Temporal Arteritis Pathology

Temporal arteritis, also known as giant cell arteritis and cranial arteritis, is a systemic vasculitis of medium-sized and large-sized arteries. It is the most common systemic vasculitis of older adults. Symptoms of temporal arteritis can be either constitutional or vascular-related. Constitutional symptoms include fever, weight loss, anemia, and fatigue. Vascular-related symptoms arise secondary to arterial inflammation with luminal stenosis and resultant end-organ ischemia.

Temporal arteritis may also involve the aorta and may be associated with aneurysm, dissection, and aortic rupture. The typical involvement of the temporal, vertebral, and ophthalmic arteries leads to the classic clinical manifestations of headache, facial pain, and vision problems. Inflammation of the ophthalmic artery can lead to irreversible blindness of sudden onset. Vision loss in temporal arteritis constitutes a medical emergency.

Temporal artery biopsy is the criterion standard for establishing the diagnosis of temporal arteritis.[1] A positive histologic diagnosis demonstrates inflammation of the arterial wall with fragmentation and disruption of the internal elastic lamina (see the image below). Multinucleated giant cells are found in fewer than 50% of cases and are not specific for the disease.

Temporal Arteritis Pathology. Temporal arteritis.

Temporal arteritis occurs in three histologic patterns: classic, atypical, and healed. Regardless of histologic subtype, the disease typically responds well to rapid administration of systemic corticosteroids.

The incidence for temporal arteritis is 15-25 cases per 100,000 persons older than 50 years,[2] with a mean age of 71 years at presentation.[3] Temporal arteritis is the most common systemic vasculitis of adults in Western countries. Women are affected at least twice as often as men.[2] Disease susceptibility is associated with northern European descent and is seldom observed in blacks and Asians.[3, 4]

The etiology of temporal arteritis is multifactorial and is determined by both environmental and genetic factors. Data indicate that the disease is probably initiated by exposure to an exogenous antigen. Numerous viruses and bacteria have been proposed as potential precipitants, including parvovirus, parainfluenza virus, varicella zoster virus,[5, 6]  Chlamydia pneumoniae, and Mycoplasma pneumoniae.

T cells are recruited to the vessel wall after initial exposure to the antigen. They release cytokines that act on local macrophages and multinucleated giant cells.[7] The response of the macrophages and multinucleated giant cells to the cytokines depends upon their location within the vessel wall.

The access of monocytes and T cells to the vascular wall is controlled by matrix metalloproteinase 9 (MMP-9), a type IV collagenase that is produced in the vasculitic lesions of giant cell arteritis. Production of MMP-9 allows T cells to pass through collagen IV–containing basement membrane.[8]

Adventitia-based macrophages produce interleukin-6 (IL-6), which further augments the inflammatory cascade. Macrophages within the media produce oxygen free radicals and metalloproteases, which degrade the arterial wall and fragment the elastic lamina. With the disruption of the internal elastic lamina, the intima becomes accessible to migrating myofibroblasts, which proliferate and lay down extracellular matrix.

This migratory process is driven by intima-based macrophages that produce platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). The net effect of these events is an arteritis with local vascular destruction and intimal hyperplasia leading to luminal stenosis and occlusion. The exuberant release of cytokines associated with this process may be responsible for the constitutional symptoms frequently encountered with the disease.[9, 10, 11, 12]

Temporal arteritis shows a predilection for the vertebral arteries, the subclavian arteries, and the extracranial branches of the carotid arteries (ie, the superficial temporal, ophthalmic, occipital, and posterior ciliary arteries). Temporal arteritis and giant cell aortitis are related; the inflammation may involve the aortic wall and, rarely, the femoral and coronary arteries.

Clinical features

The onset of symptoms in temporal arteritis may be either gradual or sudden. Arterial wall infiltration by lymphocytes and macrophages leads to luminal stenosis and occlusion of the vessel. Consequently, many of the clinical symptoms reflect end-organ ischemia. The branches of the internal and external carotid arteries are at particularly high risk. Their involvement produces the classic clinical manifestations of jaw claudication, headache, scalp tenderness, and visual disturbances.

One of the most important potential complications of temporal arteritis is complete or partial vision loss, a phenomenon that occurs in at least one eye in as many as 60% of patients.[9, 13] Blindness results from occlusion of the inflamed ophthalmic or posterior ciliary arteries with resultant ischemia of the optic nerve or tracts. Other potential visual disturbances that may precede vision loss include diplopia, amaurosis fugax, hallucinations, blurred vision, and eye pain.

Inflammation of the posterior vertebral arteries can decrease posterior cerebral perfusion and lead to dizziness, vertigo, transient ischemic attacks (TIAs), and cerebrovascular accidents (CVAs). Absent or asymmetric pulses and claudication of the arms can occur when arteritis affects the axillary, subclavian, and proximal brachial arteries. Inflammation may involve the aorta, with potential sequelae including thoracic aneurysms, dissections, and rupture. Temporal arteritis of coronary arteries may be a rare cause of refractory dialysis-related hypotension.[14]

A systemic inflammatory response frequently accompanies the vascular manifestations of temporal arteritis and produces a constellation of symptoms. Fever, myalgia, anorexia, weight loss, anemia, and malaise are often encountered. Values for acute-phase reactants (eg, erythrocyte sedimentation rate [ESR] and C-reactive protein [CRP] level) are typically elevated. The CRP level and thrombocytosis may be stronger predictors of a subsequent positive biopsy than the ESR.[15]

Polymyalgia rheumatica (PMR) is characterized by stiffness and pain of the proximal joints. It occurs in 50-75% of patients with temporal arteritis.[2, 10] Vision loss is not a feature of PMR. PMR may progress into clinical temporal arteritis and is considered by some to represent a different phase of the same disease.

The differential diagnosis for a patient who presents with only the systemic inflammatory symptoms of temporal arteritis is broad. Systemic infections, connective tissue diseases, and malignancies may have similar clinical features. Primary systemic amyloidosis can mimic the symptoms of both PMR and temporal arteritis. Patients with a monoclonal band on immunoelectrophoresis and a poor response to systemic corticosteroids should have a Congo red stain performed on a temporal artery biopsy.

The ophthalmic features of temporal arteritis can be mimicked by nonarteritic anterior ischemic optic neuropathy (NAION), a disease characterized by visual disturbances in patients with cardiovascular risk factors and a susceptible “crowded” optic disc.

Several features can be used to differentiate NAION from temporal arteritis. NAION typically occurs in a younger age group (mean age, 60 years). Constitutional symptoms are absent in NAION, and the ESR and CRP level are within normal limits. The visual changes in NAION are less severe and typically do not result in complete vision loss. On ophthalmic examination, the cup-disc ratio is reduced in NAION (hence the description of the optic disc as “crowded”), whereas it is normal in temporal arteritis.[16]

Several vasculitides and connective tissue disorders can present with similar systemic and ophthalmic manifestations, including systemic lupus erythematosus (SLE), rheumatoid arthritis, polyarteritis nodosa, Churg-Strauss syndrome, microscopic polyangiitis, Takayasu arteritis, and polymyositis. Differences in systemic organ involvement, microscopic findings, and distribution of lesions can help distinguish these entities from temporal arteritis.

Imaging studies

Compressive intracranial lesions, both malignant and benign, may also be considered in the differential; these can be ruled out with neuroimaging studies.

Imaging modalities used to diagnose temporal arteritis include ultrasonography, magnetic resonance imaging (MRI),[17] positron emission tomography (PET), and angio-computed tomography (CT) scanning[18, 19] ; ultrasonography may be the preferred initial modality.[20, 21, 22, 18, 19]

Hansen et al analyzed the examination results of 78 patients suspected of having GCA from August 2018 to June 2019, and evaluated the diagnostic accuracy of biopsy and ultrasound. Biopsy had a sensitivity of 69% and a specificity of 100%; ultrasound had a sensitivity of 63% and a specificity of 79%. Although the overall diagnostic accuracy of ultrasound was slightly lower, the investigators concluded that ultrasound is a reliable tool for first line diagnosis of GCA.[19]

Corticosteroids act to suppress the inflammatory response in temporal arteritis and limit the ischemic complications of the disease. It is universally agreed that corticosteroid therapy should be initiated as soon as the diagnosis is suspected and that steroids should be given even before the biopsy is obtained. Early initiation of therapy has been shown to reduce the risk of blindness and stroke.

There is no consensus regarding the optimal dosage and duration of corticosteroid administration. Generally, however, the greater the visual loss or potential for visual loss, the larger the steroid dose required. Individual treatment regimens are based on clinical presentation, symptom severity, response to treatment, and development of adverse side effects. To minimize the risk of complications associated with prolonged corticosteroid therapy, doses are gradually tapered to a minimally suppressive amount that induces clinical remission.

Various immunosuppressive agents are now being considered for their potential steroid-sparing effects. Conflicting results have been obtained with these agents however, and high-dose systemic corticosteroids are still the mainstay of treatment.

Segments of affected arteries develop nodular thickenings that produce stenosis of the lumen. The lesions may be associated with thrombi, which occasionally organize and transform the artery into a thick fibrous cord.

Aortic involvement by giant cell aortitis may give the luminal surface a longitudinal wrinkled look, the so-called tree-bark appearance. This finding is not pathognomonic for giant cell arteritis and is found in all types of aortitis. The tree-bark appearance is secondary to alterations occurring in the media, including elastic fiber fragmentation, loss of medial smooth muscle, and medial scarring.

For gross examination of the specimen, the size of the arterial biopsy should be described and the entire specimen processed without sectioning. After processing, the histotechnologist should cross-section the vessel at 2-3 mm intervals and place the cross-sections in embedding cassettes for paraffin embedding.

This postprocessing cutting method is optimal because it ensures good orientation of the vessel segments. The cross-sections should be cut in serial sections onto slides. Interval staining of slides is performed. If staining is negative, the tissue should be completely sectioned and depleted to ensure that any focal involvement is not missed.

The key anatomic characteristic of temporal arteritis is the segmental distribution of the inflammatory infiltrate that results in the formation of so-called skip lesions. According to some studies, skip lesions may occur in as many as 28% of cases.[23] Because of the segmental nature of the inflammation, an adequate biopsy requires a length of at least 2-3 cm and the submission of multiple sections for histologic analysis. Absence of diagnostic microscopic features on biopsy may occur in 15% of cases and does not rule out the disease.[9]

There are three main patterns of vascular damage in temporal arteritis.[24] The first is the classic pattern, characterized by marked intimal thickening and transmural inflammation. A dense inflammatory infiltrate composed of T cells and histiocytes is present. Fusion of histiocytes results in the classic microscopic appearance of granulomatous inflammation with multinucleated giant cells (foreign body and Langhans types; see the images below). This finding is present in fewer than 50% of cases and is not specific to temporal arteritis.

Temporal Arteritis Pathology. Temporal arteritis: giant cells.

Temporal Arteritis Pathology. Temporal arteritis: giant cells.

The release of inflammatory mediators causes fragmentation and distortion of the internal elastic lamina. An elastic stain is essential in the evaluation of these biopsy specimens. The intima often has a fibromyxoid appearance.[9, 25]

The second pattern is the atypical pattern, which may be an intermediate stage in the resolution of the classic type. A less dense nonspecific arteritis is seen, with an inflammatory infiltrate composed of lymphocytes, macrophages, and, rarely, eosinophils and neutrophils. Moderate or marked intimal thickening and medial fibrosis are sometimes noted (see the images below). Granulomas and multinucleated giant cells are rare. The inflammation tends to be most marked in the adventitia. Intimal fibromyxoid changes and inflammation are also found.[25]

Temporal Arteritis Pathology. Temporal arteritis: atypical features, adventitial heavy inflammation.

Temporal Arteritis Pathology. Temporal arteritis: adventitia and intimal inflammation dominating, atypical features.

The third histologic pattern is the healed pattern, which demonstrates intimal and medial fibrosis. The intima is irregularly thickened and exhibits fibromyxoid change and neovascularization; fibrosis of the media may be seen. A trichrome stain may be useful for detecting this pattern. An elastic stain highlights significant defects on the internal elastic lamina (see the images below); frequently, these defects extend over 30-50% of the circumference of the artery. Focal areas of persistent chronic inflammation remain.[25]

Temporal Arteritis Pathology. Temporal arteritis: fragmented internal elastic lamina.

Temporal Arteritis Pathology. Temporal arteritis: large gap in internal elastic lamina, best seen with elastic stain (Movat pentachrome, in this example).

Some concern exists that treatment of temporal arteritis with corticosteroids can lead to resolution of the arterial inflammation and thereby reduce the diagnostic accuracy of the temporal artery biopsy. However, corticosteroid therapy appears to have only a minimal impact on the histologic features, especially if the steroids were administered less than 14 days before the biopsy.[9]

Leukocyte common antigen (LCA) and CD15 can be used to identify inflammatory cells when no definite inflammation is observed on hematoxylin and eosin (H&E) staining. Histiocytic markers (CD68 and HAM56) can detect residual arteritis in patients with resolving disease.[26, 27]

On the basis of its familial, ethnic, and geographic distribution, temporal arteritis appears to have a genetic predisposition. Studies have shown familial clustering and monozygotic twin concordance. Most genetic factors center on the human leukocyte antigen (HLA) genes. It is likely that various HLA alleles predispose to temporal arteritis and mediate its severity.

Individuals homozygous for HLA-DR4 and the FCGR2A-131RR allele have a 6-fold greater risk of developing temporal arteritis. HLA-DR1, HLA-DR3, and HLA-DR5 may also be associated with a higher incidence of the disease. Polymorphisms in immunomodulating proteins such as interleukin-1 receptor antagonist (IL-1ra), tumor necrosis factor alpha (TNF-α), and intracellular adhesion molecule-1 (ICAM-1) have also demonstrated an increased association with temporal arteritis.

The precise role of genetic susceptibility in the pathogenesis of temporal arteritis remains unclear and requires further investigation.[3, 9, 12, 16]

Before the advent of corticosteroids, most patients afflicted with temporal arteritis lost their vision. With current adequate therapy and rapid diagnosis, the incidence of blindness has been lowered to 9-25%.[3] Once vision loss has occurred, however, it cannot be reversed by corticosteroid therapy.

Mortality for patients with treated temporal arteritis is the same as that for healthy, age-matched individuals.[28] Although most patients are symptom-free after 3 years of therapy, half of them will require ongoing management with corticosteroids. Prolonged corticosteroid therapy is associated with significant morbidity, including the development of cataracts, hypertension, myopathies, and osteopenia.[9]

In a study that evaluated disease flares (relapses and recurrences) in 174 patients with biopsy-proven temporal arteritis, the 71 (40.8%) who experienced relapses or recurrences did not show clinical differences when compared with the other patients, but they had received corticosteroid therapy for a significantly longer time.[29] The investigators concluded that a chronic inflammatory response manifested by anemia at the time of disease diagnosis (see Clinical Features and Imaging) may predict the development of disease flares.