Lung Adenocarcinoma

Adenocarcinoma of the lung is the most common NSLC, which can be seen in both non-smokers and smokers, characterised by peripheral ground-glass opacities on imaging and glandular differentiation and positive immunohistochemistry for thyroid transcription factor-1.

Description

Lung adenocarcinoma is a type of non-small cell lung cancer and is the most common subtype seen in both smokers and non-smokers. It is characterised by malignant epithelial cells with glandular differentiation or mucin production. Adenocarcinoma often arises in the peripheral lung regions and has various histological subtypes, each with distinctive clinical and pathological features.

What are the major types of lung cancer?

• Lung Cancer
  • Small Cell Lung Cancer
  • Non-small Cell Lung Cancer
    • Adenocarcinoma
    • Squamous Cell Carcinoma
    • Large Cell Carcinoma

Pathogenesis

The pathogenesis of lung adenocarcinoma is complex and multifactorial. It involves genetic and environmental factors, including smoking and exposure to carcinogens like radon or asbestos. However, some cases occur in people with no known risk factors. There is a multistep process of carcinogenesis, starting with hyperplasia, followed by dysplasia, carcinoma in situ, and finally invasive carcinoma. Genetic mutations such as EGFR, KRAS, ALK and others play a significant role in tumour growth and progression.

Epidemiology, Risk Factors & Associations

• Lung adenocarcinoma is the most common subtype of lung cancer, accounting for around 40% of all lung cancers.
• The incidence is slightly higher in women than men.
• Cigarette smoking is the most significant risk factor, however, adenocarcinoma is also the most common type of lung cancer among non-smokers.
• Other risk factors include exposure to second-hand smoke, radon gas, asbestos, and certain types of dust or chemical fumes.

Clinical Features

• Symptoms are often non-specific and may include cough, chest pain, shortness of breath, and haemoptysis.
• Some patients may present with weight loss, fatigue, and loss of appetite, which are systemic symptoms of cancer.
• Paraneoplastic syndromes can occur, including:
  • Hypercalcemia (13% of cases): Most common paraneoplastic syndrome in lung adenocarcinoma, caused by the secretion of parathyroid hormone-related peptide (PTHrP) by the tumour cells. Symptoms can include excessive thirst, frequent urination, constipation, abdominal pain, fatigue and mental confusion.
  • Hypertrophic Osteoarthropathy (~ 5% of cases): Can occur with any type of lung cancer. It results in clubbing of the fingers and toes, along with painful, swollen joints in the arms and legs.
  • Thrombophlebitis (less than 5% of cases): Lung cancers, including adenocarcinoma, can produce substances that increase blood clotting, leading to deep vein thrombosis and potentially life-threatening pulmonary embolism.
  • Endocrine syndromes (rare): Certain hormones or hormone-like substances can be produced by lung adenocarcinoma, leading to various endocrine syndromes such as SIADH or Cushing syndrome, although this is more common in small cell lung cancer.

Complications

• Local Metastasis:  Local spread may involve spread directly to the pleura, diaphragm, pericardium, or bronchi with advanced disease spreading to the mediastinum, great vessels, trachea, oesophagus, vertebral column, or adjacent lobe.
• Distant Metastasis: Lung adenocarcinoma can spread to various organs, including the brain, bones, liver, and adrenal glands.
• Miliary pattern of pulmonary metastases: May be seen in epidermal growth factor receptor (EGFR)-positive adenocarcinoma
• Pleural effusion: This can occur due to the tumour invading the pleura.
• Superior vena cava syndrome: This can occur due to compression or invasion of the superior vena cava.

Subtypes

Histological Subtypes

The 2015 WHO histological subtypes are primarily based on the dominant histological pattern of the tumour.

• Adenocarcinoma in situ (AIS): Tumour confined within alveolar or glandular structures, with no invasion beyond the basement membrane. The maximum size is up to 3 cm, and complete surgical resection often leads to near 100% disease-free survival.
• Minimally invasive adenocarcinoma (MIA): Tumours with minimal invasion into surrounding tissues, with an invasive component 5 mm or less. The tumour size can reach up to 3 cm, and complete surgical resection typically results in high disease-free survival.
• Invasive adenocarcinoma: Tumour invades the surrounding stroma significantly, with an invasive component greater than 5 mm. The prognosis depends on multiple factors, including the degree of invasion, size, stage, and adenocarcinoma subtype. Invasive adenocarcinoma can be further divided into:
  • Lepidic predominant: Characterised by cancer cells spreading along the alveolar walls in a lepidic (scaly) pattern, often presenting as ground-glass opacities on imaging. It typically shows better prognosis due to its non-invasive nature.
  • Acinar predominant: This subtype involves formation of gland-like structures (acinus). It’s the most common subtype and is usually invasive, often presenting as a solid nodule or mass on imaging.
  • Papillary predominant: Characterised by tall columnar cells arranged around fibrovascular cores forming a papillary structure. Tumours are usually peripherally located and present as solid or part-solid nodules on imaging.
  • Micropapillary predominant: Known for small clusters of cells within alveolar spaces without fibrovascular cores. It’s less common but more aggressive, often associated with lymph node metastasis and poor prognosis.
  • Solid predominant: Characterised by large areas of tumour cells forming solid nests or sheets. This subtype is often associated with a worse prognosis due to its aggressive nature.
  • Invasive mucinous adenocarcinoma: This variant produces mucin, often resulting in a pneumonia-like appearance on imaging. It can be multifocal and bilateral, distinguishing it from other subtypes. The prognosis varies depending on the extent of invasion and spread. There is a high correlation with KRAS mutation.

Molecular Subtypes

The molecular subtypes are based on the genetic alterations that drive tumour growth:

• KRAS-mutant: Tumours with mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) gene. Most common subtype (25-35% cases). High prevalence in smokers.
• EGFR-mutant: Tumours with mutations in the epidermal growth factor receptor (EGFR) gene. More common in non-smokers, women and Asians (50%, vs Caucasians 10-15%).
• ALK-rearrangement: Tumours with rearrangements in the anaplastic lymphoma kinase (ALK) gene. Seen in 3-7% of cases. Typically, younger age, non-smokers or light-smokers.
• ROS1-rearrangement: Tumours with rearrangements in the ROS proto-oncogene 1 (ROS1) gene. Seen in 1-2% of cases. Often associated with non-smokers.
• Other less common molecular alterations include mutations in the BRAF, HER2, and MET genes, among others.

A tumour’s molecular subtype often informs the choice of targeted therapy, such as EGFR inhibitors for EGFR-mutant tumours or ALK inhibitors for ALK-rearrangement tumours.

In clinical practice, a lung adenocarcinoma is typically classified by both its histological and molecular subtype. For example, a tumour might be described as an “acinar predominant adenocarcinoma with an EGFR mutation”. This allows for a comprehensive understanding of the tumour’s characteristics and informs treatment planning.

Pathological Features

Histopathology

• Macroscopic: The tumour is typically located peripherally and often forms a solitary mass, which can vary in size. On cut section, it may appear grey-white with areas of haemorrhage or necrosis.
• Microscopic: Characterised by glandular differentiation or mucin production by the tumour cells. Depending on the subtype, there may be acinar, papillary, micropapillary, solid or lepidic growth patterns.

Genetics

Various mutations as discussed above can be found, such as EGFR, KRAS, and ALK mutations.

Radiological Features

General Features by Histological Subtypes

• Adenocarcinoma in situ (AIS) and Minimally invasive adenocarcinoma (MIA): These early-stage adenocarcinomas often appear as small, well-demarcated part-solid nodules or masses with ground-glass opacity (GGO) on CT imaging. Rarely solid.
• Invasive adenocarcinoma: The radiological appearance of invasive adenocarcinomas varies according to the predominant histologic subtype:
  • Lepidic predominant: Often appears as a peripheral mass with GGO and possible cystic change.
  • Acinar and Papillary predominant: Typically present as a solid nodule or mass, often with spiculated margins.
  • Micropapillary and Solid predominant: Likely to present as a solid mass with poorly defined margins, possibly with lymph node involvement or distant metastases.
  • Invasive mucinous adenocarcinoma: Often presents as a consolidation with air bronchograms and possible cystic change.

General Features by Molecular Subtypes

• EGFR-mutant: Tumours with EGFR mutations are more likely to present as peripheral nodules or masses, often with a GGO component. EGFR-mutant tumours are also more frequently associated with pleural tail signs.
• ALK-rearrangement: These tumours are often larger and more invasive at the time of diagnosis. They can present with nodules, masses, or lymphadenopathy and are more likely to show signet ring cell features histologically.
• KRAS-mutant: These tumours are often associated with smoking and are more likely to present as a solid mass, possibly with spiculated margins. They may also show more aggressive features such as cavitation.

General Features

• Adenocarcinomas are usually found in the periphery of the lung, as opposed to small cell lung carcinomas, which are more centrally located.
• Tumour invasion into pleura, causing thickening or effusion, is also a common finding.

CT

• Ground-glass opacities (60-75% of cases) is predominantly seen in the lepidic subtype, these are areas of hazy increased lung opacity, usually due to partial filling of airspaces.
• Solid or part-solid nodules (25-40% of cases) which may have irregular, spiculated borders which is a worrisome feature for malignancy.
• Lymphadenopathy (30-40% of cases) most commonly involved are mediastinal and hilar nodes.
• Cavitation within the tumour (around 10% of cases) is associated with a poor prognosis.

PET

• Increased uptake (over 90% of cases): The tumour typically shows increased uptake on PET, indicating increased metabolic activity. Useful in staging and assessing the response to therapy.

MRI

• Brain and spinal cord metastases (10-25% of cases): Can present as single or multiple enhancing lesions.

Grading and Staging

The staging for lung adenocarcinoma follows the same TNM staging system used for all non-small cell lung cancers (NSCLCs), developed by the American Joint Committee on Cancer (AJCC).

• For lung adenocarcinomas presenting as part-solid nodules on CT, the size of the invasive component (the solid part) is used to stage the tumour according to the TNM staging system.
• The ground-glass opacities represent non-invasive or minimally invasive disease, and therefore, are not included in the measurement for staging purposes.
• The measurement should be taken at the longest dimension of the solid component on lung window settings.

Tumour

• TX: Primary tumour cannot be assessed, or tumour proven by the presence of malignant cells in sputum or bronchial washings but not visualised by imaging or bronchoscopy.
• T0: No evidence of primary tumour.
• Tis: Carcinoma in situ.
• T1: Tumour ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus.
  • T1a: Less than or equal to 1cm,
  • T1b: Greater than 1 cm but less than or equal to 2 cm
  • T1c: Greater than 2 cm but less than or equal to 3 cm.
• T2: Tumour >3 cm but ≤7 cm or with any of the following features: involves main bronchus, invades visceral pleura, associated with atelectasis or obstructive pneumonitis.
• T3:
  • Tumour >7 cm or directly invades any of the following: chest wall, diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium; or tumour in main bronchus.
  • OR Multiple tumours are present in the same lobe of the lung.
• T4:
  • Tumour of any size that invades any of the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, oesophagus, vertebral body, carina.
  • OR Multiple tumours in different lobes of the same lung are classified as T4.

Nodes

• NX: Regional lymph nodes cannot be assessed.
• N0: No regional lymph node metastasis.
• N1: Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes.
• N2: Metastasis in ipsilateral mediastinal and/or subcarinal lymph nodes.
• N3: Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph nodes.

Metastasis

• M0: No distant metastasis.
• M1: Distant metastasis present.
  • 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)
  • M1c (multiple extrathoracic metastases in one or several organs).

Stage I

• IA: T1 or T2a, N0, M0
• IB: T2b or T2a with bronchial or lung lining invasion, N0, M0

Stage II

• IIA:
  • T1 or T2a or T2b or T3, N0, M0
  • T1 or T2a, N1, M0
• IIB:
  • T3, N0, M0
  • T1 or T2a or T2b, N1, M0

Stage III

• IIIA: Any T, N2, M0 or T3, N1, M0
• IIIB: Any T, N3, M0
• IIIC: T4 (with invasion into heart, trachea, esophagus, vertebral body, or separate tumour nodules in a different lobe of the same lung), N0, N1, N2, M0

Stage IV

• IVA: Any T, Any N, M1a, M1b
• IVB: Any T, Any N, M1c

The 5-year survival rates associated with each stage, according to the American Cancer Society, are approximately as follows:

• Stage I: 60% to 80%
• Stage II: 30% to 50%
• Stage III: 10% to 30%
• Stage IV: less than 10%

Differential Diagnosis

• Lung metastases: A solitary lung nodule may represent a metastasis from a primary tumour elsewhere in the body.
• Squamous cell carcinoma of the lung: Typically centrally located and may show cavitation. Characteristic findings include keratin pearls and intercellular bridges.
• Small cell lung cancer: Usually centrally located and grows rapidly. Cells have a high nuclear to cytoplasmic ratio and often show “salt and pepper” chromatin.
• Benign pulmonary nodules: May present as a solitary nodule but usually lack the growth over time typical of malignancies.

Management

• Patients are usually managed by a multidisciplinary team, including thoracic surgeons, medical oncologists, radiation oncologists, pulmonologists, and radiologists.
• For early-stage disease, surgical resection is the treatment of choice.
• For advanced disease, a combination of chemotherapy, radiation therapy, targeted therapies or immunotherapy may be used.
• Targeted therapies are especially important for tumours with specific genetic mutations.