Effect of Temporal Artery Biopsy Length and Laterality on Diagnostic Yield

Background: Giant cell arteritis (GCA) is the most common vasculitis in adults and is associated with significant morbidity and mortality. Temporal artery biopsy (TAB) remains the gold standard for diagnosis in the United States; however, practices vary in the length of artery obtained and whether bilateral simultaneous biopsies are obtained. Methods: Retrospective chart review of all TABs performed at the Johns Hopkins Wilmer Eye Institute between July 1, 2007, and September 30, 2017. Results: Five hundred eighty-six patients underwent TAB to evaluate for GCA. Of 404 unilateral biopsies, 68 (16.8%) were positive. Of 182 patients with bilateral biopsies, 25 (13.7%) had biopsies that were positive and 5 patients (2.7%) had biopsies that were discordant, meaning only 1 side was positive. There was no significant difference in the average postfixation length of positive and negative TAB specimens (positive mean length 1.38 ± 0.61 cm, negative mean length 1.39 ± 0.62 cm, P = 0.9). Conclusions: There is no significant association between greater length of biopsy and a positive TAB result in our data. Although the rate of positive results was not higher in the bilateral group compared with the unilateral group, 2.7% of bilateral biopsies were discordant, similar to previously published rates. Overall, this suggests that initial bilateral biopsy may increase diagnostic yield, albeit by a small amount.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Effect of Temporal Artery Biopsy Length and Laterality on Diagnostic Yield Alice Shen, MD, Anna M. Gruener, BMBS, MSc, FRCOphth, Andrew R. Carey, MD, Amanda D. Henderson, MD, Ali Poostchi, MBChB, PhD, FRCOphth, Timothy J. McCulley, MD, Jessica R. Chang, MD Background: Giant cell arteritis (GCA) is the most common vasculitis in adults and is associated with significant morbidity and mortality. Temporal artery biopsy (TAB) remains the gold standard for diagnosis in the United States; however, practices vary in the length of artery obtained and whether bilateral simultaneous biopsies are obtained. Methods: Retrospective chart review of all TABs performed at the Johns Hopkins Wilmer Eye Institute between July 1, 2007, and September 30, 2017. Results: Five hundred eighty-six patients underwent TAB to evaluate for GCA. Of 404 unilateral biopsies, 68 (16.8%) were positive. Of 182 patients with bilateral biopsies, 25 (13.7%) had biopsies that were positive and 5 patients (2.7%) had biopsies that were discordant, meaning only 1 side was positive. There was no significant difference in the average postfixation length of positive and negative TAB specimens (positive mean length 1.38 ± 0.61 cm, negative mean length 1.39 ± 0.62 cm, P = 0.9). Conclusions: There is no significant association between greater length of biopsy and a positive TAB result in our data. Although the rate of positive results was not higher in the bilateral group compared with the unilateral group, 2.7% of bilateral biopsies were discordant, similar to previously published rates. Overall, this suggests that initial bilateral USC Roski Eye Institute (AS, JRC), Keck School of Medicine of the University of Southern California, Los Angeles, California; Wilmer Eye Institute (AMG, ARC, ADH, TJM, JRC), Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Ophthalmology (AMG, AP), Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom; School of Medicine (AMG), Division of Clinical Neuroscience, University of Nottingham, Nottingham, United Kingdom; and Moorfields Eye Hospital (AP), London, United Kingdom. Authors from the USC Roski Eye Institute were supported in part by an Unrestricted Departmental Grant from Research to Prevent Blindness. In the interest of full disclosure, J. R. Chang served on an advisory board for Horizon Therapeutics, which has no relation to the content of this article. The other authors report no conflicts of interest. Address correspondence to Jessica R. Chang, MD, Department of Ophthalmology, Keck School of Medicine at the University of Southern California, 1450 San Pablo Street, 4th Floor, Suite 4700, Los Angeles, CA 90033 E-mail: [e-mail] 208 biopsy may increase diagnostic yield, albeit by a small amount. Journal of Neuro-Ophthalmology 2022;42:208–211 doi: 10.1097/WNO.0000000000001535 © 2022 by North American Neuro-Ophthalmology Society G iant cell arteritis (GCA), or temporal arteritis, is a vasculitis of large-sized and medium-sized arteries and the most common vasculitis in adults (1,2). It is associated with significant morbidity and mortality and can result in irreversible vision loss in 1 or both eyes from arteritic anterior ischemic optic neuropathy (AAION) or retinal artery occlusion (2). If left untreated after initial vision loss affecting 1 eye, the contralateral eye is likely to be affected in 1 to 2 weeks (3). Accurate and prompt diagnosis is important in managing morbidity and limiting complications from unnecessary treatment with high-dose corticosteroids (4). The diagnosis of GCA is suspected based on age, symptoms, and elevation of serum inflammatory markers and is confirmed on temporal artery biopsy (TAB) (3,5). Histologic demonstration of granulomatous inflammation, typically with giant cells, located at the junction between the intima and media on TAB is the gold standard for diagnosis; however, GCA is known to produce segmental disease with noncontinuous patches of inflammation, or skip lesions, in up to 28% of patients (2,4,6). Owing to the uneven distribution of these changes, longer or bilateral specimens have been suggested to minimize falsenegative TAB rates, which have been reported to occur in 10%–20% of patients with GCA (6–8). Practices vary regarding the length of artery collected and whether or not bilateral simultaneous biopsies are obtained (2,4,9–11). We sought to determine whether longer length of biopsy or bilateral initial or sequential biopsy was associated with improved diagnostic yield in detecting changes from GCA. Shen et al: J Neuro-Ophthalmol 2022; 42: 208-211 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution METHODS Following Institutional Review Board approval, a retrospective chart review was conducted to assess the medical records and histopathology reports of all patients who underwent TAB at the Johns Hopkins Wilmer Eye Institute between July 1, 2007, and September 30, 2017. Patients were considered to have biopsy-proven GCA (BP-GCA) if histological examination of the temporal artery revealed arteritis, defined by mononuclear cell infiltration of the arterial wall with interruption of the internal elastic lamina. Patients with healed arteritis were also counted as positive biopsies. Indeterminate biopsies were counted as negative. The pathologist’s original diagnosis was relied on, and specimens were not re-examined for the purpose of this study. The biopsy length was measured after formalin fixation and noted on the gross specimen description in the pathology report. A 2-tailed t test was used to compare mean postfixation length of positive and negative TAB specimens. The rate of positive biopsies between biopsies greater than 2 cm in postfixation length vs less than 1 cm in postfixation length was compared using a x2 test. The rate of positive biopsies between unilateral vs bilateral biopsies was compared using a x2 test. P values , 0.05 were considered significant. The role of preoperative corticosteroid use was not assessed. RESULTS Patients (n = 586) who underwent TAB to evaluate for GCA were identified in the 10-year period studied. Of these patients, 423 (72%) were female, and the mean age at time of TAB was 70.5 ± 11.1 years; 93 (15.9%) TABs were positive, and 493 (84.1%) were negative. There were 404 unilateral TABs (84.1%) and 182 (31.1%) bilateral TABs; the choice of unilateral or bilateral was at the discretion of the surgeon’s and patient’s preference. There was no significant difference in the mean postfixation length of positive and negative TAB specimens (positive mean length 1.38 ± 0.61 cm and negative mean length 1.39 ± 0.62 cm, P = 0.9) (Table 1). The median postfixation length was 1.3 cm in both positive and negative samples. There were 226 patients with biopsies measuring 1 cm or less; of these, 26 (11.9%) were positive. There were 117 individual biopsies measuring at least 2 cm in length; of these, 16 (13.7%) were positive. If considering the total postfixation length of artery biopsied (combining right and left from bilateral biopsies), a total of 201 patients had at least 2 cm of artery biopsied and 27 (13.4%) had a positive TAB (Table 2). There was no significant difference in the rate of positive biopsies between the group with biopsies measuring 1 cm or less and the group with at least 2 cm of individual TAB length (P = 0.63). The shortest length of a positive TAB measured 0.4 cm (2 patients). Shen et al: J Neuro-Ophthalmol 2022; 42: 208-211 A total of 404 patients had unilateral biopsies; of these, 68 (16.8%) were positive. Of 182 patients who had bilateral biopsies, 25 patients (13.7%) were positive (Table 2). There was no significant difference in the rate of positive biopsies between the unilateral biopsy group and the bilateral biopsy group (P = 0.34). Five patients (2.7% of all bilateral TABs and 20% of all positive bilateral TABs) had discordant biopsies, meaning only 1 side was positive. Fifteen of the total bilateral biopsies were performed as sequential unilateral biopsies, and of these, only 1 was positive (6.7%). The rest of the discordant biopsies were simultaneous bilateral biopsies. In 3 of the discordant patients, their symptoms were localized to primarily 1 side. The positive TAB correlated with the symptomatic side in 2 of these patients but not the third: That patient had a right AAION and a negative right TAB but positive sequential left TAB. GCA is known to be more prevalent in northern European populations than Asian or Hispanic populations, although recent data have suggested that rates in African Americans may be higher than previously reported (12). Given that increasing age, female sex, and White race are considered risk factors that increase pretest probability, a subset of White women aged $70 years was analyzed to determine whether or not this higher risk subset had shorter TABs than the overall group. There were 151 patients in this subset, of which 39 had positive TABs (25.8%), and the mean individual TAB length was 1.38 ± 0.61 cm, which was not significantly different from the rest of the study population (1.39 ± 0.62, P = 0.82), although the proportion of positive TABs was significantly higher (25.8% vs 12.4%, P , 0.001). CONCLUSIONS The focal and discontinuous nature of inflammation in GCA limits the sensitivity of TAB (2). Increased length of TAB has been suggested to avoid false-negative biopsies; however, the minimum adequate length of TAB remains debated, and recommendations range from 0.5 to 2.8 cm (2,9,13). Some studies have found that positive TAB specimens are significantly longer (9,14,15), whereas several other studies have reported similar biopsy length between positive and negative TABs (2,16–18). Our data do not suggest that longer biopsies are more likely to be positive, and our mean length was greater than several recent studies (2,4,9). Consistent with these findings, Au et al (19) reported a stable rate of positive TAB results over a 14-year period, despite significantly increased mean postfixation length of TAB from 1.2 to 1.6 cm. The demonstrated lack of difference in the rate of positive TAB despite longer length of TAB suggests that shorter sample lengths may be sufficient. Our shortest length of positive TAB measured 0.4 cm. Recently, minimum postfixation biopsy length as short as 0.5 cm has been proposed to be sufficient by Mahr et al (17). Similarly, from a pathology 209 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution Table 1. Mean lengths of temporal artery biopsy (TAB) specimens TAB Specimen (Number of Specimens) Mean Length in cm (SD in cm) All TABs (n = 586) Positive TABs (n = 93) Negative TABs (n = 493) Unilateral TABs (n = 404) Positive (n = 68) Negative (n = 336) Bilateral TABs (n = 182) Both positive (n = 20) Both negative (n = 157) Discordant (n = 5) Bilateral TABs additive length 1.39 1.38 1.39 1.35 1.31 1.36 1.44 1.51 1.42 1.40 2.85 (±0.61) (±0.61) (±0.62) (±0.61) (±0.51) (±0.49) (±0.72) (±0.72) (±0.72) (±0.73) (±1.23) TAB, temporal artery biopsy. perspective, Poller et al (20) found that skip lesions should be apparent on specimens at least 0.6 cm long, suggesting this may be an adequate (postfixation) biopsy length to avoid false negatives because of skip lesions. Notably, arterial specimens can contract by up to 20% of their original length immediately on harvesting (prefixation) and then up to 15% after formalin fixation. Therefore, the intraoperative length should generally be at least 1.5 times the intended postfixation length to ensure an adequate specimen (2,9). Bilateral TABs have also been proposed to improve the sensitivity of TAB in GCA. Many surgeons will perform simultaneous or sequential biopsies of both temporal arteries, and studies have suggested that this does increase diagnostic sensitivity by up to 7% (10). Previous retrospective and prospective studies have evaluated discordance in bilateral TABs, with rates of discordance ranging from 2.7% to 9.2%. Boyev et al (10) performed a retrospective study in 1999 that showed 5 patients with BP-GCA and discordance of 182 simultaneous or sequential bilateral TABs (2.7%). Durling et al (4) prospectively studied bilateral simultaneous TABs and found 11 patients of 250 with discordance (4.4%). Hayreh et al (11) prospectively studied sequential TABs in patients with moderate-to-high clinical suspicion and found that 7 of 76 patients (9.2%) had discordant TABs. It seems reasonable that a sequential bilateral TAB performed only in the setting of high suspicion would have a higher rate of discordant biopsies—in our study, 1 of 15 sequential bilateral biopsies was discordant (6.7%), and 2.7% of all bilateral biopsies were discordant, similar to previously published rates (9,10,13). Overall, this suggests that bilateral biopsy may increase diagnostic yield, particularly in the right clinical setting, albeit by a small amount. Pless et al (13) reported that patients with unilateral signs and symptoms of GCA were significantly more likely to have discordant biopsies. The small number of discordant biopsies in our study precludes meaningful analysis, but it is important to note that one patient had a positive biopsy on the nonsymptomatic side. The level of clinical suspicion (pretest probability) remains a crucial factor. This study is limited by its retrospective design and sample size. Although this study population was large compared with other studies investigating TAB in GCA, the retrospective nature and sample size do not allow us to determine a cutoff minimum TAB length for better TAB yield. We found similar positivity rates for biopsies .2 cm in length compared with those ,1 cm in length. Combined with other studies of length and positivity (2,16–18), this study suggests that biopsies ,2 cm are sufficient. The risk and morbidity of bilateral vs unilateral biopsy was not assessed. Perioperative corticosteroid use was not captured in this study and could affect biopsy yield; however, this likely affects all groups similarly because it is a policy to biopsy within 2 weeks of steroid initiation, and therefore, it is unlikely this factor would change the studied outcomes. We conclude that the rate of positive biopsy was not significantly increased with increased length of TAB, suggesting shorter postfixation TAB length (,2 cm) may TABLE 2. Rates of positive temporal artery biopsy (TAB) TAB Specimen (Number of Specimens) Length #1 cm (n = 226) Length $ 2 cm (n = 117) Unilateral TABs (n = 404) Bilateral TABs (n = 182) Rate of Positive Biopsies P 11.9% 13.7% 16.8% 13.7% 0.63 0.34 TAB, temporal artery biopsy. 210 Shen et al: J Neuro-Ophthalmol 2022; 42: 208-211 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution be sufficient. Given the small percentage of discordant bilateral TABs, we also conclude that bilateral TABs may slightly increase diagnostic yield in GCA, particularly when there is high clinical suspicion. The possibility of false negatives persists no matter the length or laterality of biopsy specimens, and the decision to treat should not be entirely based on biopsy results. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: A. M. Gruener, A. R. Carey, A. D. Henderson, A. Poostchi, T. J. McCulley, and J. R. Chang; b. Acquisition of data: A. M. Gruener, A. R. Carey, A. D. Henderson, T. J. McCulley, and J. R. Chang; c. Analysis and interpretation of data: A. Shen and J. R. Chang. Category 2: a. Drafting the manuscript: A. Shen and J. R. Chang; b. Revising it for intellectual content: A. Shen, A. M. Gruener, A. R. Carey, A. D. Henderson, A. Poostchi, T. J. McCulley, and J. R. Chang. Category 3: a. Final approval of the completed manuscript: A. Shen, A. M. Gruener, A. R. Carey, A. D. Henderson, A. Poostchi, T. J. McCulley, and J. R. Chang. REFERENCES 1. Watts RA, Scott DG. Epidemiology of the vasculitides. Semin Respir Crit Care Med. 2004;25:455–464. 2. Papadakis M, Kaptanis S, Kokkori-Steinbrecher A, Floros N, Schuster F, Hübner G. Temporal artery biopsy in the diagnosis of giant cell arteritis: bigger is not always better. Am J Surg. 2018;215:647–650. 3. Salvarani C, Cantini F, Boiardi L, Hunder GG. Polymyalgia rheumatica and giant-cell arteritis. N Engl J Med. 2002;347:261–271. 4. Durling B, Toren A, Patel V, Gilberg S, Weis E, Jordan D. Incidence of discordant temporal artery biopsy in the diagnosis of giant cell arteritis. Can J Ophthalmol. 2014;49:157–161. 5. van der Geest KSM, Sandovici M, Brouwer E, Mackie SL. Diagnostic accuracy of symptoms, physical signs, and laboratory tests for giant cell arteritis: a systematic review and meta-analysis. JAMA Intern Med. 2020;180:1295–1304. Shen et al: J Neuro-Ophthalmol 2022; 42: 208-211 6. Klein RG, Campbell RJ, Hunder GG, Carney JA. Skip lesions in temporal arteritis. Mayo Clin Proc. 1976;51:504–510. 7. Lee AG, Brazis PW. Temporal arteritis: a clinical approach. J Am Geriatr Soc. 1999;47:1364–1370. 8. Breuer GS, Nesher G, Nesher R. Rate of discordant findings in bilateral temporal artery biopsy to diagnose giant cell arteritis. J Rheumatol. 2009;36:794–796. 9. Ypsilantis E, Courtney ED, Chopra N, Karthikesalingam A, Eltayab M, Katsoulas N, Tang TY, Ball RY. Importance of specimen length during temporal artery biopsy. Br J Surg. 2011;98:1556–1560. 10. Boyev LR, Miller NR, Green WR. Efficacy of unilateral versus bilateral temporal artery biopsies for the diagnosis of giant cell arteritis. Am J Ophthalmol. 1999;128:211–215. 11. Hayreh SS, Podhajsky PA, Raman R, Zimmerman B. Giant cell arteritis: validity and reliability of various diagnostic criteria. Am J Ophthalmol. 1997;123:285–296. 12. Gruener AM, Poostchi A, Carey AR, Eberhart CG, Henderson AD, Chang JR, McCulley TJ. Association of giant cell arteritis with race. JAMA Ophthalmol. 2019;137:1175–1179. 13. Pless M, Rizzo JF, Lamkin JC, Lessell S. Concordance of bilateral temporal artery biopsy in giant cell arteritis. J Neuroophthalmol. 2000;20:216–218. 14. Goslin BJ, Chung MH. Temporal artery biopsy as a means of diagnosing giant cell arteritis: is there over-utilization? Am Surg. 2011;77:1158–1160. 15. Breuer GS, Nesher R, Nesher G. Effect of biopsy length on the rate of positive temporal artery biopsies. Clin Exp Rheumatol. 2009;27(1 suppl 52):S10–S13. 16. Kaptanis S, Perera JK, Halkias C, Caton N, Alarcon L, Vig S. Temporal artery biopsy size does not matter. Vascular. 2014;22:406–410. 17. Mahr A, Saba M, Kambouchner M, Polivka M, Baudrimont M, Brochériou I, Coste J, Guillevin L. Temporal artery biopsy for diagnosing giant cell arteritis: the longer, the better? Ann Rheum Dis. 2006;65:826–828. 18. Grossman C, Ben-Zvi I, Barshack I, Bornstein G. Association between specimen length and diagnostic yield of temporal artery biopsy. Scand J Rheumatol. 2017;46:222–225. 19. Au CP, Sharma NS, McCluskey P, Ghabrial R. Increase in the length of superficial temporal artery biopsy over 14 years. Clin Exp Ophthalmol. 2016;44:550–554. 20. Poller DN, van Wyk Q, Jeffrey MJ. The importance of skip lesions in temporal arteritis. J Clin Pathol. 2000;53:137–139. 211 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.