Overdiagnosing Giant Bullous Emphysema as Metastatic Adenocarcinoma: A Case Report

Overdiagnosing Giant Bullous Emphysema as Metastatic Adenocarcinoma: A Case Report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Overdiagnosing Giant Bullous Emphysema as Metastatic Adenocarcinoma: A Case Report Jiyun Lee, Eunsu Park This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4730909/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 01 Oct, 2024 Read the published version in Journal of Cardiothoracic Surgery → Version 1 posted 11 You are reading this latest preprint version Abstract Background Giant bullous emphysema is characterized by large bullae occupying at least one-third of the hemithorax and leading to compression of the surrounding lung parenchyma. Overdiagnosis can occur because of the atypical appearance of hyperplastic type II pneumocytes, which may be mistaken for malignant cells. Case Presentation: A 48-year-old male with a history of smoking and occupational exposure presented with dyspnea and drowsiness. Initial chest X-ray revealed a tension pneumothorax, and subsequent chest CT revealed extensive bullous emphysema and lung cancer in the right middle lobe (RML). Pathologic examination initially indicated resected bullae to metastatic adenocarcinoma, but upon review, it was determined that the reactive alveolar cells were misdiagnosed as malignant. Conclusions This case emphasizes the need for thorough histopathological assessment and prudent interpretation of atypical cellular morphology. Overdiagnosis Emphysema Lung cancer Adenocarcinoma Case report Figures Figure 1 Figure 2 Figure 3 Background Giant bullous emphysema was first described in 1937. This condition is rare and characterized by the presence of large bullae occupying at least one-third of a hemithorax that leads to compression of the surrounding lung parenchyma ( 1 ). Patients afflicted with giant bullous emphysema typically have a history of cigarette smoking and COPD ( 2 , 3 ). Presenting features include progressive dyspnea, declining exercise tolerance, hypoxia, and decreased breath sounds. Disease progression can lead to pneumothorax, subcutaneous emphysema, and respiratory failure with hypoxia and hypercapnia ( 3 , 4 ). Giant bullous emphysema can closely resemble pneumothorax, and chest CT is the optimal method for distinguishing between the two conditions, making it the gold standard for differential diagnosis ( 5 ). The alveoli are usually lined by type I pneumocytes but can be populated by hyperplastic type II pneumocytes under certain conditions such as diffuse alveolar damage, radiation or drug-related toxicity, infection, and inflammatory or fibrosing conditions. This atypical appearance can be quite striking and is described as “too atypical to be malignant” ( 6 ). Herein is the report of a case of overdiagnosing metastatic adenocarcinoma as giant bullous emphysema in a 48-year-old male, written according to CARE case report guidelines. Case Presentation The patient, a 48-year-old male with a height of 169 cm and weight of 54 kg, presented to the emergency room with dyspnea and drowsiness, with an oxygen saturation of 50%. A chest X-ray revealed a tension pneumothorax in the right hemithorax (Fig. 1 ), prompting an emergency closed thoracostomy with a 24Fr chest tube. The patient had a history of coughing, sputum production, and shortness of breath with an ECOG score of 2 for the past 2 years. He had sought medical attention from a pulmonologist and was awaiting further outpatient evaluation following chest CT and PFT. The patient had a 30-year history of smoking and occupational exposure due to working in a tunnel. Chest CT showed signs of extensive bullous emphysema in both lungs and a pulmonary nodule, which was suspected of being lung cancer or organizing pneumonia in the RML (Fig. 2 ). The PFT results revealed a significantly reduced lung function indicative of a severe obstructive pattern as follows: FVC 1.92L 44% (postbronchodilator: 2.08L 47%), FEV1 0.72L 22% (postbronchodilator: 0.81L 25%), FEV1/FVC 37% (postbronchodilator: 39%), and DLCO 7.1 mL/mmHg/min 35%. PET-CT revealed a possibly malignant tumor in the RML with a SUVmax of 3.5. Blood tests revealed an alpha-1 antitrypsin level of 129 mg/dL (reference range: 90–200) and an elevated CEA level of 7.96 ng/mL (reference range: 0–5). Based on the findings and the suspicion of lung cancer, a multidisciplinary team recommended limited surgery for lung cancer and bullectomy. During the surgical procedure, bullae in the RUL, RML, and RLL of the lung were discovered, with most of them concentrated in the RUL. The pulmonary nodule in the RML was subjected to wedge resection and frozen section analysis, which revealed adenocarcinoma. Mediastinal lymph node dissection was also performed. Giant bullae were removed through multiple wedge resections using PTFE-reinforced endostaplers. The patient underwent chemical pleurodesis using Abnova Viscum-F four times to address the persistent air leakage. The chest tubes were removed on POD 20, and the patient was discharged on POD 21. Pathologic examination revealed the presence of invasive adenocarcinoma with papillary (90%) and micropapillary (10%) features, which were moderately differentiated and measured 1.3x1.0x0.8 cm. The cancer had invaded the visceral pleural surface and had metastasized to the lower paratracheal lymph node. Additionally, metastatic adenocarcinoma was found in the bullae removed by bullectomy, resulting in a diagnosis of pT2aN2aM1a (AJCC 9th edition) lung cancer. The patient is currently receiving systemic chemotherapy, the dyspnea has resolved, and the PFT results have improved compared with the preoperative findings. To preparing this case report, we carefully reviewed all the slides and found a case of overdiagnosis. The pathologist initially observed atypical cells with occasional prominent nucleoli and hobnail morphology (MOC-31(+), Calretinin(-)). Their growth pattern along the cyst wall and morphology raised concerns about metastatic adenocarcinoma. However, upon reviewing the entire slides, it was more reasonable to consider the cells as reactive alveolar cells because of their uniformly enlarged nonoverlapping vesicular nuclei with regular and smooth nuclear membranes and a single prominent nucleolus. These findings were consistent with subpleural bullous emphysema (Fig. 3 ). Discussion and Conclusions The formation of giant emphysematous bullae stems from the inflammatory destruction and loss of elasticity of small alveolar walls, leading to the coalescence of large air-filled bullae ( 7 ). Radiographically, giant bullous emphysema is characterized by bullae occupying at least one-third of the hemithorax, present in one or both upper lobes ( 8 ). This condition develops due to chronic inflammation of distal airspaces, resulting in emphysematous destruction of the lung parenchyma, subsequent breakdown of the alveolar wall, and permanent enlargement of airspaces ( 8 ). Patients with this condition have a long history of cigarette smoking, marijuana use, and COPD ( 2 , 3 ). More recently, HIV infection, Williams-Beuren syndrome, Ehlers-Danlos syndrome, and sarcoidosis have also been identified as additional risk factors ( 3 , 5 , 9 ). There are reports of an association between giant bullous emphysema and lung cancer. Emphysema is an independent risk factor for lung cancer, with multiple potential pathways implicated in this association, all involving chronic inflammation, anomalous cellular repair, and genetic polymorphisms triggering carcinogenesis ( 4 ). Although the mechanism of carcinogenesis in patients with pulmonary bullous disease remains uncertain, various theories have been proposed. Scar cancer, acquired from repeated inflammatory processes causing the formation of fibrous scar tissue around bullae, as well as impaired ventilation facilitating carcinogen deposition, could lead to metaplastic transformation of epithelial cells within bullae ( 10 ). Additionally, carcinogens may inhibit anti-elastase enzymes, leading to the destruction of the interalveolar septa and subsequent bulla formation ( 11 ). Alveoli are usually lined by type I pneumocytes, but they can also be populated by hyperplastic type II pneumocytes under certain conditions such as diffuse alveolar damage, radiation or drug-related toxicity, infection and various inflammatory or fibrosing conditions. The prominence of hyperplastic type II pneumocytes, as opposed to the typically inconspicuous type I pneumocytes, may raise concerns about adenocarcinoma with a lepidic pattern. The atypical appearance of these cells, especially in organizing diffuse alveolar damage, can be quite pronounced. This atypical appearance, referred to as “too atypical to be malignant”, contrasts with the relatively bland presentation of many adenocarcinoma with a lepidic pattern. Findings related to the underlying condition, such as acute lung injury, fibrosis, or inflammation, usually not only coexist with but also often overshadow reactive pneumocyte hyperplasia ( 6 ). In this case, we initially diagnosed giant bullae as resulting from metastatic adenocarcinoma from lung cancer in the RML, invading the visceral pleura. However, upon reviewing the slides, we found that there was an overdiagnosis of reactive pneumocytes as metastatic adenocarcinoma. This type of diagnostic error can occur because of the similarities in the cellular and morphological features of reactive pneumocytes and malignant cells. The patient displayed multiple tiny nodules and giant bullous emphysema in the contralateral lung, making confirming their association with metastatic adenocarcinoma difficult. It was deemed necessary to monitor the changes in the tiny nodules and remaining giant. Overdiagnosing reactive pneumocytes as metastatic adenocarcinoma can result in unnecessary treatments and complications. Accurate differentiation between reactive changes and malignancy is crucial to avoid overtreatment. This case highlights the importance of thorough histopathological evaluation and cautious interpretation of atypical cellular morphology. Abbreviations AJCC American Joint Committee on Cancer COPD chronic obstructive pulmonary disease CT computed tomography DLCO diffusing capacity of the lungs for carbon monoxide ECOG Eastern Cooperative Oncology Group FEV1 forced expiratory volume in the first second FVC forced vital capacity HIV human immunodeficiency virus PET-CT positron emission tomography-computed tomography PFT pulmonary function test POD postoperative day PTFE polytetrafluoroethylene RLL right lower lobe RML right middle lobe RUL right upper lobe SUVmax maximum standardized uptake value Declarations Ethics approval and consent to participate Ethics approval was obtained from the Institutional Review Board of Incheon St. Mary’s Hospital, Incheon, Republic of Korea (IRB number: OC24ZASI0090) and consent was obtained from the patient for participation in the study. Consent of publication Consent was obtained from the patient for the publication of this report and any accompanying images. Availability of data and materials All data generated or analyzed during this study are included in this published article. Competing interests The authors declare no competing interests. Funding There was no funding for this work. Author’s contributions Jiyun Lee participated in the study design, research, and manuscript writing. Jiyun Lee and Eunsu Park analyzed and interpreted the data. All authors read and approved the final manuscript. Acknowledgments Not applicable. References Garvey S, Faul J, Cormican L, Eaton D, Judge EP. Symptomatic unilateral idiopathic giant bullous emphysema: a case report. BMC Pulm Med. 2022;22. Muhamad NI, Mohd Nawi SN, Yusoff BM, Ab Halim NA, Mohammad N, Wan Ghazali WS. Vanishing lung syndrome Masquerading as bilateral pneumothorax: A case report. Respiratory Med Case Rep. 2020;31. Sohail H, Kilani Y, Osella J, Kamal ASF, Kumari B, Keftassa DE et al. Vanishing Lung Syndrome, or Idiopathic Giant Bullous Emphysema, with Pneumothorax, and Subcutaneous Emphysema in a 58-Year-Old Female Smoker with Chronic Obstructive Pulmonary Disease. Am J Case Rep. 2022;23. Velez Oquendo G, Balaji N, Ignatowicz A, Qutob H. Vanishing Lung Syndrome in a Young Male With Chronic Marijuana Use: A Case Report. Cureus. 2023. Aujayeb A. Please do not put a chest drain in my chest! Vanishing lung syndrome. Afr J Emerg Med. 2020;10:261–5. Butnor KJ. Avoiding Underdiagnosis, Overdiagnosis, and Misdiagnosis of Lung Carcinoma. Arch Pathol Lab Med. 2008;132:1118–32. Mansour M, Kessler S, Khreisat A, Morton J, Berghea R. Vanishing Lung Syndrome: A Case Report and Systematic Review of the Literature. Cureus. 2024. Piao X, Alyass F, Yousuf A. Cardiothoracic Surgery Management of Giant Bullous Lung Disease Initially Misdiagnosed as Pneumothorax: A Case Report. Cureus. 2023. Salley JR, Kukkar V, Felde L. Vanishing lung syndrome: a consequence of mixed tobacco and marijuana use. BMJ Case Rep. 2021;14. Kimura H, Saji H, Miyazawa T, Sakai H, Tsuda M, Wakiyama Y, et al. Worse survival after curative resection in patients with pathological stage I non-small cell lung cancer adjoining pulmonary cavity formation. J Thorac Disease. 2017;9:3038–44. Kaneda M, Tarukawa T, Watanabe F, Adachi K, Sakai T, Nakabayashi H. Clinical features of primary lung cancer adjoining pulmonary bulla. Interact Cardiovasc Thorac Surg. 2010;10:940–4. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 01 Oct, 2024 Read the published version in Journal of Cardiothoracic Surgery → Version 1 posted Editorial decision: Accepted 15 Sep, 2024 Reviews received at journal 04 Sep, 2024 Reviews received at journal 01 Sep, 2024 Reviewers agreed at journal 26 Aug, 2024 Reviewers agreed at journal 23 Aug, 2024 Reviews received at journal 21 Aug, 2024 Reviewers agreed at journal 21 Aug, 2024 Reviewers invited by journal 21 Aug, 2024 Editor assigned by journal 15 Jul, 2024 Submission checks completed at journal 15 Jul, 2024 First submitted to journal 12 Jul, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4730909","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":330728715,"identity":"c1faf926-e907-49a8-b0b4-d2e30d863fbf","order_by":0,"name":"Jiyun Lee","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABFElEQVRIie2RvWrDMBCAzxiSDgpeXQz1K5wItIQGP4uDwVMKgS6BhPqMwVkMXfMY7Rs4COwl3QtdDH2BjN5ayUk6pLa7dtAHpwOJj/sRgEbzDzESdS5kWHFSHWRGMClv3lifgjJsUfCtTAhGv3JEKRD6Djsp0KeYG3brLHB6A7DH8XTtPd0N4zivwXOBvVXtjUlli+EYzAw/50VgT7Id7TIIOI022KkwFDNSVR7ItPF9RkKW98EadIzfKF8RwRydCUVnJfpLyf1mfIPEWRE+jNIOZfB4zzDgqVpyVpTXL3s1C5Y8ZUWrwp/F6wdbeq6lvrJerywsE3GolyvXYmG7QlfHtVz0jb9ufnBhWHU8aTQajebEN3fPVvPoO/YgAAAAAElFTkSuQmCC","orcid":"","institution":"Incheon St. Mary's Hospital","correspondingAuthor":true,"prefix":"","firstName":"Jiyun","middleName":"","lastName":"Lee","suffix":""},{"id":330728719,"identity":"29c769f4-e4e9-4bdf-9e1f-f5f4b62d37cf","order_by":1,"name":"Eunsu Park","email":"","orcid":"","institution":"Incheon St. Mary's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Eunsu","middleName":"","lastName":"Park","suffix":""}],"badges":[],"createdAt":"2024-07-12 14:20:21","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4730909/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4730909/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13019-024-03112-z","type":"published","date":"2024-10-01T15:57:56+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":62324633,"identity":"040d4334-5e4c-423b-a199-eeb1b47c7d03","added_by":"auto","created_at":"2024-08-13 02:32:25","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":655742,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e(A)\u003c/strong\u003e Chest X-ray taken upon the patient’s arrival at the emergency room showing tension pneumothorax on the right side. \u003cstrong\u003e(B)\u003c/strong\u003e The most recent outpatient clinic chest X-ray before the development of pneumothorax revealed bullous emphysema.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4730909/v1/cab72400b0a598883bcee02b.png"},{"id":62324635,"identity":"cc031238-3526-48cb-8169-f4ce431574f3","added_by":"auto","created_at":"2024-08-13 02:32:25","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":438436,"visible":true,"origin":"","legend":"\u003cp\u003ePreoperative contrast-enhanced chest CT revealed the following: \u003cstrong\u003e(A)\u003c/strong\u003e Giant bullae in both the hemithoraces and lung cancer in the right middle lobe (white arrow) in the axial view. \u003cstrong\u003e(B)\u003c/strong\u003e Giant bullous emphysema in both the hemithoraces in the coronal view. CT, computed tomography\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4730909/v1/aa24836f3f0e743ef4a224b2.png"},{"id":62324634,"identity":"570ce47c-00b5-412e-843e-f853ebd95f4a","added_by":"auto","created_at":"2024-08-13 02:32:25","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":488345,"visible":true,"origin":"","legend":"\u003cp\u003eThe left part displays atypical cells with occasionally prominent nucleoli and hobnail morphology (MOC-31(+), Calretinin(-)). The right part exhibited flat cuboidal cells, suggesting reactive mesothelial cells (MOC-31(-), Calretinin(+)). \u003cstrong\u003e(A)\u003c/strong\u003e H\u0026amp;E staining (x200), \u003cstrong\u003e(B)\u003c/strong\u003e MOC-31 staining (x200), and \u003cstrong\u003e(C)\u003c/strong\u003e Calretinin staining (x200). H\u0026amp;E, hematoxylin and eosin; MOC-31, anti-epithelial related antigen\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-4730909/v1/fcf7e42ad13e964c3a52c9d5.png"},{"id":66096928,"identity":"721d37a1-7fa3-4c87-8c6e-13f9280ee76c","added_by":"auto","created_at":"2024-10-07 16:11:50","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2057627,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4730909/v1/034b81f5-db92-4033-8b52-02c94723e3a1.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Overdiagnosing Giant Bullous Emphysema as Metastatic Adenocarcinoma: A Case Report","fulltext":[{"header":"Background","content":"\u003cp\u003eGiant bullous emphysema was first described in 1937. This condition is rare and characterized by the presence of large bullae occupying at least one-third of a hemithorax that leads to compression of the surrounding lung parenchyma (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Patients afflicted with giant bullous emphysema typically have a history of cigarette smoking and COPD (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Presenting features include progressive dyspnea, declining exercise tolerance, hypoxia, and decreased breath sounds. Disease progression can lead to pneumothorax, subcutaneous emphysema, and respiratory failure with hypoxia and hypercapnia (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Giant bullous emphysema can closely resemble pneumothorax, and chest CT is the optimal method for distinguishing between the two conditions, making it the gold standard for differential diagnosis (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe alveoli are usually lined by type I pneumocytes but can be populated by hyperplastic type II pneumocytes under certain conditions such as diffuse alveolar damage, radiation or drug-related toxicity, infection, and inflammatory or fibrosing conditions. This atypical appearance can be quite striking and is described as \u0026ldquo;too atypical to be malignant\u0026rdquo; (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eHerein is the report of a case of overdiagnosing metastatic adenocarcinoma as giant bullous emphysema in a 48-year-old male, written according to CARE case report guidelines.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eThe patient, a 48-year-old male with a height of 169 cm and weight of 54 kg, presented to the emergency room with dyspnea and drowsiness, with an oxygen saturation of 50%. A chest X-ray revealed a tension pneumothorax in the right hemithorax (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), prompting an emergency closed thoracostomy with a 24Fr chest tube.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe patient had a history of coughing, sputum production, and shortness of breath with an ECOG score of 2 for the past 2 years. He had sought medical attention from a pulmonologist and was awaiting further outpatient evaluation following chest CT and PFT. The patient had a 30-year history of smoking and occupational exposure due to working in a tunnel.\u003c/p\u003e \u003cp\u003eChest CT showed signs of extensive bullous emphysema in both lungs and a pulmonary nodule, which was suspected of being lung cancer or organizing pneumonia in the RML (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The PFT results revealed a significantly reduced lung function indicative of a severe obstructive pattern as follows: FVC 1.92L 44% (postbronchodilator: 2.08L 47%), FEV1 0.72L 22% (postbronchodilator: 0.81L 25%), FEV1/FVC 37% (postbronchodilator: 39%), and DLCO 7.1 mL/mmHg/min 35%. PET-CT revealed a possibly malignant tumor in the RML with a SUVmax of 3.5. Blood tests revealed an alpha-1 antitrypsin level of 129 mg/dL (reference range: 90\u0026ndash;200) and an elevated CEA level of 7.96 ng/mL (reference range: 0\u0026ndash;5).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eBased on the findings and the suspicion of lung cancer, a multidisciplinary team recommended limited surgery for lung cancer and bullectomy. During the surgical procedure, bullae in the RUL, RML, and RLL of the lung were discovered, with most of them concentrated in the RUL. The pulmonary nodule in the RML was subjected to wedge resection and frozen section analysis, which revealed adenocarcinoma. Mediastinal lymph node dissection was also performed. Giant bullae were removed through multiple wedge resections using PTFE-reinforced endostaplers. The patient underwent chemical pleurodesis using Abnova Viscum-F four times to address the persistent air leakage. The chest tubes were removed on POD 20, and the patient was discharged on POD 21.\u003c/p\u003e \u003cp\u003ePathologic examination revealed the presence of invasive adenocarcinoma with papillary (90%) and micropapillary (10%) features, which were moderately differentiated and measured 1.3x1.0x0.8 cm. The cancer had invaded the visceral pleural surface and had metastasized to the lower paratracheal lymph node. Additionally, metastatic adenocarcinoma was found in the bullae removed by bullectomy, resulting in a diagnosis of pT2aN2aM1a (AJCC 9th edition) lung cancer. The patient is currently receiving systemic chemotherapy, the dyspnea has resolved, and the PFT results have improved compared with the preoperative findings.\u003c/p\u003e \u003cp\u003eTo preparing this case report, we carefully reviewed all the slides and found a case of overdiagnosis. The pathologist initially observed atypical cells with occasional prominent nucleoli and hobnail morphology (MOC-31(+), Calretinin(-)). Their growth pattern along the cyst wall and morphology raised concerns about metastatic adenocarcinoma. However, upon reviewing the entire slides, it was more reasonable to consider the cells as reactive alveolar cells because of their uniformly enlarged nonoverlapping vesicular nuclei with regular and smooth nuclear membranes and a single prominent nucleolus. These findings were consistent with subpleural bullous emphysema (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion and Conclusions","content":"\u003cp\u003eThe formation of giant emphysematous bullae stems from the inflammatory destruction and loss of elasticity of small alveolar walls, leading to the coalescence of large air-filled bullae (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Radiographically, giant bullous emphysema is characterized by bullae occupying at least one-third of the hemithorax, present in one or both upper lobes (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). This condition develops due to chronic inflammation of distal airspaces, resulting in emphysematous destruction of the lung parenchyma, subsequent breakdown of the alveolar wall, and permanent enlargement of airspaces (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Patients with this condition have a long history of cigarette smoking, marijuana use, and COPD (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). More recently, HIV infection, Williams-Beuren syndrome, Ehlers-Danlos syndrome, and sarcoidosis have also been identified as additional risk factors (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThere are reports of an association between giant bullous emphysema and lung cancer. Emphysema is an independent risk factor for lung cancer, with multiple potential pathways implicated in this association, all involving chronic inflammation, anomalous cellular repair, and genetic polymorphisms triggering carcinogenesis (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Although the mechanism of carcinogenesis in patients with pulmonary bullous disease remains uncertain, various theories have been proposed. Scar cancer, acquired from repeated inflammatory processes causing the formation of fibrous scar tissue around bullae, as well as impaired ventilation facilitating carcinogen deposition, could lead to metaplastic transformation of epithelial cells within bullae (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Additionally, carcinogens may inhibit anti-elastase enzymes, leading to the destruction of the interalveolar septa and subsequent bulla formation (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAlveoli are usually lined by type I pneumocytes, but they can also be populated by hyperplastic type II pneumocytes under certain conditions such as diffuse alveolar damage, radiation or drug-related toxicity, infection and various inflammatory or fibrosing conditions. The prominence of hyperplastic type II pneumocytes, as opposed to the typically inconspicuous type I pneumocytes, may raise concerns about adenocarcinoma with a lepidic pattern. The atypical appearance of these cells, especially in organizing diffuse alveolar damage, can be quite pronounced. This atypical appearance, referred to as \u0026ldquo;too atypical to be malignant\u0026rdquo;, contrasts with the relatively bland presentation of many adenocarcinoma with a lepidic pattern. Findings related to the underlying condition, such as acute lung injury, fibrosis, or inflammation, usually not only coexist with but also often overshadow reactive pneumocyte hyperplasia (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn this case, we initially diagnosed giant bullae as resulting from metastatic adenocarcinoma from lung cancer in the RML, invading the visceral pleura. However, upon reviewing the slides, we found that there was an overdiagnosis of reactive pneumocytes as metastatic adenocarcinoma. This type of diagnostic error can occur because of the similarities in the cellular and morphological features of reactive pneumocytes and malignant cells. The patient displayed multiple tiny nodules and giant bullous emphysema in the contralateral lung, making confirming their association with metastatic adenocarcinoma difficult. It was deemed necessary to monitor the changes in the tiny nodules and remaining giant.\u003c/p\u003e \u003cp\u003eOverdiagnosing reactive pneumocytes as metastatic adenocarcinoma can result in unnecessary treatments and complications. Accurate differentiation between reactive changes and malignancy is crucial to avoid overtreatment. This case highlights the importance of thorough histopathological evaluation and cautious interpretation of atypical cellular morphology.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAJCC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAmerican Joint Committee on Cancer\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCOPD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003echronic obstructive pulmonary disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecomputed tomography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDLCO\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ediffusing capacity of the lungs for carbon monoxide\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eECOG\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEastern Cooperative Oncology Group\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFEV1\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eforced expiratory volume in the first second\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFVC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eforced vital capacity\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHIV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ehuman immunodeficiency virus\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePET-CT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epositron emission tomography-computed tomography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePFT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epulmonary function test\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePOD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epostoperative day\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePTFE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epolytetrafluoroethylene\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRLL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eright lower lobe\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRML\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eright middle lobe\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRUL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eright upper lobe\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSUVmax\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emaximum standardized uptake value\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthics approval was obtained from the Institutional Review Board of Incheon St. Mary\u0026rsquo;s Hospital, Incheon, Republic of Korea (IRB number: OC24ZASI0090) and consent was obtained from the patient for participation in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent of publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConsent was obtained from the patient for the publication of this report and any accompanying images.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this published article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere was no funding for this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u0026rsquo;s contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJiyun Lee participated in the study design, research, and manuscript writing. Jiyun Lee and Eunsu Park analyzed and interpreted the data. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGarvey S, Faul J, Cormican L, Eaton D, Judge EP. Symptomatic unilateral idiopathic giant bullous emphysema: a case report. BMC Pulm Med. 2022;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMuhamad NI, Mohd Nawi SN, Yusoff BM, Ab Halim NA, Mohammad N, Wan Ghazali WS. Vanishing lung syndrome Masquerading as bilateral pneumothorax: A case report. Respiratory Med Case Rep. 2020;31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSohail H, Kilani Y, Osella J, Kamal ASF, Kumari B, Keftassa DE et al. Vanishing Lung Syndrome, or Idiopathic Giant Bullous Emphysema, with Pneumothorax, and Subcutaneous Emphysema in a 58-Year-Old Female Smoker with Chronic Obstructive Pulmonary Disease. Am J Case Rep. 2022;23.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVelez Oquendo G, Balaji N, Ignatowicz A, Qutob H. Vanishing Lung Syndrome in a Young Male With Chronic Marijuana Use: A Case Report. Cureus. 2023.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAujayeb A. Please do not put a chest drain in my chest! Vanishing lung syndrome. Afr J Emerg Med. 2020;10:261\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eButnor KJ. Avoiding Underdiagnosis, Overdiagnosis, and Misdiagnosis of Lung Carcinoma. Arch Pathol Lab Med. 2008;132:1118\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMansour M, Kessler S, Khreisat A, Morton J, Berghea R. Vanishing Lung Syndrome: A Case Report and Systematic Review of the Literature. Cureus. 2024.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePiao X, Alyass F, Yousuf A. Cardiothoracic Surgery Management of Giant Bullous Lung Disease Initially Misdiagnosed as Pneumothorax: A Case Report. Cureus. 2023.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSalley JR, Kukkar V, Felde L. Vanishing lung syndrome: a consequence of mixed tobacco and marijuana use. BMJ Case Rep. 2021;14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKimura H, Saji H, Miyazawa T, Sakai H, Tsuda M, Wakiyama Y, et al. Worse survival after curative resection in patients with pathological stage I non-small cell lung cancer adjoining pulmonary cavity formation. J Thorac Disease. 2017;9:3038\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKaneda M, Tarukawa T, Watanabe F, Adachi K, Sakai T, Nakabayashi H. Clinical features of primary lung cancer adjoining pulmonary bulla. Interact Cardiovasc Thorac Surg. 2010;10:940\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-cardiothoracic-surgery","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jcts","sideBox":"Learn more about [Journal of Cardiothoracic Surgery](http://cardiothoracicsurgery.biomedcentral.com)","snPcode":"13019","submissionUrl":"https://submission.nature.com/new-submission/13019/3","title":"Journal of Cardiothoracic Surgery","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Overdiagnosis, Emphysema, Lung cancer, Adenocarcinoma, Case report","lastPublishedDoi":"10.21203/rs.3.rs-4730909/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4730909/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eGiant bullous emphysema is characterized by large bullae occupying at least one-third of the hemithorax and leading to compression of the surrounding lung parenchyma. Overdiagnosis can occur because of the atypical appearance of hyperplastic type II pneumocytes, which may be mistaken for malignant cells.\u003c/p\u003e\u003ch2\u003eCase Presentation:\u003c/h2\u003e \u003cp\u003eA 48-year-old male with a history of smoking and occupational exposure presented with dyspnea and drowsiness. Initial chest X-ray revealed a tension pneumothorax, and subsequent chest CT revealed extensive bullous emphysema and lung cancer in the right middle lobe (RML). Pathologic examination initially indicated resected bullae to metastatic adenocarcinoma, but upon review, it was determined that the reactive alveolar cells were misdiagnosed as malignant.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThis case emphasizes the need for thorough histopathological assessment and prudent interpretation of atypical cellular morphology.\u003c/p\u003e","manuscriptTitle":"Overdiagnosing Giant Bullous Emphysema as Metastatic Adenocarcinoma: A Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-13 02:32:20","doi":"10.21203/rs.3.rs-4730909/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accepted","date":"2024-09-15T08:24:30+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-09-04T20:27:40+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-09-01T04:39:11+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"302559856726033778871052834492579413455","date":"2024-08-26T06:03:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"294957075624118137881152815196393024779","date":"2024-08-23T22:16:39+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-21T22:32:29+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"321861959264494864005627204111956573183","date":"2024-08-21T22:20:44+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-08-21T18:48:47+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-07-15T12:40:01+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-07-15T12:38:55+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Cardiothoracic Surgery","date":"2024-07-12T14:19:06+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-cardiothoracic-surgery","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jcts","sideBox":"Learn more about [Journal of Cardiothoracic Surgery](http://cardiothoracicsurgery.biomedcentral.com)","snPcode":"13019","submissionUrl":"https://submission.nature.com/new-submission/13019/3","title":"Journal of Cardiothoracic Surgery","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6db9fdbd-6405-4fe1-9a2e-8a506c2de672","owner":[],"postedDate":"August 13th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-10-07T16:03:49+00:00","versionOfRecord":{"articleIdentity":"rs-4730909","link":"https://doi.org/10.1186/s13019-024-03112-z","journal":{"identity":"journal-of-cardiothoracic-surgery","isVorOnly":false,"title":"Journal of Cardiothoracic Surgery"},"publishedOn":"2024-10-01 15:57:56","publishedOnDateReadable":"October 1st, 2024"},"versionCreatedAt":"2024-08-13 02:32:20","video":"","vorDoi":"10.1186/s13019-024-03112-z","vorDoiUrl":"https://doi.org/10.1186/s13019-024-03112-z","workflowStages":[]},"version":"v1","identity":"rs-4730909","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4730909","identity":"rs-4730909","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}