Neuroendocrine Hyperplasia, Pulmonary Tumorlets, and Carcinoid Tumors

Etiology, Prevalence, and Epidemiology

Normal lung tissue contains scattered neuroendocrine (Kulchitsky) cells within the bronchial and bronchiolar epithelium. These cells play a role in the detection of hypoxia as well as fetal lung development and may be involved in local epithelial cell growth and regeneration. Hyperplasia of these cells can be seen as a response to chronic airway inflammation, such as in patients with emphysema or chronic bronchitis. When no known cause can be identified, this hyperplasia is designated diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). Extension of hyperplastic neuroendocrine cells beyond the basement membrane is termed a tumorlet if the cell mass is less than 5 mm and carcinoid tumor if the cell mass is 5 mm or greater in diameter. Neuroendocrine cell hyperplasia and tumorlets may coexist with carcinoid tumors. In the absence of lung injury (leading to reactive pulmonary neuroendocrine cell hyperplasia), DIPNECH is considered a preinvasive condition that may develop into carcinoid tumors, and imaging follow-up is required.

DIPNECH typically manifests in the fifth to sixth decades of life, with women affected nearly four times as often as men. DIPNECH usually occurs in nonsmokers, but former and current smokers are occasionally affected. Tumorlets also demonstrate a female preponderance (>4 : 1) and are often seen in patients 60 to 70 years old.

In the 2015 update to the World Health Organization (WHO) classification of lung tumors, DIPNECH is classified as a preinvasive lesion. Although the diagnosis remains purely histologic, some authors have proposed the term DIPNECH syndrome be used to indicate patients with respiratory symptoms and appropriate imaging findings. Although initially thought to be rare, with few cases described in the literature, DIPNECH is likely an underrecognized condition.

Clinical Presentation

Up to half of patients with DIPNECH or tumorlets are asymptomatic, and the diagnosis is made incidentally on chest computed tomography (CT) or surgical lung biopsy performed for other reasons. When patients are symptomatic, they often present with a history of protracted nonproductive cough and/or dyspnea and are often mistakenly diagnosed with asthma. Pulmonary function tests may show obstructive or obstructive/restrictive alterations, likely caused by airway obstruction from the hyperplasia as well as constrictive bronchiolitis from peribronchial fibrosis.

Pathophysiology

Neuroendocrine cell hyperplasia (NECH) is characterized by single, clustered, or linear arrays of Kulchitsky cells confined by the basement membrane. Tumorlets are distinguished by extension beyond the basement membrane. Both of these entities show no mitoses or necrosis per 10 high-power fields on histologic examination. NECH and tumorlets are usually an incidental finding in lung parenchyma scarred by bronchiectasis or other chronic inflammatory processes.

As stated earlier, constrictive bronchiolitis in patients is secondary to submucosal fibrosis of affected airways in regions with and regions without tumorlets and NECH.

Imaging Findings

Radiography

Chest radiographs of patients with DIPNECH or pulmonary tumorlets may demonstrate pulmonary micronodules ( Fig. 19.1 ) but are more often normal. Secondary signs of constrictive bronchiolitis, including hyperinflation and attenuation of peripheral pulmonary vasculature, can occasionally be seen.