Lung cancer

Lung cancer is the second most frequent cancer, but it causes the most cancer-related deaths worldwide. Smoking is famously the biggest risk factor, and also the reason that lung cancer incidence increased dramatically during the 1900s. 85 – 90% of cases of lung cancer are attributable to smoking.

Around 95% of all primary lung tumors are carcinomas (epithelial origin), and these four types are most important:

• Non-small-cell lung cancer (NSCLC)
  • Adenocarcinoma
  • Squamous cell carcinoma (SCC)
  • Large cell lung carcinoma (LCLC)
• Small cell lung cancer (SCLC)

Non-small cell lung cancer (NSCLC) accounts for 85% of cases, while SCLC accounts for 15% of cases. Of the NSCLC, adenocarcinoma is the most common, followed by SCC and LCLC. SCLC is a neuroendocrine tumour.

Etiology

• Smoking
• Environmental exposure to carcinogens
  • Radon gas
  • Uranium
  • Asbestos
  • Polycyclic hydrocarbons
• Family history (Genetic susceptibility)

Smoking is by far the important cause of lung cancer, and it's estimated that 90% of lung cancer cases would be avoided if not for smoking and 80% of lung cancer deaths are due to tobacco use. Lung adenocarcinoma is not as strongly associated with smoking and is actually more common in nonsmokers than in smokers. The other types of lung cancer are very strongly associated with smoking.

We can compare smoking habits with a measure called “pack-year”. If you have smoked 1 pack of cigarettes (20 pcs) every day for one year you have accumulated 1 pack-year. If you smoke one half pack every day for four years you have accumulated 2 pack-years. This allows us to quantify smoking habits, and it has prognostic significance. Higher pack years means higher risk of smoking-induced cancer, as well as a poorer prognosis in the case of lung cancer.

Pathology

Localisation

The different types of lung tumors have a tendency to where they prefer to originate in the lung, either centrally or peripherally.

Centrally in this case means around the hilum and main bronchi. SCC and SCLC originate here. Central cancers usually cause symptoms earlier than peripheral cancers, because the cancers are closer to the airways. Central cancers also more frequently spread to surfaces like the mediastinum. It’s much harder to remove cancers surgically that are close to the bronchi without damaging the bronchi, so these cancers are much harder to treat surgically.

Peripherally in this case means anywhere else in the lung, often further away from the airways, often just beneath the pleural surface, subpleurally. Adenocarcinomas and LCLC originate here. These cancers will show symptoms at a much later stage than the central cancers, but they are also much easier to remove surgically.

Squamous cell carcinoma

SCC are found centrally, where they originate from major bronchi. Well-differentiated tumors will show keratinization, poorly-differentiated tumors won’t. It’s highly associated with smoking, but not with HPV, like laryngeal SCC is.

It follows the following process of development:

1. Normal bronchial epithelium
2. Basal cell hyperplasia
3. Squamous metaplasia
4. Squamous dysplasia
5. Carcinoma in situ
6. Invasive carcinoma

This development takes many years. The pathohistology slide shows this progression. These tumors usually form cavities because of central necrosis.

Adenocarcinoma

Adenocarcinomas are the most common type and are found peripherally. They’re the most common type in women and is not associated with smoking, but rather with several genetic mutations, like:

• EGFR (epidermal growth factor receptor)
• K-RAS
• ROS
• ALK/EML4
• PD-L1

These mutations are important because we have immunotherapy drugs which target the mutations specifically. The higher the cancer cells' expression of the protein, the higher the odds that the immunotherapy will be effective.

TTF-1 is a transcription factor that is expressed in lung adenocarcinomas and small cell carcinomas that is commonly used to distinguish between these types and squamous cell carcinoma, which doesn’t express TTF-1.

Neuroendocrine carcinomas

These cancers originate from neuroendocrine cells in the lung, cells that respond to nerve signals by producing endocrine hormones. They are also related to smoking. The grading system for neuroendocrine carcinomas is special; it’s dependent on the rate of mitosis in the tumor. The stages go like this:

Stage	Rate of mitosis	Name	Prognosis
I	Slow	Carcinoid	Best prognosis
II		Atypical carcinoid
III	Fast	Large-cell lung carcinoma
III	Fast	Small-cell lung carcinoma	Worst prognosis

Small cell lung carcinomas (SCLC) are found centrally. They grow very quickly (have a very high turnover, tumour doubles every 50 days) and metastasize early. Because of this is surgery very rarely possible, however, thanks to the high turnover it responds well to chemotherapy. Because they grow so quickly, mitotic bodies are usually aplenty.

Large cell lung carcinoma is actually an umbrella term for a group of very poorly differentiated carcinomas, however one subtype, large cell neuroendocrine carcinoma, is neuroendocrine in origin. Large cell carcinomas are found peripherally.

Metastasis

Lung cancer usually spreads to:

• Hilar lymph nodes
• Mediastinum
• Pleura (pleural carcinosis)
• Brain
• Adrenal gland

Pancoast tumour

Any lung tumor, regardless of subtype, is called a Pancoast tumor if it occurs in the apex of the lung. There are many structures in that area which the tumor can compress or invade, and so Pancoast tumors therefore have multiple extra consequences:

• Shoulder pain – due to compression of local nerve roots
• Pain in upper extremities – due to compression of the brachial plexus
• Horner syndrome – due to compression of the stellate ganglion
  • Horner syndrome is a triad of miosis, ptosis, and facial anhidrosis
• Superior vena cava syndrome – due to compression of the SVC
  • Dyspnoea
  • Oedema of the face
• Hoarse voice – due to compression of the recurrent laryngeal nerve

Paraneoplastic syndrome

Paraneoplastic syndromes are more frequent in lung cancer compared to other cancers, espacially in SCLC. Common occurrences include:

• ACTH secretion, leading to Cushing syndrome
• ADH secretion – leading to syndrome of inappropriate ADH (SIADH)
• Parathyroid hormone-related protein (PTHrP) secretion, leading to hypercalcaemia
• Dermatomyositis
• Acanthosis nigricans

Lymphangitis carcinomatosa may occur in the lung. It’s caused by the lymph vessels being filled up with invading malignant tumor cells. This causes the lymph vessels to dilate and become visible.

Clinical features

Lung cancer can produce many different signs and symptoms. They may be due to the intrathoracic effects, distant metastases, or paraneoplastic syndromes. Central carcinomas, like SCC and SCLC, tend to produce symptoms more often.

The most common symptom is cough, which is present in 50 – 75% of lung cancer cases at presentation. The second most common symptom is dyspnoea.

Other possible clinical features include:

• Chest pain
• Haemoptysis
• Hoarseness
• Weight loss
• Stridor (due to tracheal obstruction)
• Dysphagia (due to oesophageal obstruction)
• Bone pain (due to metastases)
• Cushing syndrome (due to paraneoplastic syndrome)
• Neurological symptoms (due to metastases)
• SIADH (due to paraneoplastic syndrome)
• Superior vena cava syndrome
• Horner syndrome
• Clubbing of the fingers (due to paraneoplastic syndrome)

Diagnosis and evaluation

The initial investigation is usually chest x-ray, which may show a solitary nodule. In this case, the patient proceeds to a contrast chest CT.

For a definite diagnosis, histopathology is required. Ideally, a large enough biopsy should be taken to allow for immunohistochemical and genetic analysis, as this has implications for treatment and prognosis. There exist multiple modalities for obtaining biopsy, including endobronchial ultrasound-guided biopsy (EBUS), transthoracic needle biopsy, transoesophageal endoscopic ultrasound, mediastinoscopy, etc.

Acquiring tissue specimens is better than acquiring cytologic specimens, as only tissue specimens yield enough material for immunohistochemistry and genetic testing. This is important for prognosis and treatment. However, cytologic specimen is usually sufficient to determine the histological subtype and to confirm the cancer diagnosis. Cytology is most commonly acquired from a malignant pleural effusion, but can also be acquired from sputum analysis and bronchoalveolar lavage.

When the diagnosis is made, several staging and preoperative investigations should be performed:

• Evaluation of performance status (ECOG)
• CT chest, abdomen, pelvis
• Pulmonary function test
• Abdominal ultrasound
• If CT finds metastases (advanced disease), then perform brain MRI for brain metastases and x-ray/bone scintigraphy for skeletal metastases

Treatment

The treatment for NSCLC and SCLC is different.

Non-small cell lung cancer (NSCLC)

For NSCLC, tumours up to and including stage IIIb are potentially curable:

• Stage I – II – surgery alone
• Stage IIIa – surgery alone
• Stage IIIb – radiochemotherapy
• Stage IIIc – IV – palliative, any combination of chemo, radio, immunotherapy

For incurable NSCLC, the genetic and immunohistochemical analysis becomes important. We have specific targeted therapy and immunotherapy for PD-L1, KRAS, EGFR, ALK, and ROS mutations, which may provide years of life if there is a good response.

The most commonly used chemotherapy drugs are cisplatin and taxanes like paclitaxel.

Small cell lung cancer (SCLC)

For SCLC, the so-called “limited disease” (cancer has not spread beyond the hemithorax, corresponds to stages I – IIIb) is curable. SCLC has a very high turnover and is therefore sensitive to radio and chemotherapy, which is the first choice. “Extensive disease” refers to cancer which has spread beyond one hemithorax and is deemed incurable, but chemotherapy may still provide months or years of life.

Prophylactic cranial irradiation is used for SCLC, as it improves survival by killing brain metastases which are often already present but not visible on scans. This can both be used curatively (for limited disease) and palliatively (for extensive disease).

Surgical treatment

Surgery is the main treatment of NSCLC stages I – IIIa. It is not used for SCLC.

Surgical options include wedge resection, segmentectomy, lobectomy, and pneumonectomy. The less invasive options are preferred if they allow for margin negative (R0) resection. Lobectomy is usually preferred over wedge resection or segmentectomy, as the risk for R1 resection is smaller, but the latter may be chosen if the patient is deemed to have insufficient pulmonary function to tolerate a lobectomy.

Surgery is preferably performed with video-assisted thoracoscopy (VATS) rather than open surgery.‎