Temporal Arteritis with Occult Malignancy: Co-existence or Causal Relationship?
A 74-year-old white male was referred to the ophthalmologist with a 3-week history of difficulty in reading and diminution of vision. He also complained of a right-sided headache, which was throbbing in nature and episodic, each episode lasting a few hours. On direct questioning his wife said that he had been getting progressively more tired over the past few weeks. There was no apparent loss of weight. He had no history of shoulder stiffness or joint pains or any other significant past medical history. Clinical examination revealed vision of 20/60 in each eye with glasses. No obvious acute ocular problem was identified. There was tenderness over the right temporal artery.
Investigations revealed an elevated erythrocyte sedimentation rate (ESR) of 77 mm in the first hour. Based on a clinical diagnosis of temporal arteritis (TA), he was started on oral prednisolone 50 mg once daily. The ophthalmologist referred the patient to us for further management and follow-up of TA. When seen in the outpatient clinic 1 month later, his symptoms had improved remarkably since the start of steroids. Clinical examination showed the patient in good health; he was afebrile and had mild hypertension. Temporal arteries were nontender and pulsatile. Systemic examination of chest, cardiovascular system, and abdomen was unremarkable. Further investigations showed complete blood count (CBC), liver function tests, renal function tests, and thyroid function tests to be normal. The ESR showed a decline from previous results. Oral steroids were continued and osteoporosis prophylaxis was initiated. He was regularly followed in the outpatient clinic.
Over the next 6 months, his steroid dose was gradually tapered in view of clinical improvement and fall in ESR. At the end of 6 months’ treatment, he had one relapse of his symptom of headache associated with a further rise in ESR. An increase in the steroid dose improved the symptoms. Subsequently, about 9 months following his first visit, while still on steroids, he complained of loss of appetite and weight and low back pain but denied any headaches. Clinically, he had a mild cushingoid appearance. Chest examination revealed scattered crackles over bases and a firm hepatomegaly 4 cm below coastal margin. Investigations revealed normal CBC. The ESR was further elevated to 71 mm in the first hour. Chest x-ray showed multiple nodular lesions suggestive of metastatic lung disease.
Ultrasound of the abdomen showed metastatic deposits in liver parenchyma. The histology of the liver lesions revealed poorly differentiated adenocarcinoma. On immunophenotyping, the tumor cells showed strong membrane expression of cytokeratin 7 and 20, which is commonly associated with pancreatic, nonperipheral cholangiocarcinoma and gastric adenocarcinoma. Further investigations to locate the primary cause were not undertaken. He was commenced on chemotherapy for metastatic malignancy. He is currently receiving palliative therapy with oral capecitabine.
Our case patient presented with typical clinical features of TA that, although not biopsy-proven, had a good clinical and laboratory response to high-dose steroids. Subsequently, he was found to have an underlying malignancy. This association prompted us to search the literature for any evidence of a relationship between TA and malignancy. Does this relationship exist? If so, what is the nature—is it causal or coincidental? Is TA a paraneoplastic manifestation or a premalignant condition? Is there any underlying common pathogenetic mechanism? How far should a patient with TA be investigated for occult malignancy? To obtain the answers, we searched MEDLINE and PubMed for published literature.
A study published in 1999 reviewed MEDLINE data for literature dealing with cancer-associated rheumatic syndromes.1 The authors found that certain rheumatic syndromes have a definite association with underlying malignancy, such as asymptomatic polyarthritis presenting in the elderly with explosive onset, rheumatoid arthritis, Sjögren’s syndrome, hypertrophic osteoarthropathy, dermatomyositis, polymyalgia rheumatica (PMR) with atypical features, Lambert-Eaton myasthenic syndrome, palmar fasciitis and arthritis, eosinophilic fasciitis poorly responsive to steroids, erythema nodosum lasting more than 6 months, and onset of Raynaud’s phenomenon or cutaneous leukocytoclastic vasculitis over age 50 years. Second, they found substantial evidence that certain longstanding rheumatic syndromes, especially rheumatoid arthritis, Felty’s syndrome, Sjögren’s syndrome, dermatomyositis, systemic lupus erythematosus, and TA, could behave like premalignant conditions. Third, presence of mono- clonal gammopathy in rheumatoid arthritis and monoclonal antibodies 17-109 in Sjögren’s syndrome are reliable signs of malignant transformation. In conclusion, the authors suggested that the presence of specific rheumatic syndromes and certain clinical and laboratory findings may justify a work-up for hidden malignancy.
A retrospective study among 111 patients (89 PMR, 14 TA, 8 PMR + TA) from the Netherlands found that malignancies were diagnosed in 12 patients.2 Most malignancies were diagnosed long before or after the diagnosis of PMR. Another prospective, controlled study from Norway among 185 patients with PMR and TA and 925 matched controls between 1978 and 1983 followed patients up to 1987 and cross-checked data with registry files.3 Malignancy was registered in 16 (24.6%) patients with biopsy-proven TA.3 The hazard rate for developing malignancy in patients with biopsy-proven TA was 2.35 times higher than controls and 4.40 times higher than the rest of the patient population. The long interval between diagnosis of PMR and TA and registration of malignancy (mean, 6.5 years) was not consistent with a paraneoplastic mechanism.3 Isolated case reports of association of TA with various malignancies have been reported. The malignancies described in association with TA include pituitary tumor,4 adenocarcinoma lung,5 temporal lobe meningioma,6 carcinoma breast and carcinoma lung (2 cases),7 carcinoma cervix uterus, acute myeloid leukemia (3 cases),8,9 multiple myeloma,10,11 myelodysplastic syndrome, and chronic myeloid leukemia (2 cases).12
A 2002 population-based study from Norway studied patients with PMR and TA and matched controls for association with malignancy.13 No differences were found in frequencies or types of malignant neoplasms between patients with PMR or TA and population controls. The exact etiopathologic relationship between inflammatory mechanism of TA and neoplastic proliferation of malignancy remains unclear. A study suggested that the PMR and TA-like picture could either be a direct consequence of tumor, effect of cancer therapy, or some other mechanism.14 Finally, it should be noted that, in general, both malignancies and TA occur at greater frequency during later life and are both considered to be age-prevalent illnesses. It is possible that the findings in this patient may not represent anything more than this age-related increase.
Several studies have been published that establish the association of TA and PMR with malignancy. Cases of TA have been described to have an underlying malignancy that may occur simultaneously or several years later. The rheumatic manifestations of malignancy include a wide spectrum of osteoarticular, muscular, glandular, endocrinologic, or systemic features that could be similar to TA and PMR and thereby pose a diagnostic challenge. The laboratory feature of raised ESR could be associated with either condition. How far to investigate the patient with TA for occult neoplasm also remains unclear. Failure of ESR to fall following steroid therapy or further rise of ESR in biopsy-proven TA could give clues for the need to search for occult malignancy. Serial follow-up and clinical examination of the patient is beneficial. However, it has been suggested that an extensive search for occult malignancy is not recommended unless accompanied by specific findings suggestive of malignancy. Further studies are needed to understand the complex relationship between the two conditions.