An unexpected diagnosis in a patient with new-onset pulmonary infiltrates during adjuvant therapy for breast cancer

An unexpected diagnosis in a patient with new-onset pulmonary infiltrates during adjuvant therapy... The differential diagnosis of new-onset pulmonary infiltrates during adjuvant therapy in a cancer patient is challenging. Opportunistic infections, pulmonary drug-induced toxicity and metastatic dissemination of the underlying cancer are the most common causes. However, although infrequent, the development of a second primary pulmonary neoplasia should be taken into account. We present the clinical case of a breast cancer patient who developed progressive pulmonary infiltrates during adjuvant therapy, who was finally diagnosed as having a second lung neoplasm of unexpected histology. INTRODUCTION on treatment with trastuzumab. Her past medical history was remarkable for a left breast cancer that was surgically removed The appearance of new-onset pulmonary infiltrates during adju- 15 months before (ductal infiltrating carcinoma grade 2 vant chemotherapy in a cancer patient represents a major chal- pT1bN0snM0, estrogen receptor negative and human epidermal lenge. The most frequent causes are opportunistic infections, growth factor receptor 2 positive). She received radiotherapy pulmonary drug-induced toxicity and metastatic dissemination of and adjuvant chemotherapy, consisting in four cycles of fluor- the underlying cancer. In this context, suspicion about the devel- ouracil, epirubicin and cyclophosphamide, followed by 8 weeks opment of a second primary pulmonary neoplasia, although infre- of paclitaxel combined with trastuzumab. After this, trastuzu- quent, should be taken into account. We present the clinical case mab at standard dose of 6 mg/kg intravenously every 3 weeks of a breast cancer patient who developed progressive pulmonary was for a planned duration up to November 2016. infiltrates during adjuvant therapy, who was finally diagnosed as On examination, the patient was afebrile, and chest auscul- having a second lung neoplasm of unexpected histology. tation revealed fine crackles in the lower lobe of the right lung. She did not report fever, dyspnea or other complaints. Blood CASE REPORT tests were normal except for a mild lymphopenia (0.7 × 109 A 55-year-old female patient presented in September 2016 with cells/l, CD4 count 260 cells/ mm3). A chest X-ray showed bilat- a 1-month history of persistent dry cough and asthenia while eral infiltrates, with micronodular pattern more prominent in Received: October 5, 2017. Accepted: November 17, 2017 © The Author(s) 2018. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/omcr/article-abstract/2018/2/omx095/4846370 by Ed 'DeepDyve' Gillespie user on 16 March 2018 An unexpected diagnosis in a patient with new-onset pulmonary infiltrates 51 right lower lobe. A chest X-ray performed previous to breast was suspected, trastuzumab was discontinued, and a course of cancer surgery was revised and found normal. A diagnosis of steroids, oral levofloxacin plus prophylaxis with trimethoprim- pulmonary toxicity from trastuzumab/organized pneumonia sulfamethoxazole was started. The patient did not improve right in the following 2 months, with persistent asthenia, cough and febricula, but no dyspnea. A new chest X-ray showed bilat- eral lung nodules, with patchy infiltrates and alveolar consoli- dations in the lower lung lobe (Fig. 1). A chest computed tomography (CT) scan showed multiple bilateral lung nodules with a confluent pattern in the lower lung lobe adopting an alveolar consolidation appearance, and some enlarged lymph nodes in the hilar and subcarinal regions. In view of those find- ings, a malignant process either metastatic or primary was sug- gested. 18F fluoro-2-D-deoxyglucose (FDG) positron emission tomography-CT (PET/CT) scan showed an extensive bilateral pulmonary infiltration, more intense in the lower lung lobes, especially on the right side, with a maximum standardized uptake value of 25.5. No abnormal accumulation of the FDG was observed in either viscera or the lymph nodes (Fig. 2). Bronchoscopy was normal. Multiple samples from bronchoal- veolar lavage (BLA) and trans-bronchial biopsies submitted for cytological and microbiological studies yielded negative results, including investigations for malignant cells, virus, fungus, bac- teria, tuberculosis and pneumocystis. An ultrasound-guided percutaneous biopsy of the lower lung lobe was performed. Microbiological investigations were again negative. Histology revealed a dense atypical infiltration of large cells, with negative immunohistochemical staining for cytokera- tins (AE1AE3, CK19), GATA3, sinaptofisin and TTF-1. Additional Figure 1: A chest X-ray following discontinuation of trastuzumab showed wor- immunohistochemical staining showed CD20 (+), bcl6 (+), bcl2 sening of the patchy infiltrates, with alveolar condensations in the lower lung (+), a high ki67 proliferation index; while CD10, CD3, and in situ lobe, and bilateral lung nodules. A Port-a-Cath has been placed in the right hybridization for Epstein–Barr virus were negative. Bone marrow infraclavicular region via the right subclavian vein. Figure 2: FDG-PET/CT before treatment: (a) MIP (maximum intensity projection). (b) Axial CT: multiple bilateral pulmonary nodules and areas of alveolar consolida- tion in right lower lobe. (c) Axial PET/CT: extensive and intense tracer uptake in both lungs. Downloaded from https://academic.oup.com/omcr/article-abstract/2018/2/omx095/4846370 by Ed 'DeepDyve' Gillespie user on 16 March 2018 52 D. Aguiar-Bujanda et al. Figure 3: FDG-PET/CT end of treatment: (a) MIP (maximum intensity projection). (b)Axial CT:almost completeresponse(remainingsmall bilateralground-glassopacities). (c) Axial PET/CT: complete metabolic response. Residual tracer uptake in both lungs. Bilateral basal infiltrates (some of them nodular) with very low uptake. biopsy was normal. Based on those findings, a diagnosis of stage CT-scan reveals bilateral involvement in more than 70% of cases, i.e. international prognostic index 1 (elevated serum lactate and less frequently diffuse reticulonodular opacities, atelectasis, dehydrogenase), primary diffuse large B-cell lymphoma (DLBCL) pleural effusion or hilar or mediastinal lymphadenopathy [1, 5, of the lung was established. 6]. Bronchoscopy with biopsies and BAL provides cytological and The patient started chemotherapy with cyclophosphamide, histological samples for microbiology, immunohistochemistry, vincristine, doxorubicin and prednisone (CHOP) with rituximab flow cytometry or molecular techniques. Image-guided percu- with excellent tolerance and a quick resolution of previous taneous transparietal aspiration and biopsies may be useful symptoms. After completing six cycles, the chest CT-scan especially for peripheral nodules or masses. Video-assisted thora- showed almost complete response with remaining small bilat- coscopic surgery or open lung biopsy may be needed especially in eral ground-glass opacities. The PET/CT showed a complete solitary lesions. metabolic response with very low-residual tracer uptake in Treatment strategies for PPL are mainly based on the histo- both lower lung lobes (Fig. 3). logical type and the extent of disease. Surgical resection is pro- posed, especially for localized resectable lesions. A complete resection with negative margins in 40% of cases and survival DISCUSSION rates at 5 year and 10 years of 67% and 56%, respectively, have Primary pulmonary lymphoma (PPL) is a rare neoplasm that com- been reported [7]. For bilateral or extended disease, chemother- prises 0.3% of all primary pulmonary malignancies, <1% of all apy with protocols employed in nodal B-cell lymphomas are lymphomas and 3–4% of all the extranodal lymphomas [1, 2]. used, such as chlorambucil-rituximab for MALT lymphoma [8] Definition of PPL implies that lymphoma is confined to the lung and CHOP with or without rituximab for DLBCL [9, 10]. For the (parenchyma and/or bronchi of one or both lungs), with or with- latter, a complete response rate in 83–94% and 5-year overall out hilar or mediastinal lymph nodes involvement at the time of survival above 80% have been reported. diagnosis or during the following 3 months [3, 4]. The most fre- In conclusion, the presence of a pulmonary neoplasia (meta- quent subtypes are extranodal marginal zone lymphoma of static or primary as in our case) must be excluded in breast cancer mucosa-associatedlymphoidtissue(MALT)lymphoma(70–90%), patients with new-onset pulmonary infiltrates while receiving and DLBCL (5–20%) [4, 5]. The diagnosis of PPL may be elusive and adjuvant therapy. Invasive techniques like bronchoscopy, imaging- thus, a high index of suspicion is needed. Radiological appearance guided percutaneous biopsy or even surgical biopsy may be needed shows isolated or multiple nodules in one or both lungs, and to reach a final diagnosis. Although rare, PPL should be taken alveolar opacities, usually associated with an air bronchogram. into account since it may be a potentially curable disease. Downloaded from https://academic.oup.com/omcr/article-abstract/2018/2/omx095/4846370 by Ed 'DeepDyve' Gillespie user on 16 March 2018 An unexpected diagnosis in a patient with new-onset pulmonary infiltrates 53 patients. Part I: primary lung and mediastinal lymphomas. A CONFLICT OF INTEREST STATEMENT project of the Italian Society of Hematology, the Italian None declared. Society of Experimental Hematology and the Italian Group for Bone Marrow Transplantation. Haematologica 2008;93:1364–71. FUNDING 5. Parissis H. Forty years literature review of primary lung lymphoma. J Cardiothorac Surg 2011;6:23. None. 6. Cardenas-Garcia J, Talwar A, Shah R, Fein A. Update in pri- mary pulmonary lymphomas. Curr Opin Pulm Med 2015;21: CONSENT 333–7. Consent for publication was obtained from the patient (Oxford 7. Ferraro P, Trastek VF, Adlakha H, Deschamps C, Allen MS, University Press Patient Consent Form). Pairolero PC. Primary non-Hodgkin’s lymphoma of the lung. Ann Thorac Surg 2000;69:993–7. REFERENCES 8. Zucca E, Conconi A, Laszlo D, López-Guillermo A, 1. Cadranel J, Wislez M, Antoine M. Primary pulmonary Bouabdallah R, Coiffier B, et al. Addition of rituximab to lymphoma. Eur Respir J 2002;20:750–62. chlorambucil produces superior event-free survival in the 2. William J, Variakojis D, Yeldandi A, Raparia K. Lymphoproli- treatment of patients with extranodal marginal-zone B-cell ferative neoplasm of the lung. Arch Pathol Lab Med 2013;137: lymphoma: 5-year analysis of the IELSG-19 randomized 382–91. study. J Clin Oncol 2013;31:565–72. 3. Isaacson PG, Norton AJ Extranodal Lymphomas. New York: 9. Aviles A, Nambo MJ, Huerta Guzman J, Silva L, Neri N. Churchill Livingstone, 1994. Rituximab in the treatment of diffuse large B-cell lymph- 4. Zinzani PL, Martelli M, Poletti V, Vitolo U, Gobbi PG, Chisesi T, oma primary of the lung. Hematology 2013;18:81–4. et al.Practiceguidelinesfor themanagementofextranodal 10. Neri N, Nambo MJ, Aviles A. Diffuse large B-cell lymphoma non-Hodgkin’s lymphomas of adult non-immunodeficient primary of lung. Hematology 2011;16:110–2. Downloaded from https://academic.oup.com/omcr/article-abstract/2018/2/omx095/4846370 by Ed 'DeepDyve' Gillespie user on 16 March 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Oxford Medical Case Reports Oxford University Press

An unexpected diagnosis in a patient with new-onset pulmonary infiltrates during adjuvant therapy for breast cancer

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Abstract

The differential diagnosis of new-onset pulmonary infiltrates during adjuvant therapy in a cancer patient is challenging. Opportunistic infections, pulmonary drug-induced toxicity and metastatic dissemination of the underlying cancer are the most common causes. However, although infrequent, the development of a second primary pulmonary neoplasia should be taken into account. We present the clinical case of a breast cancer patient who developed progressive pulmonary infiltrates during adjuvant therapy, who was finally diagnosed as having a second lung neoplasm of unexpected histology. INTRODUCTION on treatment with trastuzumab. Her past medical history was remarkable for a left breast cancer that was surgically removed The appearance of new-onset pulmonary infiltrates during adju- 15 months before (ductal infiltrating carcinoma grade 2 vant chemotherapy in a cancer patient represents a major chal- pT1bN0snM0, estrogen receptor negative and human epidermal lenge. The most frequent causes are opportunistic infections, growth factor receptor 2 positive). She received radiotherapy pulmonary drug-induced toxicity and metastatic dissemination of and adjuvant chemotherapy, consisting in four cycles of fluor- the underlying cancer. In this context, suspicion about the devel- ouracil, epirubicin and cyclophosphamide, followed by 8 weeks opment of a second primary pulmonary neoplasia, although infre- of paclitaxel combined with trastuzumab. After this, trastuzu- quent, should be taken into account. We present the clinical case mab at standard dose of 6 mg/kg intravenously every 3 weeks of a breast cancer patient who developed progressive pulmonary was for a planned duration up to November 2016. infiltrates during adjuvant therapy, who was finally diagnosed as On examination, the patient was afebrile, and chest auscul- having a second lung neoplasm of unexpected histology. tation revealed fine crackles in the lower lobe of the right lung. She did not report fever, dyspnea or other complaints. Blood CASE REPORT tests were normal except for a mild lymphopenia (0.7 × 109 A 55-year-old female patient presented in September 2016 with cells/l, CD4 count 260 cells/ mm3). A chest X-ray showed bilat- a 1-month history of persistent dry cough and asthenia while eral infiltrates, with micronodular pattern more prominent in Received: October 5, 2017. Accepted: November 17, 2017 © The Author(s) 2018. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/omcr/article-abstract/2018/2/omx095/4846370 by Ed 'DeepDyve' Gillespie user on 16 March 2018 An unexpected diagnosis in a patient with new-onset pulmonary infiltrates 51 right lower lobe. A chest X-ray performed previous to breast was suspected, trastuzumab was discontinued, and a course of cancer surgery was revised and found normal. A diagnosis of steroids, oral levofloxacin plus prophylaxis with trimethoprim- pulmonary toxicity from trastuzumab/organized pneumonia sulfamethoxazole was started. The patient did not improve right in the following 2 months, with persistent asthenia, cough and febricula, but no dyspnea. A new chest X-ray showed bilat- eral lung nodules, with patchy infiltrates and alveolar consoli- dations in the lower lung lobe (Fig. 1). A chest computed tomography (CT) scan showed multiple bilateral lung nodules with a confluent pattern in the lower lung lobe adopting an alveolar consolidation appearance, and some enlarged lymph nodes in the hilar and subcarinal regions. In view of those find- ings, a malignant process either metastatic or primary was sug- gested. 18F fluoro-2-D-deoxyglucose (FDG) positron emission tomography-CT (PET/CT) scan showed an extensive bilateral pulmonary infiltration, more intense in the lower lung lobes, especially on the right side, with a maximum standardized uptake value of 25.5. No abnormal accumulation of the FDG was observed in either viscera or the lymph nodes (Fig. 2). Bronchoscopy was normal. Multiple samples from bronchoal- veolar lavage (BLA) and trans-bronchial biopsies submitted for cytological and microbiological studies yielded negative results, including investigations for malignant cells, virus, fungus, bac- teria, tuberculosis and pneumocystis. An ultrasound-guided percutaneous biopsy of the lower lung lobe was performed. Microbiological investigations were again negative. Histology revealed a dense atypical infiltration of large cells, with negative immunohistochemical staining for cytokera- tins (AE1AE3, CK19), GATA3, sinaptofisin and TTF-1. Additional Figure 1: A chest X-ray following discontinuation of trastuzumab showed wor- immunohistochemical staining showed CD20 (+), bcl6 (+), bcl2 sening of the patchy infiltrates, with alveolar condensations in the lower lung (+), a high ki67 proliferation index; while CD10, CD3, and in situ lobe, and bilateral lung nodules. A Port-a-Cath has been placed in the right hybridization for Epstein–Barr virus were negative. Bone marrow infraclavicular region via the right subclavian vein. Figure 2: FDG-PET/CT before treatment: (a) MIP (maximum intensity projection). (b) Axial CT: multiple bilateral pulmonary nodules and areas of alveolar consolida- tion in right lower lobe. (c) Axial PET/CT: extensive and intense tracer uptake in both lungs. Downloaded from https://academic.oup.com/omcr/article-abstract/2018/2/omx095/4846370 by Ed 'DeepDyve' Gillespie user on 16 March 2018 52 D. Aguiar-Bujanda et al. Figure 3: FDG-PET/CT end of treatment: (a) MIP (maximum intensity projection). (b)Axial CT:almost completeresponse(remainingsmall bilateralground-glassopacities). (c) Axial PET/CT: complete metabolic response. Residual tracer uptake in both lungs. Bilateral basal infiltrates (some of them nodular) with very low uptake. biopsy was normal. Based on those findings, a diagnosis of stage CT-scan reveals bilateral involvement in more than 70% of cases, i.e. international prognostic index 1 (elevated serum lactate and less frequently diffuse reticulonodular opacities, atelectasis, dehydrogenase), primary diffuse large B-cell lymphoma (DLBCL) pleural effusion or hilar or mediastinal lymphadenopathy [1, 5, of the lung was established. 6]. Bronchoscopy with biopsies and BAL provides cytological and The patient started chemotherapy with cyclophosphamide, histological samples for microbiology, immunohistochemistry, vincristine, doxorubicin and prednisone (CHOP) with rituximab flow cytometry or molecular techniques. Image-guided percu- with excellent tolerance and a quick resolution of previous taneous transparietal aspiration and biopsies may be useful symptoms. After completing six cycles, the chest CT-scan especially for peripheral nodules or masses. Video-assisted thora- showed almost complete response with remaining small bilat- coscopic surgery or open lung biopsy may be needed especially in eral ground-glass opacities. The PET/CT showed a complete solitary lesions. metabolic response with very low-residual tracer uptake in Treatment strategies for PPL are mainly based on the histo- both lower lung lobes (Fig. 3). logical type and the extent of disease. Surgical resection is pro- posed, especially for localized resectable lesions. A complete resection with negative margins in 40% of cases and survival DISCUSSION rates at 5 year and 10 years of 67% and 56%, respectively, have Primary pulmonary lymphoma (PPL) is a rare neoplasm that com- been reported [7]. For bilateral or extended disease, chemother- prises 0.3% of all primary pulmonary malignancies, <1% of all apy with protocols employed in nodal B-cell lymphomas are lymphomas and 3–4% of all the extranodal lymphomas [1, 2]. used, such as chlorambucil-rituximab for MALT lymphoma [8] Definition of PPL implies that lymphoma is confined to the lung and CHOP with or without rituximab for DLBCL [9, 10]. For the (parenchyma and/or bronchi of one or both lungs), with or with- latter, a complete response rate in 83–94% and 5-year overall out hilar or mediastinal lymph nodes involvement at the time of survival above 80% have been reported. diagnosis or during the following 3 months [3, 4]. The most fre- In conclusion, the presence of a pulmonary neoplasia (meta- quent subtypes are extranodal marginal zone lymphoma of static or primary as in our case) must be excluded in breast cancer mucosa-associatedlymphoidtissue(MALT)lymphoma(70–90%), patients with new-onset pulmonary infiltrates while receiving and DLBCL (5–20%) [4, 5]. The diagnosis of PPL may be elusive and adjuvant therapy. Invasive techniques like bronchoscopy, imaging- thus, a high index of suspicion is needed. Radiological appearance guided percutaneous biopsy or even surgical biopsy may be needed shows isolated or multiple nodules in one or both lungs, and to reach a final diagnosis. Although rare, PPL should be taken alveolar opacities, usually associated with an air bronchogram. into account since it may be a potentially curable disease. Downloaded from https://academic.oup.com/omcr/article-abstract/2018/2/omx095/4846370 by Ed 'DeepDyve' Gillespie user on 16 March 2018 An unexpected diagnosis in a patient with new-onset pulmonary infiltrates 53 patients. Part I: primary lung and mediastinal lymphomas. A CONFLICT OF INTEREST STATEMENT project of the Italian Society of Hematology, the Italian None declared. Society of Experimental Hematology and the Italian Group for Bone Marrow Transplantation. Haematologica 2008;93:1364–71. FUNDING 5. Parissis H. Forty years literature review of primary lung lymphoma. J Cardiothorac Surg 2011;6:23. None. 6. Cardenas-Garcia J, Talwar A, Shah R, Fein A. Update in pri- mary pulmonary lymphomas. Curr Opin Pulm Med 2015;21: CONSENT 333–7. Consent for publication was obtained from the patient (Oxford 7. Ferraro P, Trastek VF, Adlakha H, Deschamps C, Allen MS, University Press Patient Consent Form). Pairolero PC. Primary non-Hodgkin’s lymphoma of the lung. Ann Thorac Surg 2000;69:993–7. REFERENCES 8. Zucca E, Conconi A, Laszlo D, López-Guillermo A, 1. Cadranel J, Wislez M, Antoine M. Primary pulmonary Bouabdallah R, Coiffier B, et al. Addition of rituximab to lymphoma. Eur Respir J 2002;20:750–62. chlorambucil produces superior event-free survival in the 2. William J, Variakojis D, Yeldandi A, Raparia K. Lymphoproli- treatment of patients with extranodal marginal-zone B-cell ferative neoplasm of the lung. Arch Pathol Lab Med 2013;137: lymphoma: 5-year analysis of the IELSG-19 randomized 382–91. study. J Clin Oncol 2013;31:565–72. 3. Isaacson PG, Norton AJ Extranodal Lymphomas. New York: 9. Aviles A, Nambo MJ, Huerta Guzman J, Silva L, Neri N. Churchill Livingstone, 1994. Rituximab in the treatment of diffuse large B-cell lymph- 4. Zinzani PL, Martelli M, Poletti V, Vitolo U, Gobbi PG, Chisesi T, oma primary of the lung. Hematology 2013;18:81–4. et al.Practiceguidelinesfor themanagementofextranodal 10. Neri N, Nambo MJ, Aviles A. Diffuse large B-cell lymphoma non-Hodgkin’s lymphomas of adult non-immunodeficient primary of lung. Hematology 2011;16:110–2. Downloaded from https://academic.oup.com/omcr/article-abstract/2018/2/omx095/4846370 by Ed 'DeepDyve' Gillespie user on 16 March 2018

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Published: Feb 1, 2018

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