Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH): a little known cause of thoracic lesions

Abstract

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare but important condition to consider when investigating a patient with suspected thoracic malignancy. There is very little known about DIPNECH and it is considered to be a precursor to carcinoid tumour of the lung. This case report aims to increase awareness of this largely unknown and rare condition and to better improve its consideration as a differential diagnosis in patients who remain unresponsive to conventional treatment.

Background

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare condition with little mention in the literature with only 24 cases having been reported in a 6-year period between 2005 and 2011.¹ It has come to be recognised as a preinvasive precursor to carcinoid tumour of the lung parenchyma.² The reason for its occurrence in the lung is due to the propensity of pulmonary tissue to produce bombesin and gastrin-releasing peptides.³ These peptides stimulate bronchoconstriction, chemotaxis of airway cells and stimulate local fibroblasts. This can in turn lead to peribronchiolar and interstitial fibrosis.³ It frequently presents with symptoms of obstructive airways disease and a small proportion of patients will have symptoms and evidence suggestive of carcinoid tumour at diagnosis. It is ultimately diagnosed on histology, when a diagnosis of lung malignancy is suspected in those under surveillance or by presenting for the first time with a suspicious lesion on imaging.

Treatment is focused on surveillance and removal of the lesions due to the precancerous nature of DIPNECH, but there is no consensus on how quickly this should happen or for how long regular surveillance should continue for.

Case presentation

A woman in her early 70s was urgently referred to the respiratory department after a CT scan of her thorax revealed a 12 mm focus of subpleural consolidation in the upper lobe of the right lung (figure 1). This had developed from a subtle focus of nodularity previously seen on CT 5 years previously and was thus suspicious for bronchogenic malignancy.

Figure 1.

CT scan indicating the initial area of nodularity (left image) and subsequent CT scan indicating a growth of the initial nodule 5 years later (right image).

The patient described an intermittent cough for the previous few years, which was productive of clear sputum only, as well as mild exertional dyspnoea. She also reported weight loss of almost 6 kg over the previous year. She denied fevers, night sweats and haemoptysis. She had a medical history of left-sided breast cancer, treated with mastectomy and adjuvant chemotherapy 30 years prior, as well as hyperparathyroidism and migraine. She was otherwise fit and active, and had never smoked nor been exposed to asbestos, tuberculosis or pets.

Investigations

The initial CT scan of the thorax indicated an initial area of nodularity, which subsequently developed into a 12 mm suspicious lesion that warranted more invasive investigation (see figure 1). The patient subsequently underwent fluorodeoxyglucose-positron emission tomography (FDG-PET), which showed moderate uptake in the right lung lesion (figure 2). The Herder model of FDG was calculated to be 67% (see figure 2), She also had pulmonary function tests which were normal (figure 3).

Figure 2.

Fluorodeoxyglucose-positron emission tomography scan.

Figure 3.

Pulmonary function test data.

Differential diagnosis

Lung cancer.

Treatment

Due to the location of the lesion posterior to the right internal mammary artery, CT-guided biopsy was not possible. The clinical team were concerned, given the growth in size of the nodule over the 5-year period, the FDG avidity and the history of breast cancer, that the lesion may be a lung cancer but may well also be a recurrence of her breast cancer. The patient was therefore referred for video-assisted thoracoscopic surgery and wedge resection. Histology from the resected lesion showed non-necrotising granulomatous inflammation with neuroendocrine cell hyperplasia and tumourlets, consistent with a diagnosis of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (see figure 4A, B).

Figure 4.

Histology images showing non-necrotising granulomatous inflammation with neuroendocrine cell hyperplasia and tumourlets.

Outcome and follow-up

She is now currently under surveillance with an aim to have 6 monthly follow-up CT scans to monitor for any recurrence. She has not required any somatostatin analogues (SSAs).

Discussion

DIPNECH is an exceptionally rare condition. The majority of patients are women who have symptoms indicative of airways disease. It also disproportionately affects non-smokers. Reactive hyperplasia of neuroendocrine cells in the lung is known to happen in clinical cases where there is a clear reason to explain localised tissue hypoxia, resulting in inflammation and fibrosis. Pulmonary fibrosis and obstructive airways disease lead to localised hypoxia and thus stimulate the events that lead to the development of reactive neuroendocrine hyperplasia. In DIPNECH however, there is no such evidence of airflow obstruction to explain the histological finding of neuroendocrine cell hyperplasia that defines DIPNECH.

DIPNECH is the precancerous hyperplasia of neuroendocrine cells that has, by definition, not invaded the basement membrane. Much like cervical carcinoma in situ in which the cervical cells have not locally invaded the basement membrane, DIPNECH cells are still only in the hyperplastic phase of their precancerous cycle.⁴ DIPNECH is the precursor of carcinoid tumours and tumourlets.¹ If the hyperplastic neuroendocrine cells have invaded the interstitium but to a depth less than 5 mm, then it is known as a carcinoid tumourlet. If the lesion has invaded to a depth greater than 5 mm into the interstitium, it is known as carcinoid tumour.⁴

Hypotheses have developed to explain the development of DIPNECH. One hypothesis describes how the release of gastrin-releasing peptide and bombesin stimulate local fibroblasts and smooth muscle cell proliferation, activating local inflammatory processes that lead to bronchoconstriction and thus hypoxia.³ This hypoxia stimulates hyperplasia of neuroendocrine cells in the lung parenchyma. Other hypotheses postulate epidermal growth factor receptor overexpression which may stimulate local fibrosis of lung tissue.⁵ There are usually multiple areas affected in the lung rather than a solitary lung lesion. Typically, patients have 10 or more nodules measuring less than 5 mm in size, these are considered tumourlets.⁶ A significant proportion, however, will have 10 or more nodules measuring at least 5 mm in size, these are conventionally considered as carcinoid tumours.

There is no known treatment for DIPNECH and it is considered to be a precancerous condition, thus progression to carcinoid cancer continues to be a risk. Despite this, there is no consensus on the timescale for surveillance nor on the method of surveillance.

A recent study, which conducted long-term imaging follow-up showed a mean time-interval between baseline CT and evidence of metastatic spread of 67 months. The range, however, was large; between 14 and 123 months. In this cohort, 11% of patients diagnosed with DIPNECH progressed to metastatic cancer, which included both lymph node involvement and distant metastasis.

Patient’s perspective.

My breast cancer journey began over 30 years ago, when I had three operations, the last one being a mastectomy, but no further treatment. I subsequently had reconstruction to the left and augmentation to the right breast. The cancer returned several years later. Again I had three operations, resulting in a second mastectomy with dorsal flap reconstruction, followed by chemotherapy. The left implant eventually ruptured, and at that point I had them both removed. I wonder now if that would have had anything to do with the current situation.

Learning points.

• Consider DIPNECH as a potential differential diagnosis in patients with multiple nodules on CT imaging.

• The majority of patients with DIPNECH will have long-term disease progression on imaging with 11% of those progressing to metastatic cancer by 63 months or just over 5 years on long-term follow-up.

• Consider long-term surveillance of more than 5 years in patients diagnosed with DIPNECH to monitor for progression.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).