Isolated Rare Urethral Metastasis From Primary Lung Adenocarcinoma: Case Report and Literature Review

Background: Lung adenocarcinoma is a common respiratory malignancy, however urethral metastasis of lung adenocarcinoma has not yet been reported. This study aims to present a rare case of isolated urethral metastasis in a male patient with a history of primary lung adenocarcinoma. Case Presentation: A 69 year-old male patient was admitted complaining of dysuria and nocturia for 3 months, with a history of lung adenocarcinoma after surgery. The patient was diagnosed as benign prostatic hyperplasia (BPH) and received holmium laser enucleation of the prostate, an effective transurethral procedure to treat bladder outflow obstruction due to BPH. Four months after surgery for BPH, the patient had no improvement in symptoms and continued to complain of dysuria and perineum pain. An MRI of the pelvis indicated posterior urethral mass without any regional lymphadenopathy or other sites of lesion. Urethrocystoscopy found the mass in the membranous urethra near the verumontanum, and pathology combined with immunohistochemical staining confirmed the isolated urethral metastasis of lung adenocarcinoma. The further therapeutic regimen consisting of chemotherapy (pemetrexed combined with nedaplatin) and bevacizumab was well-tolerated, and obviously relieved the patient from dysuria and perineum pain. Conclusion: This study reported the first case of isolated rare urethral metastasis from primary lung adenocarcinoma and underlined the necessity for clinicians to remain vigilant to metastasis during follow-up of primary cancer.

Background: Lung adenocarcinoma is a common respiratory malignancy, however urethral metastasis of lung adenocarcinoma has not yet been reported. This study aims to present a rare case of isolated urethral metastasis in a male patient with a history of primary lung adenocarcinoma.

Case Presentation:
A 69 year-old male patient was admitted complaining of dysuria and nocturia for 3 months, with a history of lung adenocarcinoma after surgery. The patient was diagnosed as benign prostatic hyperplasia (BPH) and received holmium laser enucleation of the prostate, an effective transurethral procedure to treat bladder outflow obstruction due to BPH. Four months after surgery for BPH, the patient had no improvement in symptoms and continued to complain of dysuria and perineum pain. An MRI of the pelvis indicated posterior urethral mass without any regional lymphadenopathy or other sites of lesion. Urethrocystoscopy found the mass in the membranous urethra near the verumontanum, and pathology combined with immunohistochemical staining confirmed the isolated urethral metastasis of lung adenocarcinoma. The further therapeutic regimen consisting of chemotherapy (pemetrexed combined with nedaplatin) and bevacizumab was well-tolerated, and obviously relieved the patient from dysuria and perineum pain.

INTRODUCTION
Lung cancer represents the most common cancer, with 228,150 estimated new cases and 142,670 estimated deaths in the United States in 2019 (1). Lung cancer is categorized into small cell lung cancer (SCLC), accounting for 15% of cases, and non-small cell lung cancer (NSCLC), around 50% of which are adenocarcinoma histology (2,3). Surgical resection still remains the single most successful option to cure patients with lung cancer, however metastasis of primary cancer exerts as a significant factor affecting cancer-specific survival. The most common metastatic sites of lung cancer include the nervous system, bone, liver, respiratory system and adrenal gland (4,5). sHowever, the metastasis to urinary system is rare, to our knowledge, this is the first report of isolated urethral metastasis from lung adenocarcinoma.

CASE PRESENTATION
A 69 year-old male patient was admitted with difficulty urinating and nocturia for 3 months. The digital rectal examination did not indicate any hardness or nodules of the prostate, and an abdominal ultrasound revealed an enlarged prostate and the prostate specific antigen (PSA) value was normal. Fourteen months prior to this admission, he had undergone video-assisted thoracic surgery for the wedge resection of left upper lung lobe due to the left upper lung mass found in chest CT scan (Figure 1A), and pathology revealed infiltrating lung adenocarcinoma with T 2 N 0 M 0 staging (Figure 2A). Reexamination of chest CT on this admission indicated no evidence of disease recurrence after lung lesion resection ( Figure 1B). Then the patient was diagnosed with benign prostatic hyperplasia (BPH) and received holmium laser enucleation of the prostate, an effective transurethral procedure to treat bladder outflow obstruction due to BPH. The pathology revealed benign prostate hyperplasia as expected. Four months after surgery for BPH, the patient had no improvement in symptoms and continued to complain of dysuria and perineum pain. Urinalysis was negative for infection and PSA was not elevated, however an MRI of the pelvis indicated posterior urethral mass without any regional lymphadenopathy or other sites of lesion. Urethrocystoscopy under general anesthesia found the mass in the membranous urethra near the verumontanum (Figure 3), and transurethral loop electrosurgical excision was conducted to remove the mass. Due to the infiltration of tumor into normal urethral tissue, the transurethral operation aimed to resect as much tumor tissue as possible, so as to facilitate pathological diagnosis, but it was difficult to guarantee negative margins. Routine hematoxylin and eosin stained sections indicated adenocarcinoma ( Figure 2B) and further immunohistochemical staining showed negative PSA, positive thyroid transcription factor 1 (TTF1) and Napsin A, confirming the urethral metastasis of lung adenocarcinoma. To identify the latent metastases to other sites and recurrence from primary lung adenocarcinoma, the patient underwent brain MRI, chest CT, abdominal ultrasound and emission computed tomography for whole-body bone scan and received negative results, suggesting isolated urethral metastases. The patient was restaged as T2N0M1 of lung adenocarcinoma, and chose 6 courses of systematic chemotherapy (pemetrexed combined with nedaplatin) plus bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor at 3 weeks intervals. The therapeutic regimen was well-tolerated, and obviously relieved the patient from dysuria and perineum pain.

DISCUSSION
Lung cancer is the most common malignancy threatening human health, and metastasis of lung cancer is a significant prognosisassociated factor for patients. Previous studies have shown that the most common metastatic sites in lung cancer are nervous system, bone, liver, respiratory system and adrenal gland (4,5). A retrospective study from a single clinical center found that the uncommon metastases from NSCLC included kidney, pancreas, spleen, peritoneum, intestine, bone marrow, eye, ovary, thyroid, heart, breast, tonsil, and nasal cavity, which were also identified as predictors for poor prognosis (6). The identity of metastasis usually comes from routine follow-up examination or specific symptoms caused by metastatic lesions. With consideration to curative treatment for lung cancer, the early detection and instant treatment for silent metastasis to brain, bone, and liver, the most common metastatic sites, conferred benefits to quality of life and survival (7). With regard to uncommon metastatic sites, choroidal metastasis was reported in several case reports and detected on clinical characteristics of reduction in visual acuity and blurred vision (8,9). Cases of gastrointestinal metastasis from lung cancer have been occasionally detected during staging work-up or based on abdominal symptoms, including gastric metastasis (10,11), small intestine (12), and colorectal metastasis (13,14). Hu et al. performed a retrospective analysis of 366 gastrointestinal metastases cases from lung cancer and found that the small intestine and colorectum were the two most common metastatic organs of lung cancer in the gastrointestinal tract.
Metastasis from lung cancer to urinary system is rare and the majority of the reported cases focus on kidney and bladder. Verma et al. reported that stereotactic body radiation therapy exerted as a safe and effective treatment to palliatively relieve renal metastases from non-small cell lung cancer (15). Bladder metastasis from lung adenocarcinoma was also reported in some reports, with clinical symptoms of hematuria (16,17). The epidemiological information about metastatic urethral cancer was scarce and reported in limited case reports (18), and the bulbar urethra is the most encountered section of the male urethra, among which acute urinary retention, lower urinary tract symptoms, and hematuria are the main symptoms. Although Tefilli et al. reported the urethral metastasis from lung carcinoma, however the case had been diagnosed as lung giant cell carcinoma with brain metastases previously (19).
There are currently no standard treatments for isolated urethral metastases given the rarity of this condition. Based on the guideline of primary urethral cancer, in locally advanced urethral carcinoma, cisplatin-based chemotherapy with curative intent prior to surgery was beneficial for survival compared to chemotherapy alone, or surgery followed by chemotherapy (20). In this case, the main lesion was located in the membranous urethra near the verumontanum, and the further treatment was selected as cisplatin-based chemotherapy and bevacizumab. Compared with the chemotherapy-alone group, the addition of bevacizumab to chemotherapy improved overall survival and progression-free survival for advanced non-squamous non-small-cell lung cancer (21). With regards to chemotherapy, combination of pemetrexed and cisplatin was recommended as the first-line option for advanced NSCLC (22,23). In this case, chemotherapy (pemetrexed and nedaplatin) plus bevacizumab were effective to relieve local symptoms with good tolerability. Moreover, increasing evidence supported to combine immunotherapy using checkpoint inhibitors with platinum-based chemotherapy as first-line treatment in advanced NSCLC, with improved response rates and survival (24,25). For oligometastatic lesion, local therapies including surgery, radiation therapy, radiofrequency ablation, or cryoablation palliated symptoms in patients with advanced NSCLC and potentially avoid switching systemic therapy prematurely (26,27).
In this report, we present the first isolated urethra metastasis from lung adenocarcinoma. This rare case could not only add new evidence for the unreported metastatic sites of lung adenocarcinoma in the literature, but also provide lessons for clinicians. The patient's chief complaint of dysuria was routinely considered to be associated with BPH and an unnecessary surgery for BPH was performed. Although ultrasound of prostate indicated enlarged prostate and pathology also confirmed the diagnosis of BPH, however BPH was not the main reason for dysuria. For a male lung cancer patient, especially when the duration of lower urinary symptoms was short, clinicians should consider the possibility of urethral metastasis in the differential diagnosis for persistent dysuria after appropriate treatment for BPH.

AUTHOR CONTRIBUTIONS
XZ: data collection and manuscript writing. HL: data collection. SL: data collection. MZ: project development, data collection, and manuscript writing.