Imaging appearances of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia

    Imaging Appearances of Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia Paul J. Foran, Sara A. Hayes, Donald J. Blair, Maureen F. Zakowski, Michelle S. Ginsberg PII: DOI: Reference:

S0899-7071(14)00266-6 doi: 10.1016/j.clinimag.2014.10.017 JCT 7713

To appear in:

Journal of Clinical Imaging

Received date: Revised date: Accepted date:

23 July 2014 5 October 2014 24 October 2014

Please cite this article as: Foran Paul J., Hayes Sara A., Blair Donald J., Zakowski Maureen F., Ginsberg Michelle S., Imaging Appearances of Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia, Journal of Clinical Imaging (2014), doi: 10.1016/j.clinimag.2014.10.017

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ACCEPTED MANUSCRIPT Title Page

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Title: Imaging Appearances of Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia.

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Authors and affiliations: Paul J. Foran a, Sara A. Hayes a, Donald J. Blair a, Maureen F.

Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, U.S.A.

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a.

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Zakowski a, Michelle S. Ginsberg a.

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E-mail addresses:

Paul J. Foran: [email protected]

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Sara A. Hayes: [email protected]

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Michelle S. Ginsberg: [email protected]

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Dr. Paul J. Foran

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Corresponding author details:

Postal address:

104 S 13th Street, Apt 1 Philadelphia PA 19107

E-mail: [email protected]

Phone: (917) 742-8410

ACCEPTED MANUSCRIPT Abstract Objectives: To describe the imaging appearances of Diffuse Idiopathic Pulmonary

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Neuroendocrine Cell Hyperplasia (DIPNECH) on CT.

Materials and Methods: Electronic medical records were searched for patients with pathology-

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proven DIPNECH who had a CT available for review. Eleven patients were included.

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Results: The most common finding on CT was small pulmonary nodules which were present in all patients and were multiple (≥5) in 7/11 patients. Other CT findings included mosaic pattern

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attenuation and bronchial wall thickening/ bronchiectasis.

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Conclusion: DIPNECH should be considered as a diagnostic possibility when multiple small

DIPNECH; pulmonary neuroendocrine cell hyperplasia.

1.

Introduction

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Keywords:

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pulmonary nodules are identified on CT, particularly if there is an associated carcinoid tumor.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare condition that forms part of the spectrum of pulmonary neuroendocrine proliferations which also includes reactive neuroendocrine hyperplasia and tumorlets [1]. DIPNECH was first recognized and named by Aguayo et al in 1992 who reported a series of six patients with idiopathic pulmonary neuroendocrine cell hyperplasia and symptomatic airflow obstruction due to bronchiolitis obliterans [2]. Approximately 100 cases have since been reported in the literature [2-13].

ACCEPTED MANUSCRIPT The histopathological appearance of DIPNECH is a widespread proliferation of pulmonary neuroendocrine cells which may comprise of scattered neuroendocrine cells, small nodules or a

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linear proliferation of pulmonary neuroendocrine cells [14]. Most patients are female, typically

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between their fifth to seventh decades, and usually present with insidious onset respiratory symptoms such as dyspnea or cough. Some patients are asymptomatic and are diagnosed

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incidentally during the work-up of other conditions, usually cancer [6].

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Reported findings on Computed Tomography (CT) in DIPNECH include pulmonary nodules, ground-glass opacities, mosaic pattern attenuation, air-trapping, bronchial wall thickening and

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bronchiectasis [3, 5, 15]. The purpose of this study was to describe the CT appearances of

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DIPNECH in a group of patients diagnosed in a tertiary cancer center.

Materials and Methods

2.1.

Patient selection and image analysis

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2.

Our institutional review board granted approval for this retrospective study and waived the requirement for informed consent from individual patients. All pathology reports at our institution between January 1, 2003 and September 5, 2013 were searched electronically for the term ‘DIPNECH’. The presence of DIPNECH was reported in the resection specimens of 24 patients. Preoperative CT scans of the chest performed within 60 days of the surgery/ intervention were available in 11 of these patients. All pathology material was reviewed by a

ACCEPTED MANUSCRIPT thoracic pathologist. The demographic and clinical information for each patient was obtained from the medical records. Patients’ age, gender, smoking history, symptoms and presence or

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history of malignancy were recorded. The preoperative CT scans of the 11 patients were

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reviewed independently by two radiologists and findings recorded. Any discrepancies were

Results

3.1

Demographic and clinical data

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3.

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resolved by a dedicated thoracic radiologist.

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The demographic, clinical, CT and pathologic findings of the 11 patients included in our study are described in Table 1. All patients were female with a mean age of 70 years, range 59-85

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years. One patient (9%) was a current smoker at the time of diagnosis: 7/11 (64%) of the patients

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had never smoked, 3/11 (27%) were ex-smokers. 5/11 (45%) of patients were asymptomatic. 6/11 (55%) reported symptoms including dyspnea, cough, wheezing, chest heaviness, postnasal

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drip & weight loss. The mean time interval between chest CT and surgery/intervention was 30 days (range 8-57 days). Of the pathologic specimens, all except one was from a lobectomy and/or wedge resection. One patient did not undergo surgery and was diagnosed based on a percutaneous lung core biopsy specimen.

3.2.

Concurrent pulmonary malignancy

Nine patients had one or more concurrent pulmonary malignancy: typical carcinoid (n=6), atypical carcinoid (n=1) or adenocarcinoma (n=5). This includes two patients with both typical

ACCEPTED MANUSCRIPT carcinoid and adenocarcinoma and one patient with both atypical carcinoid and adenocarcinoma. We had 1 case of DIPNECH in association with atypical carcinoid tumor; to our knowledge,

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only six such cases of DIPNECH have been reported previously [6, 7]. We identified 5 cases of

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pulmonary adenocarcinoma in association with DIPNECH; to our knowledge, only five such

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cases have been reported previously [8, 16].

CT findings

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The most common finding on CT was pulmonary nodules which were seen in all patients: 4/11 patients (36%) had > 10 nodules, 3/11 (27%) had 5-10 nodules, 4/11 (36%) had 1-4 nodules. All

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nodules measured ≤ 12 mm. Other CT findings included mosaic pattern attenuation 1/11 (9%)

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and bronchial wall thickening/ bronchiectasis1/11 (9%). Consolidation was identified in three patients: in one patient corresponding to a typical carcinoid that was subsequently resected; in

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one patient to mycobacterial infection; in one patient, the consolidation improved on subsequent

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CT and was considered most likely inflammatory.

4.

Discussion

4.1.

Pulmonary neuroendocrine cell hyperplasia

Pulmonary neuroendocrine cell hyperplasia (PNECH) forms part of the spectrum of pulmonary neuroendocrine cell proliferations and neoplasms which also includes tumorlets [1]. These entities arise from pulmonary neuroendocrine cells: specialized non-ciliated respiratory mucosal epithelial cells that are important in fetal lung development [17]. The normal adult lung contains

ACCEPTED MANUSCRIPT relatively few neuroendocrine cells [18]. PNECH is usually reactive, occurring as an adaptive response to hypoxia, and has been described in association with living at high altitude (19) and

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chronic airway inflammatory conditions such as chronic bronchitis [20], cystic fibrosis [21],

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diffuse panbronchiolitis [22] and eosinophilic granuloma [23]. Pulmonary neuroendocrine cell hyperplasia can occur without underlying lung disease and when diffuse is referred to as

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DIPNECH

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4.2.

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DIPNECH.

DIPNECH is defined by the World Health Organization as ‘a generalized proliferation of

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scattered single cells, small nodules or linear proliferations of pulmonary neuroendocrine cells that may be confined to the bronchial and bronchiolar epithelium, include local extraluminal

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proliferation in the form of tumorlets or extend to the development of carcinoid tumors’. Biopsy

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is required for diagnosis, as clinically and radiologically DIPNECH is indistinguishable from

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other diffuse lung diseases. Surgical biopsy is preferable to bronchoscopic biopsy or lavage due to the large tissue sample size required for identifying neuroendocrine hyperplasia [14].

4.3.

Clinical presentation of DIPNECH

DIPNECH occurs predominantly in females. The reason for this predilection for women is unknown. Most patients are between their fifth and eighth decade. There appears to be no association with smoking with only a small number of cases [6, 16, 24] described in current smokers, including one from our study. The clinical presentation of DIPNECH is typically that of insidious onset of respiratory symptoms such as dyspnea and cough [3]. The disease is

ACCEPTED MANUSCRIPT generally slowly progressive though some patients have progressed to respiratory failure and death due to DIPNECH [6, 24]. Patients generally have restrictive and/or obstructive deficits on

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pulmonary function testing. Many patients have been labelled with asthma for a number of years

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before the diagnosis is discovered [25, 26]. However, a number of cases have been described in asymptomatic patients in whom DIPNECH was discovered during the work up for other

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4.4.

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conditions, usually cancer [6, 27-29].

CT findings in DIPNECH

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In our study, the most common CT finding in patients with DIPNECH is small pulmonary nodules (Fig. 1). This correlates with findings elsewhere in the literature [6, 7]. Many of these

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nodules may represent tumorlets; benign pulmonary neuroendocrine cell proliferations

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measuring less than 5mm, which commonly occur as part of neuroendocrine hyperplasia. In a systematic review of DIPNECH in the literature, Nassar et al reported associated pulmonary

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tumorlets in 68% of cases of DIPNECH [3]. Tumorlets may be visualized as small pulmonary

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nodules on CT [30]. In patients with known malignancy, the presence of multiple tumorlets can present a diagnostic dilemma and may raise suspicion for metastatic disease [31]. This can necessitate biopsy to resolve the clinical uncertainty, as occurred with 2 of the patients in our study (Fig. 2).

Mosaic attenuation was seen in only one patient in our study (Fig. 3). Mosaic attenuation and air trapping in DIPNECH are thought to result from disturbed airflow caused by fibrous obliteration of the airways mediated by neuropeptides secreted by the neuroendocrine cells and/or intraluminal obstruction by neuroendocrine cell proliferation [2, 5]. In a systematic review of

ACCEPTED MANUSCRIPT cases of DIPNECH in the literature, Nassar et al reported mosaic attenuation in 17% of patients [3] though it appears to be more commonly detected when high resolution computed tomography

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(HRCT) is performed. Lee et al reported five cases of DIPNECH in whom HRCT was

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performed; mosaic attenuation was present in all five patients and air-trapping in all four patients

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in whom expiratory CT was performed [5].

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Bronchial wall thickening and bronchiectasis were seen in one of our patients. It likely represents

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DIPNECH and carcinoid tumor

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airway disease and mucosal thickening secondary to neuroendocrine cell hyperplasia.

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Typical carcinoid tumors are commonly seen in association with DIPNECH [3] and were

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identified in 6 patients (55%) in our study. Indeed, DIPNECH is thought to represent a preinvasive lung lesion for typical carcinoid [14]. Carcinoid tumors that develop from DIPNECH

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appear to behave similarly to those with corresponding tumors without DIPNECH [13]. Given

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the close association between DIPNECH and carcinoid tumor, any nodule ≥5mm in the setting of DIPNECH should raise suspicion for a typical carcinoid tumor.

4.6.

Limitations

Limitations of this study include small study size and selection bias inherent in referral patterns to a tertiary cancer center. In 82% of our patients there was a concomitant pulmonary malignancy, either carcinoid or adenocarcinoma, and the true incidence of DIPNECH-associated malignancy is likely lower than in this group of patients. Our cases were not performed with HRCT, which may account for the low incidence of mosaic attenuation detected. This suggests

ACCEPTED MANUSCRIPT that HRCT should be performed if DIPNECH is suggested. Air trapping was not evaluated in our

Conclusion

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patients as none of the patients had expiratory phase CT performed.

The most common CT finding in our group of patients was multiple pulmonary nodules. This

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correlates with findings from other studies in the literature. DIPNECH should be considered as a

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diagnostic possibility in patients with multiple pulmonary nodules, particularly if there is an

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associated carcinoid tumor.

ACCEPTED MANUSCRIPT References

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[1] Travis WD. Lung tumours with neuroendocrine differentiation. Eur J Radiol 2009;45:251-266.

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[2] Aguayo SM, Miller YE, Waldron JA, Bogin RM, Sunday ME, Staton GW, et al. Brief report: idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells and airways disease. New Engl J Med 1992;327(18):1285-1288.

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[3] 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(1):8-16.

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[5] Lee JS, Brown KK, Cool C, Lynch DA. Diffuse pulmonary neuroendocrine cell hyperplasia: radiologic and clinical features. J Comput Assist Tomogr 2002;26(2):180-184.

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[6] Davies SJ, Gosney JR, Hansell DM, Wells AU, du Bois RM, Burke MM, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: an under-recognised spectrum of disease. Thorax 2007;62(3):248-252.

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ACCEPTED MANUSCRIPT [12] 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.

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[13] Ruffini E, Bongiovanni M, Cavallo A, Filosso PL, Giobbe R, Mancuso M, et al. The significance of associated pre-invasive lesions in patients resected for primary lung neoplasms. Eur J Cardiothorac Surg 2004;26(1):165-172.

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[14] Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC. Pathology & Genetics: Tumours of the Lung, Pleura, Thymus, and Heart. Lyon: Iarc, 2004:69.

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[15] Koo CW, Baliff JP, Torigian DA, Litzky LA, Gefter WB, Akers SR. Spectrum of pulmonary neuroendocrine cell proliferation: diffuse idiopathic pulmonary neuroendocrine cell hyperplasia, tumorlet, and carcinoids. AJR 2010;195(3):661-668.

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[16] 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.

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[17] Van Lommel A. Pulmonary neuroendocrine cells (PNEC) and neuroepithelial bodies (NEB): chemoreceptors and regulators of lung development. Paediatr Respir Rev 2001;2(2):171-176.

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[18] Gosney JR, Sissons MC, Allibone RO. Neuroendocrine cell populations in normal human lungs: a quantitative study. Thorax 1988;43(11):878-882.

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[19] Witschi H. Responses of the lung to toxic injury. Environ Health Perspect 1990;85:5-13.

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[20] Gosney JR, Sissons MC, Allibone RO, Blakey AF. Pulmonary endocrine cells in chronic bronchitis and emphysema. J Pathol 1989;157(2):127-133. [21] Johnson DE, Wobken JD, Landrum BG. Changes in bombesin, calcitonin, and serotonin immunoreactive pulmonary neuroendocrine cells in cystic fibrosis and after prolonged mechanical ventilation. Am Rev Respir Dis 1988;137(1):123-131. [22] Watanabe H, Kobayashi H, Honma K, Ohnishi Y, Iwafuchi M. Diffuse panbronchiolitis with multiple tumorlets. A quantitative study of the Kultschitzky cells and the clusters. Acta Pathol Jpn 1985;35(5):1221-1231. [23] Aguayo SM, King TE, Jr., Waldron JA, Jr., Sherritt KM, Kane MA, Miller YE. Increased pulmonary neuroendocrine cells with bombesin-like immunoreactivity in adult patients with eosinophilic granuloma. J Clin Invest 1990;86(3):838-844. [24] Brown MJ, English J, Muller NL. Bronchiolitis obliterans due to neuroendocrine hyperplasia: high-resolution CT--pathologic correlation. AJR 1997;168(6):1561-1562.

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[25] Ge Y, Eltorky MA, Ernst RD, Castro CY. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Ann Diagn Pathol 2007;11(2):122-126.

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[26] Stenzinger A, Weichert W, Hensel M, Bruns H, Dietel M, Erbersdobler A. Incidental postmortem diagnosis of DIPNECH in a patient with previously unexplained 'asthma bronchiale'. Pathol Res Pract 2010;206(11):785-787.

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[27] 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(6):833-836.

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[28] Zulueta M, Javier F. Hiperplasia difusa idiopática de células neuroendocrinas pulmonares con tumores carcinoides múltiples sincrónicos. Arch Bronconeumol 2012;48(12):472.

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[29] 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(4):220-228.

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[30] Ginsberg MS, Akin O, Berger DM, Zakowski MF, Panicek DM. Pulmonary tumorlets: CT findings. AJR 2004;183(2):293-286.

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[31] Darvishian F, Ginsberg MS, Klimstra DS, Brogi E. Carcinoid tumorlets simulate pulmonary metastases in women with breast cancer. Hum Pathol 2006;37(7):839-844.

ACCEPTED MANUSCRIPT Figure Captions Fig. 1- 66 year old female with DIPNECH and typical carcinoid tumor. Chest CT (A)

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demonstrated a 1.2 cm right upper lobe nodule (black arrow) and multiple subcentimeter nodules bilaterally (white arrows). Right upper lobectomy was performed. Pathology (B) revealed

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clusters of neuroendocrine cells in close proximity to respiratory epithelium consistent with

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DIPNECH. The 1.2 cm nodule represented a typical carcinoid tumor.

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Fig. 2- 63 year old female with DIPNECH. She presented with a left breast mass, proven to be invasive ductal carcinoma. Further workup included a chest CT which revealed multiple bilateral

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pulmonary nodules (white arrows) suspicious for metastases. Percutaneous biopsy specimen

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obtained from a right middle lobe nodule was consistent with tumorlet and DIPNECH.

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Fig. 3- 79 year old female with DIPNECH, pulmonary adenocarcinoma and typical carcinoid tumor. Chest CT performed for workup of a cough demonstrated a mass in the superior segment of the right lower lobe (black arrow in A), multiple smaller pulmonary nodules including a right lower lobe nodule (white arrows A & B), and mosaic pattern attenuation throughout the lungs (A & B). Right lower lobectomy was performed. Pathology revealed an adenocarcinoma corresponding to the superior segment mass, clusters of neuroendocrine cells in the airways (C) consistent with DIPNECH, as well as a 6 mm typical carcinoid tumor (D) corresponding to the right lower lobe nodule.

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(B)

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(A)

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Figure 1

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Figure 2

ACCEPTED MANUSCRIPT Figure 3 (B)

(C)

(D)

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(A)

ACCEPTED MANUSCRIPT Age

Smoking

Symptoms

History

CT Findings # Nodules

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BWT/ BRC

CON

F

66

Past

None

>10

No

No

No

2

F

63

Never

None

>10

No

No

No

3

F

70

Past

Cough

3

No

Yes

Yes

4

F

85

Never

Postnasal drip

>10

No

No

No

5

F

73

Past

None

5-10

No

No

6

F

67

Never

None

2

No

7

F

59

Never

3

No

8

F

79

Current

Dyspnea, cough, chest heaviness Dyspnea

9

F

76

Never

Dyspnea, cough, wheezing

10

F

65

Never

None

11

F

72

Never

Weight loss

Type

Tumor

Extrapulmonary Malignancy

Lobectomy

TC

None

None

Breast IDC

Lobectomy, WR

ADC

None

WR

None

None

WR

TC

Breast IDC

Biopsy

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hilar LA

No

Lobectomy

ADC

Bladder ADC

No

No

WR

TC

None

No

No

WR

ADC, TC

None

MA

No

No

No

Yes

Lobectomy, WR

ADC, TC

None

5-10

No

No

No

Lobectomy

ADC, AC

Breast IDC

5-10

No

No

No

WR

TC

None

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1

bl effusions

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Yes

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>10

No

Pulmonary

Other

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1

Resection

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Sex

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Patient

Table1: Demographic, clinical, CT and pathologic findings of 11 patients with DIPNECH. Abbreviations: AC: atypical carcinoid, ADC: adenocarcinoma, bl: bilateral, BRC: bronchiectasis, BWT: bronchial wall thickening, CON: consolidation, IDC: invasive ductal carcinoma, LA: lymphadenopathy, MA: mosaic attenuation, TC: typical carcinoid, WR: wedge resection.