Necrotizing Granuloma of the Lung: Imaging Characteristics and Imaging-Guided Diagnosis

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1 Necrotizing Granuloma of the Lung Chest Imaging Clinical Observations Rennae Thiessen 1 Jean M. Seely 1 Frederick R. K. Matzinger 1 Prachi garwal 1,2 Karen L. urns 3 Carole J. Dennie 1 Rebecca Peterson 1 Thiessen R, Seely JM, Matzinger FRK, et al. Keywords: CT-guided biopsy, lung biopsy, necrotizing granuloma, pulmonary nodule, solitary pulmonary nodule DOI: /JR Received pril 9, 2007; accepted after revision June 24, Department of Diagnostic Imaging, The Ottawa Hospital, 1053 Carling ve., Ottawa, ON K1Y 4E9, Canada. ddress correspondence to J. M. Seely (jeseely@ottawahospital.on.ca). 2 Present address: Department of Radiology, University of Michigan Medical Center, nn rbor, MI. 3 Department of Pathology, The Ottawa Hospital, Ottawa, ON, Canada. JR 2007; 189: X/07/ merican Roentgen Ray Society Necrotizing Granuloma of the Lung: Imaging Characteristics and Imaging-Guided Diagnosis OJECTIVE. The purpose of this study was to assess CT findings and the sensitivities of imaging-guided fine-needle aspiration (FN) biopsy and core needle biopsy in the diagnosis of necrotizing granuloma of the lung. CONCLUSIONS. The CT characteristics of necrotizing granuloma are indistinguishable from those of malignant tumors; tissue diagnosis therefore is necessary. Core needle biopsy is a sensitive method for diagnosing necrotizing granuloma of the lung, but FN biopsy is insufficient for diagnosis. ssessment of a solitary pulmonary nodule is a common challenge for chest radiologists. Despite the existence of advanced imaging techniques, it may still be impossible to differentiate benign from malignant focal lung lesions. This problem is magnified by the increasing number of incidental or screeningdetected lung nodules and the medicolegal implications of missing a case of lung cancer [1]. t many North merican medical centers, suspicious pulmonary nodules are resected at thoracotomy without preoperative diagnosis. t others, preoperative FDG PET/CT confirmation of a metabolically active lung lesion leads to lung resection for diagnosis [2]. In areas where granulomatous lung infections are endemic, however, falsepositive PET results, in which PET shows markedly increased uptake of FDG suggesting cancer but the pathologic finding is benign, can lead to unnecessary thoracotomy [3]. Transthoracic needle biopsy (TTN) has been proved accurate in the evaluation of focal lung lesions. lthough it has been highly sensitive (70 100%) in the diagnosis of intrathoracic malignant tumors in many studies [4, 5], fine-needle aspiration (FN) biopsy (22- to 25-gauge needle) has recognized limitations in obtaining a specific benign diagnosis [6]. Therefore, when a benign entity is suspected, core needle biopsy is the optimal TTN technique for achieving a specific diagnosis [4]. In the Saint Lawrence River valley, as in several other similar North merican valley regions, there is a high prevalence of endemic fungi, predominantly those that cause histoplasmosis and blastomycosis. Infection can result in focal lung lesions that mimic lung cancer [7]. To minimize the rate of lung resection for benign disease, all patients with solitary indeterminate lung lesions undergo preoperative assessment with needle biopsy. Our practice has encountered a considerable number of necrotizing granulomas diagnosed at imaging-guided TTN of lung lesions. To our knowledge, the imaging features of these lesions have not been previously described. We undertook this study to determine the clinical and imaging features of histopathologically proven necrotizing granuloma. Our second objective was to determine the optimal method of obtaining the diagnosis of necrotizing granuloma by comparing the sensitivities of FN biopsy and core needle biopsy. Materials and Methods We performed a retrospective review of the pathology database of our institution to find patients who received the diagnosis of necrotizing granuloma in the period Hospital and referring physicians records were reviewed for prebiopsy clinical features, investigations performed, biopsy technique, and clinical and imaging follow-up. Clinical characteristics evaluated included age, sex, smoking status, history of malignant disease, and intervals of follow-up. Results of bronchoscopy, lung resection, and microbiologic stains and cultures were recorded. Imaging characteristics were evaluated in the cases of patients with pathologically proven necrotizing granuloma and chest CT scans available for review. Images were independently assessed by two inde- JR:189, December

2 Fig year-old woman with necrotizing granuloma proven with imaging-guided core needle biopsy., xial CT scan shows spiculated 2.7-cm lesion in right upper lobe surrounded by emphysema., xial CT scan at same level as obtained at mediastinal setting shows homogeneous soft-tissue attenuation of lesion. C D Fig year-old woman with necrotizing granuloma of lung proven with core needle biopsy., xial CT scan shows lobulated 3.4-cm mass in left lower lobe with surrounding ground-glass attenuation., xial CT at same level as obtained in mediastinal window setting shows mass of homogeneous soft-tissue attenuation contiguous to left hilar adenopathy. C, Photomicrograph of core needle biopsy specimen shows necrosis (arrows). (H and E, 1) D, Photomicrograph of histologic section of specimen at higher magnification shows interface of necrosis (arrows) with rim of histiocytes and scattered lymphocytes (arrowheads) in characteristic appearance of necrotizing granuloma. (H and E, 4) pendent observers. Discrepancy between observers was resolved by consensus of two experienced thoracic radiologists. Imaging features recorded included lesion size, location, margins, and distance from the pleura and the presence of calcification or cavitation, associated pleural thickening, emphysema, or lymphadenopathy. ll patients with a primary diagnosis of necrotizing granuloma were included in the determination of the sensitivity of imaging-guided biopsy. FN was performed with a 22- or 25-gauge needle. One to three aspirates were obtained, with a median of two. If the first two aspirates are acellular or nondiagnostic, it is unlikely that subsequent samples would be helpful, and cytologic architecture is often required. Therefore, we typically proceeded with core needle biopsy. Core needle biopsy was performed with a 20-gauge needle by a coaxial technique through a 19-gauge introducer needle with an automated biopsy gun (Mannan, Medical Device Technologies). range of two to 10 and a median of seven cores were obtained to maximize the diagnostic yield. cytotechnologist was present for all lung biopsies performed after July FN biopsy and core needle biopsy were performed by the same thoracic radiologists, all with more than 10 years of experience in thoracic radiology. Results total of 76 patients had a pathologic diagnosis of necrotizing granuloma. Twenty-five of these patients were excluded because another diagnosis was later confirmed, including nine additional malignant pulmonary tumors, five sarcoid tumors, and one healed granuloma. In the patients with malignant disease, the diagnosis of necrotizing granuloma was an incidental finding; that is, there were no false-positive results in the study group. Three patients were excluded because no discrete nodule was apparent, and seven were excluded because of discordance between the patient s name and the hospital medical record number. mong the 51 remaining patients, 43 (28 women, 15 men) had chest CT scans available for review. The mean patient age was 59 years (median, 61 years; range, years). Most of the patients had a smoking history (29 smokers vs 12 nonsmokers), and eight had a history of malignant disease. Imaging Features ll 43 of the patients with available chest CT scans underwent TTN. The CT scans were obtained in 2.5- and 5-mm-thick slices, some with and others without contrast enhancement, which was not recorded in our study. Dynamic contrast enhancement of the 1398 JR:189, December 2007

3 Necrotizing Granuloma of the Lung Fig year-old woman with necrotizing granuloma proven with core needle biopsy., xial CT scan shows solitary smoothly marginated 2-cm cavitary lesion in right lower lobe., xial CT scan at same level as in mediastinal window setting shows cavity has variable wall thickness. There is no associated calcification. Fig year-old man with necrotizing granuloma diagnosed with core needle biopsy., xial CT scan shows lobulated 2.4-cm lesion with adjacent cylindric bronchiectasis and emphysema in right lower lobe., xial CT scan at same level as obtained in mediastinal window setting shows multiple eccentric unusual calcifications in lesion, none of which is characteristically benign. lesions was not determined. The size of lesions ranged from 0.5 to 7.0 cm in diameter. Five lesions measured 1 cm or less; 25, cm; and 13, 2.0 cm or more. Margins were spiculated in 19 (Fig. 1), lobulated in eight (Fig. 2), and smooth in 16 cases. Sixteen patients had additional lesions in the same lobe and 22 patients, in other lobes. Eight lesions were cavitated (Fig. 3), and none had benign calcification (Fig. 4). Mediastinal lymphadenopathy TLE 1: CT Features No. (%) of Feature Patients Lesion margins Smooth 16 (37) Lobulated 8 (19) Spiculated 19 (44) dditional lesion Same lobe 16 (37) Different lobe 22 (51) Distance from the pleura (cm) buts pleura 25 (58) (12) (14) (16) Calcification (eccentric) 1 (2) Cavitation 8 (19) Size (cm) (12) (58) (30) Pleural effusion 0 Pleural thickening 7 (16) Hilar lymphadenopathy 5 (12) Mediastinal lymphadenopathy 7 (16) Emphysema 13 (30) Total 43 was present in seven patients and hilar lymphadenopathy (Fig. 2), in five patients. Most lesions were peripheral, 84% abutting or within 1 cm of the pleura (Table 1). Diagnosis Diagnosis was achieved with bronchoscopy in one patient, FN biopsy in one patient, core needle biopsy in 40 patients, and surgery in nine patients among the total of 51 patients with a pathologic diagnosis of necrotizing granuloma. FN biopsy was performed on 46 (90%) of 51 patients, leading to a definitive diagnosis of necrotizing granuloma in only one case (sensitivity, 2%). Core needle biopsy was performed on 43 (84%) of 51 patients and was diagnostic in 40 of 44 patients (sensitivity, 91%). One patient had inconclusive results of an initial core needle biopsy, but a second core needle biopsy was diagnostic. There were three false-negative results of core needle biopsy, and all diagnoses later were made with open lung biopsy. Most of the patients underwent multiple procedures. JR:189, December

4 Forty-three patients underwent both core needle biopsy and FN; three patients underwent FN, core needle biopsy, and open lung biopsy; and three patients underwent FN and open lung biopsy. Six patients needed only one procedure for diagnosis. Three patients underwent only open lung biopsy, one patient only FN, one patient only core needle biopsy, and one patient only endobronchial biopsy. No patient had an initial pathologic diagnosis of necrotizing granuloma that was later found to be a malignant tumor. Pathologic Features The pathologic features of necrotizing granuloma include aggregates of macrophages transformed into epithelium-like cells surrounded by a collar of mononuclear leukocytes, principally lymphocytes and occasional plasma cells, and a surrounding area of necrosis [8]. In the case in which the diagnosis was made with FN biopsy, the material submitted contained necrotic debris, epithelioid cells (macrophages), mixed inflammatory cells, and fibrosis. Similar abundant material in the cell block allowed the pathologist to make a confident diagnosis of necrotizing granuloma. In two patients who needed surgical resection for diagnosis, the core needle biopsy pathology report read necrotic material, fibrosis, and chronic inflammation but did not indicate a specific diagnosis of necrotizing granuloma. The other false-negative core needle biopsy result was diagnosed as organizing pneumonia. Fungal and acid-fast stains or cultures were performed for 39 (76%) of the patients, but stains were positive in only 11 (28%) of the 39 cases. No material sent for culture grew any organisms. Discussion Necrotizing granuloma of the lung is a benign entity. Ulbright and Katzenstein [9] looked at the clinical and pathologic features of solitary pulmonary granuloma in an effort to determine the cause and to provide guidelines for histologic diagnosis. They found that surgically resected pulmonary nodules contain fungal or acid-fast organisms in 70% of cases. However, Histoplasma organisms are difficult to identify, particularly in poorly stained preparations in which organisms are often initially overlooked, even when the preparations are from surgical specimens, which would presumably have less sampling error than the smaller sample obtained with core needle biopsy. In our study, only 11 (28%) of the fungal and acid-fast stains had positive results. lthough most necrotizing granulomas have an infectious cause, it is necessary to exclude noninfectious causes, such as Wegener s granulomatosis, necrotizing sarcoidosis, idiopathic bronchocentric granulomatosis, hyalinizing granuloma, and rheumatoid arthritis, which have overlapping histologic features [8]. Clinical and imaging correlation is required in each case. In our study, we excluded five patients with sarcoid and one with a healed granuloma. The literature on the imaging findings of necrotizing granulomas is limited. recent report [10] described an enhancing rim of benign solitary pulmonary nodules caused by Coccidioides immitis in an area in which this organism is endemic. The margins of these lesions were described as irregular or spiculated, as in our study, although we did not see an enhancing rim in patients to whom contrast material was administered (Fig. 2). We saw spiculated and lobulated margins in most (63%) of the cases and found that these benign lesions were indistinguishable from other malignant nodules. lthough 37% of the lesions were smoothly marginated, suggesting benignity, all lesions were suspected of being lung cancer, prompting biopsy. The lesions varied in size from 5 mm to 2 cm or greater, most (58%) measuring 1 2 cm, and 30% being 2.0 cm or larger. Only five (12%) of 43 patients had lesions measuring 5 10 mm, which likely explains the high accuracy of core needle biopsy [11]. Some authors [12] assert that 18 F-FDG PET is sufficient for differentiating benign from malignant solitary pulmonary nodules, a positive result determining the need for lung resection. lthough FDG PET can be helpful when a lung lesion is not metabolically active, falsepositive results are a problem in regions with a high prevalence of granulomatous infection because they increase the rate of unnecessary thoracotomy for benign disease [3]. The diagnostic accuracy of needle biopsy in the diagnosis of necrotizing granuloma has not been previously reported, to our knowledge. In our study, the sensitivity of FN biopsy in the diagnosis of necrotizing granuloma was 2%, and the sensitivity of core needle biopsy was 91%. These findings correlate with those of previous studies in which FN biopsy was found to have low sensitivity ( 50%) in the diagnosis of benign lung nodules [6]. The low sensitivity may be due to the nonspecific cytopathologic appearance of benign disease coupled with a small amount of histopathologic material [4]. Klein et al. [4] found similar results in a retrospective review of specific benign lesions diagnosed with core needle biopsy. The sensitivity of FN biopsy compared with core needle biopsy of benign lesions in that series was 44% versus 100% (p <0.05) [4]. In our series, FN biopsy was diagnostic of necrotizing granuloma in only one patient and had even lower sensitivity than for other benign lung lesions. This finding contrasted to those for core needle biopsy, which had a sensitivity of 91%. Only three patients who underwent core needle biopsy needed open lung biopsy for diagnosis. These findings support the essential role of core needle biopsy in confirming the diagnosis of necrotizing granuloma and the inadequacy of FN biopsy in making this diagnosis. The presence of a cytotechnologist at biopsy is helpful in converting FN to core needle biopsy if the initial aspirates appear acellular or insufficient. ronchoscopy is recognized as being less useful than TTN in the accurate diagnosis of solitary pulmonary lesions. The reported yield is as low as 28 31% for lesions smaller than 2 cm [9] and increases with lesions larger than 2 cm or in a central location [13]. Our review supports these findings. The findings at bronchoscopy were positive in only one of 18 patients. In our study, most lesions were 2 cm or smaller and in the periphery of the lung and thus were difficult to diagnose at bronchoscopy. It has been suggested [5, 9] that open lung biopsy is the best initial procedure for a solitary lung lesion in a surgical candidate with a high clinical probability of malignant disease. Most lung lesions for which patients are referred for TTN prove malignant, with an incidence of 80 85% [5]. t our institution, thoracic surgeons are reluctant to operate on a patient with a focal lung lesion without preoperative tissue diagnosis. Therefore, our experience may not be representative of centers with a different clinical approach. ecause it is highly sensitive for malignant pulmonary tumors, FN biopsy is often sufficient for diagnosis, especially when a cytopathologist is available to perform immediate review. ccording to the findings in our series of cases, if the FN biopsy finding is negative for malignancy, core needle biopsy often results in a specific benign diagnosis and precludes unnecessary thoracotomy. In our study, the imaging characteristics of pulmonary necrotizing granuloma on CT were indistinguishable from those of lung cancer. FN was insufficient for diagnosis, but core needle biopsy was highly sensitive (91%) in the diagnosis of necrotizing granuloma and obviated invasive lung resection JR:189, December 2007

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