-negative [4], and ANCA-negative GPA tends to be limited to renal GPA or severe systemic diseases are less common [5]. Currently, the 2022 American Association of Rheumatology (ACR)/European League Against Rheumatism (EU) classification criteria for vasculitis[6]:(1) clinical criteria are: (1) nasal bleeding, ulceration, crusting, congestion, or blockage, or septal defect/perforation, which is worth +3, (2) cartilage involvement (inflammation of the ear or nasal cartilage, hoarseness or stridor, bronchial involvement, or saddle nose deformity), which is worth +2, and (3) conductive or sensorineural hearing loss, which is worth +1. (2) Laboratory, imaging and biopsy criteria: (1) positive c-ANCA or anti-PR3 (+5 points), (2) Chest imaging: pulmonary nodules, masses or cavities, +2 points, (3) Other imaging tests: nasal cavity/sinus inflammation, consolidation or effusion, or mastoiditis, which is +1 point, (4) Biopsy showing granuloma, extravascular granulomatous inflammation or giant cell (+2 points), (5) Biopsy showing oligoimmune complex glomerulonephritis, scoring +1 point, (6) positive p-ANCA or anti-MPO, scored -1 point, (7) serum eosinophil count ≥ 1×109/L, scored -4. Diagnostic criteria: A score of ≥5 can be used to diagnose GPA. The clinical characteristics of this patient are as follows: (1) Elderly male, with insidious onset. Respiratory symptoms are not characteristic, and systemic symptoms are characterized by poor appetite and wasting. Chest CT showed that there were multiple irregular masses, nodules, and patches in both lungs, accompanied by lobulation, cavities, and burrs, and the lung lesions were still progressing after empirical anti-infection and anti-tuberculosis therapy. (2) Extrapulmonary organ lesions, renal impairment, anemia, fatigue, sinus lesions, etc., renal involvement manifested as hematuria and massive proteinuria, and PET-CT showed systemic multisystem involvement. (3) Pathological examination of lung mucosa showed small patchy necrosis, focal granuloma structure formation, inflammatory cell infiltration in the vascular wall, and elastic fiber+. (4) In terms of treatment, a sufficient amount of hormones combined with cyclophosphamide pulse therapy was given, and the chest CT showed that the lung lesions were reduced or absorbed. In summary, from the perspective of clinical features, imaging changes, pathology and treatment response, although c-ANCA was negative for many times, this patient was rated as 5 according to the above criteria, and the diagnosis was clear considering GPA. According to the literature, the ANCA positivity rate is about 60% for GPA confined to the respiratory tract and about 90% for GPA with multisystem involvement. ANCA-negative patients have fewer paranasal sinus involvement than ANCA-positive patients, but have higher levels of interstitial fibrosis and an increased incidence of respiratory failure, and ANCA-negative patients may be associated with oligoimmune glomerulonephritis [7]. In addition, patients who are c-ANCA negative may have a positive result several years later [8]. There are three elements that are pathologically used to diagnose GPA: (1) vasculitis, i.e., fibrinoid necrosis of the blood vessel wall, (2) focal necrosis, and (3) formation of noncaseating granulomas (heterogeneous inflammatory response with multiple cellular infiltrates, with fibrinoid necrosis of the vessel wall in the center and macrophage aggregation around it). The pathological types of renal damage caused by GPA can be focal hyperplasia/focal hyperplasia sclerosis type, proliferative sclerosis type, and crescent type, with crescent nephritis being the most common. Although the patient has a history of diabetes mellitus and the pathology does not support diabetic nephropathy, the current renal lesions in this patient may not be directly affected by GPA, but the use of hormonal therapy for focal segmental glomerulosclerosis is not contradictory. The difficulty in diagnosing this disease lies in the insidious onset and slow progression, and there are no typical vasculitis manifestations in the histopathology of the first lung lesion puncture, and ANCA is negative. In addition, compared with GPA, special infections (such as tuberculosis, pulmonary aspergillosis) and lung tumors (lung cancer, lymphoma, etc.) are relatively more common, in the process of diagnosis and treatment of this case, we repeatedly look for relevant disease clues, even after the pathological diagnosis is confirmed by bronchoscopy for the second time, we closely observe the changes of relevant indicators during the follow-up process, and finally establish the diagnosis of ANCA-negative GPA on the basis of the clear and effective treatment of hormones combined with cyclophosphamide. In conclusion, for the diagnosis of GPA, the sensitivity and specificity of c-ANCA and its PR3 positivity are high, but 10%~20% of oligoimmune complex vasculitis lack evidence of ANCA-positive. For patients with high clinical suspicion of GPA, a negative ANCA cannot rule out the diagnosis, and a histopathological diagnosis should be obtained by appropriate means as soon as possible so that timely treatment can improve the prognosis.
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