EGFR Mutated Lung Adenocarcinoma with Secondary Glaucoma as Early Manifestation: A Case Report

Ida Ayu Jasminarti Dwi Kusumawardani*, Venny Singgih, Ni Wayan Candrawati1, Putu Yuliawati, Herman Saputra, I Gusti Ayu Sri Mahendra Dewi Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, Udayana University/Sanglah General Hospital, Bali, Indonesia. Department of Ophthalmology, Faculty of Medicine, Udayana University/Sanglah General Hospital, Bali, Indonesia. Department of Pathology Anatomy, Faculty of Medicine, Udayana University/Sanglah General Hospital, Bali, Indonesia.


INTRODUCTION
Adenocarcinoma is one of the subtypes of lung cancer with the highest incidence. 1 Lung cancer, especially adenocarcinoma subtype metastasis to the ocular orbit, is a rare case. Metastasis to the orbit is obtained from 2-4.7% of cancer cases. 2 Symptoms of metastatic lung cancer to the orbit include diplopia, proptosis, blurry vision, eye pain, ptosis, or retrobulbar mass. 2 These metastatic symptoms can appear before symptoms in the primary tumor, because lung cancer often does not give specific symptoms until it reaches an advanced stage. 3 Management of lung cancer with metastases to the eye includes chemotherapy, photocoagulation, cryosurgery, surgical resection, or radiotherapy. 4 The development of targeted therapy in pulmonary adenocarcinoma with epidermal growth factor receptor (EGFR) mutations provides a therapeutic modality using tyrosine kinase inhibitors (TKI), which in some case reports provide better outcome to pulmonary adenocarcinoma with eye and orbital metastases. 5,6 A 64-year-old male patient complained of swelling, redness, painful and protruded left eye. Initially, the patient experienced a slowly-blurred left eye and narrowed vision of the left eye, resulted in complete loss of vision accompanied by eye pain. He was diagnosed with left eye neovascular glaucoma accompanied by central retinal vein occlusion and retinal detachment. Medical therapy was given, and trabeculectomy surgery and intravitreal bevacizumab injection were planned after the intraocular pressure decreased. Later on, he complained of worsening right chest pain, coughing with white sputum accompanied by weight and appetite loss. The patient also complained about lower back pain that got worse over time, spreading to the right and left legs, accompanied by tingling, weakness, and numbness in both legs. The patient worked as a gold mine worker for 10 years, and worked as a driver for 20 years. History of smoking 1 pack of cigarettes per day for 30 years, and stopped 10 years ago.

CASE
Physical examination revealed normal vital signs, physical examination of the left eye revealed proptosis, palpebral edema and hyperemia, conjunctival Chemosis, and corneal edema ( Figure 1). Physical examination of the lungs revealed decreased vocal fremitus, dimming and decreased breath sounds in the right anterior thorax at the level of the fifth and sixth intercostal spaces. Abdominal examination revealed hepatomegaly and neurological examination revealed pathological reflexes in both legs.   Bronchial mucosal biopsy showed proliferation of neoplastic cells which were infiltrative to the stroma. The neoplastic cells were round to oval with eosinophilic cytoplasm, arranged in acinar pattern. The neoplastic cells had round-to-oval, moderately-to-severely pleomorphic nuclei with irregular nuclear membrane, high N/C ratio, and some with nucleoli. Histomorphological features were consistent with adenocarcinoma Contrast-enhanced CT scan of the head and orbits showed retrobulbar intraconal mass of the left eye, which infiltrated the rectus and optic nerves, left maxillary sinus and caused proptosis; left eye retinal detachment; multiple masses in the left occipital lobe, bilateral parietal lobe and left temporal lobe, suspicious of metastasis, cerebral edema with right midline shift; and soft tissue swelling of the left periorbital space ( Figure 5).
Epidermal growth factor receptor (EGFR) examination detected deletion of exon 19, therefore tyrosine kinase inhibitor (TKI) was administered. The patient died 13 months later.

DISCUSSION
Pulmonary adenocarcinoma is a type of nonsmall cell lung carcinoma that is quite common, approximately in 20-48% of cases of lung cancer. 2 Adenocarcinoma is the most common subtype of lung cancer in women. Pulmonary adenocarcinoma is frequently found as an incidental finding (20.6%). Symptoms that can appear are cough (18.4%) and chest pain (13.7%). Some of the patients experienced symptoms from their metastases (8.7%). It is in contrast to other subtypes, which are generally preceded by complaints of respiration first. For example, squamous cell carcinoma, the most common symptoms that appeared at the beginning were cough (19.2%) and coughing up blood (24%). In this case, the patient had no previous respiratory symptoms, and the first symptom that arose was the symptom of orbital

A B
A B metastases, namely eye pain and visual disturbances.
Respiratory symptoms that appeared first were coughing and chest pain.
Pulmonary carcinoma is often found in stage 4 with metastases. The most common metastatic pathways are lymphatic and hematogenic. Hematogenic metastases occur earlier with a high incidence of recurrence, thus reducing the patient's survival.
Meanwhile, lymphatic metastases take longer. The most common metastatic sites for lung cancer are the brain, bones, and adrenal glands. Pulmonary adenocarcinoma, especially with EGFR mutations, often has metastases to the brain. 7 Adenocarcinoma is the lung cancer subtype with the most metastases, 43% of all lung cancer cases are with metastases. 1 Lung cancer metastasis to the orbit is a rare case. Orbital metastases account for 2-4.7% of cancer cases and is increasing from year to year. It is caused by improved cancer therapy that increases the median survival of cancer patients, thus providing opportunities for metastases to appear in new sites, developing diagnostic scanning tools, increasing use of fine needle biopsy, and the application of serological and molecular diagnostic techniques improve the detection of these lesions. In addition, the growing literature regarding orbital and ocular metastases raises awareness of these lesions. 2 Cancer metastasis to the orbit mostly found as breast cancer metastasis, but it can also be lung, prostate, thyroid, gastrointestinal tract, and kidney cancer metastases. 5 Lung cancer has metastases in the eye in 0.2-6% of cases. 8 Orbital metastasis generally occurs by hematogenous pathway. 9 The most common orbital metastasis sites are highly vascularized areas of the uveal tract (choroid, iris, and ciliary body), especially the posterior segments of the eye, orbit, and optic nerve. 3 Some studies indicate orbital metastases are more common in the left orbital, because the left common carotid artery is a direct branch of the aorta, thus the systemic circulation has direct access to the left orbital.
However, other studies found no significant difference between the incidence of right and left orbital metastases. 2  of the sclera and cornea have high resistance to radiation. 5 The development of targeted therapy, especially in pulmonary adenocarcinoma patients with EGFR mutations, provides a therapeutic modality using TKI, which in several case reports gave an improved response to pulmonary adenocarcinoma with eye and orbital metastases. 5,6 Pulmonary adenocarcinoma patients with metastases and EGFR mutations who received TKI therapy had a 5-year survival rate of 14.6%. Deletion of exon 19 and absence of extrathoracic and brain metastases provide better survival. 11 The prognosis for ocular metastases is very low, with a life expectancy of 7.5 to 13 months for symptomatic patients, and 1.9 months for asymptomatic patients.