Lung tumours with neuroendocrine differentiation
Introduction
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, 4, 5, 6, 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, 4, 5, 6, 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, 10, 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, 16, 17, 18, 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.
Section snippets
Classification
SCLC and carcinoid were the first NE tumours recognised. In 1972, Arrigoni and colleagues described AC as a more aggressive form of pulmonary carcinoid [12] and in 1991, Travis and colleagues described LCNEC as a high-grade NE non-small cell carcinoma [9]. A major development that allowed the recognition of the diagnosis of LCNEC was the introduction of NE immunohistochemical markers such as chromogranin and synaptophysin into routine practice of surgical pathology. Pulmonary NE tumours have
Neuroendocrine cell hyperplasia and tumourlets
NE cells are normally situated at the base of the bronchial and bronchiolar respiratory mucosa as non-ciliated, round to oval shaped cells. Cytologically, these cells demonstrate a moderate amount of cytoplasm, round to oval nuclei with finely granular chromatin [22]. There are cytoplasmic processes extending from the cell surface that rarely reach the airway lumen [23]. When clusters of four to ten NE cells are present, they are called a NE body [22]. NE cell hyperplasia may manifest as either
Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia
“Diffuse idiopathic pulmonary NE cell hyperplasia” (DIPNECH) is a very rare condition consisting of widespread peripheral airway NE cell hyperplasia and/or multiple tumourlets, with less than 40 cases reported [24, 42, 43, 44]. Patients may present with the clinical picture of interstitial lung disease characterised by airway obstruction due to small airway narrowing by the NE cell proliferation and/or bronchiolar fibrosis. DIPNECH is thought to represent a pre-invasive lesion for carcinoid
Clinical features
The mean age for TC and AC patients is 45–55 years but they can occur at any age and there is no sex predilection [46, 47, 48, 49, 50]. Up to 50% of patients with TC and AC can be asymptomatic at initial diagnosis. The most common presenting manifestations are dyspnea, haemoptysis, a cough and post-obstructive pneumonia [48, 51]. Peripheral carcinoids are more likely to present as an incidental radiologic finding in an asymptomatic patient [52].
A variety of paraneoplastic syndromes can occur
Large cell neuroendocrine carcinoma
LCNEC is a high grade non-small cell NE carcinoma that was first recognised by the WHO classification in 1999 and maintained in the 2004 WHO classification [8, 44, 85]. Historically, this tumour has been included with other tumours such as AC, large cell carcinoma, non-small cell carcinoma with NE differentiation or combined small cell carcinoma/large cell carcinoma [6, 86, 87, 88].
LCNEC is classified as a variant of large cell carcinoma [8, 44]. There are four major ways that large cell
Clinical features
Small cell lung cancer (SCLC) is the most common pulmonary NE tumour accounting for an estimated 28,000 of the 215,020 lung cancer cases diagnosed in the US in 2008 [132]. According to the US National Cancer Institute's Surveillance, Epidemiologic, and End Results (SEER) database, the proportion of SCLC cases among all lung cancers in the US has decreased from 17% to 13% in the last 30 years [133].
Virtually all SCLC patients are cigarette smokers [134]. In fact, if the diagnosis of SCLC is
Molecular changes in pulmonary neuroendocrine tumours
Genetic studies reveal important molecular differences among the spectrum of NE lung tumours. In general, LCNEC and SCLC show frequent genetic changes with fewer seen in the carcinoids. A limited number of genetic markers demonstrate significant differences between TC and AC or LCNEC and SCLC, but these findings support the concept that these tumours should be classified separately.
Onuki and colleagues demonstrated that the high-grade LCNEC and SCLC had a significantly higher frequency of loss
International registry of pulmonary neuroendocrine tumours
Because of the great need for collaboration to gather sufficient numbers of the rare subtypes of pulmonary NE tumours including TC with metastases, AC, LCNEC and surgically resected SCLC, the International Association for the Study of Lung Cancer has developed an International Registry of Pulmonary NE Tumours [159]. This will provide a network of collaborations to foster research of these tumours with the hope it will lead to development of novel molecular targeted therapies for these tumours.
Conflict of interest statement
None declared.
References (159)
- et al.
Atypical carcinoid tumors of the lung
J Thorac Cardiovasc Surg
(1972) - et al.
Neuroendocrine neoplasms of the lung. A clinicopathologic update
J Thorac Cardiovasc Surg
(1989) - et al.
Identification of tumor suppressor loci on the long arm of chromosome 5 in pulmonary large cell neuroendocrine carcinoma
Chest
(2005) - et al.
Pulmonary endocrine cells in various species in the Himalaya
J Comp Pathol
(1988) Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia as a precursor to pulmonary neuroendocrine tumors
Chest
(2004)- et al.
Methods to study neuroepithelial bodies as airway oxygen sensors
Methods Enzymol
(2004) - et al.
Bronchial carcinoid tumors: surgical management and long-term outcome
J Thorac Cardiovasc Surg
(2002) - et al.
Bronchial carcinoids. Review of 124 cases
J Thorac Cardiovasc Surg
(1985) - et al.
Assessment of outcomes in typical and atypical carcinoids according to latest WHO classification
Ann Thorac Surg
(2003) - et al.
Clinical-radiological presentation and outcome of surgically treated pulmonary carcinoid tumours: a long-term single institution experience
Lung Cancer
(2004)