Advances in Anatomic Pathology:
Analysis of the Bethesda System for Reporting Thyroid Cytopathology and Similar Precursor Thyroid Cytopathology Reporting Schemes
Wong, Lawrence Q. BS, CT(ASCP), IAC*,†; Baloch, Zubair W. MD, PhD*
*Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA
†School of Health Related Professions, University of Medicine and Dentistry of New Jersey, Newark, NJ
The authors have no funding or conflicts of interest to disclose.
Reprints: Zubair W. Baloch, MD, PhD, Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104 (e-mail: firstname.lastname@example.org).
The Bethesda System for Reporting Thyroid Cytopathology is a standardized reporting system for classifying thyroid fine-needle aspiration results comprising of 6 diagnostic categories with unique risks of malignancy and recommendations for clinical management. The majority of thyroid nodules are benign; however, up to 30% of fine-needle aspiration of thyroid nodule results are equivocal. Until 2007, various diagnostic terms were used to classify such cases, including “atypical,” “indeterminate,” and rule-out or cannot exclude malignancy. A literature review of 13 original studies was conducted to evaluate whether utilization of the Bethesda System for Reporting Thyroid Cytopathology nomenclature represent an improvement over thyroid cytopathology reporting schemes used before 2007 in diagnosing thyroid malignancy. The sensitivity and specificity of thyroid fine-needle aspiration was high in the studies that assessed the measures. However, a selection bias exists and most studies do not include indeterminate diagnosis in their calculations. Although the Bethesda System for Reporting Thyroid Cytopathology recommends a repeat fine-needle aspiration to follow-up nondiagnostic specimens, in the majority of studies, an appreciable number of cases underwent follow-up surgical biopsy or thyroidectomy. The diagnostic category of atypia/follicular lesion of undetermined significance remains heterogenous in terms of usage and clinical outcome. The majority of the studies that utilize the Bethesda System for Reporting Thyroid Cytopathology in this literature review retrospectively reclassified thyroid fine-needle aspiration into the Bethesda System for Reporting Thyroid Cytopathology nomenclature with reported malignancy rates that are similar between cases reclassified as atypia/follicular lesion of undetermined significance and follicular neoplasm/suspicious for follicular neoplasm.
Thyroid nodules are common1; it is estimated that up to 67% of people may have one or more thyroid nodules that are otherwise asymptomatic and nonpalpable.2 These are likely to be prevalent among people with iodine deficiency, the elderly, women, and those with a history of neck irradiation.3 The majority of thyroid nodules do not cause any noticeable symptoms but may begin to compress regional structures in the throat and neck as they enlarge. This may cause associated symptoms ranging from a goiter to vocal hoarseness to pain in the neck region, at which point the patient is usually referred to an endocrinologist or surgeon for further examination.4 A variety of benign and malignant lesions of thyroid present as nodules.5 According to the National Cancer Institute’s Surveillance Epidemiology and End Results, there will be 48,020 new diagnoses of thyroid cancer in the United States in 2011.6 Thyroid cancer is a relatively infrequent occurrence, accounting for <1% of all malignancies and 0.5% of deaths attributable to cancer.7 The age-adjusted incidence of thyroid cancer is 11.0 per 100,000 per year; among all races, the incidence rate for males is 5.6 per 100,000 compared with 16.3 per 100,000 for women. Although there are different types of thyroid cancers, the majority grow slowly and follow an indolent clinical course.8 This biological behavior of thyroid cancer allows sufficient lead time for proper evaluation of thyroid nodules for malignancy.
Fine-needle aspiration has proved to be the most cost effective and minimally invasive procedure to evaluate thyroid nodules for malignancy.5,9 On the basis of fine-needle aspiration cytology results, approximately 60% of the thyroid nodules are classified as benign, whereas <10% of the nodules are deemed malignant. The remaining 30% of the nodules cannot be classified as either benign or malignant and are diagnosed as indeterminate.10 Until 2007, various diagnostic terms were used to classify such cases, including “atypical,” “indeterminate,” and rule-out or cannot exclude malignancy. The lack of a uniform reporting system among laboratories often led to confusing risk assessments and unclear clinical management.11
In 2007, the National Cancer Institute hosted the Thyroid FNA State of the Science Conference to address these concerns.12 At the conclusion of the conference, the Bethesda System for Reporting Thyroid Cytopathology, a standardized system with clear categorical nomenclature including malignancy risks, was proposed.10 This system is comprised of 6 diagnostic categories with unique risks of malignancy and offers recommendations for clinical management (Table 1). In this literature review, we seek to answer whether utilization of the Bethesda System for Reporting Thyroid Cytopathology nomenclature represent an improvement over thyroid cytopathology reporting schemes used before 2007 in diagnosing thyroid malignancy.
MATERIALS AND METHODS
An electronic search of filtered databases from the Cochrane Library, TRIP Database, and the National Guideline Clearinghouse was conducted to yield relevant primary and secondary evidence-based literature studies. A total of 55 evidence-based papers were identified through the Cochrane Library. An electronic search for original research literature from unfiltered databases was also conducted. No relevant primary research studies were obtained through search of the TRIP Database or the National Guideline Clearinghouse. All literature available in the English language was reviewed and selected for inclusion in the literature review based on the following criteria: studies published utilizing a tiered thyroid fine-needle aspiration classification nomenclature containing at least 4 diagnostic categories with histology follow-up. The exclusion criteria included: limited or no surgical pathology follow-up, studies limited to a specific thyroid fine-needle aspiration diagnosis, and those that focus on ancillary techniques (molecular pathology and immunohistochemistry). After applying the inclusion and exclusion criteria, 13 studies were selected.
All articles selected for this review had used a tiered classification scheme comprising of at least 4 diagnostic categories (Table 2). Lew et al13 retrospectively reviewed a cohort of 797 thyroid fine-needle aspirations from January 2003 to October 2009. They utilized a 4 category reporting scheme that classifies thyroid fine-needle aspiration specimens as nondiagnostic, benign, indeterminate, and malignant. Indeterminate diagnosis were further subdivided as follicular neoplasm, Hurthle cell neoplasm, or suspicious for papillary thyroid cancer. The study Nayar and Ivanovic14 is a retrospective study of 5194 thyroid fine-needle aspirations from July 2000 to December 2006. These authors used the Papanicolaou Society of Cytopathology Task Force 6 category reporting scheme consisting of unsatisfactory, negative for malignancy, indeterminate for neoplasm, neoplasm, suspicious for malignancy, and positive for malignancy categories. The indeterminate for neoplasm category was further subdivided to classify cases according to cytomorphologic or adequacy-related criteria. Yang et al15 also used a similar thyroid fine-needle aspiration classification scheme in a retrospective study of 4703 thyroid fine-needle aspirations (January 1992 to May 2005) from 2 institutions. The study by Piana et al16 consists of 18,359 thyroid fine-needle aspirations (1998 to 2007). These cases were originally reported based on the Systematized Nomenclature of Medicine system but reclassified into a 5 category system of unsatisfactory/nondiagnostic, benign, indeterminate, suspicious, and malignant. Rorive et al17 reported their thyroid fine-needle aspiration specimens in 5283 patients (1986 to 2007) as unsatisfactory/nondiagnostic, benign, follicular proliferation, and malignant. The category of follicular proliferation was further subdivided into 3 grades: grade 1 includes diagnosis that cannot rule out follicular neoplasm, grade 2 favored a follicular neoplasm, and grade 3 was characterized as cannot rule out papillary carcinoma. Yassa et al18 retrospectively reviewed a cohort of 4595 thyroid fine-needle aspirations (1995 to 2004) and classified their specimens according to a modified Mayo Clinic reporting scheme: insufficient for diagnosis, no malignant cells, atypical cells of undetermined significance, suspicious for a follicular neoplasm, suspicious for papillary carcinoma, and positive for malignancy. The study by Crowe et al19 consists of a retrospective review of 1671 thyroid fine-needle aspirations from April 2006 to April 2009. These authors report the impact of implementing the Bethesda System for Reporting Thyroid Cytopathology and the subsequent effect on the risk of malignancy. Before implementing the Bethesda System for Reporting Thyroid Cytopathology, Crowe et al19 used a 6 category reporting scheme to classify thyroid fine-needle aspiration specimens as unsatisfactory, benign, reactive, atypical, suspicious, and positive for malignancy. Theoharis et al20 reviewed 3207 thyroid fine-needle aspiration specimens over a period of 1 year (2008) after implementing the Bethesda System for Reporting Thyroid Cytopathology. Wu et al21 retrospectively reviewed a cohort of 1382 thyroid fine-needle aspiration specimens (2006 to 2008) and evaluated the risk of neoplasm and malignancy using the Bethesda System for Reporting Thyroid Cytopathology nomenclature. In a similar study, Jo et al22 report the risk of malignancy in 3080 thyroid fine-needle aspirations (1992 to 2009) after reclassification of this cohort based on the Bethesda System for Reporting Thyroid Cytopathology. The study by Renshaw23 is a retrospective cohort study of 7089 thyroid nodule fine-needle aspirations over a span of 13 years (1996 to 2009) that reports the relative risk of malignancy for atypical diagnosis using a reporting system complementary to the Bethesda System for Reporting Thyroid Cytopathology. Bohacek et al24 retrospectively reviewed a cohort of 1000 thyroid fine-needle aspirations (2000 to 2010) using the Bethesda System for Reporting Thyroid Cytopathology criteria to evaluate the diagnostic accuracy of surgeon performed fine-needle aspirations with histology follow-up. The study by Kim et al25 is a prospective cohort study of 865 thyroid fine-needle aspirations (March 2007 to February 2009) which correlates the cytology results with surgical pathology follow-up and molecular studies using the Bethesda System for Reporting Thyroid Cytopathology nomenclature.
Thyroid Fine-Needle Aspiration as a Diagnostic Test
The predictive value of a test is often used to evaluate its clinical accuracy.26 This translates into the confidence of the clinicians using the test to manage their patients. Clinical sensitivity and specificity are the 2 most common predictive parameters used in the evaluation of diagnostic tests.27 The gold standard for thyroid fine-needle aspiration diagnosis is histologic follow-up.20 The clinical sensitivity of thyroid fine-needle aspiration would indicate the frequency of test results that were positive for patients with thyroid disease and clinical specificity would likewise indicate the frequency of test results that were negative for patients without thyroid disease.
Among the publications included in this review (Table 3), Yang et al15 reported a sensitivity of 94% and specificity of 98.5% for malignancy; and sensitivity of 89.3% and specificity of 74% for neoplasm. In this study there was an overall 15.3% discrepancy rate between cytology and histology diagnosis with adequacy-related issues as the most frequent contributor of false-negative results. Piana et al16 reported an overall sensitivity of 88.2% and specificity of 98.2%. Rorive et al17 reported a sensitivity of 91.5% and specificity of 99.1% for malignancy; and an overall sensitivity of 80.4% and specificity of 79.8% for both neoplasm (adenoma) and malignancy. Bohacek et al24 reported sensitivity and specificity rates of 84.4% and 98.2%, respectively, with a diagnosis of adenoma being considered as benign; without factoring in adenomas, the sensitivity was 84.4% and specificity was 98.7%. Kim et al25 reported a sensitivity of 100% and specificity of 36.4%. Theoharis et al20 calculated thyroid fine-needle aspiration as a screening test for neoplasm with a specificity of 68% and a diagnostic test for malignancy with a specificity of 93%. In both situations, the sensitivity was not calculated because of a selection bias that only selected a specific group of clinically high-risk patients for surgery.20
In the literature, the percentages for both sensitivity and specificity of thyroid fine-needle aspiration has fluctuated depending on how the measure is calculated.28 Most of the studies before the Bethesda System for Reporting Thyroid Cytopathology do not include indeterminate diagnoses while calculating sensitivity and specificity rates.15 This is because of the fact that indeterminate thyroid fine-needle aspiration diagnosis is not uniform between reporting labs and may include atypical cells, follicular and Hürthle cell neoplasm, and/or suspicious for malignancy, whereas other authors have considered an indeterminate diagnosis as a positive diagnosis because it leads to surgical resection.29 The study by Yang et al15 calculated sensitivity and specificity rates for malignancy and separately for neoplasm, suspicious, and malignant diagnoses.
In our opinion a significant limitation in the computation of sensitivity and specificity rates in the studies included in this review is the selection bias of patients referred for surgery.28 In the study by Piana et al,16 5.6% of patients with a benign fine-needle aspiration diagnosis underwent surgical excision as compared with 82.1% for suspicious and 81.5% for malignant fine-needle aspiration diagnosis. The false-negative rate in this study was 10.9%, which also includes incidental microcarcinomas (35 cases). This suggests that even in lieu of a benign fine-needle aspiration diagnosis, close clinical follow-up and surgery may be warranted because of strong clinical/radiologic suspicion.18 Rorive et al17 attributed that a patient selection bias may be responsible for the inflated false-negative rates and low sensitivity percentage in their study. Bohacek et al24 likewise reports selection bias in their cohort, with one-third of patients undergoing surgical excision with a benign diagnosis and a false-negative rate of 6.9%, higher than that reported by other studies. Interestingly, when this group of patients with high clinical suspicion was excluded from the calculations the false-negative rate decreased to 2.3%.
The false-negative rates, similar to the ones in our review of selected publications, for thyroid fine-needle aspiration have been reported by other studies. On the basis of these figures, the practice guidelines of the American Association of Clinical Endocrinologists and American Thyroid Association recommends the following to minimize false-negative thyroid fine-needle aspiration results: using ultrasound guidance to select suspicious nodule(s) within a multinodular gland, obtain an adequate and representative sample from a suspicious thyroid nodule, sample multiple sites/quadrants within the nodule, and sample solid foci within cystic nodules.5 These practice guidelines also recommend reviewing specimens with an experienced pathologist and follow-up benign fine-needle aspiration results clinically with repeat fine-needle aspiration if there is an increase in the size of the nodule.5,30
Nondiagnostic Fine-Needle Aspiration Specimens
Thyroid fine-needle aspiration specimens that are not adequate for cytologic interpretation are reported as nondiagnostic or unsatisfactory. Nondiagnostic specimens are a major limitation of thyroid fine-needle aspiration with most studies reporting rates between 10% and 20%.15,31,32 According to the Bethesda System for Reporting Thyroid Cytopathology, specimens with obscuring blood, smears that are excessively thick, air-dried smears, cyst-only fluids, and smears with an inadequate amount of follicular cells may be considered nondiagnostic.12 The recommendation for nondiagnostic specimens is for repeat fine-needle aspiration under ultrasound guidance. In the study by Lew et al,13 29 out of 37 patients with nondiagnostic results received at least 2 repeat fine-needle aspirations (Table 4). Piana et al16 reported about half of the patients with a nondiagnostic fine-needle aspiration received a repeat fine-needle aspiration, 70% of which resulted in an adequate specimen. Similarly, in the study by Yang et al15 45.6% of initial nondiagnostic patients received a repeat fine-needle aspiration with 83% resulting in an adequate specimen. Theoharis et al20 reported approximately 11% of initial nondiagnostic specimens received a repeat fine-needle aspiration with a majority resulting in an adequate specimen. The study by Jo et al22 reported 509 nondiagnostic specimens, with no other concomitant diagnosis, with 144 receiving follow-up fine-needle aspiration; however, 47.9% remained nondiagnostic after repeat fine-needle aspiration. The study by Bohacek et al24 showed 56 nondiagnostic cases with 26 receiving a repeat fine-needle aspiration and 5 remaining nondiagnostic. In the study by Yassa et al,18 282 of 476 nondiagnostic specimens received follow-up fine-needle aspiration with 26% remaining nondiagnostic.
In the majority of studies quoted above, though variable, an appreciable number of cases classified as nondiagnostic underwent follow-up surgical biopsy or thyroidectomy. In the study by Yang et al,15 14.9% of patients received surgical resection. In the study by Jo et al,22 94% (135 of 144) of repeat fine-needle aspirations underwent surgical excision, 135 of 509 overall. Nayar and Ivanovic14 had 70 of 274 nondiagnostic cases that were resected. In the study by Renshaw,23 14% of the 1671 nondiagnostic specimens had histology follow-up. Wu et al21 reported 278 nondiagnostic specimens with only 21 receiving histology follow-up. The Bethesda System for Reporting Thyroid Cytopathology implies a malignancy rate of 1% to 4% for nondiagnostic specimens.12 Rorive et al17 observed a malignancy rate of 4.2% for their nondiagnostic fine-needle aspiration specimen, however, Piana et al16 and Lew et al13 reported a higher rate of malignancy (24% each). Similar high rates of malignancy have been reported by Bohacek et al24 (26.3%) and Renshaw23 (20%) in their nondiagnostic fine-needle aspiration specimens. In the majority of the studies, papillary thyroid carcinoma was the most common malignant tumor found on surgical follow-up of nondiagnostic fine-needle aspiration specimens, aside for the study by Nayar and Ivanovic14 which reported follicular carcinoma as the most common malignant tumor (5 of 6 cases).
In the literature, various factors have been suggested to contribute to nondiagnostic thyroid fine-needle aspiration; a few of these include nodule composition (cystic vs. solid vs. fibrotic and calcified), mode and operator experience for specimen procurement.33 In the study by Piana et al16 the rate of nondiagnostic thyroid fine-needle aspiration specimens show a significant decrease from 17.4% during 1997 to 2002 to 9.1% in 2003 to 2007. These authors conclude that operator experience and familiarity with thyroid fine-needle aspiration is the most important factor that led to this appreciable decrease in the rate of nondiagnostic thyroid fine-needle aspiration specimens.16 On-site assessment by a cytologist has also been shown to significantly reduce nondiagnostic specimens.34,35 However, on the basis of the studies included in this review, on-site assessment does not significantly decrease the rate of nondiagnostic thyroid fine-needle aspiration. Some authors have suggested the use of thyroid core biopsies to combat nondiagnostic thyroid fine-needle aspiration specimens. Renshaw23 performed core needle biopsy on a limited number of thyroid fine-needle aspirations and confirmed that this procedure significantly reduced nondiagnostic rates, although atypia rates were not affected. We believe, though helpful, the evidence regarding the application of core biopsy technique in thyroid nodule diagnosis is limited and requires further assessment in a larger case cohort.
Indeterminate Fine-Needle Aspiration Diagnosis
In our review there is uniformity between the various pre-the Bethesda System for Reporting Thyroid Cytopathology reporting schemes in classifying unsatisfactory, benign, and malignant thyroid fine-needle aspiration specimens; however, there is a wide-variation in the number of cases classified as indeterminate on the basis of the criteria set by each laboratory (Table 5). Lew et al13 included cases diagnosed as follicular neoplasm, Hurthle cell neoplasm, and suspicious for papillary thyroid cancer in indeterminate category and recommended surgical resection. In the study by Nayar and Ivanovic14 the indeterminate category includes cases in which a suspicion for neoplasm is raised based on adequate specimens with overlapping morphologic features or less than adequate specimens due to a limited number of follicular cells or obscuring blood; repeat fine-needle aspiration is recommended for cases classified as indeterminate. Yang et al15 classified cellular fine-needle aspiration specimens containing follicular or oncocytic cells with scant or absent colloid cases as indeterminate. Piana et al16 includes cases of follicular neoplasm and atypia not otherwise specified in the indeterminate category. These patients were managed either by surgical resection or clinically based on high-surgical risk or refusal of surgery by the patient.16 The study by Rorive et al17 utilizes the umbrella term “follicular proliferation” as indeterminate which was further split into 3 grades; surgical resection was recommended for all patients with this diagnosis. Yassa et al18 classified thyroid fine-needle aspiration specimens containing cells with rare and/or mild abnormality as indeterminate and recommended clinical follow-up and repeat fine-needle aspiration. Similarly, repeat fine-needle aspiration was performed in cases classified as indeterminate in the study by Nayar and Ivanovic.14
In the Bethesda System for Reporting Thyroid Cytopathology, the indeterminate category was divided into 2, based on the risk of malignancy as reported in pre-the Bethesda System for Reporting Thyroid Cytopathology literature. These categories are termed as atypia/follicular lesion of undetermined significance and follicular neoplasm/suspicious for follicular neoplasm. It was suggested that the former can benefit from repeat fine-needle aspiration, whereas, the latter fine-needle aspiration diagnosis usually requires surgical excision (lobectomy in most cases) for definite diagnosis (ie, adenoma vs. carcinoma). The follow-up studies with this diagnosis has shown (as expected) that the diagnosis of atypia/follicular lesion of undetermined significance represents a heterogenous group of cases due to lack of strict morphologic criteria. The study by Jo et al22 showed that the rate of malignancy for atypia/follicular lesion of undetermined significance diagnosis is lower (17%) than for follicular neoplasm/suspicious for follicular neoplasm (25.4%) diagnosis on histologic follow-up. Interestingly, a majority of cases (53 of 101) diagnosed as atypia/follicular lesion of undetermined significance underwent surgical rather than the recommended repeat fine-needle aspiration.22 Renshaw23 found that a diagnosis of “atypical follicular cells” represents a heterogenous group of cases with appreciable different risks of malignancy. Interestingly, the cases subcategorized as atypia/follicular lesion of undetermined significance—not otherwise specified and atypia/follicular lesion of undetermined significance—rule out follicular neoplasm were seen to have a similar risk of malignancy to cases diagnosed as follicular neoplasm/suspicious for follicular neoplasm.23 These observations are in concordant with other studies that have also reported atypia/follicular lesion of undetermined significance diagnosis to have similar risk of malignancy rates as suspicious for follicular neoplasm and suspicious for Hurthle cell neoplasm.36,37 Interestingly, some authors have suggested reduction in the number of diagnostic categories or eliminating the category of atypia/follicular lesion of undetermined significance in the Bethesda System for Reporting Thyroid Cytopathology to improve the intraobserver and interobserver agreement without affecting the positive predictive value.33,36,38–41 However, other authors have suggested using classifiers to further stratify the cases diagnosed as either atypical or indeterminate.42–46
As noted by Renshaw,23 although these 2 particular atypia/follicular lesion of undetermined significance diagnoses may theoretically have similar risk of malignancy rates to suspicious for follicular neoplasm and suspicious for Hurthle cell neoplasm, their clinical management may be solely dependent on which the Bethesda System for Reporting Thyroid Cytopathology category they are placed into. The recommendation for atypia/follicular lesion of undetermined significance diagnosis is for repeat fine-needle aspiration follow-up whereas surgical excision is recommended for cases diagnosed as suspicious for follicular neoplasm and suspicious for Hurthle cell neoplasm.12
It has been suggested that one of the factors that may lead to the diagnosis of atypia/follicular lesion of undetermined significance is specimen artifacts incurred during specimen collection and processing.47 On the basis of our review, it is evident that to ensure uniformity in specimen collection and preparation technique between laboratories is close to impossible. It has been suggested that factors that may cause specimen artifacts, such as obscuring blood or issues with fixation, can be avoided with training and experience.47 The use of liquid-based preparations, in addition to conventional slides, can also increase diagnostic yield, decrease the amount of obscuring blood and inflammation, and provide a means for ancillary studies.48 Thus, with improved handling of thyroid specimens, obscuring artifacts may be minimized, allowing diagnostic benign or suspicious features to be accurately categorized and thereby decreasing the number of cases classified as atypia/follicular lesion of undetermined significance.
At present the Bethesda System for Reporting Thyroid Cytopathology provides standard reporting nomenclature and risk assessments allowing for the management of patients with thyroid nodules by clinicians. The diagnostic category of atypia/follicular lesion of undetermined significance remains heterogenous in terms of usage and clinical outcome.33,47 The majority of the studies that utilize the Bethesda System for Reporting Thyroid Cytopathology in this literature review retrospectively reclassified thyroid fine-needle aspiration into the Bethesda System for Reporting Thyroid Cytopathology nomenclature. According to these studies, the atypia/follicular lesion of undetermined significance diagnosis has limited validity, as the malignancy rates are similar between cases reclassified as atypia/follicular lesion of undetermined significance and follicular neoplasm/suspicious for follicular neoplasm. We believe, as laboratories continue to adjust and become accustomed to reporting thyroid fine-needle aspiration results with the Bethesda System for Reporting Thyroid Cytopathology nomenclature, prospective experiences will be able to determine whether the estimated malignancy risk of 5% to 15% and the recommended clinical management of repeat fine-needle aspiration for this diagnosis set by the Bethesda System for Reporting Thyroid Cytopathology needs further refinement.
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Cancer CytopathologyAre we ready to modify the Bethesda thyroid fine-needle aspiration classification scheme?Cancer Cytopathology
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