Unilateral Choroid Metastasis as an Initial Presentation of Lung Cancer-Two Case Reports

To determine the clinical incidence and characteristics of symptomatic choroidal metastasis (CM) in breast cancer. Forty-six consecutive patients with CM from breast cancer were retrospectively reviewed in respect of ocular findings, medical history and systemic disease. Clinical incidence of CM was determined and compared with the incidence predicted from prevalence data obtained in ocular screening studies. Choroidal metastasis occurred with a median interval of 42.4 months after diagnosis of breast cancer and was predominantly unilateral (63% patients) and solitary (57% affected eyes). A total of 32% of patients had no history of metastatic tumour disease, but systemic screening with CT and scintigraphy revealed metastatic disease in 100% of patients. A median number of three other organs were affected by metastasis. Median survival from diagnosis of CM was 13.1 months. The mean number of local patients diagnosed with CM was 2.9 per year, which was one order of magnitude less than predicted from clinical screening studies. Choroidal metastasis occurs in advanced metastatic breast cancer, indicating a grave vital prognosis. In a minority of patients (32%) it is the first sign of metastatic disease. The clinical incidence of CM is far smaller than predicted from prevalence data obtained from ocular screening studies.

Purpose: To report a case of choroidal metastasis as the main presentation in a patient with lung carcinoma. Method: Case report. Results: A 69-year-old woman complained of blurred vision in her right eye for 2 months. The best-corrected visual acuity was counting finger in right eye. Fundoscopy demonstrated a large choroidal mass located inferiotemporally associated with exudative retinal detachment in her right eye. B-scan ultrasound revealed the tumor had a high internal reflectivity. Magnetic resonance imaging of the orbit showed an intraocular mass that was approximately 5 mm in thickness. After enucleation, pathologic study of the enucleated eye demonstrated a choroidal metastasis. Complete systemic survey disclosed that a primary lung adeno-carcinoma with bone and choroidal metastasis count for the ocular lesion. Conclusions: Choroidal metastasis can be the first clinical manifestation of lung adenocarcinoma. Ophthalmologists should be aware of systemic malignancy in choroidal metastasis and initiate a thorough systemic evaluation for early detection of life-threatening malignancies.

Objective：The term lung cancer or known as bronchogenic carcinoma,whichrefers to malignancies that originate in the airways or pulmonary parenchyma. Lung cancers are classified as small cell lung cancer (SCLC) (13%) or non-small cell lung cancer (NSCLC) (82%). These cell types of lung cancer comprise up to 95% of all lung cancer. Only 5% of lung cancers are comprised of other cell types. Non-small cell lung cancer can be further divided into three major cell types, including squamous cell lung cancer (SCC) (20%), adenocarcinoma (ADC) (38%) and large cell carcinoma (5%). Lung cancer is the most common cancer worldwide. In the year 2009, it was estimated to have 1,600,000 new cases and 1,380,000 deaths directly related with lung cancer occurred in the US. The absolute and relative frequency of lung cancer has increased dramatically. Lung cancer has became the most common cause of cancer deaths in men since the year of 1953 and has also became the most common cause of cancer deaths in women after the year 1985. Despite the cause of lung cancer deaths in male starts to decrease, but the trend of lung cancer deaths continues to increase in female. It was estimated that approximately half of cancer deaths occur in women. In Taiwan, lung cancer has also become the leading cause of deaths since the year 1980. In the past 30 years, lung cancer remains to be the leading cause of deaths. In both men and women, the incidence of lung cancer has increased 8 times and is also the most rapidly increased cancer among all cancers. The incidence of small cell lung cancer in Taiwan is approximately 88-90% and the incidence of small cell lung cancer is about 10-12%. The primary risk factor for the development is cigarette smoking, especially in squamous cell lung cancer. The overall survival and prognosis is poor. In all lung cancer patients, the overall 5 year survival rate is about 15%. Usually, patients are in late clinical staging at the time of cancer diagnosis. In non-small cell lung cancer, nearly 30-40% of cases were in stage four. Likewise, about 60% of small cell lung cancer patients were in disseminated stage. Many factors are related with prognosis in both small cell and non-small cell lung cancer, among these, cancer stage is the most important prognostic factor. Other related prognostic factors include, clinical parameters, histopathology, molecular characterization, positron- computerizedtomography (PET-CT) findings, and whether there is any recurrence after tumor resection. Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) is also being utilized to be a diagnostic assay to detect whether there is any lymphatic metastasis in non-small cell lung cancer. The immune system is a complex and sophisticatenetwork, that is designed to protect the host from both external (such as bacteria and virus) and internal threats (such as malignant transformation). Cytokines are hormone-like proteins that enable immune cells to communicate and play an integral role in the initiating, perpetuation and subsequent downregulation of the immune response. Cytokines are as important to the termination of the immune response as they are to its initiation. Interleukine-10 (IL-10) is also known as a human cytokine synthesis inhibitor factor (CSIF). It is an important immunoinhibitory cytokine or function as an anti-inflammatory cytokine. It also plays an integral role in the complex but balanced immune network system. Previous studies have shown that interleukine-10 promoter polymorphisms at (-1082A>G, -819C>T, -592C>A) is closely related to its transcription activities. Blocking the tumor immune-surveillance by suppressing T-cell immunity could explain the important role of IL-10 in the progression of tumor. Several other studies have also observed that Il-10 promoter polymorphisms are also related to many other cancers, including diffuse B-cell lymphoma, non-Hodgkin’s lymphoma, breast cancer, gastric cancer, colon cancer, myeloma, advancedmelanoma and skin squmaous cell carcinoma occurred after renal transplantation. Squamous cell lung cancer is closely related to cigarette smoking, a procarcinogen extracted from cigarette (NNK)Nicotine-derived nitrosamine ketone, or 4-(methylnitrosamino)- 1-(3-pyridyl)-1-butanone, is a nitrosamine, which could induce the production of IL-10. It probably plays an important role in the development of lung cancer. In our previous study, we hypothesized that IL-10 haplotypes categorized by IL-10 promoter polymorphisms at (-1082A>G, -819C>T, -592C>A), might influence IL-10 expression and may be related with poor clinical outcomes and relapse in patients with non-small cell lung cancer. We have observed that lung tumors with non-ATA haplotypes had significantly higher mRNA level when compare with tumor with ATA-haplotypes. The overall survival (OS) and relapse free survival (RFS) in tumors with non-ATA haplotypes was significantly shorter then tumors with ATA-haplotypes. Furthermore, T-cells collected from peripheral blood in healthy donors when co-cultured with cancer cells, were more susceptible to apoptosis and less cytoxic to tumor cells in patients with non-ATA haplotypes than in patients with ATA-hapoltypes. T-cells apoptosis could be increased and tumor cell apoptosis could be decreased by adding IL-10 recombinant protein. On the contrary, T-cell apoptosis could be decreased and tumor cell apoptosis could be increased by adding neutralizing antibody. This was also consistent with our hypothesis that IL-10 haplotypes categorized by IL-10 promoter polymorphisms at (-1082A>G, -819C>T, -592C>A), might influence IL-10 expression and may be related with poor clinical outcomes and relapse in patients with non-small cell lung cancer. The influence of IL-10 was further demonstrated in our animal experiment. In the histological examination of TC-1 tumors in lung following intravenous injection of TC-1 cells into experiment mice. Lung metastasis was found in mice injected with IgG antibody but not in mice injected with IL-10 neutralizing antibody. We have concluded that, IL-10 can promote tumor malignancy via promoting T-cell apoptosis and tumor cell survival, and IL-10 haplotypes may be used to predict survival and relapse in resected non-small cell lung cancer. The overall survival and prognosis of lung cancer is poor, therefore we are expecting to apply and utilize the state of the art molecular technology, in predicting the response of lung cancer treatment and overall survival. Interleukin-10 (IL-10) may play an importance role in the progression of lung cancer. The objective of this study is to evaluate the different impact of IL-10 haplotypes on prognosis, including overall survival (OS) and relapse-free survival (RFS) in lung squamous cell cancer (SCC) and adenocarcinoma (ADC). Methods and Materials：In this study, we included 439 non-small cell lung cancer (NSCLC) patients recruited from Taichung Veteran General Hospital (TCVGH). Study samples were collected from immediately frozen section during surgery. Surgically resected normal lung tissues adjacent to the lung tumor were examined. Genomic DNA was extracted by conventional methods, which was prepared by prokinase K digestion and phenol-chloroform extraction; followed by ethanol precipitation. The genotypes of IL-10 were determined by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). Polymorphisms of IL-10 were determined by direct sequencing of Polymerase Chain Reaction(PCR) products amplified from the DNA of normal tissues adjacent to the tumors. For continuous or discrete data analysis, Student’s t-test and Chi-square test were applied. Kaplan-Meier method and log-rank test were used to determine the association between IL-10 promoter polymorphisms and patients’ survival. Cox regression models were used to adjust potential confounders. Statistical testing was conducted by using two-sided tests and p-values G, -819C>T, and =592G>A). The non-ATA haplotype in NSCLC is more prevalent both in nodal metastatic tumors than in non-nodal metastatic tumors (N0) (59.7% vs. 48.4%, p = 0.017). In our previous study, we have also shown that patients with non-ATA haplotypes had higher IL-10 mRNA expression levels than patients with ATA haplotypes. In tumor histology, IL-10 haplotypes also correlated with nodal metastasis (63.0% vs 40.5%, p < 0.01) and tumor stage in SCC (59.2% vs 46.3%, p = 0.047). This was not observed in ADC patients. The non-ATA haplotypes may be used as a biomarker for poor prognosis in surgically resected NSCLC. Kaplan-Meier and Cox regression analysis showed that patients with ATA haplotypes had poorer OS and RFS. (HR 1.522, 95% CI = 1.191-1.945, p=0.001 for OS; HR 1.611, 95% CI = 1.247-2.082, p < 0.01 for RFS). The median survival duration and five years survival rate of patients with non-ATA haplotypes were significantly shorter when compare with patients ATA (median OS = 25.8 vs. 42.9 months; median RFS =16.8 vs. 30.9 months; 5-year OS = 28.6% vs. 44.7% and RFS = 22.2% vs. 36.2%). SCC patient with non-ATA haplotypes had poorer OS and RFS than patients with ATA haplotypes. No prognostic value was observed in ADC patients. These results suggest that IL-10 haplotypes has different impacts on OS and RFS in SCC patients from those with ADC. Conclusion and Suggestion：The IL-10 haplotypes has been associated with lung cancer risk. A prognostic value of non-ATA haplotypes was observed for SCC, but not for ADC. Non-ATA haplotypes were associated with nodal metastasis and tumor stage. In summary, IL-10 may have a stronger influence on tumor progression in SCC than ADC.

Purpose: We present a case of choroidal metastatic tumors achieving a best corrected visual acuity of 20/20 after intravitreal injection of bevacizumab (Avastin) and focal laser photocoagulation.Method: Interventional case report.Results: A 68 y/o male has been diagnosed with pulmonary adenocarcinoma (T4N1M0) in December 2006, and had received surgical intervention, radiotherapy and chemotherapy. He visited our outpatient department in December 2009 and presented with blurred vision in his right eye. His best corrected visual acuity was 20/40. Fundus examination revealed multiple subretinal masses, light orange in color, superotemporal and inferonasal to the fovea, in the right eye. Optical coherence tomography scan showed marked subretinal fluid of the macula. A diagnosis of choroidal metastasis secondary to lung cancer was made. After discovering choroidal metastatic lesions, two sessions of intravitreal injection of bevacizumab and three sessions of focal laser photocoagulation were performed. After three months follow-up, his best corrected visual acuity regained 20/20. Scarring and flattening of choroidal lesions were noted on color fundus photography. Multiple hyperfluorescent spots without leakage were showed on fluorescein angiography. Regression of macular edema and serous detachment were evident on optical coherence tomography scan.Conclusion: For the patient with choroidal metastases who wants to preserve good visual acuity and better quality of remained life, intravitreal injection of bevacizumab plus focal laser photocoagulation may be considered. Longer follow-up period is needed for evaluation of efficacy and effectiveness of such treatment.

So far as we know, the most metastatic site in lung cancer is brain and bone. Choroid metastases rarely occur in clinical diagnosis. We report a case of 57 yearold woman presenting as right blurred vision initially. She came to our hospital for further management due to deteriorating vision. Magnetic resonance (MR) revealed a homogeneous enhancing soft tissues mass occupied in the posterior surface of right eye. Under the impression of primary melanoma, enucleation was performed in June fifth, 2006. Pathologic report proved metastatic adenocarcinoma later. Chest computerized tomography (CT) displayed a spiculated mass at RUL and multiple mediastinal lymphadenopathies. Primary adenocarcinoma of lung with choroid metastases was final diagnosed. We also reviewed related literature and emphasized the importance of differentiating diagnosis in choroidal tumor, especially in cancer patients.

Choroid metastasis from primary lung cancer is rare and has a poor prognosis. It can be treated with an external beam of radiation or by laser photocoagulation. However, visual defects or blindness are possible complications related to radiotherapy. Chemotherapy for such a condition has not been widely reported. We report a 26-year-old patient who had stage IV lung adenocarcinoma and suffered from progressive blurred vision during a scheduled chemotherapy regimen. Fundoscopy, fluorescence angiography and optic coherence tomography indicated choroidal metastasis of both eyes. We prescribed a platinum double chemotherapy regimen with pemetrexed and cisplatin. A follow-up examination demonstrated complete remission of the choroid metastasis. Herein, we report the first case of lung cancer with choroid metastasis that underwent complete remission after pemetrexed administration. We share our experience and conduct a literature review. (Thorac Med 2012; 27: 159-166)

Although metastasis to the eye is the most common ophthalmic malignancy, it is usually asymptomatic and rarely a presenting symptom that leads to the diagnosis of a primary. Here, we report a patient who was evaluated for visual symptoms and was eventually diagnosed to have disseminated adenocarcinoma of the lung. He was treated with external radiotherapy to the choroidal metastasis, attaining an excellent response that was sustained until his death. A brief review on the role of radiotherapy in the management of uveal metastases is also presented.

A 68-year-old man was referred because of an abnormal shadow in the right upper lung field on a chest X-ray film. After the diagnosis of adenocarcinoma of the lung, left upper lobectomy was done. Histologically, adenocarcinoma with foci of squamous cell carcinoma was seen. About 11 months after that operation, he suddenly noticed a decrease in visual acuity on the left side. The fundus of the eye was tested and metastatic choroidal cancer was suspected. To prevent rupture, the eyeball was enucleated. The choroidal tumor appeared to have components of squamous cell carcinoma from primary lung cancer. About 7 months after enucleation of his eyeball, the patient was disease-free with no decrease in his quality of life. As a result of a recent increase in the incidence of lung cancer, it is important to pay attention to ophthalmological tests in patients with primary lung cancer.

Lung cancer is the leading cause of cancer death in industrialized countries with persistently high mortality rates and 5-yr survival of less than 15% (1–3). According to a recent report by the United States Surgeon General, lung cancer in women has increased 600% since 1950 and has clearly reached epidemic proportions (2). Pulmonary adenocarcinoma (PAC) was once a rare form of lung cancer, but has risen dramatically during the last three decades to be the leading type of lung cancer today (4–7). PAC is particularly prominent in women (4,8,9). It is well documented that smoking is the primary risk factor for the development of lung cancer, including PAC (1–5). Among the four major histologic lung cancer types (PAC, small cell carcinoma, squamous cell carcinoma, large cell carcinoma), PAC is the malignancy that most often develops in nonsmokers. Recent studies have shown that nonsmall cell lung carcinomas (NSCLC) frequently overexpress cyclooxygenase-2 (COX-2), a trend particularly prominent in PAC (10,11). This enzyme converts arachidonic acid (AA) into several metabolites, some of which have been identified as modulators of mitogenesis, angiogenesis, and apoptosis (12–18). Accordingly, the AA cascade and COX-2 are currently being widely studied as potential targets for lung cancer prevention. However, successful chemoprevention requires an indepth understanding of the cancer-initiating and promoting cellular mechanisms. As shown by the painful experience with the Carotene and Retinol Efficacy Trial (CARET), agents that effectively inhibit lung cancer growth in preclinical models do not necessarily have similar effects in human lung cancer (19). Although carotenes and retinols produced significant chemopreventive effects in the hamster tracheo-bronchial model of squamous cell carcinoma (20,21), CARET had to be discontinued because of a 46% increase in lung cancer mortality and a 26% increase in cardiovascular mortality in the groups receiving beta-carotene and retinyl palmitate (19).

Lung cancer is the leading cause of cancer death in the world [1-2]. In patients with lung cancer, metastasis to the bone, brain, liver and adrenal gland is most frequently found [2]. Gastrointestinal metastasis is not as frequently reported [1]. Among these patients, bleeding, anemia, and acute abdomen were the common presentations. Intussusception is a relatively rare but emergent condition. Aggressive investigation and early surgery are the only methods for providing palliation to patients with gastrointestinal metastasis. However, morbidity and mortality remain high and the prognosis is poor. Herein, we report a lung adenocarcinoma patient who presented acute abdomen; the final diagnosis was the unexpected small bowel intussusception caused by metastasis. We report this rare case and review the literature.

Objective To investigate the clinical findings and diagnostic value of MRI,ultrasonography fundus fluorescein angiography (FFA) and indocyanine green angiography (ICGA) in patients with choroidal neoplasms. Methods In this retrospective study,the clinical data of 22 patients with choroidal neoplasm treated in Zhongshan Ophthalmic Center,Sun Yat-sen University from January 2008 to December 2009 was collected and analyzed.All patients were examined by ultrasound type-B and color Doppler scan.Some of them received FFA,ICGA,CT and MRI examinations.The patients with primary malignant tumor were treated with enucleation.The patients with choroidal metastasis were referred to tumor hospital and usually had systemic chemotherapy and local radiotherapy.The patients with choroidal hemangiomas usually received retinal photocoagulation or photodynamic therapy except those with uncontrolled secondary glaucoma who often had enucleation. Results The imaging of 12 patients with choroidal malignant melanoma showed typical globular or mushroom-shaped intraocular mass with brown or black color.MR1 examination revealed high signal intensities on TlWI and low signal intensities on T2WI.Flat orange-red neoplasm in the posterior pole was the main clinical characteristics of choroidal hemangioma in 7 patients.In the early phase,hyperfluorescence was observed in choroidal hemangioma with FFA/ICGA.MRI revealed low or medium signal intensity on TlWI and high signal intensity on T2WI,with high enhancement.Three cases of choroidal metastasis usually demonstrated flat gray-yellow intraocular mass in posterior pole,all of them had the primary systemic tumor in our case series,and one patient was involved bilaterally. Conclusions The diagnosis of choroidal neoplasm often can be confirmed through detail routine fundus examination in eyes with refractive media transparency.FFA/ICGA is highly valuable in the diagnosis of choroidal hemangioma.MRI and ultrasound examination contributes well to the diagnosis of choroidal neoplasm in eyes with refractive media opacity. Key words: Choroidal neoplasm; MRI; Ultrasonography; Fundus fluorescein angiography; Indocyanine green angiography

Breast cancer is the most common malignancy in women, with increasing incidence in Europe and North America. The frequency of involvement of the eye and visual pathways is reported to be as high as 30% in patients with known metastatic disease. In some cases, ophthalmic involvement can be the first sign of metastatic spread. Metastasis occurs via the haematogenous route and predominantly involves the choroid. Metastases to other ocular structures, the orbit and the visual pathways have also been described. Paraneoplastic effects are rare but significant. Different modalities are employed in the treatment of breast cancer and its metastases. These include chemotherapy and radiotherapy. The ocular adverse effects of these have been well described, but recently developed new treatment modalities, such as monoclonal antibodies, may have different side-effects. With the increasing incidence of breast cancer and the advent of new treatment strategies, the complications of the disease and the sequelae of therapy are highly relevant to both oncologists and ophthalmologists.

Aberrant Stratifin Overexpression Is Regulated by Tumor-Associated CpG Demethylation in Lung Adenocarcinoma

To report the authors experience in the use of infrared diode laser transpupillary thermotherapy in the management of selected posterior choroidal metastatic tumors. Seven eyes of seven patients were treated using 810 nm infrared diode laser. Spot sizes of 0.5 to 3 mm were selected, each lasting 1 minute. When necessary, the treatment was repeated at 8- to 10-week intervals. Disappearance of the tumor was the main outcome measure. The primary sites of carcinomas were breast, prostate, and lungs. The largest basal diameters of ocular tumors varied between 5 mm and 10 mm and the thickness ranged between 2 mm and 4.5 mm. A mean power of 612 mW was used in one to four treatment sessions. In six eyes the tumors were reduced into flat scars whereas in one case the tumor continued to grow necessitating external beam radiotherapy. In three eyes the visual acuity decreased and in three eyes the vision became better. In one eye the vision was restored after external beam radiotherapy with the disappearance of extensive subretinal fluid. There were no immediate postoperative complications. Transpupillary thermotherapy can be a reliable, convenient, and cost-cutting option in the management of small, solitary choroidal metastatic tumors with a thickness of less than 3.5 mm and which have minimal subretinal fluid. Although successful in terms of tumor control, treatment close to the fovea or optic nerve head may cause a permanent decrease in visual acuity. (Eur J Ophthalmol 2004; 14: #-9).

MEN1, which encodes the nuclear protein menin, acts as a tumor suppressor in lung cancer and is often inactivated in human primary lung adenocarcinoma. Here, we show that the inactivation of MEN1 is associated with increased DNA methylation at the MEN1 promoter by K-Ras. On one hand, the activated K-Ras up-regulates the expression of DNA methyltransferases and enhances the binding of DNA methyltransferase 1 to the MEN1 promoter, leading to increased DNA methylation at the MEN1 gene in lung cancer cells; on the other hand, menin reduces the level of active Ras-GTP at least partly by preventing GRB2 and SOS1 from binding to Ras, without affecting the expression of GRB2 and SOS1. In human lung adenocarcinoma samples, we further demonstrate that reduced menin expression is associated with the enhanced expression of Ras (p < 0.05). Finally, excision of the Men1 gene markedly accelerates the K-Ras(G12D)-induced tumor formation in the Men1(f/f);K-Ras(G12D/+);Cre ER mouse model. Together, these findings uncover a previously unknown link between activated K-Ras and menin, an important interplay governing tumor activation and suppression in the development of lung cancer.