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Clinical manifestations and diagnostic methods in pulmonary angiosarcoma: protocol for a scoping review Lim, Rachel; Harper, Lea; Swiston, John Jul 10, 2017

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PROTOCOL Open AccessClinical manifestations and diagnosticmethods in pulmonary angiosarcoma:protocol for a scoping reviewRachel Lim1* , Lea Harper2 and John Swiston3AbstractBackground: Angiosarcoma involving the lung can represent either primary or metastatic malignancy. Due to therarity of this condition, knowledge surrounding the natural history and clinical presentation is scarce. The aim ofthis scoping review is to summarize the existing literature on pulmonary angiosarcoma, particularly as it pertains tothe clinical presentation and ancillary tests used for diagnosis in addition to histopathology.Methods: We will conduct a systematic search using Ovid MEDLINE and EMBASE electronic databases. Twoinvestigators will independently screen identified titles and abstracts to select articles reporting on pulmonaryangiosarcoma. The data will be summarized in a narrative fashion and organized according to aspects ofepidemiology, risk factors, clinical presentation, diagnostic methods, and treatment.Discussion: Scoping reviews are increasingly used to synthesize the evidence on a particular topic, to identify gapsin the literature, and to determine if future systematic reviews are feasible. In order to improve the care of patientswith angiosarcoma, earlier recognition and diagnosis is required. This review will be valuable for highlighting therange of clinical presentations and the role of imaging and other diagnostic tools in the diagnosis of metastaticand primary pulmonary angiosarcoma.Systematic review registration: PROSPERO registration: CRD42017059052Keywords: Angiosarcoma, Neoplasm, Pulmonary, Scoping reviewBackgroundAngiosarcomas are rare, aggressive tumors arising from ei-ther vascular (hemangiosarcoma) or lymphatic (lymphan-giosarcoma) endothelium. These account for less than twopercent of all sarcomas and are further subdivided into cu-taneous angiosarcoma, lymphoedema-associated angiosar-coma, radiation-induced angiosarcoma, primary breastangiosarcoma, and soft-tissue angiosarcoma [1, 2].Cutaneous angiosarcoma has a median age of incidenceof approximately 60 years, and there is a slight male pre-dominance [3]. Cutaneous angiosarcoma has a predilec-tion for head and neck location but can spread to anyorgan, most commonly the lung [1–3]. If angiosarcomapresents in the lung, it more likely represents metastaticdisease rather than primary malignancy. Presentation var-ies widely including incidental findings on imaging, cough,constitutional symptoms, and hemoptysis [1].Pneumothorax is a rare phenomenon, but there are re-ports of bilateral simultaneous pneumothoraces [3–6].The association of angiosarcoma with pneumothorax islikely due to cystic lesions often found on imaging. Vari-ous mechanisms have been proposed for the develop-ment of cystic lesions including excavation of solidnodular lesions and infiltration of tumor cells into pre-existing bullae or air sacs [7]. A mechanism described in1973 postulated that necrotic nodules invade into a bron-chus and pleural space leading to bronchopleural fistulaformation [8]. In a literature review of previous case re-ports of pneumothorax from angiosarcoma, Chang et al.found that the scalp was the most common primary site[9]. An analysis of a Japanese autopsy registry observed* Correspondence: Rachel.Lim@albertahealthservices.ca1Cumming School of Medicine, University of Calgary, Foothills MedicalCentre, Room 933, North Tower, 1403-29 Street NW, Calgary, AB T2N 2T9,CanadaFull list of author information is available at the end of the article© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (, which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver( applies to the data made available in this article, unless otherwise stated.Lim et al. Systematic Reviews  (2017) 6:136 DOI 10.1186/s13643-017-0531-6that pneumothorax was limited to patients with angiosar-coma of the scalp [10].In contrast, hemoptysis has been associated with bothprimary and metastatic angiosarcoma [3, 11–13]. Lungnodules are frequently present in these cases with pul-monary hemorrhage [3, 11–13]. There is no consensuson differentiating features in presentation or imaging be-tween primary and metastatic pulmonary angiosarcoma.A review of 24 patients with metastatic angiosarcoma in-volving the lung found that the most common computedtomography (CT) signs were multiple solid nodulesfollowed by multiple thin-walled cysts [9].Other diagnostic methods have been reported with vary-ing success. Fluorine-18 fluoro-2-deoxy-D-glucose posi-tron emission tomography (18F-FDG PET) is commonlyused in the evaluation of potentially malignant tumors butmay contribute to diagnostic uncertainty in pulmonaryangiosarcoma. While reports have demonstrated PETpositivity in cardiac angiosarcoma [14], there are also re-ports of metastatic angiosarcoma lesions in the lung thatwere not metabolically active on PET-CT [1, 15].Similarly, pleural fluid analysis has a variable yield incase reports [9, 10, 12, 13]. Ultimately, diagnosis relieson histopathology. The histological examination ofangiosarcoma reveals abnormal, pleomorphic, malignantendothelial cells. Immunohistochemistry is important forconfirming the diagnosis. Factor VIII, CD 31, CD34, Fli-1, Ulex europaeus agglutinin 1, and vimentin are typicalendothelial markers [1]. The optimal method of tissuebiopsy has not been studied but transbronchial biopsy(TBB), video-assisted thoracoscopic (VAT) pleural, and/or lung biopsy and surgical lung biopsy (SLB) have beentried [12, 16]. Tissue biopsy is invasive and is not alwayspossible due to patient preferences or contraindications,particularly because angiosarcoma is often found in theelderly. Knowing which tests can aid in an earlier diag-nosis may result in the prompt institution of treatmentand may improve patient outcomes.The prognosis of metastatic pulmonary angiosarcoma re-mains dismal, with 5-year survival rates of less than 40%.Most patients die within one year after diagnosis [3, 13].Due to the rarity of this malignancy, the index of suspicionis low and diagnosis is often attained in advanced stages.The authors suspect that the current knowledge around thenatural history and clinical presentation is largely based oncase reports and case series, however, the landscape of evi-dence is unknown. The aim of this scoping review is toexamine the existing literature on pulmonary angiosarcomaand to characterize the results as it pertains to the presenta-tion and diagnosis of this rare disease.MethodsThe methods of this scoping review will be based on thefive stages outlined in the Arksey and O’Malley framework[17] as well as the guidelines from the Joanna Briggs Insti-tute [18]. We will use the Preferred Reporting Items forSystematic Review and Meta-Analysis Protocols statement(see Additional file 1 for PRISMA-P checklist) for aspectsapplicable to a scoping review. There is a checklist beingdeveloped specifically for scoping reviews but is unavail-able at this time. This protocol has been registered in theInternational Prospective Register of Systematic Reviews(PROSPERO). The study protocol registration number isCRD42017059052 and is available through PROSPERO: 1: identifying research questionsPrimary research questionI. What is known from the existing literature about theclinical manifestations in patients with primary ormetastatic pulmonary angiosarcoma?Other concepts to map existing literature, with sup-porting questions:II. Risk factors for angiosarcoma (what is the frequencyof reporting of known risk factors such as chemicalexposure in the literature?)III.Differentiation between primary and metastaticpulmonary angiosarcoma (do these differ in clinicalpresentation or imaging? What investigations shouldbe pursued in the workup for metastatic disease?)IV.Diagnostic methods (prior to pursuing biopsy, arethere ancillary tests that can aid in the diagnosis ofpulmonary angiosarcoma? What is the range ofradiographic abnormalities? What method of biopsyshould be recommended as first-line?)V. Chemotherapy (as there are no guidelines, whichpatients are clinicians deciding to treat? Are theyusing single or combination chemotherapy?)Stage 2: identifying relevant studiesTwo independent reviewers (RL and KS) will be perform-ing the search in parallel. The online databases to besearched are Ovid MEDLINE (1946–present) andEMBASE (Excerpta Medica Database). The search ofonline databases will be restricted to humans and adults.The results will be downloaded into EndNote and du-plicate results removed. The references of relevant full-length publications identified will be screened foradditional studies relevant to the research question. At-tempts will be made to contact authors to acquire full-length manuscripts for relevant abstracts if they are notreadily available, or if information is missing from full-length publications.Table 1 outlines the initial electronic search strategy.The first Boolean search will be done by using the termLim et al. Systematic Reviews  (2017) 6:136 Page 2 of 5“or” to explode (search by subject heading) and map(search by keyword) the following MeSH (Medical Sub-ject Headings) headings “hemangiosarcoma” or “vascularneoplasms” or “angiosarcoma”. The second Booleansearch will be done using the terms “or” to explode andmap “pulmonary” or “lung”. The two Boolean searcheswill be combined by using the Boolean term “and”. Assuggested by the Joanna Briggs Institute [18], an iterativeapproach will be applied by collecting and analyzing theindex terms, keywords, and title words from the studiesincluded for full-text review during the initial search. Ifthere are essential search terms missing from the initialsearch strategy then an additional search may be war-ranted using updated search terms.Stage 3: study selectionTwo investigators (RL and LH) will independently screencitation titles and abstracts and review potentially relevantarticles in full. We will consider any articles representingoriginal research involving adults with pulmonary angio-sarcoma. Included articles are required to report on theclinical presentation and diagnostic investigations pursuedin a patient with biopsy-proven angiosarcoma involvingthe lung. The diagnosis of angiosarcoma will be based oneither lung biopsy or extrapulmonary biopsy in conjunc-tion with abnormal chest imaging. Our exclusion criterionwill include non-English language publications, pediatricpopulations, animal studies, and narrative reviews. Studieswhich potentially replicate study participants will also beexcluded.If an agreement for abstract or full article inclusion can-not be reached between the two reviewers, an opinion willbe requested from a third reviewer (JS). The degree ofagreement between reviewers for each of these steps (full-text review, article inclusion) will be quantified with akappa statistic with a 95% confidence interval.Stage 4: charting the dataBoth reviewers will use the same template for data ex-traction; details are presented in Table 2. Data extractionwill be done independently by each reviewer (LH, RL).The data extraction form will be piloted on the first tenstudies to determine whether the information gatheredis serving the purpose of the study.Stage 5: collating, summarising, and reporting of resultsThe process of study inclusion in the scoping review willbe tracked through a PRISMA flow diagram. A tablemapping the distribution of studies according to thestudy design will be presented for both primary andmetastatic disease.The literature will be organized according to the afore-mentioned concepts; namely, clinical presentation, riskfactors, epidemiology, diagnostic methods, and treatment.Data will be separated for primary versus metastatic pul-monary angiosarcoma. Frequencies and percentages willbe calculated for categorical variables, and descriptive sta-tistics, including means and standard deviation, for con-tinuous variables. Analysis will be carried out in Stataversion 14.0 (StataCorp, College Station, TX, USA).Table 1 Details of electronic bibliographic database searchstrategiesOvid MEDLINE1 Exp Hemangiosarcoma/2 Hemangiosarcoma.tw3 Exp Vascular neoplasms/4 Angiosarcoma.mp5 Angiosarcoma.tw6 1 or 2 or 3 or 4 or 57 Pulmonary.mp8 Pulmonary.tw9 Exp Lung/10 Lung.mp11 6 or 7 or 8 or 912 6 and 11Table 2 Description of data extracted from each included studyType of dataStudy characteristics Year of publicationAuthorsCountry of studySample sizeStudy designPatient characteristics AgeGenderEthnicityComorbiditiesSmoking statusHistory of prior chemical or occupationalexposureHistory of prior radiationHistory of breast cancer or othermalignancyDisease characteristics Duration from symptom onset topresentationDuration from symptom onset todiagnosisRespiratory symptoms at onsetExtrapulmonary symptomsPhysical examination findingsResults of Investigations Chest radiographChest computed tomographyLung biopsy (TBB, VAT biopsy, SLB)Skin or other organ biopsies18F-FDG PETPleural fluid analysisLaboratory dataTreatment and survivaloutcomesChemotherapy regimens and durationSurgeryPalliative carePatient outcomes (rehospitalization, death)Lim et al. Systematic Reviews  (2017) 6:136 Page 3 of 5DiscussionScoping reviews require similar expertise in finding andretrieving data as systematic reviews yet serve a differentpurpose altogether. In keeping with one of the roles pro-posed by Arksey and O’Malley [17], the main purpose ofthis scoping review is to explore the existing literature asit pertains to pulmonary angiosarcoma. Secondary tothis, the authors will attempt to identify gaps in the lit-erature and also determine if a systematic review is feas-ible for any diagnostic test with enough literature.The key to improving outcomes for patients with pul-monary angiosarcoma is early recognition and accuratediagnosis, therefore, the priority of this scoping review isto focus on the clinical presentation. The lack of aware-ness of angiosarcoma often results in low clinical suspi-cion. This review will be valuable for outlining the typicalpresentations and discussing the roles played by imagingand other potential tools like 18F-FDG PET in the diagno-sis of pulmonary angiosarcoma. Regarding other organsaffected by angiosarcoma, readers can refer to a review byGaballah et al. on the clinical and radiologic features ofangiosarcoma affecting multiple organ systems includingthe breast, bone, spleen, and liver [19].In rare conditions such as angiosarcoma, population-based studies or trials are unlikely to occur without signifi-cant effort. Systematic reviews of case reports and seriesof other uncommon conditions have proven their value byguiding clinical practice and future research [20–23]. Wesuspect that the majority of the literature will be case re-ports and series, however, we will not exclude other studydesigns as is typical for scoping reviews.A limitation to scoping reviews is the lack of criticalappraisal since the focus is on determining the sum anddistribution of evidence. In addition, if the majority ofevidence stems from case reports with their inherentbiases, then it is not surprising that outcomes such asthe frequency of clinical manifestations may be influ-enced by selective reporting of more unusual presenta-tions such as bilateral pneumothoraces. The strength ofthis study will be the thorough, systematic review of allpublished literature on pulmonary angiosarcoma. Theresults of this scoping review will be valuable for inform-ing clinicians and researchers in the development of fu-ture guidelines for the diagnosis and management ofpulmonary angiosarcoma, as well as priorities for futureresearch.Additional fileAdditional file 1: PRISMA-P file, PRISMA-P 2015 Checklist. (DOCX 38 kb)Abbreviations18F-FDG PET: Fluorine-18 fluoro-2-deoxy-D-glucose positron emission tom-ography; CT: Computed tomography; EMBASE: Excerpta Medica Database;MEDLINE: Medical Literature Analysis and Retrieval System Online;MeSH: Medical Subject Headings; PRISMA-P: Preferred Reporting Items forSystematic review and Meta-Analysis Protocols; PROSPERO: InternationalProspective Register of Systematic Reviews; SLB: Surgical lung biopsy;TBB: Transbronchial biopsy; VAT: Video-assisted thoracoscopicAcknowledgementsNot applicable.FundingNot applicable.Availability of data and materialsNot applicable.Authors’ contributionsRL registered the protocol with PROSPERO and drafted the manuscript. Allauthors contributed to study design and edited the manuscript. RL and LHwill conduct the review and data analysis under the supervision of JS. RLtakes responsibility for the integrity of this manuscript. All authors read andapproved the final manuscript.Authors’ informationRL is finishing her internal medicine residency training before beginning herfellowship in pulmonary medicine at the University of Calgary. LH is acurrent fellow in pulmonary medicine at the University of British Columbia.JS is the Medical Director of the Pulmonary Hypertension Program atVancouver General Hospital and is a Clinical Associate Professor within theDivision of Respiratory Medicine at the University of British Columbia.Ethics approval and consent to participateNot applicable.Consent for publicationNot applicable.Competing interestsThe authors declare that they have no competing interests.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Author details1Cumming School of Medicine, University of Calgary, Foothills MedicalCentre, Room 933, North Tower, 1403-29 Street NW, Calgary, AB T2N 2T9,Canada. 2University of British Columbia, 7th Floor, 2775 Laurel Street,Vancouver, BC V5Z 1M9, Canada. 3Department of Medicine, 7th Floor, 2775Laurel Street, Vancouver, BC V5Z 1M9, Canada.Received: 24 March 2017 Accepted: 22 June 2017References1. 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Bybee KA, Kara T, Prasad A, Lerman A, Barsness GW, Wright RS, et al.Systematic review: transient left ventricular apical ballooning: a syndromethat mimics ST-segment elevation myocardial infarction. Ann Intern Med.2004;141(11):858–65.23. Holty JE, Bravata DM, Liu H, Olshen RA, McDonald KM, Owens DK.Systematic review: a century of inhalational anthrax cases from 1900 to2005. Ann Intern Med. 2006;144(4):270–80.•  We accept pre-submission inquiries •  Our selector tool helps you to find the most relevant journal•  We provide round the clock customer support •  Convenient online submission•  Thorough peer review•  Inclusion in PubMed and all major indexing services •  Maximum visibility for your researchSubmit your manuscript your next manuscript to BioMed Central and we will help you at every step:Lim et al. Systematic Reviews  (2017) 6:136 Page 5 of 5


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