Cancer-associated retinopathy preceding the diagnosis of a pulmonary carcinoid tumour

Abstract

Cancer-associated retinopathy (CAR) belongs to the paraneoplastic retinopathy syndromes and manifests itself by rapidly progressive vision loss, scotoma and photopsia. We herein reported the case of a 77-year-old woman without a cancer history who presents typical CAR symptoms. A complete workup followed by lung biopsy enabled the detection of a pulmonary carcinoid tumour. Treatment of oral cortisone was then initiated with dramatic improvements in the symptoms.

Background

Paraneoplastic retinopathy syndromes are a set of heterogeneous medical symptoms that arise from immunological responses triggered by extraocular tumours, comprising cancer-associated retinopathy (CAR), melanoma-associated retinopathy, paraneoplastic vitelliform maculopathy and bilateral diffuse uveal melanocytic proliferation.¹ Among these syndromes, CAR is a rare visual disorder characterised by the production of autoantibodies specific to tumour antigens that cross-react with retinal proteins leading to photoreceptors (cones and rods) degeneration.² Specific CAR symptoms include progressive vision loss, photosensitivity, ring scotoma, attenuated retinal arteriole, visual field defects and abnormal electroretinogram (ERG).³ Since Sawyer et al first described this syndrome in 1976,³ several authors have reported CAR to be associated with a variety of systemic malignancies.^4–8 Although one author already described CAR as a leading symptom for small-cell lung cancer,⁷ the authors found no published studies on its association with lung carcinoid tumours.

Case presentation

A 77-year-old woman with a past medical history of a bilateral cataract, a hysterectomy and a right adnexectomy for fibroma, consulted her ophthalmologist because of painless progressive vision loss and photopsia affecting both eyes. An ophthalmological examination without any correction revealed a visual acuity of 0.6 for both eyes. The examinations of the anterior and posterior segments as well as intraocular pressure were within the normal range. For both eyes, visual field testing showed diffuse defects and full-field ERG was below normal limits. Fluorescein angiography (figure 1) disclosed diffusion of contrast agent secondary to peripheral retinal vasculitis. As the whole clinical picture was suggestive of CAR, further investigations were then performed to detect cancer, even though the patient did not present any signs or symptoms of malignancy.

Figure 1.

Fluorescein angiography of the right eye (late frames): multiple periphlebitis in the periphery.

Investigations

A diagnostic workup for autoimmunity, including tests for antiphospholipid antibody, antineutrophil cytoplasmic antibody, antinuclear antibody, immunoelectrophoresis and rheumatoid factor, as well as a diagnostic workup for infection (Bartonella, syphilis, tuberculosis and Lyme) were both negative. Tumorous markers, comprising carcinoembryonic and carbohydrate antigens (CEA, CA19-9, CA15-3), were within the normal range. The breast palpation gave normal results with no abnormalities and the gynaecological check-up did not reveal any mass on the left adnexa. A colonoscopy detected nine sessile polyps, though a pathology analysis revealed low-grade adenomas only. The thoracic CT scan disclosed an 8 mm sized nodule in the right posterior lobe without a lymph node. It is worth noting that this nodule was already visible on a previous thoracic CT scan 8 years ago, but smaller in size. Further analyses using positron emission tomography scans confirmed an absence of both hypermetabolic activity and ¹⁸F-fluorodeoxyglucose emission at the nodule level.

Treatment

The discovery of the pulmonary nodule, even if not hypermetabolic, led to a thoracoscopy with wedge resection after multidisciplinary discussions. An extemporaneous analysis revealed a tumour proliferation suggestive of carcinoid syndrome. We thereafter performed the tumour resection and the lymph node dissection. Pathological analyses revealed the presence of a typical lung carcinoid tumour of 1.1 cm in diameter (figures 2 and 3), corresponding to pT1b pN0 R0 according to the eighth edition of the TNM classification.

Figure 2.

Typical carcinoid lung tumour: the lesion consists of nests of a homogeneous population of cells showing oval nuclei with fine chromatin (H&E, ×400).

Figure 3.

Typical carcinoid lung tumour: intense and diffuse positivity of tumour cells for synaptophysin, confirming their neuroendocrine differentiation (synaptophysin immunostain, ×400).

In addition to the tumour resection, we administered an oral cortisone treatment (1 mg/kg).

Outcome and follow-up

After a follow-up of 6 weeks, the patient reported vision improvement and the disappearance of photopsias. Ophthalmological examinations with visual field and acuity testing revealed campimetric improvements while an ERG still disclosed pathological values for both eyes.

Discussion

CAR is a rare paraneoplastic syndrome with diffuse retinal degeneration due to autoimmune reactions from underlying malignancy. In the majority of patients, CAR usually develops after the age of 45 years (the average being 65), and women are twice as likely to be affected as men.⁹ However, the diagnosis of CAR is not well defined and is generally based on ophthalmological manifestations, visual fields defects and abnormal ERG findings with dysfunction of rods and cones. In patients with progressive visual loss, concentric visual field defects and pathological ERG, a CAR syndrome must be ruled out. Serum antiretinal antibodies (SAA) such as antirecoverin, antienolase, anticarbonic anhydrase and antitransducin can confirm the diagnosis and provide useful information on cancer origin.^{9 10} It was, nevertheless, impossible to perform SAA testing in our patient, as they are currently not available in Switzerland. However, in the absence of standardised measurement methods, the diagnostic benefits of SAA testing remain limited due to its insufficient estimated sensitivity (55.6% at presentation).^10–12

The malignancy associated with CAR can be diagnosed before or after the onset of ocular manifestations. The time from cancer diagnosis to the onset of retinopathy may vary from weeks to months or years. Conversely, CAR detection is important as it may lead to an early cancer diagnosis. Therefore, in selected cases, ophthalmic findings consistent enough with the diagnosis of CAR should trigger investigations in order to detect a previously unknown malignancy.¹³ For our patient, these investigations led to the discovery of a lung carcinoid tumour.

CAR has been associated with a variety of systemic malignancies, such as (by order of appearance): breast cancer, lung cancer, melanoma, haematological malignancies, gynaecological cancer, prostate cancer and colon cancer.⁹ This syndrome has already been documented with small-cell lung cancer,⁷ whereas its association with carcinoid tumours has only been described with small-bowel malignancy.¹⁴ To the best of our knowledge, this case report is the first to investigate and highlight the association between CAR and pulmonary carcinoid tumours.

The pathophysiology of CAR remains partially understood, though molecular mimicry is the generally accepted mechanism. Neither tumour excisions nor CAR management currently disposes of specific protocols. Long-term immunosuppressive agents and most often steroids remain the cornerstone treatment. Visual prognosis is poor despite an initial improvement as in our case.¹ The overall survival depends on the underlying tumour and staging at diagnosis, as well as treatment options available. The resection of the lung carcinoid tumour at an early stage enabled to cure the patient, although we cannot assert that this lesion would have evolved aggressively without the intervention.

This paper described the first case of CAR associated with a pulmonary carcinoid tumour. This case highlights the importance of extensive workup required to detect malignancy because the onset of ocular symptoms can precede the cancer diagnosis by months to years in some patients who have not yet been diagnosed with cancer. A more complete understanding of the association between cancer and retinal pathology observed may lead to a better understanding of the cellular and molecular mechanisms of retinal degeneration, as well as inform the development of rational therapies.

Learning points.

• Cancer-associated retinopathy is a paraneoplastic retinopathy syndrome.

• Patients generally present rapidly progressive vision field loss and photopsia.

• The recognition of retinopathy as part of a paraneoplastic syndrome should prompt an immediate search for an occult neoplasm.

• Early diagnostic of this uncommon syndrome could direct aggressive immunosuppressive therapy with cortisone.