Lung tumours with neuroendocrine differentiation

Neuroendocrine (NE) tumours of the lung include the low grade typical carcinoid (TC), intermediate grade atypical carcinoid (AC) and the high grade large cell NE carcinoma (LCNEC) and small cell carcinoma (SCLC) (Table 1). NE tumours of the lung comprise approximately 20−25% of all invasive lung malignancies. The most common NE lung tumour is SCLC, which accounts for 15−20% [1], followed by LCNEC, which is about 3% in surgical series, and carcinoid, which accounts for 1−2% of lung cancers. The rarest NE lung tumour is atypical carcinoid which comprises approximately 10% of all lung carcinoids, accounting for approximately 0.1−0.2% of invasive lung cancers [2]. These tumours have certain morphologic, ultrastructural, immunohistochemical and molecular characteristics in common [3–7], but there are important differences in incidence, clinical, epidemiologic, histological, survival, and molecular characteristics [8]. Diffuse idiopathic NE cell hyperplasia (DIPNECH) is a pre-invasive lesion for carcinoid tumors, but it is very rare. There are major clinical, epidemiologic and genetic differences between carcinoid tumours and the high grade SCLC and LCNEC although they share the neuroendocrine phenotype [3–7]. LCNEC and SCLC are associated with older age, more smoking and male gender compared to TC and AC. Multiple endocrine neoplasia (MEN) type I or DIPNECH can occur in patients with TC and AC but is not recognised in LCNEC and SCLC patients [9]. Also, histological heterogeneity with other major histological types of lung carcinoma, such as adenocarcinoma or squamous cell carcinoma, can occur with both LCNEC and SCLC, but it is not characteristic of TC or AC [9– 11]. NE lung tumours are problematic for a variety of reasons. First, histological classification has also evolved over the past few decades with recognition of AC [12] and LCNEC [9]. However, widely varied terminology, diagnostic criteria and concepts including well-differentiated NE carcinoma, NE carcinoma (grade 1−3), intermediate cell NE carcinoma, malignant carcinoid and peripheral small cell carcinoma resembling carcinoid [13,14] have led to a great deal of confusion in the literature often making it difficult to understand what tumour types are included in some papers. AC and LCNEC are rare so few pathologists have much experience diagnosing them. In small biopsies, the morphologic appearance of these tumours can overlap. Surgical specimens rather than small biopsies or cytology specimens are usually required to separate TC from AC and to diagnose LCNEC. Light microscopy is sufficient to diagnose SCLC, TC and AC in most cases without the need for special tests, but the diagnosis of LCNEC still requires demonstration of NE differentiation by immunohistochemistry or electron microscopy. In some cases, immunostains are helpful in sorting out the differential diagnosis, especially in small biopsies. In addition, the high grade SCLC and LCNEC show many genetic changes, but in TC there are relatively few and in AC the changes are intermediate [15–19]. There are no specific immunohistochemical or molecular markers that allow for separation of these tumours. In addition, the optimal therapy for AC and LCNEC is not established, so once a diagnosis is established, clinicians are often unsure how to treat patients [2]. This review will focus on describing the histological spectrum of pulmonary NE lesions and diagnostic criteria. The spectrum of NE proliferations and neoplasms in the lung are summarised in Table 1. Each of these topics will be covered in this review. The diagnostic criteria for the main NE lung tumours are summarised in Table 2.