Imaging-Guided Biopsy of. Lesions: Do Lesion Location and Morphologic Features on CT Affect the Positive Predictive Value for Malignancy?

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1 Vascular and Interventional Radiology Original Research FDG-vid Extrapulmonary Lesions and Positive Predictive Value for Malignancy Vascular and Interventional Radiology Original Research My-Linh Nguyen 1,2 Debra. Gervais 2 Michael. lake 2 Peter R. Mueller 2 Dushyant V. Sahani 2 Peter F. Hahn 2 Raul N. Uppot 2 Nguyen ML, Gervais D, lake M, et al. Keywords: 18 F-fluorodeoxyglucose, imaging-guided biopsy, interventional radiology, nuclear medicine, PET/CT DOI: /JR Received pril 25, 2012; accepted after revision September 26, Harvard Medical School, Peabody Society, 260 Longwood ve, oston, M ddress correspondence to M. L. Nguyen (mylinhnguyen@post.harvard.edu). 2 Division of bdominal Imaging and Intervention, Massachusetts General Hospital, oston, M. JR 2013; 201: X/13/ merican Roentgen Ray Society Imaging-Guided iopsy of 18 F-FDG vid Extrapulmonary Lesions: Do Lesion Location and Morphologic Features on CT ffect the Positive Predictive Value for Malignancy? OJECTIVE. The purpose of our study was to analyze the effect of lesion location and morphologic appearance on CT on the positive predictive value (PPV) for malignancy of all extrapulmonary lesions that were 18 F-FDG avid on PET/CT and that were biopsied under imaging guidance. MTERILS ND METHODS. etween January 2004 and December 2010, 227 patients underwent imaging-guided biopsy of 231 PET-positive extrapulmonary lesions with diagnostic pathologic results. The PET PPV for malignancy was retrospectively calculated and stratified according to lesion location and morphologic appearance. RESULTS. The overall PET PPV for malignancy was 72%. Inflammatory processes accounted for the majority of benign biopsy results. Lesion location significantly affected the PPV (p < 0.001). one (96%) and liver (90%) lesions had significantly higher PPVs for malignancy compared with other locations, whereas lymph nodes (60%) had a significantly lower PPV for malignancy. Lesions that were morphologically suspicious and morphologically benign according to CT findings alone were associated with PPVs of 74% and 57%, respectively (p = 0.05). FDG-avid subcentimeter lymph nodes (n = 8) had a PPV for malignancy of 38%. CONCLUSION. Over half of PET-avid morphologically benign appearing lesions and one third of PET-avid subcentimeter lymph nodes were found to be malignant at biopsy, suggesting that benign morphologic appearance alone should not preclude further workup of a PET-positive lesion. iopsies of FDG-avid lesions in liver and bone yielded high rates of true malignancy, whereas biopsies of lymph nodes yielded a lower rate of malignancy compared with other lesion locations. I maging-guided biopsies allow minimally invasive tissue sampling for diagnosis. For many years, the impetus to biopsy a lesion was to determine whether lesions that were morphologically suspicious on imaging were indeed malignant. In the past 5 years, 18 F-FDG PET/ CT has made inroads in oncology as an imaging tool to identify lesions that are potentially malignant not only on the basis of abnormal morphologic appearance but also on the basis of increased metabolic function. However, because uptake of FDG is an imprecise marker for malignancy, false-positive PET results can be produced by a variety of benign conditions [1]. In determining the likelihood of malignancy of an FDG-avid lesion, it is often helpful to assess the lesion s location and morphologic appearance on CT. In patients with multiple FDG-avid lesions, stratifying lesions by likelihood of malignancy may help identify the highest yield targets for biopsy so as to mini- mize the rate of false-negative biopsies and the need for repeat procedures. lthough the positive predictive value (PPV) of PET for the diagnosis of pulmonary lesions has been well studied [2], its characterization in the diagnosis of extrapulmonary lesions is less complete. The vast majority of studies evaluating PET accuracy examined only a single disease or organ system, significantly limiting the generalizability of results [3 16]. dditionally, many studies lacked histopathologic data for all included patients and relied partly on clinical or imaging follow-up to serve as reference standards [4, 8 12, 14 16]. Very few studies have examined the effect of anatomic location on the PET PPV. Studies that have done so were not able to make statistical comparisons because of the sample size [17, 18]. The purpose of our study was to retrospectively determine the effect of lesion location and morphologic appearance on the PPV of JR:201, ugust

2 TLE 1: Positive Predictive Value (PPV) of 18 F-FDG PET Imaging ccording to Lesion Location Lesion Malignancy Status Lesion Location No. of Lesions Malignant enign PET PPV, % (95% CI) p onferroni p ll locations ( ) N N Lymph node ( ) Liver ( ) one ( ) drenal gland ( ) NS NS Intraabdominal or intrapelvic mass ( ) NS NS Extraabdominal mass ( ) NS NS Chest wall N N N Peritoneum N N N Mesentery N N N bdominal wall N N N Kidney N N N Perinephric space N N N Omentum N N N Pancreas N N N Spleen N N N Thyroid N N N Uterus N N N Note PPVs were calculated only for locations with more than five lesions. p values refer to difference in PPV for lesions within a location group compared with all lesions outside of the group. N = not applicable, NS = not significant. PET for all FDG-avid extrapulmonary lesions biopsied under imaging guidance. Materials and Methods Study Population This study was compliant with HIP and received institutional review board approval with waiver of informed consent. Our radiology procedure database was retrospectively searched for all PET-positive lesions biopsied under imaging guidance. Pulmonary lesions, defined as lesions located within the lungs, mediastinum, or hila, were excluded. Lesions were considered PET positive if they qualitatively showed abnormal FDG uptake in the last PET study preceding biopsy. ssessment of FDG uptake was performed by one of five nuclear medicine imagers with 9 20 years experience, in a consensus clinical readout of cases with an abdominal radiologist. etween January 2004 and December 2010, 248 PET-positive extrapulmonary lesions were biopsied under imaging guidance in 244 patients at our tertiary care institution. Seventeen of these lesions did not have diagnostic tissue pathologic results and were excluded. total of 231 lesions in 227 patients (102 men and 125 women; median age, 62 years; range, years) were therefore included in our study. Most patients had a history of malignancy (n = 186; 81.9%), with the most common diagnoses being lung cancer (n = 41), lymphoma (n = 37), colorectal cancer (n = 19), breast cancer (n = 19), and melanoma (n = 11). Lesions were most commonly located in lymph nodes (n = 72), the liver (n = 39), bone (n = 26), and the adrenal glands (n = 26) (Table 1). PET/CT Imaging ll PET/CT was performed on either a 16- or 64-MDCT hybrid PET/CT system (iograph 16 or 64, Siemens Healthcare) or a GE Healthcare Discovery 64-MDCT scanner. dose of 15 mci (555 Mq) of FDG was administered IV approximately 45 minutes to 1 hour before scanning. Initially, a low-dose CT was performed for attenuation correction. Subsequently, a diagnostic contrast material enhanced CT was performed after PET/CT using the following parameters: section thickness, 5 mm; table feed, 15 mm/s; pitch, 1.5; tube voltage, 120 kvp; and effective tube current time product, 200 ms. Images were reconstructed with 2-mm section thickness at 2-mm intervals. iopsy Procedure iopsies were performed under conscious sedation under CT or ultrasound guidance. In most cases, a coaxial needle (Temno, Cardinal Health) was inserted, and four fine-needle aspirates and three or four core samples were obtained. Lesions were biopsied an average of 20.8 days (median, 14.5 days; range, days) after PET. The modality of imaging guidance (CT, n = 191; ultrasound, n = 40) and type of tissue specimen obtained (fine-needle aspirate only, n = 18; core samples only, n = 49; or both specimen types, n = 164) were determined by the interventional radiologist performing the biopsy. Complications were reported according to Society of Interventional Radiology clinical practice guidelines [19], with 177 patients experiencing no complications and 50 patients experiencing minor complications requiring no therapy (small bleeds or hematomas, n = 49; small pneumothorax, n = 1). Pathologic Correlation Lesions were classified as malignant or benign according to tissue pathology reports. The classification took into account results of repeat biopsy procedures, which were performed on 14 lesions where the initial biopsy was nondiagnostic or suspected to be falsely negative. Morphologic Evaluation To determine whether lesions appeared suspicious for malignancy on the basis of morphologic characteristics alone, radiology dictation reports of CT studies performed before or at the time of biopsy were reviewed for the presence of the following: lymph nodes with a short-axis diameter of 1.0 cm or greater; new or enlarging sclerotic, lytic, 434 JR:201, ugust 2013

3 FDG-vid Extrapulmonary Lesions and Positive Predictive Value for Malignancy mixed, or ground-glass bone lesions; adrenal nodules with unenhanced attenuation greater than 10 HU; or new or enlarging masses not characterized as benign. Lesions identified in the dictation report as clearly falling into one of these categories (n = 166) were characterized as morphologically suspicious. Lesions described by the report as having no definitive CT abnormality to correlate with abnormal FDG uptake (n = 10) were classified as morphologically benign. For all other lesions (n = 55), CT images were reviewed with blinding to PET studies and tissue pathologic results by a radiologist with 8 years of experience in abdominal imaging to characterize each lesion as morphologically suspicious or morphologically benign using the previously described criteria. Overall, 201 lesions were classified as morphologically suspicious on the basis of CT, whereas 30 were classified as morphologically benign. Statistical nalysis The PPV of PET was calculated for each of the following groups: all lesions, lesions grouped by location (excluding locations with five or fewer lesions), lesions grouped by morphologic classification, lymph nodes grouped by size, lymph nodes grouped by morphologic classification, and lesions grouped by patient malignancy history. The PPV was defined as the proportion of malignant lesions in each group. PPV 95% CIs were calculated using the Wilson method. The chi-square test (or Fisher exact test for smaller sample sizes) was used to compare rates of malignancy between groups. For each location group with more than five lesions, the rate of malignancy within the group was also compared with the rate for all lesions outside of the group via a chi-square test with onferroni correction. Location groups with five or fewer lesions were excluded from this calculation because of the low likelihood that even true differences among them could be identified with statistical significance. Statistical calculations were performed using software (SS version 9.2, SS Institute). Differences were considered significant for p values less than Results Of 231 PET-positive lesions biopsied under imaging guidance, 166 lesions were found to be malignant, and 65 lesions were found to be benign. The overall PPV of PET for malignancy was therefore 71.9% (95% CI, %). The PPV varied significantly with lesion location (p < 0.001), as summarized in Table 1. Lesions located within bone (PPV, 96.2%; onferroni p = 0.021) or liver (89.7%; onferroni p = 0.039) had significantly higher PPVs compared with lesions in other locations. In contrast, lesions in lymph nodes (59.7%; onferroni p = 0.035) had a significantly lower PPV compared with lesions elsewhere. Lesion morphologic appearance also had a significant effect on PPV. Lesions that appeared morphologically suspicious on CT had a significantly higher PPV (74.1%; 149 malignant of 201 lesions) compared with lesions that appeared morphologically benign (56.7%; 17 malignant of 30 lesions; p = 0.047). mong the 17 morphologically benign lesions that were found to be malignant at biopsy (Table 2), the most common lesion location was bone, followed by the adrenal glands (Figs. 1 and 2). mong 72 lymph nodes biopsied, 64 (89%) measured at least 1.0 cm in short-axis diameter and were automatically classified as morphologically suspicious because of their size. Of the remaining eight subcentimeter nodes, five appeared morphologically benign on CT, whereas three appeared morphologically suspicious because of factors other than size, such as multiplicity of nodes or hyperenhancement. Table 3 summarizes the morphologic classification and biopsy outcome of each of the eight subcentimeter nodes. Three of the eight subcentimeter nodes were found to be malignant at biopsy, yielding a PPV of 37.5%. This PPV was less than that of lymph nodes measuring at least 1.0 cm in short-axis diameter (62.5%; 40 malignant of 64 nodes), but the difference was not statistically significant (p = 0.16). Of the five lymph nodes classified as morphologi- TLE 2: Malignant 18 F-FDG vid Lesions With enign CT Morphologic ppearance Patient No. Lesion Location CT Morphologic ppearance Pathologic Diagnosis 1 one Normal a Metastatic squamous cell carcinoma (cervical primary) 2 one Normal a Metastatic small cell carcinoma (lung primary) 3 one Normal a Metastatic adenocarcinoma (lung primary) 4 one Normal a Follicular lymphoma 5 one Normal a Diffuse large cell lymphoma 6 one Normal a Diffuse large cell lymphoma 7 one Normal b Diffuse large cell lymphoma 8 one Normal b Metastatic gastrointestinal stromal sarcoma 9 one Subtle sclerosis a Metastatic small cell carcinoma (lung primary) 10 drenal gland Normal (Fig. 1) Intravascular large cell lymphoma 11 drenal gland Thickened gland (Fig. 2) Metastatic adenocarcinoma (lung primary) 12 drenal gland Thickened gland Metastatic adenocarcinoma (lung primary) 13 Lymph node cm internal mammary node (Fig. 3) Metastatic adenocarcinoma (lung primary) 14 Lymph node cm supraclavicular node (Fig. 4) c Recurrent papillary thyroid carcinoma 15 Skeletal muscle Soft-tissue nodule in iliopsoas muscle or tendon Tenosynovial giant cell tumor 16 Skeletal muscle Soft-tissue nodule in paraspinal musculature Metastatic squamous cell carcinoma (lung primary) 17 Spleen 0.8-cm hypodensity Metastatic papillary thyroid carcinoma a Lesion showed abnormal signal intensity on MRI. b MRI not obtained. c Showed microcalcifications on ultrasound. 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4 Fig year-old man with intravascular lymphoma and intensely 18 F-FDG avid but morphologically normal adrenal glands. iopsy of left adrenal gland revealed intravascular large cell lymphoma., Contrast-enhanced CT shows morphologically normal adrenal glands (arrows)., PET shows intense FDG uptake within both adrenal glands (arrows). Fig year-old man with non small cell lung cancer and thickened lateral limb of right adrenal gland, which was PET positive. iopsy revealed metastatic lung adenocarcinoma., Contrast-enhanced CT shows mild thickening of lateral limb of right adrenal gland (arrow)., PET shows 18 F-FDG uptake within right adrenal gland (arrow). cally benign, two were found to be malignant (Figs. 3 and 4), yielding a PPV of 40.0%. This PPV was not significantly different from that of morphologically suspicious nodes (61.2%; 41 malignant of 67 nodes; p = 0.35). The PPV for patients with a history of cancer (73.7%; 140/190 lesions) was not significantly different from that for patients without a history of cancer (63.4%; 26/41 lesions; p = 0.19). Overall, 65 of the 231 (28.1%) PET-positive lesions biopsied were found to be benign. Table 4 shows the pathologic breakdown of these false-positive lesions. Inflammatory processes, including fibrosis, necrosis, and reactive lymphoid hyperplasia, were responsible for the majority of false-positive findings. Discussion Our study shows the significant effect of lesion location on the PET PPV. Lesions located in liver or bone had significantly higher PPVs (90% and 96%, respectively) compared with lesions elsewhere, whereas lesions located in lymph nodes had a significantly lower PPV (60%). lthough previous studies have attempted to stratify PET PPV by anatomic location [17, 18], to our knowledge, this is the first study of sufficient size to permit statistically significant comparisons between location groups. In patients with multiple FDG-avid lesions, such comparisons may aid in biopsy planning by helping identify the lesions most likely to be malignant. Our observed PPV for hepatic lesions is consistent with previously reported values of 90% by Sahani et al. [20], 96% by öhm et al. [21], 97% by Ramos et al. [22], and 100% by Servois et al. [23]. lthough previous studies have reported conflicting PPVs for bone lesions [16, 24, 25], our results corroborate those of Pezeshk et al. [25], who evaluated a patient population closely resembling our own. In that study, a PPV of 90% was observed for 39 FDG-avid bone lesions biopsied under CT guidance. number of studies have examined the PPV of FDG-avid lymph nodes; however, because each study focused on a specific region of nodes or a specific primary malignancy, reported PPVs have varied widely, ranging from 43% for local lymph nodes in patients with biliary cancer [26] to 100% for paraaortic lymph nodes in patients with intraabdominal malignancies [27]. PET-positive lesions that appeared morphologically benign on CT were significantly less likely to be malignant than lesions that appeared morphologically suspicious (PPVs of 57% and 74%, respectively). Nevertheless, more than half of benign-appearing FDG-avid lesions were found to be malignant at biopsy, suggesting that benign morphologic appearance alone should not preclude the further workup of a PET-positive lesion. Malignant lesions that appeared benign were most often bone lesions with a normal or subtly sclerotic appearance on CT. However, these bone lesions all had abnormal MRI examinations, when performed. Subcentimeter lymph nodes were less likely to be malignant compared with nodes measur- 436 JR:201, ugust 2013

5 FDG-vid Extrapulmonary Lesions and Positive Predictive Value for Malignancy TLE 3: iopsy Results of 18 F-FDG vid Subcentimeter Lymph Nodes Patient No. Node Location Size (cm) CT Morphologic Classification Pathologic Classification Pathologic Diagnosis 1 External iliac enign enign Normal 2 xillary enign enign Normal 3 Parotid enign enign Warthin tumor 4 Internal mammary enign (Fig. 3) Malignant Lung adenocarcinoma 5 Supraclavicular enign (Fig. 4) a Malignant Papillary thyroid carcinoma 6 Parotid Suspicious because of hyperenhancement enign Normal 7 Cervical Suspicious because of multiplicity of nodes enign Reactive hyperplasia 8 Cervical Suspicious because of multiplicity of nodes Malignant reast adenocarcinoma a ppeared suspicious on ultrasound because of presence of microcalcifications. ing at least 1 cm in short-axis diameter (PPVs of 38% and 63%, respectively). Despite this disparity, more than one third of subcentimeter lymph nodes were found to be malignant at biopsy. This finding corroborates prior reports showing the superior sensitivity of PET and PET/CT in detecting malignant subcentimeter lymph nodes compared with CT alone [28, 29]. We found that the PET PPV was not significantly affected by the presence or absence of a positive malignancy history. Prior studies by Knight et al. [30] and Lee et al. [31] in the pulmonary literature reported similar findings. Limitations Limitations of this study include its retrospective nature and its exclusion of lesions not biopsied under imaging guidance, including lesions followed by serial imaging or biopsied via non imaging-guided modalities, such as laparoscopy. Lesions were referred for imaging-guided biopsy at the discretion of clinical Fig year-old woman with non small cell lung cancer and PET-positive but morphologically benign subcentimeter internal mammary lymph node. iopsy revealed metastatic lung adenocarcinoma., Contrast-enhanced CT shows morphologically benign internal mammary lymph node (arrow) measuring cm., PET shows FDG uptake within left internal mammary lymph node (arrow). Fig year-old woman with papillary thyroid cancer who presented with small left supraclavicular node, which was PET positive. iopsy revealed papillary thyroid carcinoma., Contrast-enhanced chest CT shows small cm left supraclavicular node (arrow)., PET shows 18 F-FDG uptake within left supraclavicular space (arrow). providers, introducing potential selection bias. Clinically, at our institution, FDG uptake on PET/CT is only assessed qualitatively and not quantitatively. This standard of practice may affect the number of cases identified as having FDG uptake. Furthermore, although the inclusion of only patients with imaging-guided biopsied lesions provides a useful histopathologic reference standard proof, it also introduces potential verification bias. Conclusion PET-positive lesions in liver and bone are highly predictive of malignancy. Positive lesions in lymph nodes are relatively less predictive. enign morphologic appearance on CT should not alone preclude the further workup of a PET-positive lesion, because more than half of PET-avid benign-appearing lesions and one third of PET-avid subcentimeter JR:201, ugust

6 TLE 4: enign 18 F-FDG PET Positive Lesions (n = 65), by Category Dunphy FR, oyd JH. Correlation of fine needle aspiration biopsy and fluoride-18 fluorodeoxyglucose positron emission tomography in the as- tion of liver metastases from adenocarcinoma of the colon and pancreas: comparison of mangafodipir trisodium enhanced liver MRI and whole- Category No. (%) of Lesions sessment of locally recurrent and metastatic head and neck neoplasia. cta Cytol 1998; 42: body FDG PET. JR 2005; 185: öhm, Voth M, Geoghegan J, et al. Impact of Inflammatory process 37 (57) Normal tissue 13 (20) enign tumor 8 (12) Schwannoma 4 (6) Leiomyoma 1 (2) Neurofibroma 1 (2) Hibernoma 1 (2) Warthin tumor 1 (2) drenocortical adenoma 5 (8) Fibroadipose tissue 1 (2) Macrofollicular thyroid nodule 1 (2) lymph nodes are malignant at biopsy. 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