Physical Examination Findings
The patient at presentation was afebrile, and her vital signs revealed a BP of 120/65 mm Hg, a heart rate of 75 beats/min, and 98% oxygen saturation in ambient air. Her breathing pattern was normal with a respiratory rate of 16 breaths/min, without use of accessory muscles of respiration. Nail clubbing was absent. Palpation showed symmetry, synchrony of lung expansion, and normal transmission of vocal vibrations. Percussion produced a normal resonant volume. During lung auscultation, pathologic sounds were not detected. Cardiac examination did not reveal displacement of the apex beat, thrill, or murmurs. Jugular vein distention and peripheral edema were not observed. Inspection of ear, nose, and throat was normal, without gross abnormalities, edema, or hemorrhage. Peripheral lymph nodes were normal. The rest of the physical examination was unremarkable.
Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) was first described as a distinct pulmonary disorder in 1991 by Aguayo et al. This clinical entity included the presence of characteristic radiologic and pathologic findings, combined with symptoms of airflow obstruction. The current World Health Organization classification of tumors of the lung, pleura, thymus, and heart is limiting DIPNECH diagnostic criteria to histology. It is defined as a precursor of pulmonary carcinoids that is characterized by a proliferation of neuroendocrine cells that is confined to the mucosa of bronchi or forming tumorlets locally and may develop into carcinoid tumors. The term tumorlet refers to generalized proliferation of scattered neuroendocrine cells beyond the basement membrane (discrete neuroendocrine cell aggregates <5 mm in diameter). When nodules exceed 5 mm in diameter, they are defined as carcinoid tumors.
Several studies previously identified characteristics that favored a DIPNECH diagnosis. Middle-age, female predominance, absence of smoking habitude, presence of respiratory symptoms (cough, dyspnea), pathologic pulmonary function tests, multiple nodules, mosaic attenuation, air trapping on CT scans, tumorlets and constrictive bronchiolitis, immunohistochemical expression of TTF-1, CD10, and GRP/bombesin-like peptide in pathologic review have shown to be typical. Neuroendocrine cells produce peptides that stimulate fibroblasts, bronchoconstriction that may lead to peribronchiolar and interstitial fibrosis, and a severe, progressive obstructive ventilatory defect. This mechanism is thought to be responsible for the asthma-like symptoms and abnormal pulmonary function tests that are associated with DIPNECH. A substantial heterogeneity in disease behavior is observed because a substantial proportion of patients show normal lung function or mild symptoms.
An initial chest radiograph may reveal a pulmonary nodule and is not specific for diagnosis. CT scan-related abnormalities are multiple nodules, mosaic attenuation with air trapping, bronchial wall thickening, and bronchiectasis. Nodules are the most common findings in DIPNECH (up to 60%) and may be the sole or predominant abnormality. They are round-to-ovoid, generally of solid density or ground-glass attenuation. PET scan could be considered in patients with known or suspected DIPNECH to identify superimposed carcinoid tumors and to help direct biopsy.
Surgical lung biopsies usually are required to establish a diagnosis because nodules are too small to allow a CT-guided biopsy. Transbronchial lung biopsy could allow a confident diagnosis in the setting of high clinical suspicion for DIPNECH and in cases for which the surgical option is inappropriate. Bronchoscopy is useful foremost to exclude other possible diagnoses, mainly metastatic neoplasms.
All neuroendocrine proliferations that are observed in DIPNECH express the most common markers of neuroendocrine cell differentiation, such as chromogranin A, synaptophysin, CD56, and the less specific antibodies for neuron-specific enolase and PGP9.5. Thyroid transcription factor-1 also is expressed commonly.
Therapeutic options include observation alone, oral and inhaled steroids, chemotherapy, surgical lung resection, and lung transplantation. The majority of symptomatic patients are treated with bronchodilators and oral corticosteroids. Octreotide, a somatostatin analogue that has been proved to reduce the hormonal hypersecretion of neuroendocrine cells, has shown promising results, especially for patients whose condition expresses somatostatin receptors. Finally, the safety and efficacy of mTOR inhibitors in patients with DIPNECH is under research.
DIPNECH is a clinical entity with good prognosis, because patients remain usually stable and rarely experience a deterioration. The overall 5-year survival rate accedes to 90%. The presence of constrictive bronchiolitis is considered to be a negative prognostic factor for progression to severe airflow obstruction and respiratory failure that requires lung transplantation.
The differential diagnosis of pulmonary nodules is wide and challenging. A random distribution is usually typical of miliary infection (TB or fungi) or metastatic disease. Solid nodules of ≥6 mm and persistent part-solid nodules with solid components of ≥6 mm should be considered highly suspicious for malignancy. Furthermore, older age, smoking habitude and emphysema, irregular or spiculated margins, upper lobe location of nodules, and a history of malignancy are considered to be risk factors for neoplastic disease. Clinical investigators should consider DIPNECH as a plausible diagnosis, in the setting of unexplained randomly distributed pulmonary nodules that are accompanied by asthma-like symptoms and abnormal pulmonary function tests.
DIPNECH is a rare potential diagnosis for multiple pulmonary nodules that requires a compatible histologic pattern. The histopathologic findings in this particular case and the clinical and radiologic evidence described designate a typical DIPNECH case.
After surgery, the patient remained clinically stable and was discharged as soon as the required diagnostic tests were completed. At 1-month follow up, she was asymptomatic after an inhaled corticosteroid treatment was prescribed. The patient will have a scheduled surveillance.