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Pulmonary manifestations of urothelial carcinoma of the bladder
Respiratory Medicine 128 (2017) 65e69
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Respiratory Medicine journal homepage: www.elsevier.com/locate/rmed
Review article
Pulmonary manifestations of urothelial carcinoma of the bladder Abhinav Agrawal, M.D. a, b, Sonu Sahni, M.D. b, c, Abhinav K. Vulisha, MBBS b, Rammohan Gumpeni, M.D. d, Rakesh Shah, M.D. e, Arunabh Talwar, M.D., FCCP b, * a
Monmouth Medical Center, Department of Medicine, 300 Second Avenue Long Branch, NJ 07740, United States Northwell Health, Department of Pulmonary, Critical Care and Sleep Medicine, 410 Lakeville Rd. Suite 107, New Hyde Park, NY 11040, United States c Touro College of Osteopathic Medicine, Department of Primary Care, New York, NY 10027, United States d New York Presbyterian Hospital Queens, Department of Pulmonary Critical Care Medicine, 56-45 Main Street Flushing, NY 11355, United States e Northwell Health, Department of Radiology, 410 Lakeville Rd. Suite 107, New Hyde Park, NY 11040, United States b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 26 September 2016 Received in revised form 12 April 2017 Accepted 13 May 2017 Available online 16 May 2017
Urothelial carcinoma (Transitional cell carcinoma) of the bladder is the pre-dominant histological type of bladder cancer in the United States and Europe. Patients with bladder cancer usually present with painless hematuria. The diagnosis is often delayed, as the symptoms are similar to various other benign conditions such as urinary tract infection, prostatitis or renal calculi. In some patients, the metastatic lesions will cause the initial presenting symptoms. We conducted a MedLine/PubMED search identifying all relevant articles with “pulmonary manifestations”, “urothelial bladder cancer”, “manifestations of bladder cancer” or a combination of these terms in the title. The pulmonary manifestations of urothelial carcinoma of the bladder include metastatic disease including cavitary lesions, endobronchial, pleural, or lymph node metastasis pleural effusion and chylothorax. Pulmonary embolism and tumor embolism is another manifestation of this cancer. Intravesical Bacillus Calmette-Gurin therapy for bladder cancer has rin been associated with a range of adverse effects including the systemic spread of Bacilli Calmette-Gue immunotherapy affecting the lungs. Other drugs used to treat bladder cancer can be associated with drug-related pneumonitis. Other rare manifestations include a sarcoid like reaction and systemic granrin therapy. In this review we discuss the various pulmonary ulomatous disease to Bacilli Calmette-Gue manifestations of urothelial carcinoma of the bladder. A high index of suspicion with these presentations can lead to an early diagnosis and assist in instituting an appropriate intervention. © 2017 Elsevier Ltd. All rights reserved.
Keywords: Pulmonary manifestations Urothelial carcinoma of bladder Cavitary lung metastasis Sarcoid like reaction Tumor thromboembolism BCG-osis Pneumonitis
Contents 1. 2. 3. 4. 5. 6.
7. 8.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 Methods and materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 Pulmonary and mediastinal metastatic disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 Pleural effusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 Vascular manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 Adverse effects of bladder cancer therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 6.1. Intravesical bacillus calmette gurin (BCG) immunotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 6.2. Urothelial carcinoma of the bladder specify chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 Sarcoid like reaction & systemic granulomatous disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 Financial disclosure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
* Corresponding author. Northwell Health System - Department of Pulmonary, Critical Care and Sleep Medicine, 410 Lakeville Rd., New Hyde Park, NY 11040, United States. E-mail address: [email protected] (A. Talwar). http://dx.doi.org/10.1016/j.rmed.2017.05.006 0954-6111/© 2017 Elsevier Ltd. All rights reserved.
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1. Introduction Bladder cancer is the fifth most common carcinoma in the United States [1]. Urothelial carcinoma (transitional cell carcinoma (TCC)) of the bladder is the pre-dominant histological type accounting for 90% of all bladder cancers in the United States and Europe. Patients with bladder cancer usually present with painless hematuria. The diagnosis is often delayed, as the symptoms are similar to various other benign conditions such as urinary tract infection, prostatitis or renal calculi. While a majority of patients present with localized symptoms a few patients with advanced disease may present with pelvic or bony pain, lower-extremity edema from iliac vessel compression, or flank pain from ureteral obstruction. In a very few cases the metastatic process may be the reason for presenting complaint with the lung being a common area for metastatic disease. However due to insidious onset and vague symptomatology, in some patients with advanced disease, pulmonary manifestations are the initial presenting symptoms. Patients with urothelial carcinoma of the bladder may present with various pulmonary manifestations, one of which may be due to metastatic disease. Some manifestations include endobronchial metastasis, metastatic disease to the lungs or lymph nodes, pleural effusion, pulmonary embolism amongst others, which have been outlined in Table 1. The purpose of this article is to review the pulmonary manifestations of urothelial cancer of the bladder. 2. Methods and materials A search was conducted of the National Library of Medicine's MEDLINE/PubMed with the objective of identifying all articles published in English language between January 1980 and May 2016 with “Urothelial/Transitional Cell Carcinoma” and “pulmonary manifestations” in the title. Combinations of medical subject heading terms including “pulmonary metastasis,” “pleural effusion” and “manifestations of urothelial/transitional cell carcinoma” were used. We mainly selected recent publications, but did not exclude any older works that were widely referenced. We also searched the reference lists of all articles identified by this search strategy and selected those we judged to be relevant. All pertinent reports were retrieved and the relative reference lists were systematically searched in order to identify any potential additional
studies that could be included. All data were accessed between January and May 2016. Our comprehensive PubMed/Medline search revealed a total of 278 manuscripts of which 222 were duplicates, not of the English language or not related to our focus and were excluded from our review. This yielded a total of 56 manuscripts that were completely assessed and incorporated into this review. 3. Pulmonary and mediastinal metastatic disease The most common respiratory manifestation of urothelial cancer is metastasis to the pulmonary structures. As many as 50% of patients with muscle-invasive bladder cancer may have occult metastases that become clinically apparent within 5 years of initial diagnosis [2]. It is thought that spread of TCC of the bladder primarily occurs via regional lymphatics [3]. The patterns of pulmonary metastasis are variable and may range from parenchymal nodular disease, solitary mass lesions or interstitial micronodules [4]. In a study by Rovirosa et al. it was observed that in up to 4% of lung metastases there is evolution to a cavitary lesion [5]. The pathomechanism of cavitation is attributed to the necrosis occurring from insufficient blood supply to the tumor or due to the invasion of blood vessels by tumor cells [3,6]. Such patients will present with complaints of dyspnea, couch and hemoptysis. Cases of urothelial bladder cancer presenting as cavitary metastatic lesions have been outlined in Table 2. Thus, the presence of cavitary lung lesion in patients with a history TCC of the bladder should raise a suspicion for metastatic disease (Fig. 1) warranting further workup regarding the diagnosis, staging and treatment. While uncommon, patients may also present with endobronchial metastasis (EBM) [9,10]. The presenting symptoms include cough, wheezing, dyspnea, stridor or hemoptysis. Bronchoscopy is a valuable diagnostic tool in such patients for identifying EBM from bladder cancer. Therapeutic bronchoscopy including the use of argon plasma coagulation may also be considered in such cases to improve quality of life [11]. Patients with bladder carcinoma can also present with mediastinal lymphadenopathy due to metastatic disease [12]. Mediastinal metastasis can either be asymptomatic or may produce symptoms such as superior vena cava syndrome or dysphagia from esophageal invasion/compression [13]. In a rare instance,
Table 1 Pulmonary manifestations of urothelial carcinoma of bladder. Metastasis - Cavitary metastasis of the lung parenchyma [3] - Endobronchial metastasis [9,10] - Mediastinal Lymphadenopathy [12,13] -Pleural metastasis [4] Pleural effusion & Chylothorax [15e17]. Vascular Manifestations - Pulmonary embolism - Pulmonary Tumor Thrombotic Microangiopathy (PTTM) [22e24] Adverse effects of Intravesical Bacillus Calmette-Guerin (BCG) therapy [30,31,35,36]. - Flu like symptoms, - Interstitial pneumonitis - Sepsis including miliary nodular spread to lungs. - Systematic granulomatous disease. Adverse effects of drugs used to treat urothelial bladder cancer - MVAC/GC: Acute respiratory distress syndrome (ARDS) [37] - Gemcitabine: Hypersensitivity pneumonitis [41]. - Methotrexate: Hypersensitivity pneumonitis, opportunistic lung infections, lymphoproliferative disease of lung [43] Sarcoid like Reaction [49]
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Table 2 Cases of urothelial bladder cancer presenting with cavitary metastatic lesions. Author year
Age/Sex
Presenting pulmonary symptoms
Pulmonary manifestation
Alexander et al., 1990 [3]
52/male 56/male 65/male 76/male 69/male 59/male
Persistent cough Non-productive cough Non-productive cough, fever, weight loss Asymptomatic Productive sputum and hemoptysis Hemoptysis
Post primary TCC resection Multiple nodules, several with cavitation Post primary TCC resection Multiple nodules, several with cavitation Solitary capsulated cavernous lesion on CT Post primary TCC resection pulmonary nodules, some with cavitation Post primary TCC resection LUL cavitating mass Post primary TCC resection bilateral cavitated lesions
Angulo et al., 1993 [6] Fiorelli et al., 2011 [7] Kurian et al., 2011 [8]
appearance, specific gravity greater than 1.012 and staining of fat globules with Sudan Red stain. Diagnosis is made by measuring the triglyceride (TG) level from the aspirated fluid (TG > 200 mg/dl). The treatment and prognosis of chylothorax depends on the underlying disease process. Mulugeta et al. reported a case of chylous ascites due to retroperitoneal and mesenteric lymphadenopathy from TCC of the bladder [18]. 5. Vascular manifestations
Fig. 1. Computed Tomography of the chest demonstrating cavitary metastatic lesion in a patient with urothelial carcinoma of the bladder.
mediastinal lymphadenopathy due to metastatic disease was noted to cause pulmonary artery compression [14]. Such involvement may be associated with features of lymphangitic carcinomatosis. 4. Pleural effusion Approximately 5% of all patients with bladder cancer present with metastatic disease at the time of initial diagnosis and subsequently approximately 50% of the patients develop relapsing disease after primary resection [15]. Metastasis of the bladder urothelial carcinoma to the pleura accounts for 11% of total bladder urothelial carcinoma metastasis and is generally associated with widespread metastasis to other organs [16]. Dyspnea is the most common initial presentation of such malignancy induced pleural effusions. The initial diagnostic workup involves a thorough history, age appropriate screening for malignancy, physical examination and radiograpical imaging of the chest. The presence of pleural effusion may also indicate recurrence of the bladder carcinoma or pleural metastasis itself. Pleural effusions themselves may offer clinical suspicion and are drained for diagnostic and therapeutic purposes. Thus, in patients in remission, pleural fluid cytology should be performed along with a full investigative workup to rule out recurrent disease. If the cytology is negative, other sites of origin must be considered. TCC patients may also present with an associated chylothorax thus leading to dyspnea and cough [17]. In such a clinical setting thoracentesis should be performed for diagnostic and therapeutic purposes. The main characteristics of chyle include milky
Venous thromboembolism (VTE) in form of deep vein thrombosis (DVT) or pulmonary embolism (PE) is a common complication of any malignancy. It can result in acute respiratory failure and can at times be the presenting symptom of the malignancy. Patients with malignancy related thromboembolism usually present with sudden onset dyspnea and pleuritic chest pain. The clinical picture may also be complicated with concurrent pulmonary hypertension leading to acute or sub acute cor-pulmonale. The common presenting symptoms include dyspnea, chest pain and tachycardia. Patients may present with signs of infarction like hemoptysis and hypotension due to a massive embolus. Patients undergo a CT Angiogram of the chest for the diagnosis. While, screening for malignancy in patients with idiopathic PE is controversial, a proper history should be taken to look for risk factors for a urologic malignancy. Patients with concurrent other symptoms of bladder cancer like hematuria; weight loss and exposure to risk factors should be screened appropriately for bladder cancer. Microscopic pulmonary tumor embolism (PTTM) is a rare malignancy related pulmonary complication, which has been described in various tumors such as gastric and renal carcinomas [19]. PTTM is characterized by the presence of tumor emboli in small pulmonary arteries along with intimal proliferation and organization and recanalization of the thrombi [20,21]. PTTM has been incidentally reported in the setting of urothelial carcinoma [22e27] diagnosed both antemortem and postmortem. A few cases of PTTM have been reported in which the tumor cells were detected by pulmonary microvascular cytology (PMC) using a pulmonary artery catheter [21]. Other methods to diagnose include video-assisted thoracic surgery (VATS) and Trans-bronchial lung biopsy (TBLB but are generally less well tolerated as compared to PMC) [24]. It is essential to diagnose patients with tumor microemboli and differentiate them from pulmonary embolism to prevent hemorrhagic risk of anticoagulation and prevent delay in definitive therapy. While the use of definitive therapies for pulmonary hypertension in this setting remains controversial, Ogawa et al. reported that imatinib might be effective for treating pulmonary hypertension that is caused by PTTM [28,29]. 6. Adverse effects of bladder cancer therapies Definitive therapy of bladder/transitional cell carcinoma is complete excision of the primary tumor. However in lesion that are inoperable chemotherapeutic agents must be utilized. Though
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advances have been made in the treatment of TCC there are unavoidable adverse effects of these agents.
6.1. Intravesical bacillus calmette gurin (BCG) immunotherapy Intravesical instillation of Bacillus Calmette-Guerin (BCG), a live attenuated strain of Mycobacterium bovis, is a mainstay treatment of non-muscle invasive urothelial carcinoma of the bladder. Systemic side effects of intravescial BCG may include fever, influenza like symptoms, malaise, chills, lung infection, liver toxicity and rarely sepsis. Adverse effects specific to the respiratory system include interstitial pneumonitis. Radiological features that are consistent with interstitial pneumonitis have been reported in up in 0.7% of the patients who received BCG as part of therapy for carcinoma of the bladder [30]. It is debated as to whether this pneumonitis is caused due to a hypersensitivity reaction to BCG immunotherapy or as a manifestation of miliary disease caused by BCG itself [31]. Risk factors for developing pneumonitis include any procedures that affect the integrity of the bladder mucosa including tumor resection or a traumatic catheterization [32]. Patients with BCG induced pneumonitis may present with refractory fever requiring empiric isoniazid for three months [33]. Diagnosis may be made with a miliary nodular pattern seen on chest radiography computerized tomography (CT) most often associated with sepsis [34]. In addition, though uncommon, patients receiving BCG may present with systemic granulomatous disease accompanied with high fever, which may progress, to multi-organ failure [35,36].
6.2. Urothelial carcinoma of the bladder specify chemotherapy Muscle invasive disease or metastatic bladder cancer is treated with adjuvant chemotherapy with platinum based MVAC (Methotrexate, Vinblastine, Doxorubicin and cisplatin) or GC (Gemcitabine þ cisplatin) regimens. The most common adverse manifestations of the MVAC or GC regimens are hematologic resulting in neutropenia These patients may become septic leading to acute respiratory distress syndrome (ARDS) [37,38]. Gemcitabine-induced pulmonary toxicity can itself lead to respiratory dysfunction. A few cases of ARDS due to Gemcitabine have been reported in literature [39,40]. The pathoetiology of pulmonary damage due to gemcitabine was attributed to its ability of inducing direct endothelial damage to the pulmonary vasculature [41]. Methotrexate has also shown lung toxicity usually, after chronic low dose use but has been reported with relatively short-term use when used intravenously [42] resulting most commonly in hypersensitivity pneumonitis [43]. Other types of lung injury associated with methotrexate include organizing pneumonia, acute interstitial pneumonia or pulmonary fibrosis [44,45]. Methotrexate therapy can also compromise immune response and thus increase the risk of opportunistic lung infections including pneumocystis pneumonia, Nocardia, mycobacteria or fungi [46]. Lymphoproliferative diseases like lymphoma may appear during methotrexate therapy and can regress after discontinuation of therapy, though the exact causal mechanisms are unknown [47]. It is essential to rule out other underlying causes of pulmonary disease before attributing it to the drugs used to treat urothelial cancer of the bladder. Discontinuation of the drug is the initial step in management. In most cases, clinical improvement occurs within days of stopping the drug. Supportive care is provided. Even though clinical experience and case reports have shown a benefit of glucocorticoids in cases of pneumonitis, the routine use of this drug is controversial in these patients [48].
7. Sarcoid like reaction & systemic granulomatous disease Sarcoid like reaction refers to the formation of non-caseating epitheliod cell granuloma in patients who do not fulfill the criteria for systemic sarcoidosis. Sarcoid reaction has been observed in approximately 4e14% of patients with malignancy [49]. These lesions may be observed in localized lymph nodes, kidney, liver and mediastinal lymph nodes. Rare cases of sarcoid like reaction associated with transitional cell carcinoma have been reported in literature [2]. These lesions may result in hypermetabolic activity in 18- fluorodeoxyglucose (FDG) positron emission topography (PET) resulting in a false positive report for a malignancy. While elevated standardized uptake values (SUV) values are thought of as suspicious for malignancy [50], sarcoid nodes can be associated with SUVs approaching similar numbers [51]. A biopsy can help distinguish such reactions from malignant disease. Sarcoidosis or sarcoid reactions should be considered in differential diagnosis of oncologic patients such as those with bladder cancer who have developed FDG-avid lesions during any time of the course of the malignancy. As mentioned above, one of the complications of intravescial BCG immunotherapy includes disseminated disease, which can cause a systemic granulomatous reaction [34,52]. It is thus also essential to distinguish the findings of a sarcoid-like reaction from systemic granulomatous diseases due to BCG therapy in these sets of patients. 8. Conclusion Urothelial carcinoma of the bladder can present with multiple pulmonary manifestations. These pulmonary features can either be the presenting symptom of the disease or can occur in latter stages of the disease. Thus urothelial carcinoma of the bladder should be considered in the differential diagnosis when such symptoms occur without any apparent source. A high index of suspicion can lead to an early diagnosis and can assist in instituting an early intervention, thus improving overall prognosis. Conflict of interest None. Financial disclosure None. Acknowledgements We would like to acknowledge the Departments of Pulmonary, Critical Care & Sleep Medicine at Northwell Health, Department of Thoracic Radiology at Northwell Health and Department of Medicine at Monmouth Medical Center. References [1] R.L. Siegel, K.D. Miller, A. Jemal, Cancer statistics, 2015, CA Cancer J. Clinicians 65 (1) (2015) 5e29. [2] M. Yukawa, T. Satoh, K. Takayama, H. Yokozeki, Cutaneous sarcoid reaction in a patient with bladder cancer, Eur. J. Dermatol. EJD 20 (2) (2010) 235. [3] P.W. Alexander, C. Sanders, H. Nath, Cavitary pulmonary metastases in transitional cell carcinoma of urinary bladder, AJR Am. J. Roentgenol. 154 (3) (1990) 493e494. [4] R.J. Babaian, D.E. Johnson, L. Llamas, A.G. Ayala, Metastases from transitional cell carcinoma of urinary bladder, Urology 16 (2) (1980) 142e144. [5] A. Rovirosa, A. Salud, E. Felip, F. Capdevila, J. Giralt, J. Bellmunt, Cavitary pulmonary metastases in transitional cell carcinoma of the urinary bladder, Urol. Int. 48 (1) (1992) 102e104. [6] J.C. Angulo, J.I. Lopez, N. Flores, Cavitation of lung metastases from bladder cancer. Report of two cases, Tumori 79 (2) (1993) 141e143.
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Review article
Pulmonary manifestations of urothelial carcinoma of the bladder Abhinav Agrawal, M.D. a, b, Sonu Sahni, M.D. b, c, Abhinav K. Vulisha, MBBS b, Rammohan Gumpeni, M.D. d, Rakesh Shah, M.D. e, Arunabh Talwar, M.D., FCCP b, * a
Monmouth Medical Center, Department of Medicine, 300 Second Avenue Long Branch, NJ 07740, United States Northwell Health, Department of Pulmonary, Critical Care and Sleep Medicine, 410 Lakeville Rd. Suite 107, New Hyde Park, NY 11040, United States c Touro College of Osteopathic Medicine, Department of Primary Care, New York, NY 10027, United States d New York Presbyterian Hospital Queens, Department of Pulmonary Critical Care Medicine, 56-45 Main Street Flushing, NY 11355, United States e Northwell Health, Department of Radiology, 410 Lakeville Rd. Suite 107, New Hyde Park, NY 11040, United States b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 26 September 2016 Received in revised form 12 April 2017 Accepted 13 May 2017 Available online 16 May 2017
Urothelial carcinoma (Transitional cell carcinoma) of the bladder is the pre-dominant histological type of bladder cancer in the United States and Europe. Patients with bladder cancer usually present with painless hematuria. The diagnosis is often delayed, as the symptoms are similar to various other benign conditions such as urinary tract infection, prostatitis or renal calculi. In some patients, the metastatic lesions will cause the initial presenting symptoms. We conducted a MedLine/PubMED search identifying all relevant articles with “pulmonary manifestations”, “urothelial bladder cancer”, “manifestations of bladder cancer” or a combination of these terms in the title. The pulmonary manifestations of urothelial carcinoma of the bladder include metastatic disease including cavitary lesions, endobronchial, pleural, or lymph node metastasis pleural effusion and chylothorax. Pulmonary embolism and tumor embolism is another manifestation of this cancer. Intravesical Bacillus Calmette-Gurin therapy for bladder cancer has rin been associated with a range of adverse effects including the systemic spread of Bacilli Calmette-Gue immunotherapy affecting the lungs. Other drugs used to treat bladder cancer can be associated with drug-related pneumonitis. Other rare manifestations include a sarcoid like reaction and systemic granrin therapy. In this review we discuss the various pulmonary ulomatous disease to Bacilli Calmette-Gue manifestations of urothelial carcinoma of the bladder. A high index of suspicion with these presentations can lead to an early diagnosis and assist in instituting an appropriate intervention. © 2017 Elsevier Ltd. All rights reserved.
Keywords: Pulmonary manifestations Urothelial carcinoma of bladder Cavitary lung metastasis Sarcoid like reaction Tumor thromboembolism BCG-osis Pneumonitis
Contents 1. 2. 3. 4. 5. 6.
7. 8.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 Methods and materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 Pulmonary and mediastinal metastatic disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 Pleural effusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 Vascular manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 Adverse effects of bladder cancer therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 6.1. Intravesical bacillus calmette gurin (BCG) immunotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 6.2. Urothelial carcinoma of the bladder specify chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 Sarcoid like reaction & systemic granulomatous disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 Financial disclosure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
* Corresponding author. Northwell Health System - Department of Pulmonary, Critical Care and Sleep Medicine, 410 Lakeville Rd., New Hyde Park, NY 11040, United States. E-mail address: [email protected] (A. Talwar). http://dx.doi.org/10.1016/j.rmed.2017.05.006 0954-6111/© 2017 Elsevier Ltd. All rights reserved.
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A. Agrawal et al. / Respiratory Medicine 128 (2017) 65e69
1. Introduction Bladder cancer is the fifth most common carcinoma in the United States [1]. Urothelial carcinoma (transitional cell carcinoma (TCC)) of the bladder is the pre-dominant histological type accounting for 90% of all bladder cancers in the United States and Europe. Patients with bladder cancer usually present with painless hematuria. The diagnosis is often delayed, as the symptoms are similar to various other benign conditions such as urinary tract infection, prostatitis or renal calculi. While a majority of patients present with localized symptoms a few patients with advanced disease may present with pelvic or bony pain, lower-extremity edema from iliac vessel compression, or flank pain from ureteral obstruction. In a very few cases the metastatic process may be the reason for presenting complaint with the lung being a common area for metastatic disease. However due to insidious onset and vague symptomatology, in some patients with advanced disease, pulmonary manifestations are the initial presenting symptoms. Patients with urothelial carcinoma of the bladder may present with various pulmonary manifestations, one of which may be due to metastatic disease. Some manifestations include endobronchial metastasis, metastatic disease to the lungs or lymph nodes, pleural effusion, pulmonary embolism amongst others, which have been outlined in Table 1. The purpose of this article is to review the pulmonary manifestations of urothelial cancer of the bladder. 2. Methods and materials A search was conducted of the National Library of Medicine's MEDLINE/PubMed with the objective of identifying all articles published in English language between January 1980 and May 2016 with “Urothelial/Transitional Cell Carcinoma” and “pulmonary manifestations” in the title. Combinations of medical subject heading terms including “pulmonary metastasis,” “pleural effusion” and “manifestations of urothelial/transitional cell carcinoma” were used. We mainly selected recent publications, but did not exclude any older works that were widely referenced. We also searched the reference lists of all articles identified by this search strategy and selected those we judged to be relevant. All pertinent reports were retrieved and the relative reference lists were systematically searched in order to identify any potential additional
studies that could be included. All data were accessed between January and May 2016. Our comprehensive PubMed/Medline search revealed a total of 278 manuscripts of which 222 were duplicates, not of the English language or not related to our focus and were excluded from our review. This yielded a total of 56 manuscripts that were completely assessed and incorporated into this review. 3. Pulmonary and mediastinal metastatic disease The most common respiratory manifestation of urothelial cancer is metastasis to the pulmonary structures. As many as 50% of patients with muscle-invasive bladder cancer may have occult metastases that become clinically apparent within 5 years of initial diagnosis [2]. It is thought that spread of TCC of the bladder primarily occurs via regional lymphatics [3]. The patterns of pulmonary metastasis are variable and may range from parenchymal nodular disease, solitary mass lesions or interstitial micronodules [4]. In a study by Rovirosa et al. it was observed that in up to 4% of lung metastases there is evolution to a cavitary lesion [5]. The pathomechanism of cavitation is attributed to the necrosis occurring from insufficient blood supply to the tumor or due to the invasion of blood vessels by tumor cells [3,6]. Such patients will present with complaints of dyspnea, couch and hemoptysis. Cases of urothelial bladder cancer presenting as cavitary metastatic lesions have been outlined in Table 2. Thus, the presence of cavitary lung lesion in patients with a history TCC of the bladder should raise a suspicion for metastatic disease (Fig. 1) warranting further workup regarding the diagnosis, staging and treatment. While uncommon, patients may also present with endobronchial metastasis (EBM) [9,10]. The presenting symptoms include cough, wheezing, dyspnea, stridor or hemoptysis. Bronchoscopy is a valuable diagnostic tool in such patients for identifying EBM from bladder cancer. Therapeutic bronchoscopy including the use of argon plasma coagulation may also be considered in such cases to improve quality of life [11]. Patients with bladder carcinoma can also present with mediastinal lymphadenopathy due to metastatic disease [12]. Mediastinal metastasis can either be asymptomatic or may produce symptoms such as superior vena cava syndrome or dysphagia from esophageal invasion/compression [13]. In a rare instance,
Table 1 Pulmonary manifestations of urothelial carcinoma of bladder. Metastasis - Cavitary metastasis of the lung parenchyma [3] - Endobronchial metastasis [9,10] - Mediastinal Lymphadenopathy [12,13] -Pleural metastasis [4] Pleural effusion & Chylothorax [15e17]. Vascular Manifestations - Pulmonary embolism - Pulmonary Tumor Thrombotic Microangiopathy (PTTM) [22e24] Adverse effects of Intravesical Bacillus Calmette-Guerin (BCG) therapy [30,31,35,36]. - Flu like symptoms, - Interstitial pneumonitis - Sepsis including miliary nodular spread to lungs. - Systematic granulomatous disease. Adverse effects of drugs used to treat urothelial bladder cancer - MVAC/GC: Acute respiratory distress syndrome (ARDS) [37] - Gemcitabine: Hypersensitivity pneumonitis [41]. - Methotrexate: Hypersensitivity pneumonitis, opportunistic lung infections, lymphoproliferative disease of lung [43] Sarcoid like Reaction [49]
A. Agrawal et al. / Respiratory Medicine 128 (2017) 65e69
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Table 2 Cases of urothelial bladder cancer presenting with cavitary metastatic lesions. Author year
Age/Sex
Presenting pulmonary symptoms
Pulmonary manifestation
Alexander et al., 1990 [3]
52/male 56/male 65/male 76/male 69/male 59/male
Persistent cough Non-productive cough Non-productive cough, fever, weight loss Asymptomatic Productive sputum and hemoptysis Hemoptysis
Post primary TCC resection Multiple nodules, several with cavitation Post primary TCC resection Multiple nodules, several with cavitation Solitary capsulated cavernous lesion on CT Post primary TCC resection pulmonary nodules, some with cavitation Post primary TCC resection LUL cavitating mass Post primary TCC resection bilateral cavitated lesions
Angulo et al., 1993 [6] Fiorelli et al., 2011 [7] Kurian et al., 2011 [8]
appearance, specific gravity greater than 1.012 and staining of fat globules with Sudan Red stain. Diagnosis is made by measuring the triglyceride (TG) level from the aspirated fluid (TG > 200 mg/dl). The treatment and prognosis of chylothorax depends on the underlying disease process. Mulugeta et al. reported a case of chylous ascites due to retroperitoneal and mesenteric lymphadenopathy from TCC of the bladder [18]. 5. Vascular manifestations
Fig. 1. Computed Tomography of the chest demonstrating cavitary metastatic lesion in a patient with urothelial carcinoma of the bladder.
mediastinal lymphadenopathy due to metastatic disease was noted to cause pulmonary artery compression [14]. Such involvement may be associated with features of lymphangitic carcinomatosis. 4. Pleural effusion Approximately 5% of all patients with bladder cancer present with metastatic disease at the time of initial diagnosis and subsequently approximately 50% of the patients develop relapsing disease after primary resection [15]. Metastasis of the bladder urothelial carcinoma to the pleura accounts for 11% of total bladder urothelial carcinoma metastasis and is generally associated with widespread metastasis to other organs [16]. Dyspnea is the most common initial presentation of such malignancy induced pleural effusions. The initial diagnostic workup involves a thorough history, age appropriate screening for malignancy, physical examination and radiograpical imaging of the chest. The presence of pleural effusion may also indicate recurrence of the bladder carcinoma or pleural metastasis itself. Pleural effusions themselves may offer clinical suspicion and are drained for diagnostic and therapeutic purposes. Thus, in patients in remission, pleural fluid cytology should be performed along with a full investigative workup to rule out recurrent disease. If the cytology is negative, other sites of origin must be considered. TCC patients may also present with an associated chylothorax thus leading to dyspnea and cough [17]. In such a clinical setting thoracentesis should be performed for diagnostic and therapeutic purposes. The main characteristics of chyle include milky
Venous thromboembolism (VTE) in form of deep vein thrombosis (DVT) or pulmonary embolism (PE) is a common complication of any malignancy. It can result in acute respiratory failure and can at times be the presenting symptom of the malignancy. Patients with malignancy related thromboembolism usually present with sudden onset dyspnea and pleuritic chest pain. The clinical picture may also be complicated with concurrent pulmonary hypertension leading to acute or sub acute cor-pulmonale. The common presenting symptoms include dyspnea, chest pain and tachycardia. Patients may present with signs of infarction like hemoptysis and hypotension due to a massive embolus. Patients undergo a CT Angiogram of the chest for the diagnosis. While, screening for malignancy in patients with idiopathic PE is controversial, a proper history should be taken to look for risk factors for a urologic malignancy. Patients with concurrent other symptoms of bladder cancer like hematuria; weight loss and exposure to risk factors should be screened appropriately for bladder cancer. Microscopic pulmonary tumor embolism (PTTM) is a rare malignancy related pulmonary complication, which has been described in various tumors such as gastric and renal carcinomas [19]. PTTM is characterized by the presence of tumor emboli in small pulmonary arteries along with intimal proliferation and organization and recanalization of the thrombi [20,21]. PTTM has been incidentally reported in the setting of urothelial carcinoma [22e27] diagnosed both antemortem and postmortem. A few cases of PTTM have been reported in which the tumor cells were detected by pulmonary microvascular cytology (PMC) using a pulmonary artery catheter [21]. Other methods to diagnose include video-assisted thoracic surgery (VATS) and Trans-bronchial lung biopsy (TBLB but are generally less well tolerated as compared to PMC) [24]. It is essential to diagnose patients with tumor microemboli and differentiate them from pulmonary embolism to prevent hemorrhagic risk of anticoagulation and prevent delay in definitive therapy. While the use of definitive therapies for pulmonary hypertension in this setting remains controversial, Ogawa et al. reported that imatinib might be effective for treating pulmonary hypertension that is caused by PTTM [28,29]. 6. Adverse effects of bladder cancer therapies Definitive therapy of bladder/transitional cell carcinoma is complete excision of the primary tumor. However in lesion that are inoperable chemotherapeutic agents must be utilized. Though
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advances have been made in the treatment of TCC there are unavoidable adverse effects of these agents.
6.1. Intravesical bacillus calmette gurin (BCG) immunotherapy Intravesical instillation of Bacillus Calmette-Guerin (BCG), a live attenuated strain of Mycobacterium bovis, is a mainstay treatment of non-muscle invasive urothelial carcinoma of the bladder. Systemic side effects of intravescial BCG may include fever, influenza like symptoms, malaise, chills, lung infection, liver toxicity and rarely sepsis. Adverse effects specific to the respiratory system include interstitial pneumonitis. Radiological features that are consistent with interstitial pneumonitis have been reported in up in 0.7% of the patients who received BCG as part of therapy for carcinoma of the bladder [30]. It is debated as to whether this pneumonitis is caused due to a hypersensitivity reaction to BCG immunotherapy or as a manifestation of miliary disease caused by BCG itself [31]. Risk factors for developing pneumonitis include any procedures that affect the integrity of the bladder mucosa including tumor resection or a traumatic catheterization [32]. Patients with BCG induced pneumonitis may present with refractory fever requiring empiric isoniazid for three months [33]. Diagnosis may be made with a miliary nodular pattern seen on chest radiography computerized tomography (CT) most often associated with sepsis [34]. In addition, though uncommon, patients receiving BCG may present with systemic granulomatous disease accompanied with high fever, which may progress, to multi-organ failure [35,36].
6.2. Urothelial carcinoma of the bladder specify chemotherapy Muscle invasive disease or metastatic bladder cancer is treated with adjuvant chemotherapy with platinum based MVAC (Methotrexate, Vinblastine, Doxorubicin and cisplatin) or GC (Gemcitabine þ cisplatin) regimens. The most common adverse manifestations of the MVAC or GC regimens are hematologic resulting in neutropenia These patients may become septic leading to acute respiratory distress syndrome (ARDS) [37,38]. Gemcitabine-induced pulmonary toxicity can itself lead to respiratory dysfunction. A few cases of ARDS due to Gemcitabine have been reported in literature [39,40]. The pathoetiology of pulmonary damage due to gemcitabine was attributed to its ability of inducing direct endothelial damage to the pulmonary vasculature [41]. Methotrexate has also shown lung toxicity usually, after chronic low dose use but has been reported with relatively short-term use when used intravenously [42] resulting most commonly in hypersensitivity pneumonitis [43]. Other types of lung injury associated with methotrexate include organizing pneumonia, acute interstitial pneumonia or pulmonary fibrosis [44,45]. Methotrexate therapy can also compromise immune response and thus increase the risk of opportunistic lung infections including pneumocystis pneumonia, Nocardia, mycobacteria or fungi [46]. Lymphoproliferative diseases like lymphoma may appear during methotrexate therapy and can regress after discontinuation of therapy, though the exact causal mechanisms are unknown [47]. It is essential to rule out other underlying causes of pulmonary disease before attributing it to the drugs used to treat urothelial cancer of the bladder. Discontinuation of the drug is the initial step in management. In most cases, clinical improvement occurs within days of stopping the drug. Supportive care is provided. Even though clinical experience and case reports have shown a benefit of glucocorticoids in cases of pneumonitis, the routine use of this drug is controversial in these patients [48].
7. Sarcoid like reaction & systemic granulomatous disease Sarcoid like reaction refers to the formation of non-caseating epitheliod cell granuloma in patients who do not fulfill the criteria for systemic sarcoidosis. Sarcoid reaction has been observed in approximately 4e14% of patients with malignancy [49]. These lesions may be observed in localized lymph nodes, kidney, liver and mediastinal lymph nodes. Rare cases of sarcoid like reaction associated with transitional cell carcinoma have been reported in literature [2]. These lesions may result in hypermetabolic activity in 18- fluorodeoxyglucose (FDG) positron emission topography (PET) resulting in a false positive report for a malignancy. While elevated standardized uptake values (SUV) values are thought of as suspicious for malignancy [50], sarcoid nodes can be associated with SUVs approaching similar numbers [51]. A biopsy can help distinguish such reactions from malignant disease. Sarcoidosis or sarcoid reactions should be considered in differential diagnosis of oncologic patients such as those with bladder cancer who have developed FDG-avid lesions during any time of the course of the malignancy. As mentioned above, one of the complications of intravescial BCG immunotherapy includes disseminated disease, which can cause a systemic granulomatous reaction [34,52]. It is thus also essential to distinguish the findings of a sarcoid-like reaction from systemic granulomatous diseases due to BCG therapy in these sets of patients. 8. Conclusion Urothelial carcinoma of the bladder can present with multiple pulmonary manifestations. These pulmonary features can either be the presenting symptom of the disease or can occur in latter stages of the disease. Thus urothelial carcinoma of the bladder should be considered in the differential diagnosis when such symptoms occur without any apparent source. A high index of suspicion can lead to an early diagnosis and can assist in instituting an early intervention, thus improving overall prognosis. Conflict of interest None. Financial disclosure None. Acknowledgements We would like to acknowledge the Departments of Pulmonary, Critical Care & Sleep Medicine at Northwell Health, Department of Thoracic Radiology at Northwell Health and Department of Medicine at Monmouth Medical Center. References [1] R.L. Siegel, K.D. Miller, A. Jemal, Cancer statistics, 2015, CA Cancer J. Clinicians 65 (1) (2015) 5e29. [2] M. Yukawa, T. Satoh, K. Takayama, H. Yokozeki, Cutaneous sarcoid reaction in a patient with bladder cancer, Eur. J. Dermatol. EJD 20 (2) (2010) 235. [3] P.W. Alexander, C. Sanders, H. Nath, Cavitary pulmonary metastases in transitional cell carcinoma of urinary bladder, AJR Am. J. Roentgenol. 154 (3) (1990) 493e494. [4] R.J. Babaian, D.E. Johnson, L. Llamas, A.G. Ayala, Metastases from transitional cell carcinoma of urinary bladder, Urology 16 (2) (1980) 142e144. [5] A. Rovirosa, A. Salud, E. Felip, F. Capdevila, J. Giralt, J. Bellmunt, Cavitary pulmonary metastases in transitional cell carcinoma of the urinary bladder, Urol. Int. 48 (1) (1992) 102e104. [6] J.C. Angulo, J.I. Lopez, N. Flores, Cavitation of lung metastases from bladder cancer. Report of two cases, Tumori 79 (2) (1993) 141e143.
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