Carcinoid tumours occur in the bronchi and lungs on an infrequent basis. They represent the less malignant end of a spectrum of lung tumours showing neuro-endocrine characteristics which includes typical carcinoid (TC), atypical carcinoid (AC), large cell neuro-endocrine carcinoma (LCNEC) and small cell carcinoma (SCLC).They range in malignant potential from benign to frankly malignant but their main effect on the lungs is generally of an obstructive nature. Most can be cured by surgical resection with a low recurrence rate. Chemotherapy and radiotherapy are rarely required.

Aetiology and Epidemiology

Typical carcinoid tumours represent 2% of lung tumours and occur equally in both sexes. The mean age of incidence is younger than that for lung cancer (50 years) with many tumours presenting in young adulthood.  Carcinoid tumours are unrelated to cigarette smoking. Bronchial carcinoid can be a component of a multiple endocrine neoplasia (MEN) syndrome. As no predisposing factors are known prevention and screening do not have a role in this disease.

Pathology

Carcinoid tumours are a subset of neuro-endocrine neoplasms of the lung. Neuro-endocrine cells exist in clusters in bronchial epithelium and are responsible for the storage and release of small peptides and biogenic amines. Their origin is not clear and there is ltlle evidence for the suggestion that they have migrated from the embryonic neural crest

Small cell carcinoma and its intermediate cell variant represent the malignant end of the neuro-endocrine spectrum. Neuro-endocrine features are not uncommon in poorly differentiated large cell carcinomas of the lung.

Bronchial carcinoid tumours make up the more benign, well differentiated, low grade neuro-endocrine tumours. The terms typical for those with benign pathological features and atypical for those with more sinister features are commonly used but may be misleading. A “typical” carcinoid may metastasise and thus be clinically atypical, while an atypical carcinoid may be cured by simple excision. More recently the term well differentiated neuro-endocrine carcinoma has been introduced to emphasise that all these tumours have malignant potential, and therefore should be excised, and that there is a spectrum from benign  behaviour to frank malignancy.

Carcinoid tumours are made up of nests, trabeculae and mosaic patterns of polygonal cells with round uniform nuclei, granular “salt and pepper” chromatin, and inconspicuous nucleoli. Rosettes and small acinar structures may be present. The stroma shows numerous thin-walled small blood vessels. On electron microscopy numerous membrane-bound dense core neuro-secretory granules are apparent. Immuno-histochemical staining can help differentiate carcinoid tumours from NSCLC but not SCLC. It is not usually helpful in determining the level of malignancy of carcinoid tumours.

It is of clinical, therapeutic and prognostic importance to differentiate atypical carcinoid tumours from typical and in particular to differentiate both these tumour groups from small cell carcinoma. This may be difficult in small crushed biopsy specimens.

Clinical features suggestive of malignancy include peripheral location, large tumour size, and the presence of metastases. Pathologic features evident on gross examination which are commoner in atypical carcinoid are invasion of cartilage and lung parenchyma, and necrosis or extensive haemorrhage within the tumour itself.  Histological criteria of atypical carcinoid are:

1.    increased rate of mitotic figures (5 to 10 mitoses per 10 high powered fields)

2.    nuclear pleomorphism, hyperchromatism, and an abnormal nuclear-cytoplasmic ratio,

3.    areas of increased cellularity with disorganisation of cellular architecture and a paucity of organelles.

4.    tumour necrosis.

The molecular biological changes of carcinoid tumours are similar to those found in SCLC including allele loss in chromosomes 3p and 17p, p53 and ras mutation, and abnormal RB and MDRI gene expression.

 Tumourlets featuring neuro-endocrine staining cells occur in end stage fibrosis of the lung. Such tumourlets do not appear to behave like carcinoid tumours. The treatment is that for the underlying lung pathology and no oncological intervention is usually necessary.

Presentation

Many carcinoid tumours, particularly those occurring in the peripheral lung fields, are assymptomatic at time of presentation, being diagnosed on a chest radiograph taken for other purposes. Central carcinoid tumours cause obstructive symptoms with recurrent “chest infections” being treated over a period of years. Cough and pleuritic chest pain accompany such obstructive episodes. Stridor is often treated as asthma for a number of years before the diagnosis has become apparent. Haemoptysis, often related to a chest infection, is frequently the symptom which precipitates the diagnostic bronchoscopy. The combination of haemoptysis with pleuritic chest pain can mislead the clinician into suspecting a pulmonary embolus.

 Unlike carcinoid tumours of the gastro-intestinal tract which must metastasise to the liver in order to produce signs of a carcinoid syndrome, primary lung carcinoid tumours can release peptides directly into the systemic circulation. The peptides most frequently expressed are serotonin, bombesin, gastrin, leuko-enkephalin and ACTH. Up to 40% of patients will on questioning report symptoms of facial flushing (independent of menopause), palpitations, heartburn or angina like chest pain. While most “wheezing” is actually stridor due to obstruction of a central large bronchus, a number of patients will report bronchospasm even with a peripherally located tumour. Many of these hormonally mediated symptoms are vague and only become evident when they disappear after surgery. Though they may seem of little importance to the patient, the presence of such symptoms are of concern to anaesthetists as the release of such peptides on handling of the tumour can produce catastrophic bronchospasm or cardiovascular effects.[Carcinoid tumour peri-operative precautions]

Carcinoid case history

Examination

Examination is frequently normal though unilateral stridor may be evident on auscultation. During episodes of obstruction signs typical of a lobar pneumonia with pleuritic reaction may be evident.

Diagnosis

As for NSCLC chest radiography, CT scan, FNA and bronchoscopy are the means used to confirm the diagnosis.

 Small central tumours frequently do not appear on radiographs though the features of obstructive pneumonitis may be apparent. Peripheral tumours appear as rounded shadows similar to carcinoma though frequently less spiculated. CT scan will often demonstrate a central tumour which is not apparent on chest radiograph in addition to the parenchymal changes due to obstruction. Exfoliative sputum cytology is rarely diagnostic as these benign tumours rarely shed cells.

Fine needle aspirate of a peripheral tumour or small bronchial biopsies with crush artefact may  be suggestive of a neuro-endocrine tumour but frequently there is insufficient tissue to clearly delineate a diagnosis of small cell carcinoma, neuro-endocrine carcinoma or non small cell carcinoma with neuro-endocrine features. Caution must be taken when applying some of these more malignant diagnoses to a tumour which may in fact be benign.

Bronchoscopy demonstrates most central carcinoid tumours as smooth rounded polypoid endo-bronchial masses. As the tumours are frequently covered by normal bronchial mucosa biopsy can be misleading. There exists a reluctance on the part of many bronchoscopists to take deeper biopsies because of the propensity of these tumours to bleed. Use of a larger rigid bronchoscope can allow a diagnostic biopsy to be taken with safe control of the airway and will also allow the surgeon to plan appropriate lung conserving surgery.

Staging

The staging system for carcinoid tumours of the lung is the same as that for carcinoma. Staging procedures such as mediastinoscopy, anterior mediastinotomy and thoracoscopy are directed by CT findings but are usually not required in the more benign typical carcinoid tumours. The frequent pneumonitis found with carcinoid tumours which obstruct pulmonary lobes is associated with hilar and mediastinal lymhadenopathy. CT findings should not be over-interpreted without histological confirmation. Somatostatin receptor scintigraphy using the labelled somatostatin analogue, octreotide, may illuminate secondary disease which may not be apparent on CT, or rule out metastases in otherwise enlarged nodes. Hepatic metastases may need ultrasound evaluation and fine needle aspiration for cytological examination.

Treatment

The main treatment is aimed at ablating the primary disease and preventing obstructive damage to lung tissue. Where secondary disease is present there is the added aim of controlling any symptoms due to peptide release. Such peptide release can occur during surgical handling of a primary tumour and there exist anecdotal reports of severe bronchospasm, hypertension, arrhythmias and even cardiac arrest during surgery for carcinoid. Peri-operative treatment with somatostatin has been used to reduce such incidents. While radiation has also been used to “de-activate” hormonally active tumours, reports on its use for this purpose are scanty.

Endoscopic treatments.

Where surgical resection is deemed to be impossible or the patient is unfit for the required resection, endoscopic ablation is a useful palliative modality. It may also be used as a precursor to resection in an attempt to reduce the amount of lung parenchyma which needs to be resected. Neodymium-YAG laser via flexible bronchoscopy is probably to be preferred to mechanical debridement due to the vascularity of carcinoid tumours. Endoscopic ablation is rarely curative as much of the tumour is extra-bronchial, often forming a “dumbbell tumour”.

Surgery

Surgery should aim to remove all the primary tumour and draining lymph nodes as for malignant carcinoma. As these are benign tumours and field changes of squamous metaplasia and dysplasia are unlikely to be a feature a more conservative surgical margin can be tolerated thus preserving as much normal lung parenchyma as possible. As many tumours arise near the origin of major bronchi most procedures will entail lobectomy, removing the tumour and the destroyed distal lung. For tumours of major bronchi bronchotomy and wedge resection of the bronchial wall or sleeve resection in association with lobectomy will preserve maximal lung parenchyma.

Where peptide release causes difficulties on tumour handling emphasis should be placed on early ligation of veins draining the tumour.

Radiotherapy

Carcinoid tumours are relatively insensitive to radiotherapy. However, radiotherapy has been used in the postoperative setting where lymph nodes have been involved and for symptomatic relief in inoperable tumours. Radiation can reduce the hormonal activity of a tumour providing useful symptom relief in inoperable tumours. There are also anecdotal reports of its effectiveness preoperatively in patients with carcinoid syndrome.

Chemotherapy

While some atypical carcinoid tumours, particularly those which tend towards the malignant end of the neuro-endocrine carcinoma spectrum may respond to chemotherapy. Most series have used standard small cell carcinoma regimes with modest success, albeit in small numbers.

Hormonal therapy

Bronchial carcinoid tumours, like other neuro-endocrine tumours, have somatostatin receptors which not only aid diagnosis and staging but can be used for therapeutic intervention. Subcutaneous injection of somatostatin analogues (Octreotide, Lanreotide and Pentetreotide) can induce rapid, marked symptomatic relief.

There is an inhibitory effect on tumour growth and though this is modest, prolonged stabilisation can be achieved. Efforts to label somatostatin with tumorocidal isotopes is as yet experimental.

Prognosis

The prognosis of typical carcinoid tumours which have not metastasised is excellent if all tumour has been excised with clear margins. Even when complete tumour excision has not been possible prolonged survival can be obtained as these are slow growing tumours. Atypical carcinoid tumours or well differentiated neuro-endocrine carcinomas have a worse prognosis with complete resection being less common. Even so, with adjuvant hormonal and chemotherapy, prolonged survival is common.