Typical carcinoids are characterized by organoid, trabecular, insular, palisading, ribbon, or rosette-like growth patterns separated by a fibrovascular stroma. The tumor cells are small and polyhedral with small, round, or oval nuclei and eosinophilic, finely granular cytoplasm. Mitoses are rare or absent, and the proliferative rate is usually low. Atypical carcinoids are characterized by nuclear pleomorphism, hyperchromatism, abnormal nuclear-to-cytoplasmic ratio, prominent nucleoli, and areas of increased cellularity with disorganized architecture. Mitoses are more frequent, and necroses may be found (Fig. 10.2a–c). At electron microscopy, typical carcinoids have abundant membrane-bound secretory granules, while atypical carcinoids have fewer granules, distributed in the cytoplasm [13].

Lung carcinoids are epithelial in origin and stain positive for cytokeratin. Most of the tumors also stain positive for the neuroendocrine markers chromogranin A (Fig. 10.2d), synaptophysin, and neuron-specific enolase. In addition, positive immunohistochemistry for various hormones, including serotonin, gastrin-releasing peptide (mammalian bombesin), pancreatic polypeptide, gastrin, human chorionic gonadotropin alpha subunit, leucine enkephalin, VIP, somatostatin, calcitonin, ACTH, and growth-hormone-releasing hormone is found in a majority of tumors. Positive staining for multiple hormones is not uncommon [13, 14]. Expression of S-100 protein may occur, usually in peripheral tumors [15, 16]. The standard (hematopoietic) form of the adhesion molecule CD44 (CD44s) is usually expressed in lung carcinoids and may be used for prognostic evaluation in typical carcinoids [17]. Positive staining for the retinoblastoma gene protein is also common in typical carcinoids [18, 19]. The oncoproteins p53 and bcl–2, however, are usually negative in typical carcinoids but more frequently positive in atypical carcinoids [20, 21]. Thyroid transcription factor-1 (TTF-1) is positive in 28–69 % of lung carcinoids [22, 23] and may help to differentiate a primary lung carcinoid from a metastasis from a neuroendocrine tumor originating elsewhere.

Deletions in the MEN1 locus at 11q are common in both typical and atypical carcinoids [24]. Homozygous somatic inactivation of the MEN1 gene is detected in 36 % of sporadic lung carcinoids [25]. Atypical carcinoids frequently have deletions in 10q or 13q [24]. Aneuploidy has been reported in 5–32 % of typical carcinoids and 17–79 % of atypical carcinoids [4, 26–28].

A substantial number of patients (13–51 %) are asymptomatic, and the tumor is diagnosed incidentally on routine chest X-ray or CT scan. Common symptoms on presentation include cough, hemoptysis, wheezing, recurrent pneumonias with or without persisting lung infiltrate on chest X-ray, dyspnea, and chest pain [14, 29–31]. Some patients may have several years’ delay in the correct diagnosis due to misdiagnosis as asthma. Like other neuroendocrine tumors, lung carcinoids may secrete hormones. Endocrine symptoms are however rare. Despite serotonin immunoreactivity is present in up to 84 % of the tumors, the classical carcinoid syndrome with flush, diarrhea, bronchoconstriction, right-sided valvular heart disease, and elevated urinary 5-hydroxyindolacetic acid is seen in only about 2–12 % of the patients, usually when liver metastases are present [32–34]. This low frequency may in part be due to the high pulmonary content of monoamine oxidase, which metabolizes serotonin, but also to the fact that most lung carcinoids do not give rise to distant metastases. An atypical carcinoid syndrome with generalized flushing, edema, lacrimation, asthma, and diarrhea may occasionally be seen. This syndrome, which must not be confused with atypical carcinoids, is caused by secretion of histamine. An ectopic Cushing’s syndrome, caused by production of adrenocorticotropic hormone (ACTH) or corticotropin-releasing factor, may be seen in 2–6 % of patients with lung carcinoids. These tumors are often small and difficult to detect with conventional radiologic imaging. Acromegaly, caused by secretion of growth-hormone-releasing hormone, is infrequent [35, 36].

Typical carcinoids metastasize in 5–20 % of patients, while up to 70 % of patients with atypical carcinoids develop metastases. Metastases most frequently occur in regional lymph nodes but also distantly to the liver, bones, brain, subcutaneous tissue, mammary glands, eyes, and adrenals [1, 32, 37, 38]. Metastases may occur late, up to 30 years after surgery for the primary tumor.

In more than 60 % of the patients, the tumor is visible on chest X-ray. Peripheral tumors are seen as round or oval nodules. Patients with central tumors may have signs of bronchial obstruction and have peripheral atelectasis or pneumonic infiltrates which may be persistent. Computerized tomography (CT) scan (Fig. 10.3a) is more sensitive than chest X-ray and should always be performed in order to identify enlarged lymph nodes, delineate tumor growth, and detect satellite lesions (tumorlets). Magnetic resonance imaging (MRI) may be an alternative to CT scan but is less sensitive in detecting small intrapulmonary lesions.

About 70 % of lung carcinoids express somatostatin receptors and are demonstrable on Octreoscan (scintigraphy with ¹¹¹In-octreotide) [39]. Positron emission tomography (PET) with ⁶⁸Ga-DOTATCOC or ⁶⁸Ga-DOTATATE (Fig. 10.3b) is a newer, more sensitive method to detect somatostatin receptor-positive neuroendocrine tumors. ⁶⁸Ga-PET or Octreoscan should always be performed preoperatively for staging of the disease and clarify whether these methods may be used for postoperative follow-up to detect recurrence or metastases. Patients with Cushing’s syndrome often have small tumors, which are difficult to detect on CT scan. Up to 12 years delay has been described in localizing the tumor [40]. In these patients, PET with ⁶⁸Ga or Octreoscan is especially useful to obtain the correct diagnosis. An alternative is PET with ¹¹C-5-HTP (Fig. 10.3c), which is a sensitive tool for detection of neuroendocrine tumors [41]. The value of PET with ¹⁸ F-fluorodeoxyglucose (FDG) is controversial. Some authors claim that it is of limited value in detecting lung carcinoids, since these tumors often display lower uptake than expected for malignant tumors [42, 43], while others have found this method useful in patients with both typical and atypical carcinoids [44].

Central tumors are accessible via bronchoscopy (Fig. 10.1), which is performed in most patients. Since the tumor is often covered by a layer of normal mucosa, brushing or sputum cytology is frequently negative. To obtain a preoperative diagnosis, it is thus important to take biopsies, despite the risk of bleeding. It is generally safe to take biopsies, both through a flexible and a rigid bronchoscope [45]. Peripheral tumors may be reached by transthoracic CT-guided core-needle biopsy, although misdiagnosis is not uncommon, since the differential diagnosis to small-cell lung carcinoma may be difficult. Staining the tissue sample for the proliferation marker Ki67 may aid in the differential diagnosis between these entities [46, 47].

Plasma chromogranin A should always be measured preoperatively but is usually normal if the tumor is confined to the lung. If chromogranin A is elevated, intense search for distant metastases is warranted. Measurement of urinary 5-hydroxyindolacetic acid, urinary cortisol, and plasma ACTH is not recommended routinely but is only indicated if the patient has endocrine symptoms.

Alternative diagnoses when a tumor is found on chest X-ray or CT scan include other benign or malignant lung neoplasms, hamartoma, and metastasis from another primary tumor. The histopathological differentiation, both via bronchoscopy and transthoracically, between atypical carcinoid and SCLC may sometimes be difficult, but is important since patients with carcinoids are often cured by surgery, which is generally not performed in patients with SCLC. High proliferative rate, Ki67 > 25 %, favors the diagnosis of SCLC, while a low Ki67 index indicates lung carcinoid [46, 47].

The main treatment for patients with lung carcinoids is surgery, which offers the only chance for cure. External radiotherapy is mainly used for palliation of bone or brain metastases. Patients with metastatic disease or inoperable tumors can be treated with various chemotherapy combinations, peptide receptor radionuclide therapy (PRRT) with ¹⁷⁷Lu-DOTA-octreotate or ⁹⁰Y-DOTA-octreotide, biotherapy (somatostatin analogues, alpha-interferon), or newer targeted therapies such as everolimus or sunitinib. Patients with liver metastases may undergo hepatic arterial embolization with particles, chemotherapeutic agents, or ⁹⁰Y-labeled microspheres (SIR-Spheres® or TheraSpheres®). Symptomatic treatment for patients with carcinoid syndrome includes somatostatin analogues and alpha-interferon. Patients with metastatic tumors and Cushing’s syndrome are generally subjected to bilateral adrenalectomy; symptom relief may be obtained with ketoconazole, metyrapone, somatostatin analogues, or mitotane.

Most patients with typical lung carcinoids are cured by surgery, even in the presence of lymph node metastases, and have an excellent prognosis. Five- and 10-year survivals are 87–100 % and 82–95 %, respectively [7, 14, 61–63]. Poor prognostic factors include lymph node metastases at diagnosis, presence of tumorlets, and high Ki67 index. On the other hand, positive immunohistochemistry for the standard form of the adhesion molecule CD44 (Fig. 10.4a) and positive nuclear staining for the metastasis suppressor gene nm23 (Fig. 10.4b) correlate with decreased risk for distant metastases and death [17, 64]. The prognosis for patients with atypical carcinoids is worse, although many of these patients are also cured by surgery. Five- and 10-year survivals are 40–69 % and 31–59 %, respectively [14, 30, 62, 65]. Since metastases may develop late, up to 30 years after primary surgery, patients with lung carcinoids must be followed for long time, at least 10–15 years. The follow-up should include measurement of plasma chromogranin A, CT scan of the thorax and abdomen, and PET with ⁶⁸Ga-DOTATAOC/DOTATATE (in patients with somatostatin receptor-positive tumors) or MRI of the vertebral column. In selected patients, repeated bronchoscopies are indicated. Special attention should be paid to patients with atypical carcinoids or high proliferative rate.

Large-cell neuroendocrine carcinomas constitute about 3 % of all lung cancers. Almost all patients are smokers. The disease is most frequent in older patients; mean age is between 59 and 66 years. Men are affected more often than women and constitute 55–86 % of the cases [4, 66, 67].