Cancer-associated retinopathy as an initial presentation of gynecologic small-cell carcinoma

Abstract

A 56-year-old female presented with bilateral progressive blurred vision over 1 month. She has no known malignancy before her initial visit to our ophthalmologic clinic. Her best-corrected visual acuity decreased to hand motion from 30 cm in both eyes. Optical coherence tomography exhibited parafoveal thinning of outer retinal layers bilaterally. Fluorescein angiography and indocyanine green angiography disclosed hypofluorescent spots in late phase in both eyes. The suspicion of cancer-associated retinopathy (CAR) prompted us to investigate and refer for further systemic disease including occult malignancy. The patient was diagnosed with small-cell carcinoma of the endometrium or cervix, which is an extremely rare and aggressive neuroendocrine tumor. The patient was treated with oral prednisone with improved visual acuity. The patient expired from sepsis 2 months after her initial visit to our ophthalmologic clinic. In selected cases, CAR may present before the diagnosis of primary cancer. It is essential to recognize its ophthalmic manifestation for early discovery of primary malignancy.

Introduction

Cancer-associated retinopathy (CAR) is one of the paraneoplastic retinopathy syndromes that usually present with acute or subacute onset of bilateral and painless visual loss, photopsia, light sensitivity, and nyctalopia.[1] Typical ophthalmic manifestation includes decreased visual acuity, loss of color vision, and peripheral or ring scotomas.[2] Most of the CAR patients reported vision loss after the diagnosis of their primary malignancies.[1] Herein, we aim to present a case of CAR whose ophthalmologic presentation precedes the diagnosis of her gynecologic cancer.

Case Report

A 56-year-old Asian female presented to our ophthalmologic clinic with bilateral progressive blurred vision for 2 months and getting worse in recent weeks. Systemic disease including hypertension and type 2 diabetes mellitus was stated. On initial examination, best-corrected visual acuity (BCVA) was 20/200 in the right eye and 20/60 in the left eye; however, BCVA became hand motion from 30 cm 3 days later in both eyes. Intraocular pressure and anterior segment examination was within the normal range. Funduscopic examination showed Grade I vitreous opacity with Grade II vitreous cells, as well as attenuation of retinal arteries and pallor disc [Figure 1]. B-scan ultrasonography also showed vitreous opacity in both eyes. Optical coherence tomography (OCT) demonstrated thinning of outer retinal layers and parafoveally diminished of photoreceptor layer in both eyes [Figure 2]. Hyper-reflective dots were also noted in the outer retinal layer within the perifoveal region on OCT, corresponding to the hypoautofluorescent spots observed in fundus autofluorescence [Figure 2]. Fluorescein angiography (FA) and indocyanine green angiography (ICG) also disclosed hypofluorescent spots in late phase at the same location in both eyes [Figure 3]. However, electroretinogram (ERG) and anti-retinal antibody test were not preformed since they are not accessible locally and would need to transfer to a different medical care center. Due to the patient’s frail condition and ongoing palliative treatment, undergoing the test would not be in the patient’s best interest.

Figure 1.

Vitreous opacity, attenuation of retinal arteries, and pallor disc were noted at initial presentation on fundus photography in both eyes

Figure 2.

Generalized thinning of outer nuclear layer and diminish of parafoveal photoreceptor layer showed on optical coherence tomography (OCT). Hyper-reflective dots were also noted in the outer retinal layer within the perifoveal region on OCT (yellow arrows), corresponding to the hypoautofluorescent spots observed in fundus autofluorescence (FAF). Prominent vitreous opacities were observed in the FAF. (a) OCT of the right eye. (b) OCT of the left eye. (c) FAF of the right eye. (d) FAF of the left eye

Figure 3.

Fluorescein angiography (left) and indocyanine green angiography (right) showed hypofluorescent spots in late phase in both eyes. Note that there was moderate vitreous opacity. (a) Right eye. (b) Left eye

A diagnostic workup for infection, autoimmune, and malignancy was performed. Her routine blood cell counts showed leukocytosis (17900/mm³) with 81.6% segment, and anemia (hemoglobin: 10.5 g/dL) was also noted. Biochemical data showed poor renal function (Blood urea nitrogen [BUN]: 45 mg/dL and creatinine: 1.56 mg/dL). Immunological profile (including rheumatoid factor, antinuclear antibody, C3, and C4), screening of antibodies related to viral infection (including herpes simplex virus, cytomegalovirus, and toxoplasma) and serological test for syphilis rapid plasma, Treponema pallidum particle agglutination assay, and human immunodeficiency virus screening were all unremarkable. Chest X-ray showed no pulmonary sarcoidosis, and magnetic resonance imaging of the brain revealed no primary central nervous system lymphoma or other tumor lesions. Taking into consideration the aforementioned clinical presentation and examinations, along with the fact that the patient was not taking any medication known to cause retinal toxicity and did not have issues with selective or reduced dietary intake, inherited retinal disorders, nutrition deficiency retinopathy, and toxic retinopathy have all been ruled out.

Due to the presentation of posterior uveitis, an oral prednisolone course started at 60 mg daily (body weight: 75 kg) for 3 weeks, and followed by a taper to 45 mg daily for an additional 4 weeks. Meanwhile, we referred the patient to nephrology and urology for her poor renal function and on suspicion of CAR. Right hydronephrosis was noted by renal ultrasound. Elevated tumor markers were noted for carcinoembryonic antigen (6.8 ng/mL) and CA-125 (353.1 U/mL). Abdominal and pelvic computerized tomography scan disclosed differential diagnoses of T3N1M1 stage for cervical cancer or T3N2M1 stage for endometrial cancer (endometrial or cervical cancer with vaginal, right adnexal, and para-adnexal extension, urinary bladder and rectal wall invasion, extensive nodal metastasis, and complicated right obstruction uropathy) [Figure 4]. The patient was then referred to the gynecology department, and the pathology report of endometrial biopsy demonstrated the aggregation of atypical hyperchromatic cells with salt-and-pepper chromatin infiltrating in desmoplastic stroma and marked tumor necrosis [Figure 5]. Immunohistochemical study for the tumor cells revealed positive reactivity for p16, CD56 and synaptophysin antibodies, focal reactive for cytokeratin, chromogranin A antibodies, and negative reactivity for thyroid transcription factor-1, p63, and leukocyte common antigen antibodies. The findings are suggestive of a small-cell carcinoma. However, it is difficult to know whether it originated from the cervix or endometrium. Subsequently, she was referred to the oncology department for chemotherapy.

Figure 4.

Abdominal and pelvic computerized tomography scan disclosed endometrial or cervical cancer with extensive invasion (red arrow) and complicated right obstruction uropathy (yellow arrow)

Figure 5.

(a) Atypical hyperchromatic cells with salt-and-pepper chromatin infiltrating in desmoplastic stroma (yellow arrows). (b) Marked tumor necrosis was seen on the right lower part on this slide

Diagnosis of CAR was ultimately made on the basis of her clinical presentation and ophthalmological findings. After a follow-up of 6 weeks, her BCVA improved to 6/20 in both eyes. Fundus examination showed a decrease of vitreous opacity, whereas general attenuation of arteries was noted bilaterally. Two months after her initial visit to the ophthalmologic clinic, the patient expired from neutropenic fever and sepsis.

Discussion

CAR is an uncommon paraneoplastic syndrome that usually develops after 45 years old, with an average age of 65 years. Women are twice more likely to be involved.[3] Common ocular manifestation includes retinal arterioles narrowing, retinal pigmentation mottling, and pale optic disc.[2] Intraocular inflammation might be present, and it usually leads to the investigation of other causes of uveitis before CAR is diagnosed, as in our case. One of the most frequent and helpful diagnostic signs is the parafoveal loss of the outer retinal layer in OCT. Consistently, our patient had this finding in both eyes. In some cases, visual field defects such as central scotoma, ring scotoma, or peripheral scotoma may be present. ERG findings are typically abnormal with defects in rod and cone functions, demonstrating with severely decreased signal or even extinguished a-wave and b-wave (flat ERG).[2] The role of serum anti-retinal antibodies is unclear at this point.[4,5]

The pathophysiology of CAR has not been well understood. The generally accepted mechanism is molecular mimicry.[5] Autoantibodies against tumor antigens penetrate the blood–retinal barrier, damage retinal cells (rods, cones, bipolar cells, or retinal pigment epitheliums), and lead to diffuse retinal dysfunction.[1,2]

Among the relevant autoantibody, anti-recoverin antibody is thought to be the most common one implicated in CAR patients. Recoverin (23kDA) is a photoreceptor-specific calcium-binding protein, usually expressed by the malignant tissue of a patient with CAR. It is localized on chromosome 17p13.1, a region rich with cancer-related loci such as p53. The expression of recoverin might be stimulated or affected by a single mutation inactivating p53.[4] Other target antigens such as α-enolase (46 kDa), carbonic anhydrase II (30 kDa), and transducin-α (40 kDa) are also associated with CAR.[1,4]

However, the diagnostic role of the anti-retinal antibodies is still in controversy since the estimated sensitivity is 55.6% and specificity is also low.[5] Serum autoantibodies may not be detectable in about 35% of patients with a paraneoplastic retinopathy.[4] Furthermore, anti-recoverin antibodies could only be detected in 10% of CAR patients with visual symptoms.[4]

Most of CAR occurs in patients with solid malignancies such as lung cancer, thymic carcinoma, breast cancer, or gynecologic cancers. Hematological malignancies were also reported in 12.6% of patients with CAR.[1,4] The most frequent one is small-cell lung carcinoma.[6] Small-cell carcinoma is a type of neuroendocrine cancer most commonly found in the lungs and is well known for its association with paraneoplastic syndrome.[6,7] Interestingly, our patient was a case of small-cell carcinoma from endometrial biopsy, which is an aggressive neuroendocrine cancer.[6] Small-cell carcinoma of the cervix accounts for only 2% of all cervical cancers. Moreover, primary small-cell carcinoma of the endometrium is an extremely rare type of endometrial cancer.[6] Although the origin of the small-cell carcinoma could not be determined in our case (either from the cervix or endometrium), it was still a rare situation. To the best of our knowledge, this is the first case report of a CAR with small-cell carcinoma of the endometrium or cervix.

Vision loss occurs after the diagnosis of malignancies in most of the patients (85%), and only 15% of patients reported vision loss near the time or preceding the discovery of their primary cancer.[1] Although CAR is rare, recognizing its ophthalmic manifestation is important. The early diagnosis of CAR may help the clinicians to investigate for previous unknown malignancy, having substantial impact on systemic health.[5] Our patient presented with visual symptoms before she has gynecologic or urologic symptoms. Fundus photography, OCT, FA, and ICG were all consistent with our impression. Although ERG and serum autoantibody were not examined, her clinical presentation still triggered our further evaluation for the cause of intraocular inflammation and potential malignancy that may exist.

There was no well-defined management for CAR. Systemic steroids are commonly used with variable outcome. It is worth to note that the removal of primary cancer alone and the decreased level of serum autoantibody did not affect the course of CAR.[4] In our case, her BCVA and intraocular inflammation have much improved after giving oral prednisolone. However, small-cell carcinoma of the endometrium or cervix is reported to have strong invasiveness and a poor prognosis,[6] and our patient expired 2 months after her first visit to our ophthalmologic clinic.

In conclusion, we report a case of CAR with ophthalmic manifestation preceding the diagnosis of her gynecologic cancer, which is an extremely rare case of small-cell carcinoma either from the cervix or endometrium. Recognizing and early diagnosis of CAR is essential since it helps with the investigation of life-threatening malignancy.

Declaration of patient consent

The authors have obtained the patient’s consent form, in which she has given her permission for her images and other clinical information to be reported in the journal. The patient acknowledges that her name and initials will not be published, and every effort will be made to ensure the concealment of her identity. However, complete anonymity cannot be guaranteed.

Data availability statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Conflicts of interest

Dr. Cheng-Kuo Cheng, an editorial board member at the Taiwan Journal of Ophthalmology, had no role in the peer-review process of or decision to publish this article. The other authors declared no conflicts of interest in writing this paper.

Funding Statement

Nil.