DIPNECH: when to suggest this diagnosis on CT

doi:10.1016/j.crad.2014.10.012

Clinical Radiology

Volume 70, Issue 3, March 2015, Pages 317-325

https://doi.org/10.1016/j.crad.2014.10.012 Get rights and content

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is an under-recognized disease characterized by proliferation of neuroendocrine cells in the bronchial wall. It is considered a pre-invasive lesion for lung carcinoid tumours and is found in 5.4% of patients undergoing surgical resection for lung carcinoid tumours. Other manifestations of DIPNECH include bronchial obstruction and formation of tumorlets. DIPNECH preferentially affects middle-aged women. Patients are either asymptomatic or present with long-standing dyspnoea due to obstructive syndrome that can be mistaken for asthma. At CT, mosaic attenuation with multiple small nodules is very suggestive of DIPNECH. The aim of this review is to describe DIPNECH-related CT features and correlate them with histology, in order to help radiologists suggest this diagnosis and distinguish DIPNECH from other causes of mosaic perfusion.

Introduction

Pulmonary neuroendocrine cells (PNECs), also known as Kulchitsky-type cells, are epithelial cells of the pulmonary bronchial wall, found from the trachea to the terminal bronchioles. They play a role in lung development during foetal life and act as chemoreceptors to hypoxaemia in adulthood.¹ It has been known for decades that lung carcinoid tumours originate from PNEC and that PNEC can show reactive hyperplasia to chronic lung diseases.² However, it was only in 1992 that diffuse idiopathic PNECs proliferation (DIPNECH) was reported as a separate entity by Aguayo et al.² Seven years later, this new condition has been recognized by the 1999 World Health Organization International Histological Classification of Tumours as the only pre-invasive lesion for lung carcinoid tumours.³

Although DIPNECH reported prevalence among patients with resected lung carcinoid tumours reaches 5.4%⁴ it remains an under-recognized disease and symptomatic patients often have a long history of respiratory symptoms before diagnosis. In those patients, several CT airway abnormalities can lead to the right diagnosis. DIPNECH diagnosis is more difficult in asymptomatic patients, especially those undergoing CT for cancer follow-up, in which nodules must not be mistaken for diffuse lung metastases. An awareness of DIPNECH imaging features can help diagnosis and distinction from other airways diseases.

The aim of this review is to describe DIPNECH-related CT features, and correlate them with histology, in order to help radiologists diagnose this under-recognized condition and distinguish it from other causes of mosaic perfusion due to blood flow redistribution observed in other airway diseases or of thromboembolic origin.

Section snippets

Pathophysiology

During foetal life, PNECs are the first cells to form and differentiate in the lung epithelium.¹ They play a part in paracrine regulation of lung development.² They are specialized epithelial cells, located throughout the entire respiratory tract, and usually exist as solitary cells, but sometimes aggregate to form small nodules termed neuro-epithelial bodies.¹ During foetal life, PNECs release various amine and peptides, including serotonin, calcitonin, neuron-specific enolase, chromogramin A,

Clinical presentation

Demographic characteristics of DIPNECH are different from those of reactive PNECs proliferation and of carcinoid tumours unrelated to DIPNECH. DIPNECH preferentially affects women (89%) with a mean age of 58 years.¹⁰ In contrast, carcinoid tumours preferentially occur in younger patients (average age of 46 years) without marked sex predilection.¹¹ There is no evidence of female predominance in reactive proliferation of PNECs.⁹ By definition, patients with DIPNECH are free of diseases that might

Pathology

DIPNECH is defined as a proliferation of pulmonary neuroendocrine cells that do not cross the basement membrane.⁷ The histological appearance may comprise a generalized proliferation of scattered PNECs, small nodules (neuroendocrine bodies), or a linear proliferation of pulmonary endocrine cells (Fig 1). Although it is diffuse, DIPNECH shows spatial heterogeneity; more severe involvement of lung bases has been reported in a few cases.¹⁵

Secretion of peptides by hyperplasic PNECs can lead to

CT findings

Because DIPNECH is characterized by cell proliferation in the bronchial wall, CT signs are those of airway-related diseases, and include bronchial wall thickening, mild bronchiectasis, mucoid impactions, with mosaic perfusion being the most important and suggestive feature. Lesions are almost always bilateral—only one case of unilateral involvement has been reported to date.²⁴ A case of normal CT in a patient with histologically proven DIPNECH has also been reported but expiratory CT was not

Differential diagnosis

Clinically, patients are often misdiagnosed with asthma.12, 13, 16, 18, 19 Histologically, PNEC hyperplasia, tumorlets, and carcinoid tumours can be seen as distinct entities and are not necessarily associated with DIPNECH. Unique or multiple DIPNECH-unrelated tumorlets are incidental findings of no clinical significance that can be encountered in the same conditions as reactive PNEC hyperplasia. Similarly, the vast majority of carcinoid tumours are not associated with DIPNECH, which are

Positive diagnosis

CT is insufficient to establish a definite diagnosis, as radiological signs are non-specific and inconstant. However, the association of mosaic perfusion with multiple lung nodules in a middle-aged woman referred for chronic cough and wheezing should point first towards the diagnosis of DIPNECH³⁶ (Figure 9, Figure 10).

A positive diagnosis always requires histopathological confirmation of diffuse PNEC proliferation.¹⁷ Due to spatial heterogeneity of PNEC hyperplasia, biopsy specimens should be

Management and prognosis

To date, there are no evidence-based guidelines for the management of DIPNECH. The various treatments reported in the literature vary from conservative management, oral and inhaled steroids, somatostatin analogues, chemotherapy to surgical lung resection, and even lung transplantation.2, 10, 17 Despite being a pre-invasive condition leading to lung carcinoid, DIPNECH typically remains an indolent disorder. Data on long-term follow-up and outcome are limited, but prognosis may not depend on

Conclusion

DIPNECH is an under-recognized disease characterized by small airway obstruction of variable severity. Expiratory CT can help detection by demonstrating air-trapping. Although often associated with lung carcinoids tumours, which for DIPNECH is regarded as pre-invasive condition, prognosis mainly depends on respiratory symptoms. DIPNECH should be suspected when diffuse mosaic perfusion in middle-aged women is demonstrated at CT, particularly if multiple lung nodules are also seen.

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Radiological–pathological correlation in diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH): imaging and histopathology
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To review histologically confirmed diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) cases and carry out a detailed pathological–radiological correlation to see if computed tomography (CT) can be used to confidently identify DIPNECH.
Twenty-three histologically confirmed DIPNECH patients in the shared database of two NHS Trusts were reviewed. CT images were reviewed by two independent radiologists, each of them with >10 years of experience in thoracic imaging. All histological specimens were reviewed by a single pathologist with >25 years of experience. The diagnosis of DIPNECH was made according to the current World Health Organization (WHO) definition included in the WHO 2015 classification of pulmonary tumours. The results on histology were compared to the presence of nodules and air trapping on CT. Demographic information and, when available, molecular imaging studies and pulmonary function tests were also considered.
There are prototypal clinical and radiological findings reflecting the presence of underlying histological DIPNECH: middle-aged women with multiple small and scattered nodules due to the clustering and proliferation of neuroendocrine cells. At least one larger, dominant, lung nodule reflecting a carcinoid tumour is very common and mosaic attenuation/air trapping is seen approximately in 50% of cases in inspiratory scans. Airflow obstruction is rarely associated with histological bronchial or peribronchial fibrosis, which suggests other mechanisms must be involved in its development.
CT can be used to predict pathological DIPNECH in the appropriate clinical setting. It is important to consider DIPNECH to avoid overdiagnosis of more sinister conditions such as lung cancer or metastases.
An Unexpected Cause of Lung Disease Identified After Lung Transplantation
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A 54-year-old woman with systemic lupus erythematosus with associated interstitial lung disease (ILD) presented to the lung transplant clinic for assessment of candidacy for transplantation. She was initially diagnosed with ILD based on clinical and radiographic features (never underwent lung biopsy). In addition, she had associated mixed group I/III pulmonary arterial hypertension. The patient had no family history of pulmonary disease and had never used tobacco and did not have a history of illicit drug use. She was maintained on systemic immunosuppression with hydroxychloroquine, mycophenolate mofetil, and nintedanib for ILD as well as inhaled treprostinil, sildenafil, and macitentan for pulmonary arterial hypertension. Given her progressive symptoms on maximal medical therapy, she was referred for consideration to undergo lung transplantation.
Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: A rare and under-diagnosed condition
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Prognostic Significance of Pulmonary Multifocal Neuroendocrine Proliferation With Typical Carcinoid
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Citation Excerpt :
Therefore, the complex pathophysiology and the real clinical meaning of MNEP with TC remain to be better clarified.24-26 The assessment of preoperative imaging studies, risk factors, and clinical symptoms may be crucial to confirm the clinical origin of pulmonary neuroendocrine tumors.26-28 In the PNECH setting, a high-resolution CT scan with an expiratory study has a role in detecting mosaic attenuation, bronchial wall thickening, air trapping, and bronchiectasis in association with pulmonary nodules.2,16,28,29
The clinical significance of multifocal pulmonary neuroendocrine proliferation (MNEP), including tumorlets and pulmonary neuroendocrine cell hyperplasia, in association with typical carcinoid (TC), is still debated.
We evaluated a retrospective series of TC with long-term follow-up data prospectively collected from 2 institutions and compared the outcome between TC alone and MNEP plus TC. Several baseline covariates were imbalanced between the MNEP plus TC and TC groups; therefore, we conducted 1:1 propensity score matching and inverse probability of treatment weighting in the full sample. In the matched group, the association of clinical, respiratory, and work-related factors with the group was determined through univariable and multivariable conditional logistic regression analysis.
A total of 234 TC patients underwent surgery: 41 MNEP plus TC (17.5%) and 193 TC alone (82.5%). In the MNEP plus TC group, older age (P < .001), peripheral tumors (P = .0032), smaller tumor size (P = .011), and lymph node spread (P = .02) were observed compared with the TC group. Relapses occurred in 8 patients in the MNEP plus TC group (19.5%) and 7 in the TC group (3.6%). After matching, in 36 pairs of patients, a significantly higher 5-year progression-free rate was observed for the TC group (P < .01). Similar results were observed using inverse probability of treatment weighting in the full sample. The odds of being in the MNEP plus TC group was higher for those with work-related exposure to inhalant agents (P = .008), asthma or bronchitis (P = .002), emphysema, fibrosis, and inflammatory status (P = .032), or micronodules on the chest computed tomography scan and respiratory insufficiency (P = .036).
The association with MNEP seems to represent a clinically and prognostic relevant factor in TC. Hence, careful preoperative workup, systematic pathologic evaluation, including nontumorous lung parenchyma, and long-term postoperative follow-up should be recommended in these patients.
Neuroendocrine neoplasms of the lung
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The pathologic diagnosis of neuroendocrine tumors of the lung requires integration of histologic and cytologic findings with clinical and radiologic consideration. Despite advances in diagnosis, challenges remain in their accurate classification. A search of relevant literature in PubMed was conducted with terms that included neuroendocrine, lung, and the terms in the chapter subheadings of individual entities combined with lung. In addition, a review of archived cases in the file of Weill Cornell Pathology was conducted.
Neuroendocrine tumors, including preinvasive lesions, were described from the perspective of classification, clinical presentation, pathology, ancillary studies, molecular findings, and treatment impact. New information focused on diagnostic criteria for large cell neuroendocrine carcinoma including overlap with small cell carcinoma and adenocarcinoma, mitotic counting, specificity of CD56, utility of INSM1, and potential diagnostic pitfalls. Molecular advances have led to new insights on the origin and classification of neuroendocrine tumors, especially of neuroendocrine carcinomas. The integration of clinical and radiologic findings to enhance diagnostic certainty was addressed.
Emerging knowledge supports the classification of neuroendocrine tumors into low, intermediate, and high grade categories. Use of Ki-67 to distinguish high from low grade lesions is established but not as a replacement for mitotic counting in well-preserved samples and excisions. Molecular data in large cell neuroendocrine carcinoma show some heterogeneity in this category with potential treatment implications. New data support the observation that most carcinoids and atypical carcinoids do not progress into higher grade lesions; however, this may occur in a small subset of cases. In addition, there appear to be atypical carcinoid tumors with mitotic rates higher than 10 in 2 mm²; their biologic behavior needs to be better defined. The consideration of rare entities in the differential diagnosis of neuroendocrine tumors is prompted by unusual epidemiology, histology, and clinical presentation.
A case of multiple lung carcinoid tumors localized in the right lower lobe
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Citation Excerpt :
HR-CT features include more peripheral multiple small nodules than in segmental bronchi, mosaic perfusion, and air trapping sings. MIP reformation is useful for the detection of peripheral nodules, while MinIP reformation is useful for the detection of mosaic perfusion [11]. Mosaic perfusion reflects the attenuation of vessels and the pulmonary parenchyma following constrictive bronchiolitis, which bronchial obstruction arising from NECH causes.
Typical pulmonary carcinoid (TC) tumors are low-grade neuroendocrine tumors and usually detected as indolent solitary tumors. We herein report a case of multiple pulmonary carcinoid tumors and tumorlets localized in the right lower lobe with no underlying lung disorders suggesting diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). A 28-year-old man with multiple 1-to-8-mm pulmonary nodules in the peripheral pulmonary parenchyma of the right lower lobe was referred to our hospital. The patient underwent a surgical biopsy. Pathological examination revealed multiple nodules composed of spindle cells, and immunohistochemistry revealed staining for chromogranin A, synaptophysin, and CD56, suggesting neuroendocrine tumors. He was diagnosed as having multiple TC tumors and tumorlets. Neuroendocrine cell hyperplasia (NECH) was also observed on some bronchioles. A follow-up CT scan after 6 months showed no changes in the sizes of the nodules and no new lesions. The present case was histopathologically compatible with DIPNECH but it occurs mainly in elderly women. The patient might be in an early stage of DIPNECH before progression to symptomatic DIPNECH. In conclusion, clinicians should consider the possibility of carcinoid tumors and tumorlets in cases with multiple pulmonary nodules even if they are localized in one lobe.

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