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Lung cancer

Introduction and epidemiology

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
  • 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. 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.

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 less strongly associated with smoking. It’s strongly associated with several genetic mutations, like:

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

These mutations are important because we have drugs which target the mutations specifically.

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.

Clinical features

Lung cancer usually spreads to:

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

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.

Symptoms of lung cancer include:

• Cough
• Haemoptysis
• Progressive dyspnoea
• Weight loss

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 syndromes are common in lung cancer, 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