Spontaneous pneumothoraces and hemothoraces are rare manifestations of sarcomas occurring more commonly in specific histologic types, chemotherapy and/or anti-angiogenic therapy. Early identification of spontaneous pneumothoraces and hemothoraces improves the clinical outcomes. In this article, we present a case series of three patients with soft tissue and bone sarcomas who developed spontaneous pneumothoraces and/or hemothoraces and discuss the current literature highlighting the evidence behind these complications

Ezzeddine, Fatima

Jalal, Shadia

Cureus

IUPUIScholarWorks

Spontaneous Pneumothoraces and Hemothoraces in Sarcomas

Received 10/27/2017 Review began  11/22/2017 Review ended  11/27/2017 Published 12/03/2017© Copyright 2017Ezzeddine et al. This is an openaccess article distributed under theterms of the Creative CommonsAttribution License CC-BY 3.0.,which permits unrestricted use,distribution, and reproduction in anymedium, provided the originalauthor and source are credited.Spontaneous Pneumothoraces andHemothoraces in SarcomasFatima Ezzeddine  , Shadia Jalal 1. Internal Medicine, Indiana University School of Medicine 2. Indiana University Melvin and Bren SimonCancer Center, Indiana University School of Medicine Corresponding author: Fatima Ezzeddine, fmezzedd@iu.edu Disclosures can be found in Additional Information at the end of the articleAbstractSpontaneous pneumothoraces and hemothoraces are rare manifestations of sarcomas occurringmore commonly in specific histologic types, chemotherapy and/or anti-angiogenic therapy.Early identification of spontaneous pneumothoraces and hemothoraces improves the clinicaloutcomes. In this article, we present a case series of three patients with soft tissueand bone sarcomas who developed spontaneous pneumothoraces and/or hemothoraces anddiscuss the current literature highlighting the evidence behind these complications.Categories: OncologyKeywords: hemothoraces, pazopanib, pneumothoraces, sarcomasIntroductionPrimary and metastatic sarcomas have been reported to be associated with spontaneouspneumothoraces and hemothoraces [1-4]. With the emergence and increased use ofmultitargeted tyrosine kinase inhibitors with anti-angiogenic effects, the risk of developingthese complications is even higher [5-7]. We present a case series of the three patients withsarcomas complicated by pneumothoraces and/or hemothoraces followed by a literature reviewhighlighting the evidence behind these complications.Case PresentationCase oneAn 18-year-old female presented in December 2015 with acute chest pain. A computedtomography (CT) scan of her chest revealed a pericardial effusion which was negative formalignancy. The presumptive diagnosis was viral pericarditis. In February 2016, she developedrecurrent left-sided chest pain and was found to have cardiac tamponade. An enhancing masswas identified in the right atrium on imaging (Figure 1). She underwent a pericardial windowprocedure which revealed a vascular tumor invading the pericardium. The frozen section of thespecimen was consistent with sarcoma. In March 2016, she underwent pericardiectomy withbiopsy of the tumor revealing angiosarcoma of the right atrium. After the procedure, she wasstarted on a neoadjuvant cycle of doxorubicin (25 mg/m2, one to three days) and ifosfamide (1.8g/m2, one to five days). She was then treated with four other cycles of doxorubicin andifosfamide followed by four cycles of paclitaxel 80 mg/m2 weekly for three of four weeks. Followup imaging revealed an increase in the tumor size with interval development of small volumemetastasis to the right lung. In November 2016, she underwent the surgical resection of theright atrial tumor after she was found to have metastatic lung nodules. The pathology showed1 2 Open Access CaseReport  DOI: 10.7759/cureus.1905How to cite this articleEzzeddine F, Jalal S (December 03, 2017) Spontaneous Pneumothoraces and Hemothoraces inSarcomas. Cureus 9(12): e1905. DOI 10.7759/cureus.1905angiosarcoma with the treatment effect and evidence of invasion of the cardiac muscle andfibrous connective tissue. New pulmonary nodules were evident on subsequent imaging whichled to further chemotherapy treatment. She initially received a cycle of gemcitabine 900 mg/m2followed by four cycles of gemcitabine 1500 mg/m2 and dacarbazine 500 mg/m2. A week prior toreceiving her fifth cycle, she developed severe chest tightness and was found to have left-sidedpneumothorax requiring surgical management with left-sided video-assisted thoracoscopicbullectomy. The pathology was negative for metastasis. Currently, she is doing well with plansto resume further chemotherapy.FIGURE 1: The cardiac magnetic resonance imaging (A) andthe computed tomography (B) of the chest illustrating rightatrial mass extending into the pericardial sac and amultiloculated fluid collection lateral to the left heart border.Case twoA 39-year-old male reported concerns of progressive right calf swelling for two years. A lowerextremity magnetic resonance image (MRI) revealed a mass suspected to be a sarcoma. Fineneedle aspirate of the mass was consistent with low-grade monophasic synovial cell sarcoma. Astaging CT of his chest showed multiple small bilateral pulmonary nodules. He underwent threecycles of neoadjuvant cyclophosphamide, doxorubicin, and dacarbazine followed byamputation above the right knee. After the surgery, he underwent 10 more cycles ofcyclophosphamide, doxorubicin, and dacarbazine with complete resolution of the pulmonarynodules. On follow-up CT of his chest two and a half years later, a left lower lobe metastaticlung nodule was noted. He was re-started with chemotherapy with ifosfamide, mesna, andpegfilgrastim (Neulasta). After three cycles, his chest CT showed disease progression withbilateral pulmonary metastases. The left and right video-assisted thoracoscopy with noduleresections were done, and the surgical specimen pathology was consistent with metastaticsynovial sarcoma. At this time, given his progressive disease with chemotherapy, the decisionwas made to start pazopanib. Two weeks after receiving pazopanib for three months, he wasadmitted for chest pain and was found to have a pneumothorax which was managed by talcpleurodesis. Pazopanib was resumed, and after receiving it for 29 months, it was temporarilystopped due to uncontrolled diarrhea. Four months later, he developed chest tightness whileplaying golf and was found to have a recurrent hemothorax six months after the initial one(Figure 2). Both hemothoraces required emergent evacuation and blood transfusions. Theexamination of the pleural fluid was negative for malignancy. After resolution of his secondhemothorax, pazopanib was resumed, and currently, he is doing well.2017 Ezzeddine et al. Cureus 9(12): e1905. DOI 10.7759/cureus.1905 2 of 6FIGURE 2: The computed tomography of the chest (A) and x-ray (B) revealing large left-sided hemithorax.Case threeA 20-year-old male presented in August 2016 with distal left thigh pain of a few monthsduration. A left lower extremity MRI revealed distal femoral metadiaphysis mass withsurrounding periosteal reaction. The biopsy of the mass revealed osteoblastic osteosarcoma. Astaging CT of his chest showed a 3 mm right upper lobe lung nodule. He underwent three cyclesof neoadjuvant cisplatin (25 mg/m2, one to three days) and doxorubicin (25 mg/m2, one tothree days). Two weeks after his first cycle, he developed a left pneumothorax, which recurredtwo weeks later. Given his increased risk for the recurrent pneumothoraces, the pleurodesis wasperformed. In December 2016, he underwent radical resection of the left distal femur with lefttotal knee arthroplasty and distal femur replacement. The resected tumor showed 50% necrosis.Therefore, the decision was made to pursue three additional cycles of ifosfamide/doxorubicinalternating with ifosfamide/cisplatin. The cumulative doses of ifosfamide, cisplatin anddoxorubicin were 27 g/m2, 80 mg/m2 and 150 mg/m2, respectively. Three days prior to receivinghis cycle two of ifosfamide/cisplatin, he started to have right-sided chest pain and was found tohave bilateral pneumothoraces on imaging (Figure 3). Being hemodynamically stable, he wasinitially given his planned chemotherapy cycle of ifosfamide/cisplatin followed by chestimaging. A CT of his chest showed three bilateral subpleural cystic lesions which were notdemonstrated on prior imaging. He underwent bilateral video-assisted thoracoscopy with lungnodule resection and pleurodesis. The follow-up imaging confirmed the resolution of hispneumothoraces. Currently, he is doing well with plans to perform a chest CT every twomonths in the first year to detect incidental asymptomatic recurrent pneumothoraces.2017 Ezzeddine et al. Cureus 9(12): e1905. DOI 10.7759/cureus.1905 3 of 6FIGURE 3: The chest x-ray showing large bilateralpneumothoraces.DiscussionMalignancy-related spontaneous pneumothorax is a rare event accounting for 0.05% to 1% ofall spontaneous pneumothoraces [1-2]. Its prevalence in soft tissue sarcoma patients is 1.9%[3], while in the patients with primary lung cancers, it is estimated at 0.32% [4]. In 2010, acomprehensive review of spontaneous pneumothoraces complicating sarcoma was publishedcompiling 100 separate articles with a total of 153 patients described [3]. In the MedicalLiterature Analysis and Retrieval System Online (Medline) and the Excerpta Medica Database(Embase) searches, we have found 21 more articles addressing the same issue with a total of 33patients which have been published since 2010. We included our three patients (case one, casetwo, and case three) for a total of 189 patients. The osteogenic sarcoma (31.7%), angiosarcoma(17.5%), and synovial cell sarcoma (11.1%) were the most commonly reported histologies.Furthermore, the chemotherapy and surgery were risk factors for the development ofpneumothorax.Spontaneous hemothorax has also been reported in sarcomas. Our literature review revealed 66manuscripts reporting hemothorax as a complication of sarcoma with 71 patients described. Weincluded our patient (case 2) for a total of 72 patients. The angiosarcoma cases accounted foraround half (51.4%) of the cases. Approximately 50% of the patients had pulmonaryinvolvement, whether primary or metastatic as documented on imaging, surgical biopsy orpost-mortem examination. Most cases were initial presentations that led to the diagnosis ofcancer. Our patient with metastatic synovial sarcoma developing recurrent hemothoracesfollowing the treatment with pazopanib is the first case noting the occurrence of thiscomplication following pazopanib which might be a cumulative dose effect after receiving itover a prolonged period. In our case, this was preceded by the treatment with pazopanib for 292017 Ezzeddine et al. Cureus 9(12): e1905. DOI 10.7759/cureus.1905 4 of 6months.With the emergence and increased use of antiangiogenic therapy in the patients with refractorysoft tissue sarcomas, the prevalence of pneumothorax complicating soft tissue sarcomas mightbe higher. Pazopanib is a tyrosine kinase inhibitor that is approved in the United States,European Union, and Japan for the treatment of the patients with refractory or recurrentmetastatic soft tissue sarcomas following the chemotherapy. In 2014, the JapaneseMusculoskeletal Oncology Group (JMOG) study revealed that the prevalence of pneumothoraxin 32 patients treated with pazopanib was 9.4% [5]. The risk factors associated with thedevelopment of pneumothorax included: pathological diagnosis of synovial sarcoma, thepresence of lung lesions greater than 30 mm in diameter, and a personal history ofpneumothorax [6]. Other trials with pazopanib in urothelial cancer, renal cell cancer,pancreatic neuroendocrine tumors and cervical cancer did not report pneumothorax as anadverse event. This might be explained by either underreporting of this adverse effect in othercancer types or the natural course of soft tissue tumors that metastasize predominantly to thelungs with pleural or subpleural involvement.When examining other anti-angiogenic agents, a phase I trial evaluating the combination ofsorafenib, bevacizumab and low-dose cyclophosphamide in children and young adults withrefractory solid tumors revealed that 11 of 44 patients (25%) developed pneumothoraxpotentially related to the therapy [7]. Eight of the 11 patients (72.7%) who developedpneumothorax had pulmonary metastases at the entry of this study. By blocking vascularendothelial growth factor signaling, anti-angiogenic agents disrupt the vasculature of thetumor tissue, and in combination with antiproliferative chemotherapy, they lead to pulmonarynodule necrosis, subsequent rupture of the necrotic nodule, and pneumothorax formation.ConclusionsIn conclusion, the spontaneous pneumothoraces and hemothoraces are potential complicationsof soft tissue and bone sarcomas noted at a higher incidence in certain histologic types,following chemotherapy and/or antiangiogenic therapy. Early recognition of primary ormetastatic sarcomas as part of their differential diagnosis is likely associated with the improvedoutcomes. The sarcomas should be in the differential diagnosis of spontaneous hemothoraxwhich can be their initial presentation.Additional InformationDisclosuresHuman subjects: Consent was obtained by all participants in this study. Conflicts of interest:In compliance with the ICMJE uniform disclosure form, all authors declare the following:Payment/services info: All authors have declared that no financial support was received fromany organization for the submitted work. Financial relationships: All authors have declaredthat they have no financial relationships at present or within the previous three years with anyorganizations that might have an interest in the submitted work. Other relationships: Allauthors have declared that there are no other relationships or activities that could appear tohave influenced the submitted work.AcknowledgementsWe would like to thank Dr. Daniel Rushing for his expert advice and review of this article.References1. Steinhauslin CA, Cuttat JF: Spontaneous pneumothorax. A complication of lung cancer? .2017 Ezzeddine et al. Cureus 9(12): e1905. DOI 10.7759/cureus.1905 5 of 6Chest. 1985, 88:709–13. 10.1378/chest.88.5.7092. Le Garff G, Lena H, Corbineau F, et al.: Unusual cause of recurrent pneumothorax: Excavatedmetastasis of osteosarcoma. Ann Thorac Surg. 2001, 72:2111–3. 10.1016/S0003-4975(01)02694-73. Hoag JB, Sherman M, Fasihuddin Q, et al.: A comprehensive review of spontaneouspneumothorax complicating sarcoma. Chest. 2010, 138:510–8. 10.1378/chest.09-22924. Lai RS, Perng RP, Chang SC: Primary lung cancer complicated with pneumothorax . Jpn J ClinOncol. 1992, 22:194–7.5. Nakano K, Inagaki L, Tomomatsu J, et al.: Incidence of pneumothorax in advanced and/ormetastatic soft tissue sarcoma patients during pazopanib treatment. Clin Oncol. 2014, 26:357.10.1016/j.clon.2014.02.0106. Nakano K, Motoi N, Tomomatsu J, et al.: Risk factors for pneumothorax in advanced and/ormetastatic soft tissue sarcoma patients during pazopanib treatment: a single-instituteanalysis. BMC Cancer. 2016, 16:750. 10.1186/s12885-016-2786-z7. Interiano RB, McCarville MB, Wu J, et al.: Pneumothorax as a complication of combinationantiangiogenic therapy in children and young adults with refractory/recurrent solid tumors. JPediatr Surg. 2015, 50:1484–9. 10.1016/j.jpedsurg.2015.01.0052017 Ezzeddine et al. Cureus 9(12): e1905. DOI 10.7759/cureus.1905 6 of 6

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Spontaneous Pneumothoraces and Hemothoraces in Sarcomas

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