Small Cell Lung Cancer

• Aggressive, high-grade neuroendocrine ca. Cigarette smoking.
• Bulky, infiltrative central pulmonary mass with bulky mediastinal lymphadenopathy
• Typically chemo ± radio

Description

Small Cell Lung Cancer (SCLC), also known as oat cell carcinoma, is a highly aggressive subtype of bronchogenic carcinoma that is strongly associated with cigarette smoking. It’s characterised by small cells that proliferate rapidly and have a high propensity for early metastasis. SCLC accounts for approximately 15% of all lung cancer cases.

Small cell lung cancer is considered a neuroendocrine tumour of the lung.

Pathogenesis

The pathogenesis of SCLC is closely linked to tobacco smoking, with more than 95% of cases occurring in smokers or former smokers. The carcinogens in tobacco smoke cause DNA damage, leading to mutations in numerous genes. The high rate of mutation, coupled with the rapid growth rate of the cells, leads to an aggressive disease course.

Epidemiology, Risk Factors & Associations

• SCLC is most commonly diagnosed in individuals between the ages of 60 and 80, with an average age at diagnosis of 70.
• Cigarette smoking is the primary risk factor. The risk increases with the amount and duration of smoking and decreases after smoking cessation, but never returns to that of a never-smoker.
• Other risk factors include exposure to secondhand smoke, radon gas, asbestos, and certain other occupational exposures.

Clinical Features

Patients with SCLC often present with symptoms related to local tumour growth (cough, haemoptysis, chest pain, dyspnoea), metastatic disease (brain, liver, bone), or paraneoplastic syndromes, which are caused by hormone-like substances produced by the tumour. Common paraneoplastic syndromes associated with SCLC include:

• Syndrome of Inappropriate Antidiuretic Hormone (SIADH): Most common paraneoplastic syndrome (15%). Characterised by excessive release of antidiuretic hormone (ADH) from the posterior pituitary gland or other sources. Leads to water retention and hyponatraemia, which may cause neurological symptoms such as confusion, seizures, and in severe cases, coma.
• Cushing’s Syndrome: Occurs in about 2-5% of patients. Results from prolonged exposure to high levels of cortisol. Symptoms include weight gain, particularly around the abdomen and face, thinning skin, easy bruising, and in women, excessive hair growth and irregular menstrual cycles.
• Lambert-Eaton Syndrome: An uncommon disorder of the neuromuscular junction leading to muscle weakness (1-3% of cases): Symptoms typically include weakness of the proximal muscles (those closest to the trunk), reduced deep tendon reflexes, and autonomic dysfunction (dry mouth, impotence, constipation).Unlike myasthenia gravis, another neuromuscular junction disorder, symptoms in Lambert-Eaton syndrome often improve with repeated use of the muscles.
• SVC Syndrome: SCLC is the most common cause (50% of cases of SVC syndrome). Due to mass effect or involvement of the SVC, featuring swelling and redness of the face, neck, and upper chest; shortness of breath; and difficulty swallowing.

Pathological Features

Histopathological

• Composed of small cells with scant cytoplasm, ill-defined cell borders, finely granular nuclear chromatin, and absent or inconspicuous nucleoli.
• There is a high mitotic rate and extensive necrosis.

Biochemical

• Neuroendocrine markers such as chromogranin, synaptophysin, and CD56 are often positive in SCLC.
• A high Ki-67 index, which indicates a high proliferation rate, is also a common finding.

Radiological Features

General Features

• Best diagnostic clue: Central pulmonary nodule or mass, bulky mediastinal &/or hilar lymphadenopathy, and encasement/invasion of mediastinal structures.
• SCLC is not known to cavitate, unlike squamous cell carcinoma.
• Location: The lesions are typically centrally located. Peripheral pulmonary nodule or mass is uncommon.

Radiography

• Central pulmonary nodule or mass extending to hilum/mediastinum which may produce atelectasis and volume loss. This can be visualised as a hilar/perihilar mass usually with mediastinal widening due to lymph node enlargement.
• Bulky mediastinal &/or hilar lymphadenopathy is common, with mediastinal lymphadenopathy often inseparable from hilar lymphadenopathy.
• Post-obstructive atelectasis: S-sign of Golden (indicates left upper lobe collapse secondary to hilar mass) and Luftsichel sign (hyperlucent area between the aortic arch and the collapsed left upper lobe) may be present.
• Pleural effusion may be observed.

CT

Non-contrast CT:

• Central pulmonary nodule or mass (90-95%) is observed, often producing atelectasis.
  • Peripheral pulmonary nodule or mass is uncommon.
• Mediastinal (92%) &/or hilar (84%) lymphadenopathy is common, and can appear similar to lymphoma with numerous enlarged nodes. Direct infiltration of adjacent structures is typical.
• Small cell lung cancers usually appear as a mass lesion where necrosis (central hypodensity) and haemorrhage are common.

Contrast-enhanced CT:

• Useful in evaluating vascular involvement and for assessment of lymphadenopathy and metastases.
• Extrathoracic metastases are common (Bone: 19-38%; liver: 17-34%; adrenal glands: 10-17%; brain: 14%)
• Superior vena cava (SVC) syndrome (most common cause is SCLC), due to both compression/thrombosis and/or direct infiltration, manifested by decreased or absent opacification of SVC and collateral vessels in chest wall, neck, &/or mediastinum.

MR

• Thoracic MR is not routinely used but can be indicated in the assessment of local invasion and imaging of brain (preferably with MR) which is recommended for all patients as metastases can occur in 10-15% of neurologically asymptomatic patients.
• Contraindications to IV contrast: Renal dysfunction, severe allergy to IV contrast.

NM

• PET/CT: Most tumours, affected lymph nodes, and metastases demonstrate intense FDG uptake as SCLC is very metabolically active. It is excellent for initial staging and may be used for evaluation of treatment response &/or restaging.

Staging

With the 8th edition of the TNM classification (from 2017), the same staging system is recommended for both SCLC and NSCLC. However, many clinicians still use the Veterans Administration Lung Study Group (VALSG) two-stage system for SCLC given its aggressive nature and tendency for early metastases.

TNM Staging System (8th edition)

T Stages

• Tis: Carcinoma in situ.
• T1: Tumours ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without invasion more proximal than the lobar bronchus (i.e. not involving the main bronchus).
  • T1mi: Minimally invasive adenocarcinoma.
  • T1a: Tumours ≤1 cm in greatest dimension.
  • T1b: Tumours >1 cm but ≤2 cm in greatest dimension.
  • T1c: Tumours >2 cm but ≤3 cm in greatest dimension.
• T2: Tumours >3 cm but ≤7 cm; or tumours with any of the following features (main bronchus, 2 cm or more distal to the carina; invades visceral pleura; associated with atelectasis or obstructive pneumonitis).
  • T2a: Tumours >3 cm but ≤5 cm.
  • T2b: Tumours >5 cm but ≤7 cm.
• T3: Tumours >7 cm or directly invading any of the following: chest wall, diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium; or tumours in the main bronchus <2 cm distal to the carina but without involvement of the carina; or associated atelectasis or obstructive pneumonitis of the entire lung.
• T4: Tumours of any size that invade any of the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina; separate tumour nodules in a different ipsilateral lobe to the primary.

N Stages

• N0: No regional lymph node metastasis.
• N1: Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
• N2: Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
• N3: Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).

M Stages

• M0: No distant metastasis.
• M1: Distant metastasis.
  • M1a: Separate tumour nodule(s) in a contralateral lobe; tumour with pleural nodules or malignant pleural (or pericardial) effusion.
  • M1b: Single extrathoracic metastasis in a single organ (including involvement of a single non-regional node).
  • M1c: Multiple extrathoracic metastases in one or several organs.

Veterans Administration Lung Study Group (VALSG)

• Limited Stage: The cancer is on one side of the chest, confined to a single radiation field. This generally includes stages I, II, and III of the TNM system.
• Extensive Stage: The cancer has spread beyond a single radiation field, including metastasis to the other lung, the pleural fluid, or other parts of the body. This generally corresponds to stage IV of the TNM system.

Differential Diagnosis

Imaging-based

• Non-Small Cell Lung Carcinoma (NSCLC): This represents a group of histologically different lung cancers that behave similarly at a clinical level. These include adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. NSCLC generally grows and spreads more slowly than SCLC, and the cells are larger under the microscope. Radiologically, NSCLCs can appear as peripheral lung masses with or without cavitation. They may also show signs of local invasion into the chest wall or mediastinum.
• Metastatic Small Cell Carcinoma from Another Primary Site: Small cell carcinoma can arise from locations outside the lung (e.g., the cervix, prostate, gastrointestinal tract). A history of malignancy elsewhere, radiological evidence of a primary tumour elsewhere or absence of a primary lung lesion, and pathologic confirmation can help differentiate.
• Carcinoid Tumour: Carcinoid tumours are neuroendocrine tumours that are generally slow-growing and can be benign or malignant. They can also secrete hormones, leading to symptoms such as flushing or diarrhoea. Under the microscope, the cells are larger and have a “salt-and-pepper” chromatin pattern. Radiologically, carcinoid tumours often present as a well-defined solitary pulmonary nodule, which may demonstrate intense enhancement on contrast CT due to its high vascularity.
• Lymphoma: Primary pulmonary lymphoma is rare and can mimic other lung cancers. However, lymphoma may be suggested by bilateral lung involvement, mediastinal lymphadenopathy, or extrathoracic involvement. On histopathology, the presence of lymphoid cells would indicate lymphoma. Radiologically, lymphomas can appear as consolidation, masses, or nodules, often with associated mediastinal lymphadenopathy and may demonstrate homogenous enhancement on contrast-enhanced CT.
• Fibrosing mediastinitis: Compression of airways and vessels. Dystrophic calcifications are often present.

Management

• Due to its aggressive nature and tendency for early metastasis, SCLC is typically treated with systemic chemotherapy and/or radiotherapy rather than surgery.
• Prophylactic cranial irradiation is often given to patients with limited stage disease who respond to initial therapy, due to the high risk of brain metastases.
• Despite initial high response rates to treatment, the majority of patients unfortunately experience a relapse.