1

What are the causes of a benign pulmonary tumour?

Well-differentiated carcinoid tumour.

Chondroid hamartoma.

Sclerosing haemangioma.

Lipoma.

Leiomyoma.

Inflammatory pseudotumour.

Solitary fibrous tumour of the pleura (SFTP).

2

What is a carcinoid tumour?

A carcinoid tumour is a neuroendocrine tumour (NET), which has been subclassified by the World Health Organisation (WHO) (Table 1) as:

a)

well-differentiated carcinoid tumour (low grade, G1) – which was previously known as a ‘typical carcinoid’ and represents a benign, indolent lesion that rarely metastasises to locoregional lymph nodes (2-4%). No more than one mitosis is usually seen per high-powered field (HPF). Overall 5-year survival approaches 100%;

b)

moderately-differentiated carcinoid tumour (intermediate grade, G2) – which was previously known as an ‘atypical carcinoid’ and represents a lesion with features suggestive of invasiveness but without invasion of the basement membrane. Moderate mitotic figures (2-20 mitoses per HPF) can be seen;

c)

poorly-differentiated carcinoid tumour (high grade, G3) – which represents a malignant lesion that invades the basement membrane, metastasises and is associated with a worse prognosis. Nodal or systemic metastases are seen in 4-14% of patients at presentation. Higher mitotic figures (>20 mitoses per HPF) are seen with features of degeneration, necrosis and lymphovascular invasion. Overall 5-year survival is 25-78%.

The grade (G) refers to the biological aggressiveness of the tumour.

NETs develop from cells that originate from the embryological endodermal layer. They share the characteristics of amine precursor uptake and decarboxylation (APUD) cells, which describe the ability of these endocrine cells to produce active amine substances from amine precursors that are taken up inside the cells, where they are decarboxylated into the active amine and stored in secretory vesicles.

NETs can also be subclassified as functional or non-functional tumours.

Functional NETs are associated with certain clinical syndromes, caused by excessive production of hormones by the tumour cells. These cells contain intracellular neurosecretory vesicles, which release hormones and hormone precursors, including serotonin, adrenocorticotropic hormone (ACTH), melanocyte-stimulating hormone (MSH), vasoactive intestinal peptide (VIP) and anti-diuretic hormone (ADH).

Examples of functional NETs include a carcinoid tumour (which can result in carcinoid syndrome), insulinoma, gastrinoma, VIPoma, glucagonoma and somatostatinoma.

Recently, the Ki-67 propagation index has been described to help distinguish the grade of carcinoid tumour and prognosticate the disease-free survival.

Ki-67 is an antibody that adsorbs to the nuclear MKI67 protein, which is required for mRNA transcription. As MKI67 is present in the G1, S, G3 and mitosis phases of a dividing cell but not in the resting phase G0, it can be used as a surrogate for mitosis.

Well-differentiated carcinoid tumours are thought to represent the opposite end of the spectrum to small cell carcinoma, as they have well-characterised and easily recognised histological features.

Although a mixture of histological features can coexist in one specimen, a direct mechanism of transformation from well-differentiated benign carcinoid to small cell carcinoma has not been demonstrated.

3

What is the epidemiology of bronchopulmonary carcinoid tumours?

Bronchopulmonary carcinoid tumours represent 10% of all carcinoid lesions, with the gastrointestinal tract being the commonest location for these lesions.

They represent 1-2% of all lung tumours, with an incidence of 0.2 per 100,000 per year in Europe and an equal distribution between males and females.

Well-differentiated carcinoid tumours occur four times more frequently than moderately- or poorly-differentiated carcinoid tumours and can present at any age, with the peak age of presentation at 40-50 years of age.

The majority of bronchopulmonary carcinoid tumours (85%) are located centrally (subsegmental, segmental, lobar or main bronchus). They rarely appear in the trachea.

4

What are the clinical features of a bronchopulmonary carcinoid tumour?

Central lesions – which can lead to distal infection, airway obstruction or bronchiectasis (if longstanding). Symptoms include cough, haemoptysis, recurrent chest infections, asthma or unilateral wheeze. Central lesions tend to be well-differentiated carcinoid lesions with a better prognosis (Figure 1).

Peripheral lesions – which usually present as an incidental radiological finding of a solitary pulmonary nodule. They can be differentiated from lung carcinoma, as they lack the spiculation, necrosis or pleural effusion associated with lung cancer. Peripheral lesions tend to be moderately- or poorly-differentiated carcinoid tumours, with a worse prognosis.

Carcinoid syndrome – which rarely occurs in association with bronchopulmonary carcinoid tumours, except in the presence of hepatic metastases.

Paraneoplastic syndromes including:

a)

lung carcinoid-related Cushing’s syndrome;

b)

ectopic growth hormone-releasing hormone (GHRH) syndrome.

5

What is carcinoid syndrome?

Carcinoid syndrome occurs due to the secretion of serotonin into the bloodstream by a carcinoid tumour.

It occurs in only 2% of patients with a bronchopulmonary carcinoid tumour, which is less frequent than with gastrointestinal carcinoid lesions.

Patients present with night-time diarrhoea, dry skin flushing (without sweating), palpitations, wheeze and sleep disorders.

Diagnostic tests for carcinoid syndrome include:

a)

urinary 5-hydroxy-indole-acetic-acid (5HIAA) (24-hour collection) – which is a metabolite of serotonin;

b)

chromogranin A serum levels – which are elevated with carcinoid tumours;

c)

computed tomography (CT) scan of the thorax, abdomen and pelvis.

6

What are the characteristic features of lung carcinoid-related Cushing’s syndrome?

Lung carcinoid-related Cushing’s syndrome occurs due to the secretion of ACTH, generally by small peripheral masses, including 1% of lung carcinoid lesions.

Patients present with polyuria, polydipsia, hypertension, cushingoid habitus, acne, hypokalaemic alkalosis, muscle weakness, hyperglycaemia, weight gain, hirsutism, abdominal striae and skin pigmentation.

Diagnostic tests for lung carcinoid-related Cushing’s syndrome include:

a)

diurnal levels of serum ACTH, cortisol and cortisol precursors (corticotrophin-like intermediate lobe peptide, pro-opiomelanocortin);

b)

metyrapone suppression test;

c)

dexamethasone suppression test;

d)

bilateral sinus petrosus venous sampling for ACTH to confirm ectopic source;

e)

CT head (pituitary), thorax (carcinoid nodule) and abdomen (adrenals).

ACTH-producing carcinoid tumours are associated with a good prognosis, even in the presence of distant metastases.

7

What are the characteristic features of ectopic growth hormone-releasing hormone syndrome?

Bronchopulmonary carcinoid tumours account for the majority of GHRH-secreting tumours but <1% of acromegalic patients.

Patients may present with secondary signs, including carpal tunnel syndrome, soft tissue swelling, acne and skin changes, hypertension, impaired glucose tolerance, sleep apnoea, joint pains and acromegaly.

Diagnostic tests for ectopic GHRH syndrome include:

a)

bilateral sinus petrosus venous sampling for GHRH;

b)

diurnal levels of GH and insulin-like growth hormone-1 (IGH-1);

c)

glucose tolerance test;

d)

CT head (pituitary) and thorax (carcinoid nodule).

8

What are the investigative findings in a patient with a bronchopulmonary carcinoid tumour?

Chest radiograph (CXR) – which may demonstrate the tumour itself or changes related to distal obstruction, including atelectasis, consolidation, pneumonia, bronchiectasis or hyperinflation.

Computed tomography (CT) scan – which can further delineate the lesion, demonstrate any changes related to distal obstruction (Figure 2) and identify evidence of nodal or metastatic spread.

Positron emission tomography (PET) scan – which can determine the metabolic activity of the lesion to determine malignancy.

Somatostatin receptor scintigraphy (SRS) or octreotide scan – where radiolabelled octreotide is used to detect primary or secondary carcinoid deposits. Approximately 90% of carcinoid tumours have somatostatin receptors.

Rigid bronchoscopy and biopsy – for central carcinoid lesions. As carcinoid tumours are very vascular, application of an adrenaline-soaked peanut before and after the biopsy can reduce the risk of bleeding (Figure 3).