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Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH)
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Available online at www.sciencedirect.com
www.elsevier.com/locate/semdp
Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) Alberto M. Marchevsky, MDn, Ann E. Walts, MD Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California
article info
abstract
Keywords:
Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a pre-invasive
Idiopathic
generalized proliferation of pulmonary neuroendocrine (PNE) cells, which has been
Neuroendocrine cell hyperplasia
described in combination with carcinoid tumorlets, obliterative bronchiolitis, and other
Lung
fibrotic lung changes. Since its first recognition as a distinct syndrome in 1992, variable
DIPNECH
clinico-pathologic features have been used to diagnose DIPNECH in small case series and case reports. We recently proposed the use of the following criteria for the pathologic diagnosis of the syndrome on lung resection specimens: the presence of multifocal neuroendocrine cell hyperplasia, as defined by the presence of 5 or more PNE cells in at least 3 separate small airways combined with 3 or more carcinoid tumorlets. At diagnosis, 53% of DIPNECH patients present with a synchronous carcinoid tumor and 24% have obliterative bronchiolitis. To our knowledge, only 1 patient has been diagnosed with a carcinoid tumor subsequent to a DIPNECH diagnosis and the syndrome is not associated with an increased incidence of high-grade neuroendocrine neoplasms. Patients have usually a stable disease and only 26% experience clinical and/or radiographic deterioration. There is no evidence that treatment with octreotide or other medications improves the prognosis of DIPNECH patients. & 2015 Elsevier Inc. All rights reserved.
Pulmonary neuroendocrine (PNE) cells were first identified in the intestine and lung by Feyrter1,2 in 1938. They occur in the small airways as individual cells (Fig. 1A) or in aggregates known as neuroendocrine bodies first described by Froelich3 in 1949 (Fig. 1B). The PNE cells have paracrine functions that play an important role in lung development.4,5 While frequent in the airways of fetal and neonatal lung, the PNE cells decrease in density with age and are found only focally in lung specimens from adult patients. The PNE cells can undergo hyperplasia as a result of hypoxia in individuals living at high altitude and in patients with chronic, fibrotic lung diseases such as bronchiectasis and interstitial fibrosis.4,6–16 They can also become hyperplastic in children, as described in this volume in the article by Cutz et al.4 The PNE n
cells are thought to be the cells of origin of low-grade and intermediate-grade malignancy pulmonary tumors that are currently classified as typical and atypical carcinoid tumors, respectively, and the precursors of smaller (r5 mm in diameter) lesions designated as carcinoid tumorlets.17 The diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare disorder currently classified by the World Health Organization (WHO) Classification of Tumors of the Lung, Pleura, Thymus, and Heart as a preinvasive lesion.18 It is defined by the WHO as “a generalized proliferation of pulmonary neuroendocrine cells (PNEs) that may be confined to the mucosa of airways (with or without luminal protrusion), may invade locally to form tumourlets, or may develop into carcinoid tumours.”
Correspondence to: 8700 Beverly Blvd Room 8709, West Hollywood, CA 90048-1804. E-mail address: [email protected] (A.M. Marchevsky).
http://dx.doi.org/10.1053/j.semdp.2015.08.002 0740-2570/& 2015 Elsevier Inc. All rights reserved.
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Fig. 1 – (A and B) Pulmonary neuroendocrine cells are infrequent in the small airways of adults and occur as individual cells (A) or in aggregates associated with small nerves (B). The pulmonary neuroendocrine cells are shown with immunostain for synaptophysin [peroxidase–antiperoxidase (PAP), 100 and 200 ]. Aguayo et al.7 are given credit for the first description of DIPNECH with their 1992's report of 6 patients with idiopathic diffuse hyperplasia of the PNE cells and airway disease characterized by the presence of peribronchiolar fibrosis obliterating the small airways. Of 6 of their patients, 2 were treated with chemotherapy for a brief period of time without progression to a metastatic neoplasm and 3 others, each with multiple carcinoid tumors or tumorlets, were not treated with chemotherapy. Aguayo et al.7 proposed that the condition is idiopathic and that the obliterative bronchiolitis is secondary to neuropeptides secreted by the neuroendocrine (NE) cells. There are several previous reports of PNE cell hyperplasia associated with lung neoplasms.2 Felton et al.19 reported a patient with peripheral and multiple bronchial adenomas in 1953. In 1978, Miller et al.20 reported the presence of multiple peripheral pulmonary carcinoids and tumorlets of carcinoid type in a 53-year-old woman with an 8-year history of pulmonary nodules. The patient also had obstructive airways disease attributed to extensive bronchiolar involvement. Gould et al.21 described a spectrum of neuroendocrine cell changes ranging from hyperplasia to dysplasia and neoplasms and suggested progression of the neoplasms from non-neoplastic PNE cells. Our recent systematic review of the English literature found only 199 patients with clinico-pathologic features consistent with DIPNECH, reported in individual case reports or small case series of up to 30 patients each.22 Davies et al.23 suggested that DIPNECH may not be such a rare condition and that some cases are probably unrecognized.
Demographic information Patients with DIPNECH range from 36 to 84 years of age, with a median age of 66 years old.8,12,22–32 In total, 93% of the patients are women.22
Clinical findings The majority (83%) of patients with DIPNECH are smokers. Approximately 20% are asymptomatic at presentation, while
66% present with cough and 48% present with dyspnea; hemoptysis or wheezing is less frequent.6,9,10 Fessler et al.33 described a DIPNECH patient who developed acromegaly secondary to overproduction of growth hormone. Cameron et al.12 described an unusual patient with DIPNECH and cyclical ectopic adrenocorticotrophic syndrome. Pulmonary function tests in DIPNECH patients can show restrictive, obstructive, or mixed restrictive/obstructive changes.22 Although the presence of obliterative bronchiolitis has been described as characteristic of DIPNECH by Aguayo and in several subsequent reports, only about 30% of patients with published pulmonary function test data have shown obstructive changes. For example, obstructive defect with an FEV1 of 42% predicted was observed in only 31% of our DIPNECH patients.22 The majority of DIPNECH patients are not clinically diagnosed as DIPNECH prior to lung biopsies or resections. For example, none of our 30 recently reported DIPNECH cases was diagnosed prior to pathologic examination.22 The majority of our patients who had undergone wedge resection or lobectomy for a carcinoid tumor (Fig. 2A and B) or another neoplasm and multiple tumorlets (Fig. 2C) were unexpectedly found during an evaluation of the carcinoid tumors and/or tumorlets, when immunohistochemical stains for chromogranin and synaptophysin demonstrated increased numbers of PNE cells in a variable number of bronchioles (Fig. 2D).
Imaging features Overall, 81% of DIPNECH patients present with multiple pulmonary nodules with or without an associated lung mass (Fig. 3A–C).6,11,14,29,34,35 The presence of multiple pulmonary nodules in a patient with a previous malignancy such as breast or prostatic cancer is of particular interest, as it can result in a misdiagnosis of metastatic disease if lung biopsies are not performed to confirm the diagnosis.31 In 30% of DIPNECH cases air trapping and mosaic attenuation are present in chest computerized tomograms (CT). Other findings such as interstitial fibrosis (Fig. 3D), adenopathy,
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Fig. 2 – (A–D) The majority of our DIPNECH patients had undergone resection of a carcinoid tumor and the presence of pulmonary neuroendocrine cell hyperplasia and multiple carcinoid tumorlets was an unexpected finding. (A) A carcinoid tumor after wedge resection. Reexamination of the gross specimen shows the presence of multiple small gray nodules (arrow) corresponding to carcinoid tumorlets. (B) The larger tumor is a typical carcinoid tumor composed of neuroendocrine cells with round to oval nuclei and “salt-and-pepper” chromatin pattern (Hematoxylin and Eosin, 200 ). (C) Multiple smaller carcinoid tumorlets (Hematoxylin and Eosin, 40 ). (D)Neuroendocrine cell hyperplasia in several bronchioles; the cells show synaptophysin immunoreactivity (PAP, 40 ). bronchiectasis, and cystic lung cases are each seen in less than 5% of patients.9,22
Pathology In most DIPNECH cases, a gross examination of lung tissue shows no pathology other than one or more carcinoid tumors (Fig. 1A). In some instances, the presence of multiple small gray nodules corresponding to carcinoid tumorlets can be seen (Fig. 1) and/or palpated. Microscopically, the PNE cells have round, oval, or spindle nuclei with salt-and-pepper chromatin and clear or eosinophilic cytoplasm (Fig. 4).17,27 PNE cell hyperplasia is manifested by the presence of intramucosal monolayers of cells or small cellular aggregates that elevate the respiratory epithelium of terminal bronchioles (Fig. 5). While it can be difficult to diagnose these cells as PNE cells on hematoxylin-andeosin-stained sections, neuroendocrine differentiation of the PNE cells is readily demonstrated in sections immunostained for chromogranin (Fig. 6), synaptophysin (Fig. 7), and/or CD56. Histochemical and immunohistochemical stains such as Grimelius and nonspecific neuron enolase (NSE) are no longer used. Hyperplastic PNE cells spread into the peribronchiolar tissues (Fig. 8) and the surrounding lung parenchyma and form carcinoid tumorlets (Fig. 9) that exhibit a characteristic nesting pattern, infiltrative edges, and desmoplastic stromal reaction (Fig. 10).
Obliterative bronchiolitis (Fig. 11), originally reported as a characteristic histopathologic finding of DIPNECH by Aguayo et al.,7 has been reported in only 24% of subsequent DIPNECH cases.22 As cases of DIPNECH with carcinoid tumorlets often show peribronchiolar fibrosis, deeper cuts may be necessary to identify obliterative bronchiolitis, a pathologic finding that can be focal, patchy, and difficult to find.36 The WHO book and other publications illustrate typical cases of DIPNECH showing prominent number of the PNE cells within and/or adjacent to bronchiolar epithelium (Fig. 12), but they do not provide specific criteria regarding the minimum number of the PNE cells and/or tumorlets necessary to establish the histopathologic diagnosis of this unusual syndrome.17,23 In addition, although several reports in the literature emphasize the importance of obliterative bronchiolitis as a significant clinical problem, it is not entirely clear whether a diagnosis of DIPNECH can be established in the absence of this finding.6,24,33,36–39 In our experience, lung biopsies or lobectomy specimens with multiple carcinoid tumorlets and a single or multiple carcinoid tumors often show bronchioles with a variable number of the PNE cells that are more prominent than seen in normal specimens (Fig. 13), but they are not as obviously hyperplastic as those illustrated in books and review publications. We suspect that the lack of specific criteria by which to define PNE cell hyperplasia and DIPNECH has contributed to the likely underdiagnosis of the syndrome postulated by Davis and others.23,39 Indeed, Miller and Muller38 reported PNE cell hyperplasia in 76% of 25 consecutive patients undergoing lung resection for carcinoid tumors.
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Fig. 3 – (A–D) In imaging studies, the DIPNECH patients often show a lung mass associated with multiple smaller pulmonary nodules. Interstitial fibrosis, mosaic attenuation, and other non-neoplastic findings can also be present. Fig. 3A shows, using the lung window setting of a chest computerized tomogram (CT), a lung mass (arrow), and smaller pulmonary nodules (arrowheads). (B) Additional multiple small pulmonary nodules. (C) Multiple small pulmonary nodules that are more clearly visible with the use of pulmonary window setting. (D) Multiple pulmonary nodules and interstitial fibrosis in lower lung zones. We have recently proposed the use of at least 5 PNE cells in a minimum of 3 separate bronchioles associated with 3 or more carcinoid tumorlets as the minimal criteria for a histologic diagnosis of DIPNECH in lung specimens from adult patients.27 In our experience with 30 DIPNECH cases, these features were associated with a significant increase in the incidence of carcinoid tumors, supporting a possible preneoplastic potential. However, the study evaluated only consecutive cases diagnosed with PNE cell hyperplasia in our hospital rather than a large group of consecutive lung specimens resected for various reasons. To our knowledge, studies utilizing immunostains for neuroendocrine markers to report the incidence of PNE cells in a large series of consecutive lung
Fig. 4 – Pulmonary neuroendocrine cells are difficult to identify on hematoxylin and eosin sections. They have basal round (arrow), oval, or spindle nuclei and clear or eosinophilic cytoplasm (Hematoxylin and Eosin, 400 ).
resection specimens and to determine the frequency of normal PNE cells and PNE cell hyperplasia in normal lung and in various pathologic conditions are not available, other than in studies of individuals living at high altitudes. Typical carcinoid tumors are present in 53% of DIPNECH patients at diagnosis. Atypical carcinoid tumors are considerably less frequent having been described in less than 3% of patients.10,22,23 Interestingly, DIPNECH is not associated with an increased incidence of small cell carcinoma of the lung. In all, 3 of our consecutive 70 patients with lung biopsies or resection specimens showing PNE cell hyperplasia and/or 2 or
Fig. 5 – Pulmonary neuroendocrine cell hyperplasia is manifested by the intramucosal proliferation of cells with similar cytologic features to those shown in Fig. 4. The cells do not infiltrate through the epithelial basement membrane. The arrows highlight the absence of stromal invasion (Hematoxylin and Eosin, 100 ).
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Fig. 6 – Pulmonary neuroendocrine cell hyperplasia: The neuroendocrine cells show chromogranin immunoreactivity (PAP, 40 ).
Fig. 9 – Carcinoid tumorlets measuring up to 5 mm in diameter are usually peribronchiolar and are composed of irregular solid nests of neuroendocrine cells admixed with a fibrotic stroma (Hematoxylin and Eosin, 40 ).
Fig. 7 – Pulmonary neuroendocrine cell hyperplasia: the neuroendocrine cells show synaptophysin immunoreactivity that is usually considerably stronger than immunoreactivity for chromogranin (PAP, 40 ).
Fig. 10 – Trichrome stain showing fibrotic stroma in a carcinoid tumorlet (Masson's trichrome stain, 40 ).
Fig. 8 – Hyperplastic pulmonary neuroendocrine cells grow through the basement membrane (arrow) forming carcinoid tumorlets (Hematoxylin and Eosin, 100 ). more carcinoid tumorlets without PNE cell hyperplasia had an associated large cell neuroendocrine carcinoma, but none of the patients diagnosed with DIPNECH using the criteria listed above did, underscoring the concept that DIPNECH does not increase the risk for development of a high-grade neuroendocrine carcinoma.22,27 Adenocarcinomas and other nonsmall-cell carcinomas of the lung have been described in
Fig. 11 – Obliterative bronchiolitis was described as a characteristic finding of DIPNECH in the initial report by Aguayo et al. However, it is seen in only approximately 20%30% of cases. The photomicrograph shows a bronchiole (adjacent to arrows) with lumen completed, obliterated by fibrous tissue. The adjacent arteriole is normal (Masson's trichrome stain, 40 ). association with DIPNECH, but the incidence of this syndrome is so rare in patients who have these carcinomas with frequent neoplasms that the association is probably coincidental.22
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classified into 3 clinico-pathologic groups: patients who present with a lung mass and upon histopathologic examination show the unexpected finding of DIPNECH, patients who present with multiple pulmonary nodules that can simulate metastatic disease, and patients who present with progressive respiratory problems secondary to obliterative bronchiolitis, bronchiectasis, and cystic and/or interstitial lung disease.22,27
Treatment
Fig. 12 – Pulmonary neuroendocrine cell hyperplasia can be readily identified when bronchioles have a large number of neuroendocrine cells forming aggregates that spread along the bronchiolar epithelium (PAP, chromogranin, 40 ).
Clinico-pathologic classification of DIPNECH patients Davies et al.23 proposed that DIPNECH patients could be classified into 2 clinical groups: those who present with lung neoplasms such as carcinoid tumor, carcinoma, or others and those who present with symptoms secondary to obstructive airway disease. In our view, DIPNECH patients can be best
Patients with DIPNECH and a carcinoid tumor are treated with surgical resection and can be treated with octreotide/somatostatin analogs (SSA) or other medications.22 Only one of the 3 DIPNECH patients, who was treated with long-acting release (LAR) octreotide reported improvement in carcinoid syndrometype symptoms (diarrhea and flushing). A total of 16 of the 17 patients in the literature, who were treated with somatostatin analogs received LAR octreotide and 1 received lanreotide; of these, 7 of them reported subjective improvement in respiratory symptoms.14,25 Other medications that have been used to treat DIPNECH include long- and short-acting beta agonists and inhaled corticosteroids without unequivocal clinical benefits.22
Prognosis Most DIPNECH patients remain stable over many years while about 30% experience clinical and/or radiographic deterioration. Progression of obstructive pulmonary disease resulting from obliterative bronchiolitis and/or other fibrotic lung changes is the most common cause of deterioration in pulmonary function. Death has been attributed to a pulmonary cause in only 5 DIPNECH patients. Of these, some were probably related to other causes such as post-lung-transplant complications rather than directly to DIPNECH.7,14,22
Is DIPNECH a preneoplastic condition?
Fig. 13 – It is more difficult to assess whether pulmonary neuroendocrine cells are hyperplastic in bronchioles showing several scattered neuroendocrine cells. We proposed a minimum of 5 pulmonary neuroendocrine cells in 3 separate bronchioles to define hyperplasia in lung specimens with suspected DIPNECH (PAP, chromogranin, 40 ).
The literature generally refers to DIPNECH as a preneoplastic condition, while the WHO uses the less specific term “preinvasive” condition. The concept that DIPNECH is preneoplastic is based on the reasonable assumption that the neuroendocrine tumors probably evolved through the sequence of intraepithelial PNE cell hyperplasia, followed by the development of peribronchiolar carcinoid tumorlets that exceed 5 mm in diameter over time and eventually become carcinoid tumors. Nevertheless, the classification of a syndrome as preneoplastic or pre-invasive has important clinical implications. It not only raises questions as to whether the patient should be told that she/he has an increased risk of developing a neuroendocrine neoplasm in the future, but also creates dilemmas as to whether particular frequencies of surveillance, medications, or other treatments should be recommended in an effort to prevent or delay development of a neoplasm. To our knowledge, there is very limited data to support the assumption for patient care purposes that DIPNECH is a preneoplastic or pre-invasive condition, as only 1 patient has been diagnosed with a carcinoid tumor and no
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patients have developed a high-grade neuroendocrine carcinoma after an initial diagnosis of DIPNECH.10,22
r e f e r e n c e s
1. Feyrter F. Uber Diffuse Endokrine Epitheliale Organe. 1938. 2. Modlin IM, Bodei L, Kidd M. A historical appreciation of bronchopulmonary neuroendocrine neoplasia: resolution of a carcinoid conundrum. Thorac Surg Clin. 2014;24:235–255. 3. Froelich F. Die helle Zelle der Bronchialschleimhaut und ihre Beziehungen zum Problem der Chemoreceptoren. Franz Z Pathol. 1949;60:517–559. 4. Cutz E, Yeger H, Pan J. Pulmonary neuroendocrine cell system in pediatric lung disease—recent advances. Pediatr Dev Pathol. 2007;10(6):419–435. 5. Dvorackova J, Macak J, Buzrla P. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: case report and review of literature. Cesk Patol. 2013;49:99–102. 6. Adams H, Brack T, Kestenholz P, Vogt P, Steinert HC, Russi EW. Diffuse idiopathic neuroendocrine cell hyperplasia causing severe airway obstruction in a patient with a carcinoid tumor. Respiration. 2006;73:690–693. 7. Aguayo SM, Miller YE, Waldron JA Jr, et al. Brief report: idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells and airways disease. N Engl J Med. 1992;327:1285–1288. 8. Al-Ayoubi AM, Ralston JS, Richardson SR, Denlinger CE. Diffuse pulmonary neuroendocrine cell hyperplasia involving the chest wall. Ann Thorac Surg. 2014;97:333–335. 9. Armas OA, White DA, Erlandson RA, Rosai J. Diffuse idiopathic pulmonary neuroendocrine cell proliferation presenting as interstitial lung disease. Am J Surg Pathol. 1995;19:963–970. 10. Aubry MC, Thomas CF Jr, Jett JR, Swensen SJ, Myers JL. Significance of multiple carcinoid tumors and tumorlets in surgical lung specimens: analysis of 28 patients. Chest. 2007;131:1635–1643. 11. Benson RE, Rosado-de-Christenson ML, Martinez-Jimenez S, Kunin JR, Pettavel PP. Spectrum of pulmonary neuroendocrine proliferations and neoplasms. Radiographics. 2013;33:1631–1649. 12. Cameron CM, Roberts F, Connell J, Sproule MW. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: an unusual cause of cyclical ectopic adrenocorticotrophic syndrome. Br J Radiol. 2011;84:e14–e17. 13. Carmichael MG, Zacher LL. The demonstration of pulmonary neuroendocrine cell hyperplasia with tumorlets in a patient with chronic cough and a history of multiple medical problems. Mil Med. 2005;170:439–441. 14. Carr LL, Chung JH, Duarte Achcar R, et al. The clinical course of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Chest. 2015;147:415–422. 15. Cohen AJ, King TE Jr, Gilman LB, Magill-Solc C, Miller YE. High expression of neutral endopeptidase in idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells. Am J Respir Crit Care Med. 1998;158:1593–1599. 16. Coletta EN, Voss LR, Lima MS, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia accompanied by airflow obstruction. J Bras Pneumol. 2009;35:489–494. 17. Travis WD. WHO. Lyon: IARC Press; 2015;2015. 18. Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG. WHO Classification of Tumors of the Lung, Pleura, Thymus, and Heart. Geneva, Switzerland: IARC Press; 2015;2015. 19. Felton WL 2nd, Liebow AA, Lindskog GE. Peripheral and multiple bronchial adenomas. Cancer. 1953;6:555–567. 20. Miller MA, Mark GJ, Kanarek D. Multiple peripheral pulmonary carcinoids and tumorlets of carcinoid type, with restrictive and obstructive lung disease. Am J Med. 1978;65: 373–378.
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21. Gould VE, Linnoila RI, Memoli VA, Warren WH. Neuroendocrine cells and neuroendocrine neoplasms of the lung. Pathol Annu. 1983;18(Pt 1):287–330. 22. Wirstchafter E, Walts A, Marchevsky A. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia of the lung (DIPNECH): current best evidence. Lung. 2012;118(3):612–619. 23. Davies SJ, Gosney JR, Hansell DM, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: an underrecognised spectrum of disease. Thorax. 2007;62:248–252. 24. Falkenstern-Ge RF, Kimmich M, Friedel G, Tannapfel A, Neumann V, Kohlhaeufl M. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: 7-year follow-up of a rare clinicopathologic syndrome. J Cancer Res Clin Oncol. 2011;137:1495–1498. 25. Gorshtein A, Gross DJ, Barak D, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia and the associated lung neuroendocrine tumors: clinical experience with a rare entity. Cancer. 2012;118:612–619. 26. Gosney JR, Williams IJ, Dodson AR, Foster CS. Morphology and antigen expression profile of pulmonary neuroendocrine cells in reactive proliferations and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). Histopathology. 2011;59:751–762. 27. Marchevsky AM, Wirtschafter E, Walts AE. The spectrum of changes in adults with multifocal pulmonary neuroendocrine proliferations: what is the minimum set of pathologic criteria to diagnose DIPNECH? Hum Pathol. 2015;46:176–181. 28. Mireskandari M, Abdirad A, Zhang Q, Dietel M, Petersen I. Association of small foci of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) with adenocarcinoma of the lung. Pathol Res Pract. 2013;209:578–584. 29. Nassar AA, Jaroszewski DE, Helmers RA, Colby TV, Patel BM, Mookadam F. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: a systematic overview. Am J Respir Crit Care Med. 2011;184:8–16. 30. Oba H, Nishida K, Takeuchi S, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia with a central and peripheral carcinoid and multiple tumorlets: a case report emphasizing the role of neuropeptide hormones and human gonadotropin-alpha. Endocr Pathol. 2013;24:220–228. 31. Patel C, Tirukonda P, Bishop R, Mulatero C, Scarsbrook A. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) masquerading as metastatic carcinoma with multiple pulmonary deposits. Clin Imaging. 2012;36:833–836. 32. Warth A, Herpel E, Schmahl A, Storz K, Schnabel PA. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) in association with an adenocarcinoma: a case report. J Med Case Rep. 2008;2:21. 33. Fessler MB, Cool CD, Miller YE, Schwarz MI, Brown KK. Idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells in a patient with acromegaly. Respirology. 2004;9:274–277. 34. Gosney JR. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia as a precursor to pulmonary neuroendocrine tumors. Chest. 2004;125:108S. 35. Walker CM, Vummidi D, Benditt JO, Godwin JD, Pipavath S. What is DIPNECH? Clin Imaging. 2012;36:647–649. 36. Fuehrer NE, Marchevsky AM, Jagirdar J. Presence of c-KITpositive mast cells in obliterative bronchiolitis from diverse causes. Arch Pathol Lab Med. 2009;133:1420–1425. 37. Ge Y, Eltorky MA, Ernst RD, Castro CY. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Ann Diagn Pathol. 2007;11:122–126. 38. Miller RR, Muller NL. Neuroendocrine cell hyperplasia and obliterative bronchiolitis in patients with peripheral carcinoid tumors. Am J Surg Pathol. 1995;19:653–658. 39. Rizvi SM, Goodwill J, Lim E, et al. The frequency of neuroendocrine cell hyperplasia in patients with pulmonary neuroendocrine tumours and non-neuroendocrine cell carcinomas. Histopathology. 2009;55:332–337.
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32 (2015) 438–444
Available online at www.sciencedirect.com
www.elsevier.com/locate/semdp
Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) Alberto M. Marchevsky, MDn, Ann E. Walts, MD Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California
article info
abstract
Keywords:
Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a pre-invasive
Idiopathic
generalized proliferation of pulmonary neuroendocrine (PNE) cells, which has been
Neuroendocrine cell hyperplasia
described in combination with carcinoid tumorlets, obliterative bronchiolitis, and other
Lung
fibrotic lung changes. Since its first recognition as a distinct syndrome in 1992, variable
DIPNECH
clinico-pathologic features have been used to diagnose DIPNECH in small case series and case reports. We recently proposed the use of the following criteria for the pathologic diagnosis of the syndrome on lung resection specimens: the presence of multifocal neuroendocrine cell hyperplasia, as defined by the presence of 5 or more PNE cells in at least 3 separate small airways combined with 3 or more carcinoid tumorlets. At diagnosis, 53% of DIPNECH patients present with a synchronous carcinoid tumor and 24% have obliterative bronchiolitis. To our knowledge, only 1 patient has been diagnosed with a carcinoid tumor subsequent to a DIPNECH diagnosis and the syndrome is not associated with an increased incidence of high-grade neuroendocrine neoplasms. Patients have usually a stable disease and only 26% experience clinical and/or radiographic deterioration. There is no evidence that treatment with octreotide or other medications improves the prognosis of DIPNECH patients. & 2015 Elsevier Inc. All rights reserved.
Pulmonary neuroendocrine (PNE) cells were first identified in the intestine and lung by Feyrter1,2 in 1938. They occur in the small airways as individual cells (Fig. 1A) or in aggregates known as neuroendocrine bodies first described by Froelich3 in 1949 (Fig. 1B). The PNE cells have paracrine functions that play an important role in lung development.4,5 While frequent in the airways of fetal and neonatal lung, the PNE cells decrease in density with age and are found only focally in lung specimens from adult patients. The PNE cells can undergo hyperplasia as a result of hypoxia in individuals living at high altitude and in patients with chronic, fibrotic lung diseases such as bronchiectasis and interstitial fibrosis.4,6–16 They can also become hyperplastic in children, as described in this volume in the article by Cutz et al.4 The PNE n
cells are thought to be the cells of origin of low-grade and intermediate-grade malignancy pulmonary tumors that are currently classified as typical and atypical carcinoid tumors, respectively, and the precursors of smaller (r5 mm in diameter) lesions designated as carcinoid tumorlets.17 The diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare disorder currently classified by the World Health Organization (WHO) Classification of Tumors of the Lung, Pleura, Thymus, and Heart as a preinvasive lesion.18 It is defined by the WHO as “a generalized proliferation of pulmonary neuroendocrine cells (PNEs) that may be confined to the mucosa of airways (with or without luminal protrusion), may invade locally to form tumourlets, or may develop into carcinoid tumours.”
Correspondence to: 8700 Beverly Blvd Room 8709, West Hollywood, CA 90048-1804. E-mail address: [email protected] (A.M. Marchevsky).
http://dx.doi.org/10.1053/j.semdp.2015.08.002 0740-2570/& 2015 Elsevier Inc. All rights reserved.
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Fig. 1 – (A and B) Pulmonary neuroendocrine cells are infrequent in the small airways of adults and occur as individual cells (A) or in aggregates associated with small nerves (B). The pulmonary neuroendocrine cells are shown with immunostain for synaptophysin [peroxidase–antiperoxidase (PAP), 100 and 200 ]. Aguayo et al.7 are given credit for the first description of DIPNECH with their 1992's report of 6 patients with idiopathic diffuse hyperplasia of the PNE cells and airway disease characterized by the presence of peribronchiolar fibrosis obliterating the small airways. Of 6 of their patients, 2 were treated with chemotherapy for a brief period of time without progression to a metastatic neoplasm and 3 others, each with multiple carcinoid tumors or tumorlets, were not treated with chemotherapy. Aguayo et al.7 proposed that the condition is idiopathic and that the obliterative bronchiolitis is secondary to neuropeptides secreted by the neuroendocrine (NE) cells. There are several previous reports of PNE cell hyperplasia associated with lung neoplasms.2 Felton et al.19 reported a patient with peripheral and multiple bronchial adenomas in 1953. In 1978, Miller et al.20 reported the presence of multiple peripheral pulmonary carcinoids and tumorlets of carcinoid type in a 53-year-old woman with an 8-year history of pulmonary nodules. The patient also had obstructive airways disease attributed to extensive bronchiolar involvement. Gould et al.21 described a spectrum of neuroendocrine cell changes ranging from hyperplasia to dysplasia and neoplasms and suggested progression of the neoplasms from non-neoplastic PNE cells. Our recent systematic review of the English literature found only 199 patients with clinico-pathologic features consistent with DIPNECH, reported in individual case reports or small case series of up to 30 patients each.22 Davies et al.23 suggested that DIPNECH may not be such a rare condition and that some cases are probably unrecognized.
Demographic information Patients with DIPNECH range from 36 to 84 years of age, with a median age of 66 years old.8,12,22–32 In total, 93% of the patients are women.22
Clinical findings The majority (83%) of patients with DIPNECH are smokers. Approximately 20% are asymptomatic at presentation, while
66% present with cough and 48% present with dyspnea; hemoptysis or wheezing is less frequent.6,9,10 Fessler et al.33 described a DIPNECH patient who developed acromegaly secondary to overproduction of growth hormone. Cameron et al.12 described an unusual patient with DIPNECH and cyclical ectopic adrenocorticotrophic syndrome. Pulmonary function tests in DIPNECH patients can show restrictive, obstructive, or mixed restrictive/obstructive changes.22 Although the presence of obliterative bronchiolitis has been described as characteristic of DIPNECH by Aguayo and in several subsequent reports, only about 30% of patients with published pulmonary function test data have shown obstructive changes. For example, obstructive defect with an FEV1 of 42% predicted was observed in only 31% of our DIPNECH patients.22 The majority of DIPNECH patients are not clinically diagnosed as DIPNECH prior to lung biopsies or resections. For example, none of our 30 recently reported DIPNECH cases was diagnosed prior to pathologic examination.22 The majority of our patients who had undergone wedge resection or lobectomy for a carcinoid tumor (Fig. 2A and B) or another neoplasm and multiple tumorlets (Fig. 2C) were unexpectedly found during an evaluation of the carcinoid tumors and/or tumorlets, when immunohistochemical stains for chromogranin and synaptophysin demonstrated increased numbers of PNE cells in a variable number of bronchioles (Fig. 2D).
Imaging features Overall, 81% of DIPNECH patients present with multiple pulmonary nodules with or without an associated lung mass (Fig. 3A–C).6,11,14,29,34,35 The presence of multiple pulmonary nodules in a patient with a previous malignancy such as breast or prostatic cancer is of particular interest, as it can result in a misdiagnosis of metastatic disease if lung biopsies are not performed to confirm the diagnosis.31 In 30% of DIPNECH cases air trapping and mosaic attenuation are present in chest computerized tomograms (CT). Other findings such as interstitial fibrosis (Fig. 3D), adenopathy,
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Fig. 2 – (A–D) The majority of our DIPNECH patients had undergone resection of a carcinoid tumor and the presence of pulmonary neuroendocrine cell hyperplasia and multiple carcinoid tumorlets was an unexpected finding. (A) A carcinoid tumor after wedge resection. Reexamination of the gross specimen shows the presence of multiple small gray nodules (arrow) corresponding to carcinoid tumorlets. (B) The larger tumor is a typical carcinoid tumor composed of neuroendocrine cells with round to oval nuclei and “salt-and-pepper” chromatin pattern (Hematoxylin and Eosin, 200 ). (C) Multiple smaller carcinoid tumorlets (Hematoxylin and Eosin, 40 ). (D)Neuroendocrine cell hyperplasia in several bronchioles; the cells show synaptophysin immunoreactivity (PAP, 40 ). bronchiectasis, and cystic lung cases are each seen in less than 5% of patients.9,22
Pathology In most DIPNECH cases, a gross examination of lung tissue shows no pathology other than one or more carcinoid tumors (Fig. 1A). In some instances, the presence of multiple small gray nodules corresponding to carcinoid tumorlets can be seen (Fig. 1) and/or palpated. Microscopically, the PNE cells have round, oval, or spindle nuclei with salt-and-pepper chromatin and clear or eosinophilic cytoplasm (Fig. 4).17,27 PNE cell hyperplasia is manifested by the presence of intramucosal monolayers of cells or small cellular aggregates that elevate the respiratory epithelium of terminal bronchioles (Fig. 5). While it can be difficult to diagnose these cells as PNE cells on hematoxylin-andeosin-stained sections, neuroendocrine differentiation of the PNE cells is readily demonstrated in sections immunostained for chromogranin (Fig. 6), synaptophysin (Fig. 7), and/or CD56. Histochemical and immunohistochemical stains such as Grimelius and nonspecific neuron enolase (NSE) are no longer used. Hyperplastic PNE cells spread into the peribronchiolar tissues (Fig. 8) and the surrounding lung parenchyma and form carcinoid tumorlets (Fig. 9) that exhibit a characteristic nesting pattern, infiltrative edges, and desmoplastic stromal reaction (Fig. 10).
Obliterative bronchiolitis (Fig. 11), originally reported as a characteristic histopathologic finding of DIPNECH by Aguayo et al.,7 has been reported in only 24% of subsequent DIPNECH cases.22 As cases of DIPNECH with carcinoid tumorlets often show peribronchiolar fibrosis, deeper cuts may be necessary to identify obliterative bronchiolitis, a pathologic finding that can be focal, patchy, and difficult to find.36 The WHO book and other publications illustrate typical cases of DIPNECH showing prominent number of the PNE cells within and/or adjacent to bronchiolar epithelium (Fig. 12), but they do not provide specific criteria regarding the minimum number of the PNE cells and/or tumorlets necessary to establish the histopathologic diagnosis of this unusual syndrome.17,23 In addition, although several reports in the literature emphasize the importance of obliterative bronchiolitis as a significant clinical problem, it is not entirely clear whether a diagnosis of DIPNECH can be established in the absence of this finding.6,24,33,36–39 In our experience, lung biopsies or lobectomy specimens with multiple carcinoid tumorlets and a single or multiple carcinoid tumors often show bronchioles with a variable number of the PNE cells that are more prominent than seen in normal specimens (Fig. 13), but they are not as obviously hyperplastic as those illustrated in books and review publications. We suspect that the lack of specific criteria by which to define PNE cell hyperplasia and DIPNECH has contributed to the likely underdiagnosis of the syndrome postulated by Davis and others.23,39 Indeed, Miller and Muller38 reported PNE cell hyperplasia in 76% of 25 consecutive patients undergoing lung resection for carcinoid tumors.
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Fig. 3 – (A–D) In imaging studies, the DIPNECH patients often show a lung mass associated with multiple smaller pulmonary nodules. Interstitial fibrosis, mosaic attenuation, and other non-neoplastic findings can also be present. Fig. 3A shows, using the lung window setting of a chest computerized tomogram (CT), a lung mass (arrow), and smaller pulmonary nodules (arrowheads). (B) Additional multiple small pulmonary nodules. (C) Multiple small pulmonary nodules that are more clearly visible with the use of pulmonary window setting. (D) Multiple pulmonary nodules and interstitial fibrosis in lower lung zones. We have recently proposed the use of at least 5 PNE cells in a minimum of 3 separate bronchioles associated with 3 or more carcinoid tumorlets as the minimal criteria for a histologic diagnosis of DIPNECH in lung specimens from adult patients.27 In our experience with 30 DIPNECH cases, these features were associated with a significant increase in the incidence of carcinoid tumors, supporting a possible preneoplastic potential. However, the study evaluated only consecutive cases diagnosed with PNE cell hyperplasia in our hospital rather than a large group of consecutive lung specimens resected for various reasons. To our knowledge, studies utilizing immunostains for neuroendocrine markers to report the incidence of PNE cells in a large series of consecutive lung
Fig. 4 – Pulmonary neuroendocrine cells are difficult to identify on hematoxylin and eosin sections. They have basal round (arrow), oval, or spindle nuclei and clear or eosinophilic cytoplasm (Hematoxylin and Eosin, 400 ).
resection specimens and to determine the frequency of normal PNE cells and PNE cell hyperplasia in normal lung and in various pathologic conditions are not available, other than in studies of individuals living at high altitudes. Typical carcinoid tumors are present in 53% of DIPNECH patients at diagnosis. Atypical carcinoid tumors are considerably less frequent having been described in less than 3% of patients.10,22,23 Interestingly, DIPNECH is not associated with an increased incidence of small cell carcinoma of the lung. In all, 3 of our consecutive 70 patients with lung biopsies or resection specimens showing PNE cell hyperplasia and/or 2 or
Fig. 5 – Pulmonary neuroendocrine cell hyperplasia is manifested by the intramucosal proliferation of cells with similar cytologic features to those shown in Fig. 4. The cells do not infiltrate through the epithelial basement membrane. The arrows highlight the absence of stromal invasion (Hematoxylin and Eosin, 100 ).
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Fig. 6 – Pulmonary neuroendocrine cell hyperplasia: The neuroendocrine cells show chromogranin immunoreactivity (PAP, 40 ).
Fig. 9 – Carcinoid tumorlets measuring up to 5 mm in diameter are usually peribronchiolar and are composed of irregular solid nests of neuroendocrine cells admixed with a fibrotic stroma (Hematoxylin and Eosin, 40 ).
Fig. 7 – Pulmonary neuroendocrine cell hyperplasia: the neuroendocrine cells show synaptophysin immunoreactivity that is usually considerably stronger than immunoreactivity for chromogranin (PAP, 40 ).
Fig. 10 – Trichrome stain showing fibrotic stroma in a carcinoid tumorlet (Masson's trichrome stain, 40 ).
Fig. 8 – Hyperplastic pulmonary neuroendocrine cells grow through the basement membrane (arrow) forming carcinoid tumorlets (Hematoxylin and Eosin, 100 ). more carcinoid tumorlets without PNE cell hyperplasia had an associated large cell neuroendocrine carcinoma, but none of the patients diagnosed with DIPNECH using the criteria listed above did, underscoring the concept that DIPNECH does not increase the risk for development of a high-grade neuroendocrine carcinoma.22,27 Adenocarcinomas and other nonsmall-cell carcinomas of the lung have been described in
Fig. 11 – Obliterative bronchiolitis was described as a characteristic finding of DIPNECH in the initial report by Aguayo et al. However, it is seen in only approximately 20%30% of cases. The photomicrograph shows a bronchiole (adjacent to arrows) with lumen completed, obliterated by fibrous tissue. The adjacent arteriole is normal (Masson's trichrome stain, 40 ). association with DIPNECH, but the incidence of this syndrome is so rare in patients who have these carcinomas with frequent neoplasms that the association is probably coincidental.22
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classified into 3 clinico-pathologic groups: patients who present with a lung mass and upon histopathologic examination show the unexpected finding of DIPNECH, patients who present with multiple pulmonary nodules that can simulate metastatic disease, and patients who present with progressive respiratory problems secondary to obliterative bronchiolitis, bronchiectasis, and cystic and/or interstitial lung disease.22,27
Treatment
Fig. 12 – Pulmonary neuroendocrine cell hyperplasia can be readily identified when bronchioles have a large number of neuroendocrine cells forming aggregates that spread along the bronchiolar epithelium (PAP, chromogranin, 40 ).
Clinico-pathologic classification of DIPNECH patients Davies et al.23 proposed that DIPNECH patients could be classified into 2 clinical groups: those who present with lung neoplasms such as carcinoid tumor, carcinoma, or others and those who present with symptoms secondary to obstructive airway disease. In our view, DIPNECH patients can be best
Patients with DIPNECH and a carcinoid tumor are treated with surgical resection and can be treated with octreotide/somatostatin analogs (SSA) or other medications.22 Only one of the 3 DIPNECH patients, who was treated with long-acting release (LAR) octreotide reported improvement in carcinoid syndrometype symptoms (diarrhea and flushing). A total of 16 of the 17 patients in the literature, who were treated with somatostatin analogs received LAR octreotide and 1 received lanreotide; of these, 7 of them reported subjective improvement in respiratory symptoms.14,25 Other medications that have been used to treat DIPNECH include long- and short-acting beta agonists and inhaled corticosteroids without unequivocal clinical benefits.22
Prognosis Most DIPNECH patients remain stable over many years while about 30% experience clinical and/or radiographic deterioration. Progression of obstructive pulmonary disease resulting from obliterative bronchiolitis and/or other fibrotic lung changes is the most common cause of deterioration in pulmonary function. Death has been attributed to a pulmonary cause in only 5 DIPNECH patients. Of these, some were probably related to other causes such as post-lung-transplant complications rather than directly to DIPNECH.7,14,22
Is DIPNECH a preneoplastic condition?
Fig. 13 – It is more difficult to assess whether pulmonary neuroendocrine cells are hyperplastic in bronchioles showing several scattered neuroendocrine cells. We proposed a minimum of 5 pulmonary neuroendocrine cells in 3 separate bronchioles to define hyperplasia in lung specimens with suspected DIPNECH (PAP, chromogranin, 40 ).
The literature generally refers to DIPNECH as a preneoplastic condition, while the WHO uses the less specific term “preinvasive” condition. The concept that DIPNECH is preneoplastic is based on the reasonable assumption that the neuroendocrine tumors probably evolved through the sequence of intraepithelial PNE cell hyperplasia, followed by the development of peribronchiolar carcinoid tumorlets that exceed 5 mm in diameter over time and eventually become carcinoid tumors. Nevertheless, the classification of a syndrome as preneoplastic or pre-invasive has important clinical implications. It not only raises questions as to whether the patient should be told that she/he has an increased risk of developing a neuroendocrine neoplasm in the future, but also creates dilemmas as to whether particular frequencies of surveillance, medications, or other treatments should be recommended in an effort to prevent or delay development of a neoplasm. To our knowledge, there is very limited data to support the assumption for patient care purposes that DIPNECH is a preneoplastic or pre-invasive condition, as only 1 patient has been diagnosed with a carcinoid tumor and no
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patients have developed a high-grade neuroendocrine carcinoma after an initial diagnosis of DIPNECH.10,22
r e f e r e n c e s
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