Case Report: Combined Small Cell Lung Cancer in a Lung Transplant Recipient A. Moniodisa,*, E. Racilab, and M. Divoa a Department of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Clinics Building PBB 311, 75 Francis Street, Boston, Massachusetts, USA; and bDepartment of Pathology, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts, USA
ABSTRACT Lung transplantation confers an increased risk of lung cancer, especially for single lung transplant recipients, due to both the epidemiologic risk factors associated with the patient population and the posttransplantation immunosuppression required. We report what we believe to be the first case of combined small cell lung carcinoma identified in the native lung of a single lung transplant recipient. Combined small cell lung cancer is an increasingly recognized subtype of small cell carcinoma, and its possible presence is an important consideration in the interpretation of fine-needle aspiration biopsies. In our case, initial fine-needle aspiration suggested squamous cell carcinoma, and it was only after lobectomy that the diagnosis of small cell carcinoma was made. The case highlights the increased risk of malignancy in lung transplant recipients and suggests a role for adaptation of lung cancer screening guidelines to address this high-risk population.
L
UNG transplantation can be a life-saving treatment for patients with end-stage pulmonary disease; however, recipients are at increased risk for developing malignancy [1]. In particular, the prevalence of lung cancer in transplant recipients is estimated to be between 2.5% and 9%, with an expectation of increasing incidence as the average age of transplant recipients increases [2], and potentially as the life expectancy of recipients posttransplantation increases. This increased risk is attributable to several factors, including duration, intensity, and type of immunosuppression [3]. Patient factors such as age and environmental exposures also play a role, with single lung transplant patients having the highest risk due to factors affecting the native lung, such as previous tobacco use and the presence of emphysema or fibrosis [4]. In advanced-stage cancers, the prognosis is less favorable than that in the general population with similarly staged disease [5]. CASE DESCRIPTION
Fig 1. Computed tomography (CT) of the chest. Left lower lobe nodule measuring 1.9 1.6 cm, new in comparison to CT from 2 years earlier.
A 70-year-old woman with a previous 50 pack-year smoking history presented with cough. She had received a right single lung transplant 5 years earlier for chronic obstructive pulmonary disease. Her explanted lung was notable only for emphysema. Immunosuppression was per protocol, and she was maintained on a regimen of prednisone, tacrolimus, and mycophenolate mofetil. After year 1,
*Address correspondence to Anna Moniodis, Department of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Clinics Building PBB 311, 75 Francis Street, Boston, MA 02115. E-mail: [email protected]
0041-1345/15 http://dx.doi.org/10.1016/j.transproceed.2015.01.019
852
ª 2015 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
Transplantation Proceedings, 47, 852e854 (2015)
COMBINED SCLC IN A LUNG TRANSPLANT RECIPIENT
853
Fig 2. Hemotoxylin-eosin (AeD) and immunohistochemistry (EeH) stains of biopsy (A) and lobectomy specimen (BeH) of combined squamous cell/small cell/ adenocarcinoma tumor. Biopsy obtained 1 month before tumor resection shows squamous cell carcinoma (A). Squamous cell carcinoma (B), small cell carcinoma (C), and adenocarcinoma (D) components of the resected tumor. The SCC component shows p63 nuclear expression (E) and an average Ki-67 proliferation index of 60% (G). The SCLC component shows chromogranin expression (F) and has an average proliferation index >95% (H). mycophenolate and subsequently its replacement agent azathioprine were discontinued due to leukopenia. At the time of the patient’s presentation with cough, computed tomography (CT) of the chest revealed a new 1.9 1.6 cm nodule in the left lower lobe (Fig 1). Positron emission tomography showed that the nodule had a maximal standardized uptake value of 3.6, with no radiologic evidence of metastasis. Cytology of CT-guided fine-needle aspirate was suggestive of squamous cell carcinoma (Fig 2A), and the patient underwent left lower lobe lobectomy. Pathologic examination of the mass showed findings consistent with combined small cell carcinoma made up of 80% squamous cell carcinoma, 10% small cell carcinoma, and 10% adenocarcinoma (Figs 2Be2D). In the focus of small cell carcinoma, immunohistochemical staining for Ki-97
demonstrated a proliferation index of 90%, and stains for synaptophysin and chromogranin were positive (Figs 2Ee2H). The patient subsequently underwent left pneumonectomy due to an air leak at her previous resection site, and pathologic examination showed focal high-grade squamous dysplasia at the resection margin. Unfortunately, the patient developed an empyema postoperatively, and she died of refractory sepsis. Autopsy was notable for no evidence of metastatic carcinoma.
DISCUSSION
Small cell lung cancer (SCLC) is much less common after lung transplantation than nonesmall cell lung cancer
854
(NSCLC) [6]. Many case series of lung cancer after lung transplantation are composed exclusively of NSCLC [2], with 1 case series having 1 of 9 with SCLC, although 5 isolated case reports are noted [7e9]. To our knowledge, this is the first reported case of combined small cell carcinoma in a lung transplant recipient. Combined small cell carcinoma (CSCLC) is classified as a subtype of SCLC, and defined as a tumor with a mixture of SCLC and at least 10% of cells that are of nonesmall cell histologic subtype [10]. Previously underestimated in incidence, it is currently estimated that up to 30% of SCLCs have a nonesmall cell component [11]. Immunophenotypic and genotypic analyses suggest a close genetic relationship between the small cell and nonesmall cell components, with the NSCLC regions likely the result of a common precursor cell with divergent morphologic differentiation [12]. Our case is somewhat atypical because in most combined tumors SCLC is the predominant component [10]; however, autopsy reviews comparing initial diagnostic pathology and postmortem analysis suggest that the percentage of SCLC component can be variable and can change over time [11]. Thus, if our patient’s tumor had been obtained earlier or later in her course, the SCLC component may have been predominant. A crucial consideration in regard to CSCLC is the potential for misclassified pathologic diagnosis. The multiple components of CSCLC may lead to sampling error [13], as in the case of our patient, in whom initial biopsy suggested NSCLC. The presence of SCLC overrides the NSCLC component and defines the course of subsequent therapy [10]. This can make the difference between surgical resection with the goal of cure vs chemotherapy with the high likelihood of metastases. Our patient also was found to have a distinctly separate lesion at the bronchial margin with high-grade squamous dysplasia. Although CSCLC can develop metastases of NSCLC histology [14], this focus of pathologic abnormality was in an early precursor stage, suggesting an independently developing tumor. It most likely represents a synchronous dysplastic lesion unrelated to the patient’s CSCLC that likely would have developed into a secondary primary malignancy [15]. The potential for our patient to have 2 primary lung cancers supports a field of effect of carcinogenesis [16], and further emphasizes the significance of her combined risk factors of cigarette exposure and systemic immunosuppression. In conclusion, this unusual case report of CSCLC highlights the increased risk of lung cancer of multiple histologic phenotypes in lung transplant recipients as well as suggests potential for development of multiple primary lung cancers in these patients. It also serves as a reminder to consider the possibility of a combined malignancy in patients with diagnosis by fine-needle aspirate and those with tumors displaying atypical clinical behavior. Lastly, it highlights the
MONIODIS, RACILA, AND DIVO
poor prognosis of transplant recipients with malignancy and reinvigorates the discussion of lung cancer screening in this patient population. The formulation of guidelines has been previously suggested [17] but not implemented. However, because more recent evidence supports routine CT screening as a means of reducing lung cancer mortality in other high-risk patients [18], it may well be time to establish similar screening guidelines for lung transplant recipients. REFERENCES [1] Engels EA, Pfeiffer RM, Fraumeni Jr JF, et al. Spectrum of cancer risk among U.S. solid organ transplant recipients: The Transplant Cancer Match Study. JAMA 2011;306:1891e901. [2] Raviv Y, Shitrit D, Amital A, et al. Lung cancer in lung transplant recipients: experience of a tertiary hospital and literature review. Lung Cancer 2011;74:280e3. [3] Mathew J, Kratzke RA. Lung cancer and lung transplantation: a review. J Thorac Oncol 2009;4:753e60. [4] Espinosa D, Baamonde C, Illana J, et al. Lung cancer in patients with lung transplants. Transplant Proc 2012;44:2118e9. [5] Olland AB, Falcoz PE, Satelmo N, Kessler R, Massard G. Primary lung cancer in lung transplant recipients. Ann Thorac Surg 2013;98:362e71. [6] Venyo A, Sheikh F. Malignancy after lung transplantation: a literature review. WebMedCentral Transplantation 2012;3: WMC003293. [7] De Soyza AG, Dark JH, Parums DV, Curtis A, Corris PA. Donor-acquired small cell lung cancer following pulmonary transplantation. Chest 2001;120:1030e1. [8] Picard C, Grenet D, Copie-Bergman C, et al. Small cell carcinoma of recipient origin after bilateral lung transplantation for cystic fibrosis. J Heart Lung Transplant 2006;25:981e4. [9] Miao J, Li H, You B, Hou S, Hu B. Mediastinal small-cell lung carcinoma after right lung transplant for pulmonary interstitial fibrosis. Tumori 2012;98:39ee42e. [10] Travis WD. Update on small cell carcinoma and its differentiation from squamous cell carcinoma and other non-small cell carcinomas. Mod Pathol 2012;25(Suppl 1):S18e30. [11] Nicholson SA, Beasley BM, Brambilla E, et al. Small cell lung carcinoma (SCLC): a clinicopathologic study of 100 cases with surgical specimens. Am J Surg Pathol 2002;26: 1184e97. [12] Wagner PL, Kitabayashi N, Chen Y, Sagi A. Combined small cell lung carcinomas: genotypic and immunophenotypic analysis of the separate morphologic components. Am J Clin Pathol 2009;131:376e82. [13] Mangum MD, Greco FA, Hainsworth JD, Hande KR, Johnson DH. Combined small-cell and non-small-cell lung cancer. J Clin Oncol 1989;7:607e12. [14] Adelstein DJ, Tomashefski Jr JF, Snow NJ, et al. Mixed small cell and non-small cell lung cancer. Chest 1986;89:699e704. [15] Martini N, Melame MR. Multiple primary lung cancers. J Thorac Cardiocvasc Surg 1975;70:606e12. [16] Chai H, Browne RE. Field effect in cancerdan update. Ann Clin Lab Sci 2009;39:331e7. [17] Robbins HY, Arcasoy SM. Malignancies following lung transplantation. Clin Chest Med 2001;32:342e55. [18] National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365:395e409.
ABSTRACT Lung transplantation confers an increased risk of lung cancer, especially for single lung transplant recipients, due to both the epidemiologic risk factors associated with the patient population and the posttransplantation immunosuppression required. We report what we believe to be the first case of combined small cell lung carcinoma identified in the native lung of a single lung transplant recipient. Combined small cell lung cancer is an increasingly recognized subtype of small cell carcinoma, and its possible presence is an important consideration in the interpretation of fine-needle aspiration biopsies. In our case, initial fine-needle aspiration suggested squamous cell carcinoma, and it was only after lobectomy that the diagnosis of small cell carcinoma was made. The case highlights the increased risk of malignancy in lung transplant recipients and suggests a role for adaptation of lung cancer screening guidelines to address this high-risk population.
L
UNG transplantation can be a life-saving treatment for patients with end-stage pulmonary disease; however, recipients are at increased risk for developing malignancy [1]. In particular, the prevalence of lung cancer in transplant recipients is estimated to be between 2.5% and 9%, with an expectation of increasing incidence as the average age of transplant recipients increases [2], and potentially as the life expectancy of recipients posttransplantation increases. This increased risk is attributable to several factors, including duration, intensity, and type of immunosuppression [3]. Patient factors such as age and environmental exposures also play a role, with single lung transplant patients having the highest risk due to factors affecting the native lung, such as previous tobacco use and the presence of emphysema or fibrosis [4]. In advanced-stage cancers, the prognosis is less favorable than that in the general population with similarly staged disease [5]. CASE DESCRIPTION
Fig 1. Computed tomography (CT) of the chest. Left lower lobe nodule measuring 1.9 1.6 cm, new in comparison to CT from 2 years earlier.
A 70-year-old woman with a previous 50 pack-year smoking history presented with cough. She had received a right single lung transplant 5 years earlier for chronic obstructive pulmonary disease. Her explanted lung was notable only for emphysema. Immunosuppression was per protocol, and she was maintained on a regimen of prednisone, tacrolimus, and mycophenolate mofetil. After year 1,
*Address correspondence to Anna Moniodis, Department of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Clinics Building PBB 311, 75 Francis Street, Boston, MA 02115. E-mail: [email protected]
0041-1345/15 http://dx.doi.org/10.1016/j.transproceed.2015.01.019
852
ª 2015 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
Transplantation Proceedings, 47, 852e854 (2015)
COMBINED SCLC IN A LUNG TRANSPLANT RECIPIENT
853
Fig 2. Hemotoxylin-eosin (AeD) and immunohistochemistry (EeH) stains of biopsy (A) and lobectomy specimen (BeH) of combined squamous cell/small cell/ adenocarcinoma tumor. Biopsy obtained 1 month before tumor resection shows squamous cell carcinoma (A). Squamous cell carcinoma (B), small cell carcinoma (C), and adenocarcinoma (D) components of the resected tumor. The SCC component shows p63 nuclear expression (E) and an average Ki-67 proliferation index of 60% (G). The SCLC component shows chromogranin expression (F) and has an average proliferation index >95% (H). mycophenolate and subsequently its replacement agent azathioprine were discontinued due to leukopenia. At the time of the patient’s presentation with cough, computed tomography (CT) of the chest revealed a new 1.9 1.6 cm nodule in the left lower lobe (Fig 1). Positron emission tomography showed that the nodule had a maximal standardized uptake value of 3.6, with no radiologic evidence of metastasis. Cytology of CT-guided fine-needle aspirate was suggestive of squamous cell carcinoma (Fig 2A), and the patient underwent left lower lobe lobectomy. Pathologic examination of the mass showed findings consistent with combined small cell carcinoma made up of 80% squamous cell carcinoma, 10% small cell carcinoma, and 10% adenocarcinoma (Figs 2Be2D). In the focus of small cell carcinoma, immunohistochemical staining for Ki-97
demonstrated a proliferation index of 90%, and stains for synaptophysin and chromogranin were positive (Figs 2Ee2H). The patient subsequently underwent left pneumonectomy due to an air leak at her previous resection site, and pathologic examination showed focal high-grade squamous dysplasia at the resection margin. Unfortunately, the patient developed an empyema postoperatively, and she died of refractory sepsis. Autopsy was notable for no evidence of metastatic carcinoma.
DISCUSSION
Small cell lung cancer (SCLC) is much less common after lung transplantation than nonesmall cell lung cancer
854
(NSCLC) [6]. Many case series of lung cancer after lung transplantation are composed exclusively of NSCLC [2], with 1 case series having 1 of 9 with SCLC, although 5 isolated case reports are noted [7e9]. To our knowledge, this is the first reported case of combined small cell carcinoma in a lung transplant recipient. Combined small cell carcinoma (CSCLC) is classified as a subtype of SCLC, and defined as a tumor with a mixture of SCLC and at least 10% of cells that are of nonesmall cell histologic subtype [10]. Previously underestimated in incidence, it is currently estimated that up to 30% of SCLCs have a nonesmall cell component [11]. Immunophenotypic and genotypic analyses suggest a close genetic relationship between the small cell and nonesmall cell components, with the NSCLC regions likely the result of a common precursor cell with divergent morphologic differentiation [12]. Our case is somewhat atypical because in most combined tumors SCLC is the predominant component [10]; however, autopsy reviews comparing initial diagnostic pathology and postmortem analysis suggest that the percentage of SCLC component can be variable and can change over time [11]. Thus, if our patient’s tumor had been obtained earlier or later in her course, the SCLC component may have been predominant. A crucial consideration in regard to CSCLC is the potential for misclassified pathologic diagnosis. The multiple components of CSCLC may lead to sampling error [13], as in the case of our patient, in whom initial biopsy suggested NSCLC. The presence of SCLC overrides the NSCLC component and defines the course of subsequent therapy [10]. This can make the difference between surgical resection with the goal of cure vs chemotherapy with the high likelihood of metastases. Our patient also was found to have a distinctly separate lesion at the bronchial margin with high-grade squamous dysplasia. Although CSCLC can develop metastases of NSCLC histology [14], this focus of pathologic abnormality was in an early precursor stage, suggesting an independently developing tumor. It most likely represents a synchronous dysplastic lesion unrelated to the patient’s CSCLC that likely would have developed into a secondary primary malignancy [15]. The potential for our patient to have 2 primary lung cancers supports a field of effect of carcinogenesis [16], and further emphasizes the significance of her combined risk factors of cigarette exposure and systemic immunosuppression. In conclusion, this unusual case report of CSCLC highlights the increased risk of lung cancer of multiple histologic phenotypes in lung transplant recipients as well as suggests potential for development of multiple primary lung cancers in these patients. It also serves as a reminder to consider the possibility of a combined malignancy in patients with diagnosis by fine-needle aspirate and those with tumors displaying atypical clinical behavior. Lastly, it highlights the
MONIODIS, RACILA, AND DIVO
poor prognosis of transplant recipients with malignancy and reinvigorates the discussion of lung cancer screening in this patient population. The formulation of guidelines has been previously suggested [17] but not implemented. However, because more recent evidence supports routine CT screening as a means of reducing lung cancer mortality in other high-risk patients [18], it may well be time to establish similar screening guidelines for lung transplant recipients. REFERENCES [1] Engels EA, Pfeiffer RM, Fraumeni Jr JF, et al. Spectrum of cancer risk among U.S. solid organ transplant recipients: The Transplant Cancer Match Study. JAMA 2011;306:1891e901. [2] Raviv Y, Shitrit D, Amital A, et al. Lung cancer in lung transplant recipients: experience of a tertiary hospital and literature review. Lung Cancer 2011;74:280e3. [3] Mathew J, Kratzke RA. Lung cancer and lung transplantation: a review. J Thorac Oncol 2009;4:753e60. [4] Espinosa D, Baamonde C, Illana J, et al. Lung cancer in patients with lung transplants. Transplant Proc 2012;44:2118e9. [5] Olland AB, Falcoz PE, Satelmo N, Kessler R, Massard G. Primary lung cancer in lung transplant recipients. Ann Thorac Surg 2013;98:362e71. [6] Venyo A, Sheikh F. Malignancy after lung transplantation: a literature review. WebMedCentral Transplantation 2012;3: WMC003293. [7] De Soyza AG, Dark JH, Parums DV, Curtis A, Corris PA. Donor-acquired small cell lung cancer following pulmonary transplantation. Chest 2001;120:1030e1. [8] Picard C, Grenet D, Copie-Bergman C, et al. Small cell carcinoma of recipient origin after bilateral lung transplantation for cystic fibrosis. J Heart Lung Transplant 2006;25:981e4. [9] Miao J, Li H, You B, Hou S, Hu B. Mediastinal small-cell lung carcinoma after right lung transplant for pulmonary interstitial fibrosis. Tumori 2012;98:39ee42e. [10] Travis WD. Update on small cell carcinoma and its differentiation from squamous cell carcinoma and other non-small cell carcinomas. Mod Pathol 2012;25(Suppl 1):S18e30. [11] Nicholson SA, Beasley BM, Brambilla E, et al. Small cell lung carcinoma (SCLC): a clinicopathologic study of 100 cases with surgical specimens. Am J Surg Pathol 2002;26: 1184e97. [12] Wagner PL, Kitabayashi N, Chen Y, Sagi A. Combined small cell lung carcinomas: genotypic and immunophenotypic analysis of the separate morphologic components. Am J Clin Pathol 2009;131:376e82. [13] Mangum MD, Greco FA, Hainsworth JD, Hande KR, Johnson DH. Combined small-cell and non-small-cell lung cancer. J Clin Oncol 1989;7:607e12. [14] Adelstein DJ, Tomashefski Jr JF, Snow NJ, et al. Mixed small cell and non-small cell lung cancer. Chest 1986;89:699e704. [15] Martini N, Melame MR. Multiple primary lung cancers. J Thorac Cardiocvasc Surg 1975;70:606e12. [16] Chai H, Browne RE. Field effect in cancerdan update. Ann Clin Lab Sci 2009;39:331e7. [17] Robbins HY, Arcasoy SM. Malignancies following lung transplantation. Clin Chest Med 2001;32:342e55. [18] National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365:395e409.
