Original Article. Increase in the length of superficial temporal artery biopsy over 14years ABSTRACT INTRODUCTION

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1 bs_bs_banner Clinical and Experimental Ophthalmology 2016; 44: doi: /ceo Original Article Increase in the length of superficial temporal artery biopsy over 14years Cheryl P Au MBBS, Neil S Sharma FRANZCO, Peter McCluskey FRANZCO and Raf Ghabrial FRANZCO Royal Prince Alfred Hospital, Sydney, New South Wales, Australia ABSTRACT Background: Giant cell arteritis is a systemic inflammatory vasculitis of large-sized and medium-sized arteries. Superficial temporal artery biopsy of at least 20 mm has traditionally been the standard length for histopathology to accurately diagnose giant cell arteritis. Recent studies suggest than a post-fixation superficial temporal artery biopsy length of 7 to 10 mm is adequate for diagnosing giant cell arteritis. Design: This is a retrospective observational study. Participants or samples: The participants were all patients who underwent superficial temporal artery biopsy at Royal Prince Alfred Hospital, a large tertiary teaching hospital in Sydney, Australia, from 2008 to Methods: Patients were identified using computerized hospital databases. Superficial temporal artery biopsy lengths were obtained from the histopathology reports. Main outcome measures: We aimed to compare the superficial temporal artery biopsy lengths performed at a large tertiary hospital over the past 7 years, to those performed from 2000 to 2005, and to determine the frequency of diagnosis of giant cell arteritis over the two time periods. Results: There was a total of 96 superficial temporal artery biopsies performed from 2008 to The superficial temporal artery biopsy mean (standard deviation) length was 16.0(7.3) mm. This represented a significant (P = 0.015) increase in mean superficial temporal artery biopsy length when compared with a previous audit performed from 2000 to 2005 where the mean (standard deviation) superficial temporal artery biopsy was 11.7(6.2) mm. Of the 96 TABs, 20 (20.8%) were positive for giant cell arteritis, compared with a giant cell arteritis positivity rate of 20.4% for the previous audit period from 2000 to Conclusion: There has been a significant improvement in the length of superficial temporal artery biopsy performed at a tertiary hospital. Despite the increase in superficial temporal artery biopsy lengths, the giant cell arteritis positivity rate has remained stable. Key words: biopsy. giant cell arteritis, length, temporal artery INTRODUCTION Giant cell arteritis (GCA) is a systemic immunemediated vasculitis affecting medium-sized and large arteries, especially those derived from the carotid system, including the superficial temporal, occipital, vertebral, ophthalmic and posterior ciliary arteries. 1 Involvement of these vessels can lead to visual disturbance or loss because of amaurosis fugax, ischaemic optic neuropathy, retinal artery occlusion or cerebral ischaemia. 2 GCA has a yearly incidence of 15 25/ ,3 It affects individuals over the age of 50. Prompt diagnosis and urgent treatment with systemic corticosteroids are essential to prevent serious vascular ischemic complications leading to blindness, aneurysmal formation and stroke. 4 6 The American College of Rheumatology (ACR) developed five criteria to diagnose GCA, including j Correspondence: Dr Raf Ghabrial, Department of Ophthalmology, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia. rafg@bigpond.com Received 12 September 2015; accepted 17 February Competing/conflicts of interest: None. Funding sources: None.

2 Length of temporal artery biopsies 551 age older than 50 years, elevated erythrocyte sedimentation rate (ESR), decreased temporal artery pulsation or tenderness, new onset temporal headache or exercise-induced jaw pain, and positive biopsy specimen with infiltrate, granuloma formation or multinucleated giant cells. 7 They reported a sensitivity and specificity of 93.5% and 91.2%, respectively, for diagnosing temporal arteritis when three of the clinical criteria were met. Revised criteria have excluded erythrocyte sedimentation rate and included scalp tenderness and claudication of the jaw or tongue on chewing (sensitivity of 95.3% and specificity of 90.7%). However, recent critics of the American College of Rheumatology classification criteria include the European League Against Rheumatism consensus group, where 38% of the committee was dissatisfied with the definition. 8 Given the non-specific nature of the presenting symptoms, patients may present to various specialties including rheumatology, general medicine and ophthalmology. Superficial temporal artery biopsy (STAB) is the gold standard for establishing a diagnosis of GCA and is central to the investigative pathway for establishing a diagnosis of GCA. 9,10 STAB is a safe procedure performed under local anaesthesia. A positive STAB result prevents future doubt about the accuracy of the diagnosis, especially when the patient suffers adverse corticosteroid side effects or fails to respond promptly to therapy. Conversely, a negative biopsy may allow the early withdrawal of unnecessary corticosteroid therapy. Many clinicians believe that to effectively exclude GCA, bilateral STABs need to be negative as there can be a false negative STAB biopsy result of up to 10%. 11 It is recognized that corticosteroid treatment for up to 2 weeks does not affect the biopsy result, whereas STAB findings would be less typical after 4 weeks or more of treatment. 9,12,13 Superficial temporal artery biopsy length remains a controversial issue. The widely accepted consensus is that a long STAB segment should be excised to maximize the chance of visualizing disease components because of the skipping nature of the inflammatory involvement in GCA. 14,15 Furthermore, there is contraction of the STAB specimen after excision and histologic processing. Small studies have suggested that this is 20% from excision to fixation (because of artery contraction) and a further 8% following fixation in formalin. 16,17 Thus, it was commonly recommended that STAB samples of over 20 mm be taken; 4,18 20 however. the length yielding optimal diagnostic sensitivity remains unknown. According to the latest British Society of Rheumatology and British Health Professionals in Rheumatology guidelines, STAB length should be at least 10 mm. 21 This recommendation was based on a multicentre retrospective study of 1520 biopsies 22 that found no statistically significant difference in STAB length between positive (13.4 mm) and negative (13.3 mm) biopsies, and in fact suggested 5 mm as an adequate length; furthermore, the guidelines did not specify whether the 10 mm target was the surgical specimen length or post-fixation length. This retrospective audit aimed to determine the length of STAB specimens performed by different specialties at a large tertiary hospital in Sydney, Australia from 2008 to A similar audit was performed at the same hospital from 2000 to 2005, where the mean (standard deviation [SD]) postfixation STAB length was 11.7 (6.2) mm, substantially shorter than the recommended length of 20 mm at the time. 23 Subsequently, this data were presented at various national and local surgical and ophthalmology meetings, including at Royal Prince Alfred Hospital (RPAH). We aimed to determine whether this education was effective in increasing the post-fixation length of STAB specimens performed at our hospital, and whether there was a corresponding increase in the GCA positivity rate. METHODS We reviewed the histopathological reports of all cases of temporal artery biopsies performed from January 2008 to December 2014 at Royal Prince Alfred Hospital, the largest tertiary teaching hospital in Sydney, Australia. This study was approved by the Sydney Local Health District Ethics Review Committee (LNR/15/RPAH/176). Patients who underwent STAB were identified from the computerized hospital database. Operational coding of temporal artery biopsy was crossreferenced with anatomical pathological coding for temporal artery biopsy to identify all possible cases. Superficial temporal artery biopsy was performed under local anaesthesia using recognized surgical techniques, by vascular surgeons, ophthalmologists, other specialist surgeons or surgical trainees. The experience of individual surgeons was variable. The pathology department customarily measured the lengths of formalin fixed STAB samples on macroscopic examination and recorded them in their reports. The specimens were processed using standard protocols to paraffin wax blocks. The entire specimen was embedded, and histopathological sections, cut at three levels or more, were examined after staining with haematoxylin and eosin. The abstracted information included sex, patient s age, post-fixation STAB length and histological findings. Histological findings were recorded with respect to the presence of inflammatory cell infiltrate, giant cells, intimal proliferation and fragmentation of the internal elastic lamina. 24 Details on the precise number of sections and levels examined were mentioned in most reports.

3 552 Au et al. Statistical analysis Continuous data were described as mean (SD), and categorical variables were presented as percentages (%). Comparisons between groups were made using the Student s t-test for independent continuous variables. To analyze categorical data, we performed the χ 2 test. Statistical significance was defined as P RESULTS There were a total of 96 STAB performed between January 2008 and December The mean (SD) age of patients who underwent STAB was 72 (10) years. There was a female preponderance, with 58 (60%) women and 38 (40%) men out of 96 individuals. Of the 96 STAB, 20 (20.8%) were positive for GCA, 3 (3.1%) showed features suggestive of treated GCA and 73 (76.0%) were negative for GCA. There were no indeterminate results. The GCA positivity rate from January 2000 to December 2005 was 20.4%. 23 The STAB post-fixation length ranged from 5 to 50 mm, and the mean (SD) was 16.0 (7.3) mm. The mean post-fixation length (SD) of STAB was 19.2 (9.3) mm for the GCA positive results, compared with 15.2 (6.2) mm (P = 0.09) for negative results. The majority of STAB was performed by the vascular surgery (52.6%) and ophthalmology (40.6%) teams. The remaining STAB was performed by other surgical teams (Table 1). The STAB post-fixation lengths obtained by the various specialties are shown in Table 1. The shortest post-fixation STAB length was 5 mm, performed by the vascular surgery team, and the highest length was 50 mm, performed by the ophthalmology team. The mean (SD) postfixation length of STAB was 15.2 (5.4) mm for the ophthalmology team and 17.3 (8.3) mm for the vascular surgery team. There was no significant difference in the post-fixation STAB lengths between the two teams (P = 0.17). A previous audit on STAB post-fixation lengths performed at the same hospital from January 2000 Table 1. The distribution of STAB lengths performed by the various specialties at Royal Prince Alfred Hospital Team n (%) STAB length (mm) Standard deviation (mm) Ophthalmology 39 (40.6) Vascular surgery 50 (52.6) Ear, nose and throat surgery 1 (1.0) 25.0 Plastic and reconstructive 1 (1.0) 16.0 surgery Melanoma/surgical 4 (4.2) oncology Head and neck surgery 1 (1.0) 7.0 to January 2005 showed the mean (SD) length to be 11.7 (6.2) mm. 23 There has been a significant increase in the STAB post-fixation length from the period 2000 to 2005 compared with the period 2008 to 2014 (P = 0.015). DISCUSSION In this study, we examined whether the post-fixation length of STAB performed at a large tertiary hospital in Sydney, Australia, had increased since the previous audit. 23 The results of the previous audit from 2000 to 2005 showed that the mean (SD) STAB post-fixation length was 11.7 (6.2) mm. This was substantially shorter than the recommended guideline of 20 mm at the time Subsequently, the results of this audit were published in the Australasian and New Zealand Journal of Surgery, as well as presented at various local and national meetings for surgeons and ophthalmologists. These included the RPAH Patron s Prize Research Symposium that was well attended by medical and surgical trainees and consultants, as well as the Royal Australian and New Zealand College of Ophthalmologists annual scientific congress in Since then, our present audit showed that there has been a significant increase in the length of STAB, with the mean (SD) STAB post-fixation length being 16 (7.5) mm. Allowing for a post-excision and fixation contraction of 28%, 16,17 it can be inferred that the mean STAB length that surgeons were taking at the time of the biopsy was around 22 mm. Furthermore, there was no significant difference in the mean STAB lengths performed by the vascular surgery team compared with the ophthalmology team. If the sufficiency of STAB length is considered a surrogate marker for the quality of the surgical procedure, our data thus suggest that both our vascular and ophthalmology trainees performed this procedure to a similar standard. However, to this day, there is no unanimous consensus regarding the optimal length of biopsy, and the literature reveals a wide range of lengths considered adequate from 5 to 50 mm. 4,10,18 23,25 29 Taylor-Gjevre and colleagues postulated that a threshold length of 10 mm post-formalin fixed arterial segment was associated with increased diagnostic yield of GCA. 10 These authors recommended a minimum STAB length of 15 mm to allow for tissue shrinkage during fixation, which was estimated to be approximately 10%. The study by Mahr et al., the largest study to date containing 1534 biopsies, found no significant difference in the mean STAB lengths between positive (12.3 mm) and negative (12 mm) biopsies. 22 The authors suggested that a minimum fixed STAB length of 5 mm was sufficient to make a histological diagnosis of GCA. A more recent study by Ypsilantis et al. confirmed STAB length as an independent factor predicting the

4 Length of temporal artery biopsies 553 histopathological diagnosis of GCA. 25 In their cohort of 966, biopsies with a post-fixation length of at least 7 mm had a positivity rate of 24.8%, double that of specimens smaller than 7 mm (12.9%). Other than specimen length differences, there was no significant variation in surgical technique of STAB across the different hospitals. Allison et al. and others have also demonstrated an average biopsy length of 7 mm, with higher positive rates. 9 They also speculated that larger specimens may have revealed evidence of more residual foci of active inflammation or healed arteritis. Achkar and colleagues reviewed 535 patients with an average biopsy length of 36 mm and obtained a positive rate of 33%. 12 A small retrospective study found significantly greater STAB lengths for positive results (18.4 mm) compared with negative results (12.9 mm) and recommended a biopsy length of >20 mm to increase diagnostic accuracy. 20 In our study, there was no significant difference in the mean STAB post-fixation length of positive results (19.2 mm) versus negative results (15.2 mm). Thus, there continues to remain great heterogeneity in findings. However, it is important to note that a negative STAB does not rule out the diagnosis of GCA. The pattern granulomatous inflammation in GCA can be segmental or patchy, where the granulomatous process is thought to skip over sections of the artery. 24 These characteristically described skip lesions could occur in 10 to 28% of cases. 14,15 Thus, retrieval of an adequate length of temporal artery is recommended as histological changes may be missed in a STAB taken in an arteritis-free segment. Our present study showed that even though the mean post-fixation length of STAB had increased from 11.7 to 16.0 mm over a 14-year period, our rate of histologically positive results (20.8%) had not significantly increased from 20.4%. However, also reassuring was that the GCA positivity rate had not decreased. Higher rates of positive STAB have been reported in the literature. These differences may be attributed to a higher quality in performing and analyzing STAB, more restrictive indications for ordering them, or the use of broader histological definitions for the diagnosis of GCA. 30 Limitations of our study, because of its retrospective nature, are that we could not assess whether patients were already on corticosteroid treatment and for how long prior to STAB. Histological findings were not correlated with follow-up. We also relied on data in electronic medical record databases. As STAB length was not routinely measured or recorded intraoperatively, all measurements referred to the post-fixation length as measured by histopathology. Additionally, there might be indication bias, with longer arterial segments having been removed in cases where the index of suspicion of GCA was lower. Nonetheless, it is unlikely that a surgeon s decision concerning the length of STAB was systematically influenced by pre-biopsy or intraoperative diagnostic probability, but instead by the symptomatic side and any symptomatic areas in the sample. In conclusion, STAB is a valuable diagnostic tool in GCA that may confirm the clinical diagnosis, assess the inflammatory activity and give guidance on the need for and duration of systemic corticosteroid therapy. Although the importance of long STAB for the detection of GCA has been repeatedly stressed in the literature, there is still considerable debate regarding the optimum STAB length. The increase in STAB post-fixation length over 14 years, although not associated with an increase in GCA positivity rate, at our institution could be attributed to a series of educational campaigns both locally and nationally to increase awareness amongst surgeons and ophthalmologists on the importance of STAB length in the diagnosis of GCA. 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