LUNG TUMORS WITH NEUROENDOCRINE MORPHOLOGY

Lung tumors with neuroendocrine (NE) morphology constitute only 20% of lung malignancies, yet no other group of lung neoplasms has generated so much interest and conflicting opinions among pathologists over the past several decades. The classification of these tumors has evolved with our understanding of the human NE system. Diverse morphologic patterns, a never-ending variety of immunohistochemical markers demonstrating NE function, and molecular techniques have led to complex classification schemes and confusion among not only clinicians, tumor registries, and patients, but also among the surgical pathologists responsible for reproducible tumor diagnoses. For many years lung tumors with NE morphology were diagnosed as either bronchial carcinoid tumors or small cell carcinomas (SCLC). Since 1972, these lesions have been classified as low-grade, intermediate-grade, and high-grade carcinomas. 10 The recently published 1999 World Health Organization (WHO) Histological Typing of Lung and Pleural Tumors serves as an impetus to review our current understanding of pulmonary NE cells, present the current classification scheme, and explore some of the peculiarities of lung NE tumors. Neuroendocrine cells, also known as Kulchitsky's cells, were first recognized by Feyrter 14 in 1938 and referred to as epithelial clear cells as part of a "diffuse epithelial endocrine system." The ability of these cells to take up and decarboxylate amine precursors including 3,4-dihydroxyphenylalanine (l-dopa) and 5-hydroxytryptophan (serotonin) led to the term amine precursor uptake and decarboxylase cells , which were thought to be neural crest cells. 46 The currently accepted dispersed NE system theory postulates that NE cells in different sites of the body are linked by a common NE phenotype and that these cells originated from pluripotent cells that differentiated locally under the control of unique site or organ factors. These cells are postulated to be of three derivations: (1) neural crest derivatives, such as adrenal medulla, paraganglia, and melanocytes; (2) neural tube and ridge-derived cells, such as epiphyseal, hypophyseal, and hypothalamic cells; and (3) derivatives of the NE programmed ectoblast including the gastroenteropancreatic system and bronchopulmonary tree. 47 Frohlich 16 first described NE cells of the lung in 1949 and he postulated that the solitary and nodular cellular aggregates in the walls of bronchi had a chemoreceptive or neurosecretory function. The nonciliated basally located cylindrical cells with clear cytoplasm are individually scattered throughout the bronchi and bronchioles and when clustered in groups of 4 to 10 cells with neural attachments are known as neuroepithelial bodies . NE cells are not found along the alveolar septa. Serotonin immunoreactive pulmonary NE cells are first seen at 8 weeks of gestation, increase in density through embryonic and fetal life, and peak in density at term suggesting a role in pulmonary morphogenesis and maturation. 12 Pulmonary NE cell hyperplasia is seen in a variety of physiologic and pathologic states. Increased numbers and small clusters of pulmonary NE cells are seen in persons living at high altitude; in children with bronchopulmonary dysplasia, cystic fibrosis, and bronchiectasis; in cigarette smoke–associated adult pulmonary diseases, including lung cancer; and in patients with carcinoid tumors. 19,21,30 Increased concentrations of bombesin-like peptides in bronchoalveolar lavage fluid of cigarette smokers and nonsmokers with diffuse idiopathic NE cell hyperplasia with obliterating small airways disease have also been reported. 1,2,21 In 1954, Feyrter 15 suggested that bronchial carcinoid tumors arose from NE cells, and in the mid-1960s Bensch et al 5 and Gmelich et al 18 first described the ultrastructural appearance of NE cells and related these cells to bronchial carcinoid tumors and SCLC. Many now consider the NE cell to be the cell of origin for most NE tumors of the lung, 4,20 a concept that impacts not only on histogenesis but also on classification. One group of investigators describes dysplastic NE cells in the lungs of patients with pulmonary neoplasms and chronic bronchitis and bronchiectasis, 21 and larger aggregates of NE at least partially outside the confines of airway basement membrane are termed carcinoid tumorlets (Fig. 1). These possible precursor lesions usually are incidental lesions found in normal lung or in patients with lung cancer, carcinoid tumors, pulmonary fibrosis, and granulomatous nodules. 10 Rare lymph node metastases have been reported, sometimes in the setting of multiple tumorlets. 13 Interestingly, one recent study reported that almost one third of patients, predominantly women, with resected peripheral carcinoid tumors also had diffuse NE cell hyperplasia and obliterative bronchiolitis. 40 These findings support the association between tumorlets and carcinoid tumors and raise the possibility that the NE hyperplasia causes obliterative bronchiolitis, and not vice versa as previously believed. 40 Although tumorlets of macroscopic size and carcinoid tumor merge as a pathologic entity, 9,39 an arbitrary 0.5 cm cutoff is used by the WHO to distinguish between these entities. 66 It must be emphasized that despite early speculation that carcinoid tumorlets might represent early or in situ SCLC, 6,48 there is no established clinical or pathologic association between these lesions. The current WHO classification recognizes four distinct tumors with NE morphology among the nine major histologic types of malignant epithelial neoplasms 66 : Squamous cell carcinoma Small cell carcinoma Adenocarcinomas Large cell carcinoma Large cell neuroendocrine carcinoma Adenosquamous carcinoma Carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements Carcinoid tumor Typical carcinoid tumor Atypical carcinoid tumor Carcinomas of salivary gland type Unclassified carcinoma Typical carcinoid tumor (TC) is a low-grade carcinoma; atypical carcinoid tumor (AC) is an intermediate-grade carcinoma; SCLC and large cell NE carcinoma (LCNEC) are considered high-grade carcinomas (Table 1). Although consideration was given to a conceptual grouping of tumors with NE morphology, differences in epidemiologic, clinical, and biologic characteristics argue against such a classification (Tables 2 and 3).