Choroidal metastasis resembling hemangioma on angiogram as initial manifestation of lung adenocarcinoma

Dear Editor,

We present a case of choroidal metastasis (CM)masquerading as circumscribed choroidal hemangioma as initial manifestation of lung adenocarcinoma. The study procedures were in accordance with the Declaration of Helsinki and were approved by the Institutional Review Board of the Second Affiliated Hospital of Zhejiang University School of Medicine. Written informed consent was obtained from the patient.

A 61-year-old Chinese female came to the clinic and reported to have suffered from unilateral painless vision decrease with occasional floaters for 1mo. The patient denied discomfort during eye movement, amaurosis, double vision, dizziness, nor did she report any systemic symptom. She had been diagnosed with hypertension for 10y and with breast fibroadenoma for more than 1y.

Her visual acuities were 0.097 logarithm of the minimum angle of resolution (logMAR) for the right eye and 1.0 logMAR for the left one. Intraocular pressures were 17.3 mm Hg for the right eye and 15.0 mm Hg for the left one. Anterior segment examination revealed shallow anterior chamber and mild lens opacity in both eyes. Ophthalmoscopic examination showed a prominent solid yellow-orange choroidal mass involving the macula in the left eye, with extensive subretinal fluid (SRF)ranging from the posterior pole to inferior retina. She failed to complete fundus photography examination due to her poor vision, so that scanning laser ophthalmoscopy (SLO) was applied to capture the lesion instead (Figure 1A). Scattered spots of pigment could also be observed on the surface of the mass (Figure 1A). No retinal abnormality was found in the right eye. B-scan ultrasound of the left eye demonstrated a smoothly elevated mass with homogeneously high internal reflectivity,and a crooked hyper-reflective line indicative of detached retina (Figure 1B). Significant elevation of retinal pigmented epithelium (RPE)/Bruch’s membrane complex, caused by the large choroidal mass, prevented optical coherence tomography(OCT) from detailed recognition (Figure 1C). However, the altered structure of ellipsoid zone could be observed on OCT,and SRF was vaguely detected underneath the poorly-defined speckles-dotted RPE. Orbital enhanced magnetic resonance imaging (MRI) reported irregularly thickened posterior wall of the left eye (maximal thickness of 4.4 mm) that was hypointensive in both T1 (Figure 1D) and T2 (Figure 1E) weighted images, with suspicious enhancement (Figure 1F).

A week later, her visual acuity of the left eye decreased to finger count at 30 cm, and an exacerbation of retinal detachment was observed (Figure 2A). To ensure the safety of mydriasis before angiography, laser peripheral iridotomy(LPI) was carried out. Both fundus fluorescein angiography(FFA) and indocyanine green angiography (ICGA) showed irregular areas of hyper-fluorescence in the lesion during the early phase, which reflected a filling of intrinsic vascular architecture within the mass (Figure 2C, 2D). Scattered hyperfluorescent pinpoints over the mass, blocked by patchy hypofluorescence, persisted in the venous phase and late phase(Figure 2E-2H). The hypo-fluorescent areas on FFA (Figure 2G) partially conformed to the pigment spots recognized by ophthalmoscopy (Figure 1A). According to the angiographic manifestations, the clinician suspected circumscribed choroidal hemangioma, but advised further screening of malignancy considering her onset age and rapid progression.

為了進一步提升間接信任的準確性,本文在已有模型的基礎上提出了推薦信任權重分配方案。本文將為集合Cf中的c個節點根據其偏離度大小來分配權重,偏離程度越小的推薦信任權重越大。定義集合Cf中節點推薦信任的總偏移度D(t)如下:

After enhancement, CMs generally show bright signal on T1-weighted and low signal on T2-weighted images, while choroidal hemangiomas show bright signal on both T1- and T2-weighted images. Orbital MRI of our patient displayed hypo-intense signals on both T1- and T2-weighted images,which might suggest metastasis. Nonetheless, localized enhancement detected on T2-weighted images tended to indicate hemangioma.

2014年至2017年，西達里亞油田共實施提液、加大機泵拉升功率、控井筒流量、調驅擾動水竄等低成本措施16井次，累計實現效益增油0.74萬噸。

As for angiography, ICGA outweighs FFA in the differential importance of choroidal masses. Classic features of CM in FFA should be hypo-fluorescent in the early phase and heterogeneously hyper-fluorescent in the late phase. However,sometimes the FFA of CM is hyper-fluorescent at all phases,leading to a misdiagnosis of hemangioma

. ICGA pattern of CM, on the other hand, is usually defined as hypo-fluorescent at all phases on an underlying iso-fluorescent background

.Compared to FFA, the mottled hyper-fluorescence of the mass in the late phase is seldom described in ICGA. Even in a case report that misdiagnosed CM for hemangioma while presented ICGA result, ICGA still appeared hypo-fluorescent

. In circumscribed choroidal hemangioma, the angiogram is intense and achieves rapid hyper-fluorescence in both FFA and ICGA due to its rich intrinsic vasculature

. Therefore, the hyperfluorescent feature in FFA and ICGA of our patient favored the diagnosis of circumscribed choroidal hemangioma instead of CM.

網板主要由絲網、網框和掩膜圖形等組成。具體參數設置包括網板開孔尺寸、厚度及開孔方向。網板開孔尺寸主要由印刷板對應焊盤的尺寸決定；網板的越厚則開孔越小，越不有利于焊膏釋放；焊膏釋放在焊盤的長度方向與印刷方向一致時，印刷效果較好。常見網板設計工藝見表1。

1.1 資料來源 選取2015年11月-2016年1月在上海市第一婦嬰保健院定期產檢并最終分娩的孕28～34周的子癇前期高危孕婦271例。高危孕婦應符合以下入組條件之一：①年齡≥35周歲；②孕前BMI>27 kg/m2；③妊娠期糖尿病；④前次妊娠子癇前期病史；⑤子癇前期家族史；⑥一級親屬高血壓；⑦孕后初發型高血壓，不伴蛋白尿；⑧孕后初發蛋白尿，不伴有高血壓；⑨嚴重水腫、肝酶升高等臨床表現。排除標準：①年齡<18歲；②多胎孕婦；③胎兒畸形或胎兒染色體異常。

B-scan ultrasound is an important screening method to assess choroidal masses. Typical CMs on B-scan ultrasound would show multilobular flat or dome-shaped masses of heterogeneous reflectivity with irregular surface

.Circumscribed choroidal hemangioma, on the other hand,is characteristic of a slightly dome-shaped mass with homogeneous hyper-reflectivity internally and with acoustic solidity similar to the surrounding choroid

. In our case,although the slightly elevated morphology of the mass could indicate both CM and hemangioma, the solitary lesion, the smooth surface and the generally homogeneous reflectivity favored the diagnosis of circumscribed choroidal hemangioma.In OCT, the lesion of CM would appear to be lumpy bumpy with alterations in RPE and morphological changes in photoreceptors

, while choroidal circumscribed hemangioma mostly would appear as a distinct elevation with smooth surface delimited from choriocapillaris interface

. Although the OCT images of our patient were greatly influenced by the extensive retinal detachment, the obvious alterations of RPE supported the diagnosis of CM.

Previous studies showed that CMs were iso-intense on T1-weighted images and hypo-intense on T2-weighted images,while choroidal hemangiomas were hyper-intense on T1-weighted images and iso-intense on T2-weighted images

.

In the following two weeks, the patient showed no clinically significant finding in abdominal ultrasound, abdominal enhanced computed tomography (CT), transvaginal ultrasound,breast ultrasound, and brain MRI. However, elevated levels of carcinoembryonic antigen (CEA, 8.6 ng/mL), cancerantigen-199(CA-199, 86.7 U/mL), CA-211 (5.8 ng/mL), CA-125 (40.6 U/mL),CA-153 (123.6 U/mL), and neuronspecific enolase (NSE,26.5 ng/mL), were detected in serum. More importantly, chest high resolution (HR)-CT revealed that a mass characterized of lobular and spiculate boundary, sized 35.1×37.6×33.1 mm

, was located on the left upper lobe. The patient was then admitted by oncology department for CT-guided lung puncture biopsy and radionuclide bone imaging. The biopsy results confirmed lung adenocarcinoma, showing positive for thyroid transcription factor-1 (TTF-1), cytokeratin 7 (CK7), and Napsin A, while negative for programmed death 1 ligand (PD-L1) and anaplastic lymphoma kinase-lung (ALK-lung) in immunohistochemistry.Genetic test indicated exon deletion mutation on epidermal growth factor receptor 19 (EGFR 19). Radionuclide bone imaging demonstrated multiple bone metastases. The patient was finally diagnosed with lung adenocarcinoma and began targeted therapy with gefitinib.

CM is considered the most common form of intraocular malignancy. However, the prevalence of symptomatic cases is reported to be less than 3%

. Lung cancer was the primary cancer site of CM in 21% cases, accounting 40% cases of males and 12% cases of female

. A Meta-analysis of CM from lung malignancy reported that 42% were adenocarcinomas

.Among choroidal masses, choroidal metastases present highly various clinical manifestations

. Therefore, differential diagnosis of CM from other choroidal masses was important for prompt systemic evaluation. Both CM and choroidal hemangioma could display yellow-orange mass on funduscopic examination, and are frequently associated with wide range of exudative retinal detachment. Spots of pigment accumulation are also common signs of both diseases. In this case, the main challenges for diagnosis are as follows: first, the morphology and reflectivity distribution on B-scan ultrasound were not typical of CM; second, a wide range of elevated retina caused by exudative retinal detachment interfered with clear structure detection in OCT and FFA/ICGA; most importantly, the relatively rich blood supply of the choroidal mass, reflected by FFA/ICGA and MRI enhancement, complicated the diagnosis process, for it accorded with the characteristics of circumscribed choroidal hemangioma rather than those of common CM

. Choroidal tuberculoma, nevertheless, could displayed various characteristics which can be delusive, and should be addressed in areas with heavy burden of tuberculosis patients. Yellow-orange lesion with exudative retinal detachment could be observed in some cases

, but would mostly accompany other features of uveitis

. A lack of anterior uveitis, insufficient evidence of lung tuberculosis, and biopsy result could decrease the possibility of tuberculosis, although a specific lab examination on

would be more convincing.

In summary, unusual pattern of a smooth morphology and a relatively rich vascularization could be detected in CMs.Multimodal imaging examinations as well as appropriate systemic screening are necessary in diagnosing choroidal masses.

ACKNOWLEDGEMENTS

Authors’ contributions: Wang Y performed the initial and follow-up visits, evaluated clinical data, and revised the manuscript. Liu X assembled the data and was a major contributor in writing the manuscript. Ma J was also a contributor in writing the manuscript. Su ZT assisted in literature review. Zhang L and Fang XY reviewed the manuscript. The authors read and approved the final manuscript.

Foundation: Supported by Medical Scientific Research Foundation of Zhejiang Province, China (No.201130184).

Conflicts of Interest: Liu X, None; Ma J, None; Su ZT,None; Zhang L, None; Fang XY, None; Wang Y, None.

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