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Unilateral Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia and Multiple Carcinoids Treated with Surgical Resection
CASE REPORT
Unilateral Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia and Multiple Carcinoids Treated with Surgical Resection Sheeba Irshad,* Emma McLean,† Sheila Rankin,‡ Sally Barrington,§ George Santis,储¶ James Spicer,*¶ and Loic Lang-Lazdunski#
D
iffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare pulmonary disorder with less than 50 reported cases in the literature. DIPNECH belongs to the group of preinvasive lesions defined by the 1999 World Health Organization classification, including atypical adematous hyperplasia and squamous dysplasia– carcinoma in situ.1 DIPNECH refers to collections of scattered single cells, small nodules, or linear proliferations of neuroendocrine cells, without invasion beyond the basement membrane, sometimes accompanied by chronic inflammation or fibrosis1. It is reserved only for cases in which the hyperplasia is diffuse and primary in nature. DIPNECH has a predilection for nonsmoking middle-aged females and is associated with a predominantly obstructive ventilatory defect, typically in association with obliterative bronchiolar fibrosis2. The most common symptoms include nonproductive cough and exertional dyspnea, and patients are commonly misdiagnosed as bronchial asthma or chronic bronchitis.
CASE REPORT A 36-year-old Caucasian woman presented to the chest clinic with a 6-week history of persistent dry cough. She denied any symptoms of night sweats, fevers, hemoptysis, or weight loss. She had previously had two courses of oral antibiotics, prescribed by her family doctor, with no improvement in her symptoms. She denied history of any chronic pulmonary disorders or major systemic diseases. She was a lifelong nonsmoker. Physical examination revealed diminished breath sounds in the right lung. Chest radiography showed extensive nodular infiltrate limited to the right lung. Departments of *Medical Oncology, †Histopathology, and ‡Radiology, §PET Imaging Centre, Guy’s and St Thomas’ NHS Foundation Trust, and #King’s College London, Guy’s Hospital, Great Maze Pond, London, United Kingdom; Departments of 储Respiratory Medicine, and ¶Thoracic Surgery, Guy’s and St Thomas’ NHS Foundation Trust, and #King’s College London, Guy’s Hospital, Great Maze Pond, London, United Kingdom. Disclosure: The authors declare no conflicts of interest. Address for correspondence: James Spicer, MD, Medical Oncology, Guy’s Hospital, Great Maze Pond, London SE1 9RT, United Kingdom. E-mail: [email protected] Copyright © 2010 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/10/0506-0921
Journal of Thoracic Oncology • Volume 5, Number 6, June 2010
This was a very unusual distribution being so widespread and also unilateral (Figure 1). Chest computed tomography confirmed multiple, well-defined soft tissue density lesions confined to the right hemithorax (Figure 1). Our working diagnosis was of a pulmonary artery sarcoma. However, the transthoracic echocardiogram showed no tumor in the right heart cavities and the pulmonary trunk. Pulmonary function tests were unremarkable. An 18-FDG-positron emission tomography-computed tomography showed low-grade FDG uptake within the nodules in the right lung (maximum survival 3.6 years) and no uptake in the left lung or mediastinum (Figure 2). Standard blood investigations were normal. Specifically, inflammatory markers were not raised, and autoimmune and vasculitis screen tests are proved to be negative. At bronchoscopy, there was mild airway inflammation but otherwise appearance was normal to subsegmental level. Transbronchial biopsy revealed a nonspecific mild, chronic inflammatory infiltrate. The bronchial aspirate grew Moraxella cateralis for which she was given a further course of antibiotics. To obtain a definitive histologic diagnosis, she underwent a right video-assisted thoracoscopic surgery lung biopsy; this demonstrated diffuse neuroendocrine hyperplasia (DIPNECH) with multiple tumorlets and multiple typical carcinoids (Figure 3). Tumorlets are the localized regions of neuroendocrine cell proliferation of ⬍5 mm in diameter and usually found in association with damaged small airways. On immunohistochemical staining, the tumor cells were positive for MNF116, CD56, synaptophysin, and chromogranin, with focal epithelial membrane antigen positivity, confirming the diagnosis. Such florid unilateral proliferation was very unusual and she subsequently had a left-sided transbronchial biopsy that ruled out any microscopic neuroendocrine hyperplasia in the tissues sampled. A gallium-68 dotatate positron emission tomography scan was undertaken as agents binding somatostatin receptors have been reported to have higher uptake in low-grade neuroendocrine tumors than 18-FDG.3 In this case, however, uptake in the nodules was not only less marked than with FDG but also indicated that disease was confined to the right lung. Clinically, there were no signs suggestive of Cushing’s or any other paraneoplastic syndromes and the 24-hour urinary 5-hydroxyindoleacetic acid level was normal.
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Journal of Thoracic Oncology • Volume 5, Number 6, June 2010
Irshad et al.
FIGURE 1. Chest radiography at presentation showing multiple nodules within the right lung only.
FIGURE 2. An 18-FDG-positron emission tomography-computed tomography scan showing low-grade FDG uptake only within the nodules in the right lung (maximum survival 3.6 years).
Because of the uniqueness of this case and lack of guidance in the literature regarding management, opinions were widely sought. It was finally concluded that she should be managed with surgical resection. The patient underwent an uncomplicated right pneumonectomy with radical hilar and mediastinal lymphadenectomy. Final histology confirmed multiple typical carcinoids in the right lung with multiple carcinoid tumorlets and diffuse neuroendocrine hyperplasia. There was no pleural invasion but vascular invasion was seen. Lymph node stations 3R, 4R, and 10R were free of tumor but there were foci of metastatic typical carcinoid tumor present in station 7. One year after her surgery, our patient has recovered completely and her exercise capacity is nearly back to baseline.
DISCUSSION FIGURE 3. Example of the differing sizes of neuroendocrine proliferations, i.e., Carcinoid tumors and tumorlets (H&E stain, ⫻4 lens).
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We report for the first time a case of unilateral DIPNECH in the presence of multiple tumorlets and typical carcinoids. Although the case reported here was typical of DIPNECH in that it occurred in a nonsmoking middle-aged woman, it was highly unusual in that florid hyperplasia was
Copyright © 2010 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology • Volume 5, Number 6, June 2010
seen only in one lung. The Literature on the management of DIPNECH is lacking but Swigris et al.2 studied four cases of DIPNECH with 2 to 14 years follow-up and reported an excellent long-term prognosis. The management of patients with DIPNECH is predominantly close surveillance; the role of surgical intervention is not clearly defined. Palliative resection for recurrent pulmonary hemorrhage in a patient with DIPNECH has been reported.4 As in our case, for patients with carcinoid tumor formation, complete resection of the carcinoid tumor, accompanied by a systematic mediastinal and hilar lymph node dissection is a reasonable approach. DIPNECH is assumed to be a preinvasive lesion, with extension of the pulmonary neuroendocrine cell proliferation beyond the basement membrane into the peribronchial soft tissue forming aggregates that are called tumorlets (diameter ⬍5 mm) or carcinoid tumors (diameter ⬎5 mm).1 Typical carcinoids are classified as having ⬍2 mitoses per 2 mm2 and lacking necrosis (atypical carcinoids have 2–10 mitoses per 2 mm2 and/or necrosis). A study looking at 1090 patients, undergoing resection for primary lung tumors, found that the overall prevalence of synchronous preinvasive lesions was
DIPNECH and Multiple Carcinoids
6.7%. Only three of these 1090 cases were typical carcinoids associated with DIPNECH.5 None of these cases developed local or distant relapse at follow-up and all were alive and well at 30, 35, and 37 months from surgery. Thus, it would seem that resected neuroendocrine neoplasms and associated DIPNECH behave similarly to corresponding neuroendocrine tumors without DIPNECH. Better understanding of the biology of DIPNECH may provide an insight into the tumorigenesis of neuroendocrine neoplasms of the lung. REFERENCES 1. Kerr KM. Pulmonary preinvasive neoplasia. J Clin Pathol 2001;54:257– 271. 2. Swigris J, Ghamande S, Rice T, et al. Diffuse idiopathic neuroendocrine cell hyperplasia: an interstitial lung disease with airway obstruction. J Bronch 2005;12:62– 64. 3. Al-Nahhas A, Win Z, Szyszko T, et al. Gallium-68 PET: a new frontier in receptor cancer imaging. Anticancer Res 2007;27(6B):4087– 4094. 4. Johney E, Pfannschmidt J, Rieker R, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia and a typical carcinoid tumor. J Thorac Cardiovasc Surg 2006;131:1207–1208. 5. Ruffini E, Bongiovanni M, Cavallo A, et al. The significance of associated pre-invasive lesions in patients resected for primary lung neoplasms. Eur J Cardiothorac Surg 2004;26:165–172.
Copyright © 2010 by the International Association for the Study of Lung Cancer
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Unilateral Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia and Multiple Carcinoids Treated with Surgical Resection Sheeba Irshad,* Emma McLean,† Sheila Rankin,‡ Sally Barrington,§ George Santis,储¶ James Spicer,*¶ and Loic Lang-Lazdunski#
D
iffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare pulmonary disorder with less than 50 reported cases in the literature. DIPNECH belongs to the group of preinvasive lesions defined by the 1999 World Health Organization classification, including atypical adematous hyperplasia and squamous dysplasia– carcinoma in situ.1 DIPNECH refers to collections of scattered single cells, small nodules, or linear proliferations of neuroendocrine cells, without invasion beyond the basement membrane, sometimes accompanied by chronic inflammation or fibrosis1. It is reserved only for cases in which the hyperplasia is diffuse and primary in nature. DIPNECH has a predilection for nonsmoking middle-aged females and is associated with a predominantly obstructive ventilatory defect, typically in association with obliterative bronchiolar fibrosis2. The most common symptoms include nonproductive cough and exertional dyspnea, and patients are commonly misdiagnosed as bronchial asthma or chronic bronchitis.
CASE REPORT A 36-year-old Caucasian woman presented to the chest clinic with a 6-week history of persistent dry cough. She denied any symptoms of night sweats, fevers, hemoptysis, or weight loss. She had previously had two courses of oral antibiotics, prescribed by her family doctor, with no improvement in her symptoms. She denied history of any chronic pulmonary disorders or major systemic diseases. She was a lifelong nonsmoker. Physical examination revealed diminished breath sounds in the right lung. Chest radiography showed extensive nodular infiltrate limited to the right lung. Departments of *Medical Oncology, †Histopathology, and ‡Radiology, §PET Imaging Centre, Guy’s and St Thomas’ NHS Foundation Trust, and #King’s College London, Guy’s Hospital, Great Maze Pond, London, United Kingdom; Departments of 储Respiratory Medicine, and ¶Thoracic Surgery, Guy’s and St Thomas’ NHS Foundation Trust, and #King’s College London, Guy’s Hospital, Great Maze Pond, London, United Kingdom. Disclosure: The authors declare no conflicts of interest. Address for correspondence: James Spicer, MD, Medical Oncology, Guy’s Hospital, Great Maze Pond, London SE1 9RT, United Kingdom. E-mail: [email protected] Copyright © 2010 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/10/0506-0921
Journal of Thoracic Oncology • Volume 5, Number 6, June 2010
This was a very unusual distribution being so widespread and also unilateral (Figure 1). Chest computed tomography confirmed multiple, well-defined soft tissue density lesions confined to the right hemithorax (Figure 1). Our working diagnosis was of a pulmonary artery sarcoma. However, the transthoracic echocardiogram showed no tumor in the right heart cavities and the pulmonary trunk. Pulmonary function tests were unremarkable. An 18-FDG-positron emission tomography-computed tomography showed low-grade FDG uptake within the nodules in the right lung (maximum survival 3.6 years) and no uptake in the left lung or mediastinum (Figure 2). Standard blood investigations were normal. Specifically, inflammatory markers were not raised, and autoimmune and vasculitis screen tests are proved to be negative. At bronchoscopy, there was mild airway inflammation but otherwise appearance was normal to subsegmental level. Transbronchial biopsy revealed a nonspecific mild, chronic inflammatory infiltrate. The bronchial aspirate grew Moraxella cateralis for which she was given a further course of antibiotics. To obtain a definitive histologic diagnosis, she underwent a right video-assisted thoracoscopic surgery lung biopsy; this demonstrated diffuse neuroendocrine hyperplasia (DIPNECH) with multiple tumorlets and multiple typical carcinoids (Figure 3). Tumorlets are the localized regions of neuroendocrine cell proliferation of ⬍5 mm in diameter and usually found in association with damaged small airways. On immunohistochemical staining, the tumor cells were positive for MNF116, CD56, synaptophysin, and chromogranin, with focal epithelial membrane antigen positivity, confirming the diagnosis. Such florid unilateral proliferation was very unusual and she subsequently had a left-sided transbronchial biopsy that ruled out any microscopic neuroendocrine hyperplasia in the tissues sampled. A gallium-68 dotatate positron emission tomography scan was undertaken as agents binding somatostatin receptors have been reported to have higher uptake in low-grade neuroendocrine tumors than 18-FDG.3 In this case, however, uptake in the nodules was not only less marked than with FDG but also indicated that disease was confined to the right lung. Clinically, there were no signs suggestive of Cushing’s or any other paraneoplastic syndromes and the 24-hour urinary 5-hydroxyindoleacetic acid level was normal.
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Journal of Thoracic Oncology • Volume 5, Number 6, June 2010
Irshad et al.
FIGURE 1. Chest radiography at presentation showing multiple nodules within the right lung only.
FIGURE 2. An 18-FDG-positron emission tomography-computed tomography scan showing low-grade FDG uptake only within the nodules in the right lung (maximum survival 3.6 years).
Because of the uniqueness of this case and lack of guidance in the literature regarding management, opinions were widely sought. It was finally concluded that she should be managed with surgical resection. The patient underwent an uncomplicated right pneumonectomy with radical hilar and mediastinal lymphadenectomy. Final histology confirmed multiple typical carcinoids in the right lung with multiple carcinoid tumorlets and diffuse neuroendocrine hyperplasia. There was no pleural invasion but vascular invasion was seen. Lymph node stations 3R, 4R, and 10R were free of tumor but there were foci of metastatic typical carcinoid tumor present in station 7. One year after her surgery, our patient has recovered completely and her exercise capacity is nearly back to baseline.
DISCUSSION FIGURE 3. Example of the differing sizes of neuroendocrine proliferations, i.e., Carcinoid tumors and tumorlets (H&E stain, ⫻4 lens).
922
We report for the first time a case of unilateral DIPNECH in the presence of multiple tumorlets and typical carcinoids. Although the case reported here was typical of DIPNECH in that it occurred in a nonsmoking middle-aged woman, it was highly unusual in that florid hyperplasia was
Copyright © 2010 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology • Volume 5, Number 6, June 2010
seen only in one lung. The Literature on the management of DIPNECH is lacking but Swigris et al.2 studied four cases of DIPNECH with 2 to 14 years follow-up and reported an excellent long-term prognosis. The management of patients with DIPNECH is predominantly close surveillance; the role of surgical intervention is not clearly defined. Palliative resection for recurrent pulmonary hemorrhage in a patient with DIPNECH has been reported.4 As in our case, for patients with carcinoid tumor formation, complete resection of the carcinoid tumor, accompanied by a systematic mediastinal and hilar lymph node dissection is a reasonable approach. DIPNECH is assumed to be a preinvasive lesion, with extension of the pulmonary neuroendocrine cell proliferation beyond the basement membrane into the peribronchial soft tissue forming aggregates that are called tumorlets (diameter ⬍5 mm) or carcinoid tumors (diameter ⬎5 mm).1 Typical carcinoids are classified as having ⬍2 mitoses per 2 mm2 and lacking necrosis (atypical carcinoids have 2–10 mitoses per 2 mm2 and/or necrosis). A study looking at 1090 patients, undergoing resection for primary lung tumors, found that the overall prevalence of synchronous preinvasive lesions was
DIPNECH and Multiple Carcinoids
6.7%. Only three of these 1090 cases were typical carcinoids associated with DIPNECH.5 None of these cases developed local or distant relapse at follow-up and all were alive and well at 30, 35, and 37 months from surgery. Thus, it would seem that resected neuroendocrine neoplasms and associated DIPNECH behave similarly to corresponding neuroendocrine tumors without DIPNECH. Better understanding of the biology of DIPNECH may provide an insight into the tumorigenesis of neuroendocrine neoplasms of the lung. REFERENCES 1. Kerr KM. Pulmonary preinvasive neoplasia. J Clin Pathol 2001;54:257– 271. 2. Swigris J, Ghamande S, Rice T, et al. Diffuse idiopathic neuroendocrine cell hyperplasia: an interstitial lung disease with airway obstruction. J Bronch 2005;12:62– 64. 3. Al-Nahhas A, Win Z, Szyszko T, et al. Gallium-68 PET: a new frontier in receptor cancer imaging. Anticancer Res 2007;27(6B):4087– 4094. 4. Johney E, Pfannschmidt J, Rieker R, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia and a typical carcinoid tumor. J Thorac Cardiovasc Surg 2006;131:1207–1208. 5. Ruffini E, Bongiovanni M, Cavallo A, et al. The significance of associated pre-invasive lesions in patients resected for primary lung neoplasms. Eur J Cardiothorac Surg 2004;26:165–172.
Copyright © 2010 by the International Association for the Study of Lung Cancer
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