Why Do Temporal Arteries Go Wrong?

Principles and Pearls From a Clinician and a Pathologist

Yara Banz; John H. Stone

Disclosures

Rheumatology. 2018;57(2):ii3-ii10. 

In This Article

How We Are Led Astray

Inadequate Biopsy Specimen Length

Ask any pathologist what he or she most often requests, having agonized inconclusively at the microscope over a tiny (2 mm2) piece of temporal artery tissue, and the answer will be, Give me more tissue; that is, a longer segment of the artery. However, the trend in recent years has been to reduce the size of biopsy specimens as a push toward minimally invasive diagnostic procedures.[9] So significant is this issue that pathologists are now commonly asked to report on the adequacy of the biopsy specimen before giving their diagnostic opinion.[10]

Although the value of a (positive) temporal artery biopsy has been accepted for decades, the ideal biopsy length to ensure optimal sensitivity is still a matter of debate. The often-cited rule of thumb that a temporal artery biopsy specimen should not be < 2.0 cm is seldom accomplished in practice. Moreover, a temporal artery biopsy specimen that is 2.0 cm upon removal in the operating room often shrinks substantially after processing in the pathology laboratory. The optimal biopsy length associated with increased diagnostic yield varies between studies from >0.5 cm (post-fixation) to 0.7 or ⩾1.0 cm.[11–13]

Whatever the minimum acceptable length of a biopsy specimen, the adequacy of the sample should receive as much attention as the diagnosis itself in the setting of a negative temporal artery biopsy result.

Inadequate Histological Work-up

Histopathological work-up of vascular specimens, like other small biopsy samples, usually involves sectioning or serial sectioning of the sample in addition to specific stains. The idea behind the technique of sectioning through the tissue (or at least part of it) is to minimize the possibility of false-negative results, specifically, in patients with GCA, to avoid missing skip lesions. Early studies highlighted the need for examination of multiple histological sections (in addition to adequate biopsy length) to detect skip lesions.[14]

Although specific guidelines dictating the number of sections that is appropriate for temporal artery biopsy specimens have not been published, consensus statements on the processing of cardiovascular surgical specimens are available.[15] These recommend three or more sections for tissue samples, which is routinely practised by most histopathology laboratories. However, it should be taken into consideration that sectioning still means that the pathologist will see only a fraction of the sample (a biopsy sample 1.5 cm in length consisting of six sections of 3-μm thickness equates to 0.12% of the entire sample).

Temporal Arteries Not Involved

The temporal arteries are not part of the vascular distribution in which arterial compromise leads to blindness in GCA. Blindness results from involvement of the ophthalmic, retinal and posterior ciliary vessels. These vessels run a course behind the eye and track along the optic nerve. The temporal artery stems from a different branch of the external carotid artery and traces a path anterior to the tragus of the ear, near the course of branches of the facial nerve, up and over the temple, lying just under the skin and therefore accessible to biopsy. The temporal artery is biopsied because it is comparatively easy to do so, not because it necessarily reflects what is going on elsewhere in the large- and medium-sized vessel circulation or that its involvement predicts patients at higher or lower risk for vision loss. In short, temporal arteries that are free from inflammation do not exclude the presence of active GCA in other vascular distributions.

Involved Side Not Biopsied

In most cases, if a temporal artery biopsy is worth doing, it is worth performing on both sides. Occasionally, a patient may have a classic history and floridly abnormal temporal arteries (tender, swollen, nodular lesions). Such cases might justify unilateral biopsy, but these are in the minority. Most of the time, the importance of getting it right and the data available on the usefulness of bilateral biopsy argue for taking biopsy specimens from both sides.

A retrospective study performed by Boyev et al.[16] evaluated 186 patients who underwent bilateral temporal artery biopsy at Johns Hopkins Hospital. Only six patients (3%) had unilateral arteritis. Although this might be regarded as a small percentage not worth the additional effort and expense of bilateral procedures, those six patients represented at least 20% of the total number of patients whose GCA was diagnosed through biopsy. Similar conclusions were reached in another retrospective study that evaluated bilateral biopsy.[17] Among the 60 patients examined in that study, eight (13%) had GCA identified on only one side. However, those eight patients comprised 40% of the total number of patients diagnosed with GCA by biopsy. These studies suggest that once the decision has been made to pursue temporal artery biopsy, routine performance of bilateral procedures is justified.

Inadequate Surgical Experience and Performing Biopsy on the Wrong Portion of the Vessel

When performing temporal artery biopsy, surgeons attempt to locate the artery by finding a pulse. However, a pulsatile segment of the vessel is not necessarily the portion of the artery that is most likely to yield a diagnosis, and therefore is not the most desirable segment to biopsy. Given that a pulseless artery is sometimes difficult to locate, the skill of the surgeon is an important determinant of the success of temporal artery biopsy. Unfortunately, at many centres, the least-experienced surgeon is usually sent to perform these procedures.

The pulse of the temporal artery is often most easily palpable just anterior to the tragus of the ear. Surgeons often perform biopsy here, but this can be problematic for two reasons: first, as mentioned previously, an artery with a robust pulse is not the best site for biopsy; and second, biopsy of the artery in this area risks damage to the facial nerve that courses through the same region. A more fruitful and less risky biopsy targets the frontal branch of the superficial temporal artery just above the temple.

Some patients with suspected temporal arteritis have been sent to undergo biopsy only to return with a statement from the surgeon that no pulsatile vessel could be identified. Difficulty finding a pulse should cause the surgeon to redouble efforts to locate a branch of the temporal artery, not abandon the procedure. Some surgeons use intra-operative US to assist in the identification of arteries with faint pulses.

Pathological Interpretation Wrong

Pathologists are often hampered by inadequate biopsy specimen length, as noted previously. Less commonly, they miss the diagnosis because of human error. Experience plays a major role in the pathologist's ability to discern more subtle features that might be compatible with GCA.

There are two common causes of just missing it: first, early changes in which incipient inflammation is not clear and, second, inflammation in the temporal artery (temporal arteritis) that is not GCA. A diagnosis of temporal arteritis is not synonymous with GCA. Some of the variations in the histological specimens of cross sections through temporal artery biopsies are depicted in Figure 1. Advances in the treatment of individual forms of vasculitis now dictate the importance of precision in diagnosis.

Figure 1.

Histological images of cross sections through temporal artery biopsies
(A) and (B) (haematoxylin and eosin staining) show a case of florid GCA with transmural infiltration of lymphocytes, macrophages and the presence of several giant cells (black arrows). (C) (haematoxylin and eosin staining) shows a case of clinically positive GCA without noticeable inflammation on histological work-up. The lumen [as in the case in (A)] is compromised by significant circumferential intimal hyperplasia. An elastica van Gieson stain (D) shows minimal media fibrosis as well as evident disruption of the internal elastic lamina (black arrow), a subtle but not entirely specific sign of possible GCA.

Confounders in Diagnosing GCA: Previous Therapy

It is widely accepted that the diagnosis of GCA can be made by temporal artery biopsy even 2 weeks after initiation of glucocorticoids and sometimes much longer;[5] however, there is little doubt that glucocorticoid treatment alters the underlying histopathology in the blood vessel wall. Both the pathological interpretation of the temporal artery biopsy and the clinical decision-making that follows must take this into account.

The full impact of glucocorticoid administration on histological results is a matter of debate. Although some studies clearly show a time-dependent reduction in positive biopsy results after glucocorticoid treatment,[18–20] others have not been able to demonstrate a clear relationship between glucocorticoid use and reduction of inflammation.[5,21,22]

Giant Cells are Important But not Required for This Diagnosis

The presence of giant cells in a temporal artery biopsy specimen is strongly suggestive of GCA and giant cells are probably the most carefully sought feature when GCA is suspected. However, the frequency with which giant cells are identified is substantially lower than the name of the disease suggests.[23–25] In some cases, multiple cuts of an artery are necessary to identify giant cells, and giant cells are not detected in ~12% of clinically diagnosed cases of GCA.[26]

Giant cells not only have a high positive predictive value for GCA, they may also predict the occurrence of cranial ischaemic events.[27] The presence of giant cells in biopsy specimens has also been strongly associated with the presence of jaw claudication and elevated serological markers of inflammation, suggesting that the presence of giant cells reflects a more acute and aggressive form of the disease.[28]

In the absence of giant cells, more subtle histopathological changes must suffice as clues to possible presence of GCA.[29] Experience on the part of the pathologist is crucial to the proper interpretation of intimal thickening, focal infiltration by lymphocytes and macrophages, and localized scarring in the arterial wall, all of which are compatible with diagnosis but not necessarily diagnostic themselves in the absence of careful clinical correlation. Clinicians and pathologists should sit down at the microscope together whenever possible.

Atherosclerosis Causing Intimal Changes Poses Challenges in Differentiation

Another confounding factor is atherosclerosis, which can cause intimal hyperplasia similar to that of GCA. Arterial hypertension, dyslipidaemia and diabetes all affect the integrity of the vessel wall and may complicate histological interpretation in a patient with suspected GCA.

Although atherosclerotic changes were observed in a cohort of 40 steroid-treated patients with GCA, the changes were not significantly different from those in age-matched controls.[30] Premature atherosclerosis has been reported in several pro-inflammatory rheumatological conditions and may be accelerated in vasculitis.[31] Much attention is focused on the internal elastic lamina and its fragmentation in the setting of GCA. However, fragmentation of the elastic laminae by elastolysis is a feature common to both atherosclerosis and GCA.[32]

Variations in the appearance of laminar fragmentation and its relationship to fibrosis, as well as nuances of intimal hyperplasia, may provide important clues to help differentiate changes associated with atherosclerosis from those caused by vasculitis. In many cases, such histological subtleties make the pathologist's job as much an art as a science.

What is Healed Arteritis and What is its Relationship to GCA?

The term healed arteritis was used many years ago by Allsop and Gallagher[33] to distinguish a small subgroup of patients who did not fall into either the large category of patients with florid inflammation or the category of purely arterio-/atherosclerotic patients. Although studies are limited, results of some investigations of patients with so-called healed arteritis imply that this histopathology predicts a lower risk for disease recurrence, suggesting that the finding of healed arteritis is a biologically relevant state or subtype of vasculitis (or a different disease state completely) that does not necessitate the use of the high-dose glucocorticoids typically used to treat GCA.[34]

In a recent study by Maleszewski et al.,[35] patients with an initial positive result from temporal artery biopsy who were receiving treatment underwent a second biopsy after 3 months to 1 year. The multi-nucleated giant cells and granulomatous inflammation observed in the majority of positive biopsy results at presentation disappeared over time (and with treatment). Although signs of vascular remodelling were common to both the first and the second biopsies, medial fibrosis seemed to indicate a long-term healing process.

Unfortunately, healed arteritis is an elusive histopathological finding. None of the histological findings often attributed to healed arteritis—reduplication or rupture of the internal and external elastic laminae, calcification, fibrosis and neovascularization—are specific for GCA that is no longer active. In short, reliable differentiation between healed (i.e. quiescent) GCA and arteriosclerosis may simply not be possible by routine histopathology.[36] When confronted with the finding of healed arteritis on a temporal artery biopsy report, the clinician must rely more on the clinical features presented than on the histopathological findings when deciding whether to treat the patient for GCA.

Utility of Staining for CD68-positive Macrophages

Correctly identifying macrophages by routine histology is something that the most junior of pathologists learn, and immunohistochemical staining is rarely performed in routine cases of inflammation to confirm the presence of macrophages outside of research protocols. However, when the presence of (isolated) macrophages can tip the scale towards one diagnosis or another, the use of an antibody against CD68, a glycoprotein on monocytes and macrophages,[37] may aid in visualization of the number and distribution of tissue macrophages. In theory, the identification of macrophages around the internal elastic lamina, a finding facilitated by CD68 stains, provides additional support for the diagnosis of GCA, particularly in cases in which the histopathology is otherwise unconvincing.

However, this theory has not been studied sufficiently. A retrospective study of 60 patients aimed to predict the biopsy characteristics suggestive of response to glucocorticoid treatment and characteristics distinguishing GCA, PMR or arteriosclerosis using immunophenotyping. In that study, CD68 positivity was a predictor of the success of glucocorticoid treatment in patients with GCA and distinguished GCA from PMR in the absence of GCA.[38] All patients examined had histologically proven GCA; therefore, the value of immunohistochemistry in ambivalent cases or cases with subtle histological abnormalities was not clarified by this study.

In a larger retrospective study that used a three-tier system to distinguish among positive, indeterminate or negative biopsies, the value of CD68 lay in aiding a decision in indeterminate cases.[25] The authors concluded correctly that the ultimate diagnosis of GCA in such cases depends heavily on clinical judgement and clinicopathological correlation rather than simply on pathology. Although CD68 staining facilitates the identification of macrophages within the arterial wall,[39] it does not resolve all problems related to the diagnosis of GCA.

Histologically Equivocal Cases

Dealing with histologically equivocal cases is part of the daily life of a pathologist. Although vasculitis is defined simply (or over-simply) as 'inflammation of blood vessel walls at least at some time during the course of the disease',[40] correctly identifying this histologically is often tricky. At what time point are aggregated lymphocytes considered inflammatory infiltrates? Does the presence of inflammatory infiltrates equate to disease? A recent study by Jia et al.[41] revealed that patients with lymphocytic inflammation involving small blood vessels or the adventitia of the temporal artery in the absence of transmural arteritic damage were not at increased risk for temporal arteritis-like adverse events. Therefore, it is frequently difficult for pathologists to know where to draw the line between disease and possible disease. Distinguishing perivasculitis from inflammation that truly targets and damages the blood vessel wall also frequently raises challenges.

Mimickers of GCA

These challenges aside, there is no doubt that other bona fide forms of vasculitis can affect the temporal artery. That is, diseases other than GCA can cause temporal arteritis and be misdiagnosed by pathologists who are not aware of this possibility. Non-GCA diseases most likely to affect the temporal arteries include the ANCA-associated vasculitides (granulomatosis with polyangiitis, microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis), polyarteritis nodosa and mixed cryoglobulinaemia.[42]

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