Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: Case report and review of literature

Overview

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia is a rare condition affecting mostly women in the fifth and sixth decades of life. Here we present a case of its accidental finding in the lung parenchyma of a 56-year-old non-smoker female. In the periphery of the right middle lobe, linear and nodular proliferations were detected in the wall of the small bronchi and terminal and respiratory bronchioles. Under the pleura, several tumorlets were located. Immunohistologically, neuroendocrine cells were positive with antibodies against chromogranin A, synaptophysin, CD56, serotonin (weak positivity of some cells only), calcitonin, GRP/bombesin, cytokeratin 7 and TTF-1.

Keywords:
diffuse idiopathic pulmonary neuroendocrine cell hyperplasia – tumorlets – neuroendocrine tumors – immunohistochemistry

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare condition. As of the year 2011, only 49 cases were published (1). According to the World Health Organization (WHO) DIPNECH is considered as a generalised proliferation of scattered single cells, small nodules (neuroendocrine bodies), or linear proliferations of pulmonary neuroendocrine cells in the mucosa and submucosa of the small bronchi and bronchioles (2,19). Initially, there is linear proliferation mostly beneath the superficial columnar epithelium. As a rule, the lesions are found in the periphery of the lung. The patients have no significant clinical symptoms and the condition is usually diagnosed accidentally during general examination. Most commonly, women in the fifth and sixth decades of life are affected (2,3). However, the disease may develop at any age. DIPNECH is considered to be a precursor of tumorlets and certain G1 and G2 neuroendocrine tumors (carcinoids and atypical carcinoids) (18). Centrally located G1 and G2 tumors are more frequent and typically characterized by more prominent clinical signs associated with narrowing of the larger bronchi. In their proximity, hyperplastic neuroendocrine cells may also appear but these changes do not correspond to DIPNECH (3,4). The study of DIPNECH may aid in understanding the development of pulmonary neuroendocrine tumors.

MATERIAL AND METHODS

A 65-year-old female patient with no significant complaints reported frequent coughs six years previously. An X-ray of the lungs as part of a preventive physical examination revealed a poorly defined lesion of approximately 4 cm in diameter in the periphery of the right middle lobe. The bronchoscopy was not performed. Subsequently, a right middle lobectomy was performed.

Immunohistochemistry. Immunohistochemical evaluation was carried out using the avidin-biotin complex (ABC) method. Positive and negative controls were used. The following antibodies were used (with working dilutions stated in brackets): CK20, clone Ks 20.8 (prediluted); CK7, clone OV-TL 12/13 (1:50); polyclonal rabbit anti-human gastrin (1:2000); polyclonal rabbit anti-human somatostatin (1:1000); monoclonal mouse anti-human serotonin, clone 5HT-H209 (1:100); and polyclonal rabbit anti-human glucagon (1:1000); all antibodies produced by Dako Glostrup, Denmark; monoclonal rabbit anti-TTF-1, clone G21-G (1:100), DB Biotech; synaptophysin, clone 27G12 (1:100); chromogranin A, clone 5H7 (1:100); and monoclonal mouse anti-CD56 (NCAM), clone 1B6; produced by Novocastra, Newcastle-upon-Tyne, UK; monoclonal mouse anti-neuron-specific enolase (NSE), clone MIG-N3 (prediluted); Biogenex; rabbit anti-pancreatic polypeptide, clone 18-0043 (1:100); Invitrogen GmbH, Lofer, Austria; vasoactive intestinal peptide (VIP) (1:500); Immunostar USA; polyclonal rabbit anti-GRP/bombesin, RPN 1692, Amersham, USA.

RESULTS

In a 65-year-old non-smoking female with no clinical signs, X-ray revealed a poorly defined lesion in the right middle lobe. Just below the pleura, a grey lesion poorly differentiated from the surrounding lung parenchyma was found, sized approximately 1.8 x 2.3 x 1.5 cm.

Histologically, several bronchi, terminal and respiratory bronchioles with linear or nodular hyperplasia of NECs were found (Fig. 1). As a rule, the NECs accumulation affected only a part of the bronchial mucosa. In some foci, there was a band-like linear proliferation of NECs which spread beneath the surface mucosal epithelium. In some small bronchi, NECs encircled their lumen. In other areas, there was a polypoid nodular bulging into the bronchial lumen (Fig. 2), with its diameter being reduced. In yet other places, it was apparent that hyperplastic NECs proliferated under the basal membrane and grew in the bronchial submucosa, reaching as far as bronchial cartilage. Therefore, the bronchial lumen was narrowed. In these cases, fibroproliferation around the NECs was apparent. Moreover, several tumorlets were found, with the largest one sized 600 μm (Fig. 3). Tumorlets located under the pleura were close to each other, separated by pulmonary parenchyma.

Immunohistochemical evaluation yielded positive findings with antibodies against chromogranin, synaptophysin, serotonin (weak positivity of certain NECs), calcitonin (Fig. 4A), bombesin (Fig. 4B), CD56 (the most NECs are positive) (Fig. 4C), CK7 and TTF-1 (intranuclear positivity of the most NECs in tumorlets and linear proliferations of the bronchial mucosa) (Fig. 4D). With the other antibodies, the immunohistochemical findings were negative.

DISCUSSION

The amount of NECs in the lungs depends on an individual’s age. Whereas in the fetal period the NECs are relatively abundant, they are relatively sparse in adulthood (5). The first peptide hormone in pulmonary NEC discovered was gastric-releasing peptide (GPR), a 27-amino acid mammalian homologue of the 14-amino acid amphibian peptide bombesin (6). Other hormones have been detected as well, such as calcitonin, serotonin or growth hormone-releasing hormone. Rarely, DIPNECH produces adrenocorticotrophic hormone (ACTH) with clinical manifestations of Cushing’s syndrome (7). Similarly, melanin production in NECs in neuroendocrine tumors has been rarely reported (8). During the fetal period, the amount of bombesin in pulmonary NECs is likely to be related to growth and maturation of the lung parenchyma (6). Bombesin and calcitonin are most frequently found in adult patients with DIPNECH.

In addition to rare DIPNECH, proliferating pulmonary NECs may also form tumorlets. According to the WHO classification of lung tumors (2), it is nodular benign proliferation of NECs which is not greater than 5 mm. Larger lesions are referred to as G1 and G2 neuroendocrine tumors. Leslie at al. (17) stated that “classical carcinoids” are typically significantly larger, sized 2-4 cm. Similar to DIPNECH, tumorlets are mostly asymptomatic. They are made up of rather uniform cells of benign appearance with hyperchromatic nuclei of mostly oval shape. In their proximity, fibrosis develops. This is probably due to the production of peptide hormones such as bombesin (9). Despite the fact that tumorlets are generally considered benign lesions, cell atypia and metastasis to lymph nodes have been observed (3,10,11).

Unlike DIPNECH and tumorlets, G1 and G2 neuroendocrine tumors affect males more frequently than females (3). They develop in the mucosa and submucosa of the larger bronchi and are found in the central lung areas. Patients develop cough, dyspnea (wheezing) and recurring bronchial and pulmonary infections.

Although DIPNECH, tumorlets and neuroendocrine tumors may be defined histologically, an important criterion for their classification into categories is their size. It may be speculated that an increasing number of genetic aberrations causes transformation of one category into another. In DIPNECH, linear or nodular proliferation of NECs in the mucosa or submucosa of the small bronchi and respiratory and terminal bronchioles is most prevalent. After some time, tumorlets or G1 and G2 neuroendocrine tumors may occur. These neuroendocrine tumors are mostly indolent, with no signs of histological atypia. Yet Nassar et al. (12), in a group of 24 patients reported over a period of six years, found two cases of histologically indolent neuroendocrine tumors metastasizing to lymph nodes. It has been shown that between DIPNECH and neuroendocrine tumors, there is a continuous line of gradual steps. This was also observed in our case between DIPNECH and tumorlets. There are conflicting opinions on the relationship between DIPNECH and neuroendocrine tumors. According to some authors (13), the presence of DIPNECH could be demonstrated in only 5.4 % of neuroendocrine tumors. Others (14) found the relationship to be up to 77 %.

Some authors (15) claim that the amount of NECs is increased in people living at high altitudes for a long time. Cameron (7) stated that NEC hyperplasia and neuroendocrine lung tumors are associated with bronchiectasis, pulmonary fibrosis and broncho-obstructive disease. These cases, however, do not progress to neuroendocrine tumors (2). The original assumption that DIPNECH is more frequent in smokers was not confirmed (5,16). In a group of patients whose data were published between 2004 and 2010, the majority (66 %) were found to be non-smokers (12). It seems that DIPNECH may be a precursor of tumorlets and some G1 and G2 neuroendocrine tumors. Recently (20) it was described that there are fundamental differences in cell kinetics between pulmonary neuroendocrine cell proliferation as a reaction to pulmonary injury and DIPNECH.

The clinical diagnosis of DIPNECH requires a resection of the lung parenchyma and subsequent biopsy evaluation. Only a small proportion of patients is diagnosed by transbronchial biopsy (12). The therapy involves a resection of the affected part of the lung, inhalation of steroids as well as lung transplantation. In cases with a stable course and no clinical manifestations, the wait-and-watch approach is used. Given the small number of cases, no algorithm for treating these patients has been developed (4,5,12).

At present, there are no genetic markers that would distinguish DIPNECH from reactive proliferation of NECs in association with the above lung diseases.

ACKNOWLEDGEMENTS

The authors thank MUDr. M. Mitták, Ph.D. for providing the patient’s clinical data.

Correspondence address:

Prof. MUDr. Jirka Mačák, CSc.

Department of Pathology

University Hospital Ostrava

17. listopadu 1790, 708 52 Ostrava, Czech Republic

e-mail: macak.jirka@seznam.cz