An unusual case of tracheo-pleural fistula and cardiac metastases in oropharyngeal carcinoma: a case report and review of the literature
© The Author(s) 2016
Received: 19 August 2016
Accepted: 21 November 2016
Published: 15 December 2016
Oropharyngeal cancer is frequently associated with human papilloma virus, that also represents a strong prognostic factor. Local relaps and treatment-related complications are frequent, whereas distant metastases occur in about 25% of patients.
A 49 years-old male presented with a loco-regionally advanced oropharyngeal squamous cell carcinoma and was treated with concomitant chemoradiation. A complete clinical and pathological response was achieved, but the occurrence of necrotising tracheo-esophagitis, with tracheo-mediastino-pleural fistula formation, further complicated the subsequent clinical course. The patient died suddenly. Autopsy revealed multiple myocardial and epicardial metastases from oropharyngeal squamous cell carcinoma.
Even in case of a transient complete local response, the potential occurrence of severe complications and distant metastases, although infrequent, should be considered. Cardiac metastases are frequently underestimated, as they are often asymptomatic, but may lead to sudden death. Further efforts are needed to improve diagnosis and therapy in this setting.
KeywordsOropharyngeal carcinoma Tracheo-pleural fistula Cardiac metastases Chemoradiotherapy Risk factors
Increasing oropharyngeal cancer incidence has been observed in numerous developed nations over the past few decades, though with marked difference between countries. It has been extensively demonstrated that alcohol intake and smoke are risk factors for head and neck cancer (HNC) development; recently, human papilloma virus (HPV), particularly HPV-16 subtype, was shown to be etiologically related to oropharyngeal tumors [1, 2].
In addition, a fair number of studies demonstrated the prognostic relevance of HPV, with a strikingly better prognosis and improved responsiveness to chemotherapy (CHT) and radiotherapy (RT) for HPV-positive oropharyngeal cancer .
Head and neck cancer tends to recur loco-regionally, and distant metastases are found in less than 30% of patients [4–7]. Common sites of distant metastases are lungs and liver, less frequently the central nervous system. Cardiac metastases from HNC are extremely rare [8, 9] and the few cases reported in literature are mainly found in patients affected by tongue cancer [10, 11]. Metastases to the heart and pericardium are much more common than primary cardiac tumors, originating in most cases from a carcinoma of the lung .The autoptic frequency of cardiac metastases varies from 0.7% to 3.5% in the general population, but may increase to 9.1% in patients with known malignancies [13–16]. The probability of cardiac involvement depends on the anatomy of the primary site, disease stage, intrinsic tumor and host biology. Tumors involving the heart are mainly represented by lung cancer (36-39% of cardiac metastases), breast cancer (10-12%), leukemias (10-21%), gastric, renal and pancreatic carcinoma, mesothelioma and melanoma [17–19]. Since cardiac metastases are usually clinically silent, they are frequently unrecognized and diagnosed only post-mortem.
A 49-year-old male was admitted to our hospital in November 2012, with a two-month history of a sore throat and difficulties in swallowing. The oropharyngeal inspection revealed the presence of an ulcerated mass of the right tonsil extending to the base of the tongue, to the epiglottis and to the right pyriform sinus. In addition, bilateral neck lymphadenopaties were palpable. A biopsy was performed and an HPV- negative squamous cell oropharyngeal carcinoma was diagnosed. The patient was a heavy smoker (20 packs/year) but denied alcohol intake. Head and neck computed tomography (CT) scan and whole body fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) scan confirmed the presence of tumor in the right tonsil area with bilateral lymph nodes involvement in levels I-III. The largest nodes measured 2-4 cm in maximum diameter. No distant metastases were found. The TNM clinical stage was cT3N2c. Following a multi-disciplinary discussion, the patient was judged suitable for concomitant chemoradiotherapy (CRT) and underwent protective tracheostomy; then, from April to May 2013, he was treated with a combination of intensity-modulated radiation therapy (IMRT) for a 70 Gy total dose, and weekly cisplatin for a total dose of 280 mg/m2.
The course of treatment was poorly tolerated, due to hematologic toxicity (grade 2 neutropenia) and grade 4 oropharyngeal mucositis, eliciting severe pain and requiring the placement of a percutaneous endoscopic gastrostomy (PEG) feeding tube. One month after the end of concomitant CRT, the patient’s clinical conditions slowly improved.
The CT scan performed at the end of treatment was negative, and a right tonsil biopsy did not reveal any residual cancer cell.
In July 2013, the patient was hospitalized because of the sudden onset of dysphagia, oral pain and extensive oral mycosis. Fiberoptic endoscopy revealed erosions and ulcerations of the tracheal, hypopharyngeal and esophageal mucosa, with fungal colonization. Biopsies confirmed the presence of Candida species hyphae and the absence of cancer cells, suggesting the diagnosis of a post-radiation tracheo-esophagitis with fungal colonization.
In October 2013, a total-body CT scan was performed; it showed no evidence of malignant disease and the resolution of the fistula. Two months later, the patient was urgently hospitalized for loss of consciousness secondary to hypotension. Anemia (hemoglobin 8 g/dL), probably caused by a minor oropharyngeal bleeding from the tracheostoma, was observed in blood tests. A thoracic CT scan, the electrocardiogram and a two-dimensional echocardiogram (ECHO) revealed normal findings with the exception of the presence of sinus tachycardia. The patient died suddenly two days after hospitalization.
Patients affected by oropharyngeal cancer have a slightly better prognosis compared to different sites HNC patients, but severe clinical complications, either due to the tumor itself or to loco-regional and systemic therapy, can seriously compromise survival and quality of life. The poor prognosis in our case might be influenced by the negativity of HPV status and by the presence of well- known risk factors such as heavy smoking, implying a more aggressive disease . However such a series of events is unusual in oropharyngeal cancer, particularly when loco-regional control of the tumor has been achieved.
In our case a tracheo-mediastino-pleural fistula formation unexpectedly altered the course of the disease after concomitant CRT. Documented complications of HNC surgery are mainly pharyngocutaneous fistulae . Tracheo-pleural fistulae are rare consequences of lung surgery; esophago-pleural fistulae have been reported as post-surgical complications in a case of peptic ulcer perforation, in variceal sclerotherapy, or secondary to infections, usually tuberculosis or mycosis [21–24].
To our knowledge, this is the first report of tracheo-mediastino-pleural fistula occurrence in a patient treated with concomitant CRT for HNC. In our case, the occurrence of the fistula was probably due to a combination of tumor spread, Candida mycosis, and inflammatory reaction sustained by cytokines production. A case of tracheo-pleural fistula has been reported as a consequence of chemoradiation and bevacizumab therapy in non-small cell lung cancer; it was successfully treated by the endoscopic insertion of a silicone stent covered by a metal sheath, as in our case .
Although the endoscopic treatment of a fistula is feasible and often successful, cardiac dissemination of HNC is almost invariably fatal, leading sometimes to sudden death. In our case the occurrence of cardiac metastases further complicated the patient’s clinical course and probably was the cause of his death.
Cardiac metastases are rarely diagnosed ante mortem as they are frequently asymptomatic, but they are found in up to 24% of autopsied patients, mainly affected by tongue cancer . Head neck cancer has limited propensity to give rise to distant metastases, and only sporadic cases of cardiac involvement have been reported, particularly in advanced stage [27–30], although it has been occasionally observed also in the absence of local recurrence . Metastatic spread may be due to dissemination in the bloodstream or in the lymphatic system, or to intracavitary diffusion through the inferior vena cava or pulmonary veins .
Cardiac metastases cause non-specific symptoms that depends on the size and location of the metastases, mimicking a myocardial infarction, or presenting with ventricular tachycardia, pericardial effusion and cardiogenic shock [27–29, 32, 33]. However, cardiac metastases do not generally lead to clinical findings at an early stage and may be diagnosed, if suspected, by ECHO and cardiac Magnetic Resonance (MR) or CT scan [34–36]. In our case the ECHO was negative for metastases shortly before the onset of the terminal symptoms leading to sudden death. An FDG PET/CT scan was not repeated, as a consequence of the absence of metastases on CT scan. It would be of interest to evaluate the presence of increased FDG activity in the form of cardiac deposits, even in case of negative CT, but the rapid and fatal course in our case prevented further clinical evaluations. Cardiac MR is a validated tool for tissue characterization of cardiac masses, but prospective trials with the aim of studying the prognostic implications of cardiac metastases among patients with systemic disease are lacking .
The rare complications reported in this case highlight the need to carefully monitor the clinical evolution and the onset of new symptoms in all patients affected by HNC.
PET/CT Fluorodeoxyglucose positron emission tomography/computed tomography
Head and neck cancer
Human papilloma virus
Intensity-modulated radiation therapy
Percutaneous endoscopic gastrostomy
Our data manager, Gabriela Cassinelli, helped to draft the manuscript.
No funding resource available.
Availability of data and material
Clinical charts, tissue samples, plain radiograms, CT, MR and FDG PET/CT scans archived and available.
DF and PF were major contributors in the conception and writing of the manuscript. CC, GV, BB, FB, FC, MV, AL collected the patient’s medical history and interpreted the data; DB, LM, GB performed the histological examination; All authors read and approved the final manuscript.
The authors declare that they have no competing interest.
Consent for publication
Written informed consent for publication was obtained from the patient before writing this case report.
Ethics approval and consent to participate
The patient was treated according to international and local guidelines (standard treatment).
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Mathur S, Conway DI, Worlledge-Andrew H, Macpherson LM, Ross AJ. Assessment and prevention of behavioural and social risk factors associated with oral cancer: protocol for a systematic review of clinical guidelines and systematic reviews to inform Primary Care dental professionals. Syst Rev. 2015;4(1):184.View ArticlePubMedPubMed CentralGoogle Scholar
- Agalliu I, Gapstur S, Chen Z, Wang T, Anderson RL, Teras L, et al. Associations of Oral α-, β-, and γ-Human Papillomavirus Types With Risk of Incident Head and Neck Cancer. JAMA Oncol. 2016; doi:10.1001/jamaoncol.2015.5504
- Guo T, Rettig E, Fakhry C. Understanding the impact of survival and human papillomavirus tumor status on timing of recurrence in oropharyngeal squamous cell carcinoma. Oral Oncol. 2016;52:97–103.View ArticlePubMedGoogle Scholar
- Lindberg RD. Sites of first failure in head and neck cancer. Cancer Treat Sympt. 1983;2:21–31.Google Scholar
- Vikram B, Strong EW, Shah JP, Spiro R. Failure at distant sites following multimodality treatment for advanced head and neck cancer. Head Neck Surg. 1984;6:730–3.View ArticlePubMedGoogle Scholar
- Hong WK, Bromer RH, Amato DA, Shapshay S, Vincent M, Vaughan C, et al. Patterns of relapse in locally advanced head and neck patients who achieved complete remission after combined modality therapy. Cancer. 1985;56:1242–5.View ArticlePubMedGoogle Scholar
- Bathia R, Bahadur S. Distant metastasis in malignancies of the head and neck. J Laryngol Otol. 1987;101:925–8.View ArticleGoogle Scholar
- Betka J. Distant metastases from lip and oral cavity cancer. ORL J Otorhinolaryngol Relat Spec. 2001;63(4):217–21.View ArticlePubMedGoogle Scholar
- Pattni N, Rennie A, Hall T, Norman A. Cardiac metastasis of oral squamous cell carcinoma. BMJ Case Rep. 2015; doi:10.1136/bcr-2015-211275
- Duband S, Paysant F, Scolan V, Forest F, Péoc'h M. Sudden death due to myocardial metastasis of lingual squamous cell carcinoma. Cardiovasc Pathol. 2011;20(4):242–3.View ArticlePubMedGoogle Scholar
- Ito T, Ishikawa N, Negishi T, Ohno K. Cardiac metastasis of tongue cancer may cause sudden death. Auris Nasus Larynx. 2008;35:423–5.View ArticlePubMedGoogle Scholar
- Chiles C, Woodard PK, Gutierrez FR, Link KM. Metastatic involvement of the heart and pericardium: CT and MR imaging. Radiographics. 2001;21:439–49.View ArticlePubMedGoogle Scholar
- Gowen GF, Desuto-Nagy G. The incidence and sites of distant metastases in head and neck carcinoma. Surg Gynec Obstet. 1963;116:603–7.PubMedGoogle Scholar
- O’Brien PH, Carlson R, Steubner EA, Stanley CT. Distant metastases in epidermoid cell carcinoma of the head and neck. Cancer. 1971;27:304–7.View ArticlePubMedGoogle Scholar
- Nishijima W, Takooda S, Tokita N, Takayama S, Sakura M. Analyses of distant metastases in squamous cell carcinoma of the head and neck and lesions above the clavicle at autopsy. Arch Otolaryngol Head Neck Surg. 1993;119(1):65–8.View ArticlePubMedGoogle Scholar
- Butany J, Leong SW, Carmichael K, Komeda MA. A 30-year analysis of cardiac neoplasms at autopsy. Can J Cardiol. 2005;21:675–80.PubMedGoogle Scholar
- Nagata S, Ota K, Nagata M, Shinohara M. Cardiac metastasis of head and neck squamous cell carcinoma. Oral Maxillofac Surg. 2012;41(12):1458–62.View ArticleGoogle Scholar
- Bussani R, De-Giorgio F, Abbate A, Silvestri F. Cardiac metastases. J Clin Pathol. 2007;60:27–34.View ArticlePubMedPubMed CentralGoogle Scholar
- Lam K, Dickens P, Chan AC. Tumors of the heart. A 20-year experience with a review of 12,485 consecutive autopsies. Arch Pathol Lab Med. 1993;117(10):1027–31.PubMedGoogle Scholar
- Liang JW, Li ZD, Li SC, Fang FQ, Zhao YJ, Li YG. Pharyngocutaneous fistula after total laryngectomy: A systematic review and meta-analysis of risk factors. Auris Nasus Larynx. 2015;42(5):353–9.View ArticlePubMedGoogle Scholar
- Behera G, Dutta P, Manjhi R, Pothal S, Samal S, Panda R. Esophago-pleural fistula with pulmonary tuberculosis. J Coll Physicians Surg Pak. 2007;17:238–9.PubMedGoogle Scholar
- Nari GA, Huerta CG, Revelez RB, González AS. Spontaneous esophago-pleural fistula secondary to candidiasis in a patient with human immunodeficiency virus infection. An infrequent complication of esophageal moniliasis. Acta Gastroenterol Latinoam. 2010;40(1):65–7.PubMedGoogle Scholar
- Jover R, Girona E, Verdú C, Casellas JA, Pérez-Mateo M. Esophago-pleural fistula complicating variceal sclerotherapy. Rev Esp Enferm Dig. 1999;91(1):78–9.PubMedGoogle Scholar
- Andersson R, Nilsson S. Perforated Barrett's ulcer with esophago-pleural fistula. A case report. Acta Chir Scand. 1985;151(5):495–6.PubMedGoogle Scholar
- Machuzak MS, Santacruz JF, Jaber W, Gildea TR. Malignant tracheal-mediastinal-parenchymal-pleural fistula after chemoradiation plus bevacizumab: management with a Y-silicone stent inside a metallic covered stent. J Bronchology Interv Pulmonol. 2015;22(1):85–9.View ArticlePubMedGoogle Scholar
- Manojlovic S. Metastatic carcinomas involving the heart. Review of postmortem examination. Zentralbl Allg Pathol. 1990;136:657–61.PubMedGoogle Scholar
- Werbel GB, Skom JH, Mehlman D, Michaelis LL. Metastatic squamous cell carcinoma to the heart. Unusual cause of angina decubitus and cardiac murmur. Chest. 1985;88:468–9.View ArticlePubMedGoogle Scholar
- Rivkin A, Meara JG, Li KK, Potter C, Wenokur R. Squamous cell metastasis from the tongue to the myocardium presenting as pericardial effusion. Otolaryngol Head Neck Surg. 1999;120:593–5.View ArticlePubMedGoogle Scholar
- Schwender FT, Wollner I, Kunju LP, Nakhleh RE, Chan KM. Squamous cell carcinoma of the buccal mucosa with metastases to the pericardial cavity, lung and thyroid. Oral Oncol. 2002;38:114–6.View ArticlePubMedGoogle Scholar
- Kavanagh MM, Janjanin S, Prgomet D. Cardiac metastases and a sudden death as a complication of advanced stage of head and neck squamous cell carcinoma. Coll Antropol. 2012;36(2):19–21.PubMedGoogle Scholar
- McKeag N, Hall V, Johnston N, McClements B. Cardiac metastasis from a squamous cell carcinoma of the tongue in the absence of local recurrence. Ulster Med J. 2013;82(3):193–4.PubMedPubMed CentralGoogle Scholar
- Browning CM, Craft JF, Renker M, Schoepf UJ, Baumann S. Squamous cell carcinoma of the tongue with metastasis to the right ventricle. Am J Med Sci. 2015;349(5):461–2.View ArticlePubMedGoogle Scholar
- Joopmann M, Steiger M, Rudack C, Eckardt L, Stenner M. Giant right ventricular metastasis of hypopharyngeal cancer complicated by ventricular tachycardia and cardiogenic shock. Eur Heart J Cardiovasc Imaging. 2014;15(10):1179.View ArticleGoogle Scholar
- Ekmektzogloua KA, Samelisb GF, Xanthosa T. Heart and tumors: location, metastasis, clinical manifestations, diagnostic approaches and therapeutic considerations. J Cardiovasc Med. 2008;9:769–77.View ArticleGoogle Scholar
- Butany J, Nair V, Naseemuddin A, Nair GM, Catton C, Yau T. Cardiac tumors: diagnosis and management. Lancet Oncol. 2005;6:219–28.View ArticlePubMedGoogle Scholar
- O’Donnell DH, Abbara S, Chaithiraphan V, Yared K, Killeen RP, Cury RC. Cardiac tumors: optimal cardiac MR sequences and spectrum of imaging appearances. AJR Am J Roentgenol. 2009;193:377–87.View ArticlePubMedGoogle Scholar
- Pun SC, Plodkowski A, Matasar MJ, Lakhman Y, Halpenny DF, Gupta D, et al. Pattern and prognostic implications of cardiac metastases among patients with advanced systemic cancer assessed with cardiac magnetic resonance imaging. J Am Heart Assoc. 2016;5(5), e003368.View ArticlePubMedPubMed CentralGoogle Scholar
- Hudzik B, Miszalski-Jamka K, Glowacki J, Lekston A, Gierlotka M, Zembala M, et al. Malignant tumors of the heart. Cancer Epidemiol. 2015;39:665–72.View ArticlePubMedGoogle Scholar