McMaster Pathophysiology Review

Lung cancer
Overview
Clin Chest Med. 2011 Dec;32(4):605-44.
Canadian Cancer Society: Canadian Cancer Statistics 2012

Lung cancer is the leading cause of cancer-related death in Canada and

worldwide (about 27% of cancer deaths in Canada).
Overall incidence of lung cancer is:
Higher in men than women
Declining for men since 1980s
Declining for women since mid-2000s (reversal of increasing trend
since 1980s)
Second highest cancer incidence in both sexes after prostate (males)
and breast (females) cancers.
Lung cancer has a poor prognosis, which means incidence closely matches
mortality. The five-year relative survival rate of lung cancer is 16% in Canada.
Small-cell lung carcinoma (SCLC, 15% of all lung cancer) and non-small-
cell lung carcinoma (NSCLC, 85%) are the two major forms of lung cancer.
Non-small-cell lung cancer is further classified into squamous-cell
carcinoma, adenocarcinoma, and large-cell carcinoma.
Smoking is the single most important risk factor for lung cancer, which can
cause all types of lung cancer but is more strongly linked with SCLC and
squamous-cell carcinoma.

Etiology
 Surg Oncol Clin N Am. 2011 Oct;20(4):605-18.
Clin Chest Med. 2011 Dec;32(4):605-44.
Biochem Pharmacol. 2011 Oct 15;82(8):1015-21.

Cigarette smoking
Cigarette smoking is the leading cause of lung cancer, accounting for about
85% of lung cancers. Risk for lung cancer increases with the duration,
intensity and depth of smoke inhalation.
Second-hand (passive) smoking also causes lung cancer, but is less
strongly associated compared to active smoking.
Cigarettes contain multiple carcinogens (more than 60) that have been
shown to induce cancers in laboratory settings.
J Natl Cancer Inst. 2004 Jan 21;96(2):99-106.
Polycyclic aromatic hydrocarbons (PAH) such as benzo[α]pyrene
produce mutations in the p53 gene. G to T transversion within the p53
gene is a molecular signature of lung tumours caused by tobacco
mutagens.
N-nitroso compounds are a major group of chemicals found in tobacco
smoke, several of which are potent animal carcinogens.
Nicotine: causes addiction to cigarette smoking and is also a promoter for
carcinogenesis.
Sympathetic/parasympathetic activation: nicotine binds to and
activates nicotinic cholinergic receptors, which are located on both
sympathetic and parasympathetic postganglionic neurons. The
endogenous ligand for this receptor is acetylcholine (nicotine is not
naturally found in humans). Therefore, smoking stimulates both
sympathetic (increased heart rate, blood pressure) and parasympathetic
(intestinal motility, relaxation) systems, releasing a whole range of
hormones and neurotransmitters into the circulation.
Addiction: nicotine causes dopamine release from the nucleus
accumbens, mediating reward and addiction
Carcinogen: nicotine does not initiate carcinogenesis, but it does
promote initiated cells by nicotinic cholinergic receptor signalling in the
lungs. Nicotine has been shown to inhibit apoptosis, proliferate cells,
 and cause angiogenesis in lung tumours.
Distribution of carcinogens: Cigar and pipe tobacco smoking produces
relatively large particles that only reach the upper airways, unlike cigarette
smoking, which produces fine particles that reaches the distal airways. Thus,
cancer risk is lower with cigar and pipe smoking. The addition of anti-irritants
(e.g. menthol) to cigarettes allows deeper inhalation and a more rapid rise in
serum nicotine levels, increasing the addictiveness of cigarettes.
Smoking cessation: smokers at all ages can benefit from the cessation of
smoking; however, the risk still remains elevated compared to never smokers.

Never smokers
Defined as people who smoked fewer than 100 cigarettes in their lifetime.
Accounts for 25% of lung cancers worldwide and is seen as a distinct lung
cancer type.
Associated with: female cases, East Asian populations, family history,
adenocarcinoma type, EGFR mutations, and better prognosis (23% 5-year
survival vs 16% for smokers).

Environmental exposure
A number of environmental risk factors have been identified, most of which
relates to occupational exposures such as asbestos, tar, soot, and a number
of metals such as arsenic, chromium, and nickel.
Air pollution has also been linked to increased risk of lung cancer.
Indoor radon-222, a radioactive gas that percolates up soil and becomes
concentrated inside buildings, have been posed as a significant risk factor for
lung cancer.
Health Phys. 2004 Jul;87(1):68-74.
Smoking potentiates the effect of a number of occupational lung carcinogens
(e.g. asbestos), such that risk is multiplicative instead of additive.

Genetics
 There is an increased risk of lung cancer among first-degree relatives,
indicating a genetic susceptibility.
Candidate gene studies have identified several enzymes in the cytochrome
P-450 system as risk factors for lung cancer. One such gene is CYP1A1,
which codes for aryl hydrocarbon hydroxylase. Certain alleles of CYP1A1 are
thought to increase the risk of lung cancer through increased metabolic
activation of procarcinogens derived from cigarette smoke.

Precursor lesions
Precursor lesions are of increasing interest due to implication in lung cancer
screening.
Currently there are 3 types of recognized precursor lesions:
Squamous dysplasia and carcinoma: precursor lesion for squamous-cell
carcinoma.
Adenomatous hyperplasia: precursor lesion for bronchioalveolar
carcinoma, a form of adenocarcinoma.
Idiopathic pulmonary neuroendocrine cell hyperplasia: precursor for
pulmonary carcinoids.
Precursor lesion for SCLC is unknown.

Pathogenesis
N Engl J Med. 2008 Sep 25;359(13):1367-80.
Clin Chest Med. 2011 Dec;32(4):703-40.
Am J Respir Cell Mol Biol. 2005 Sep;33(3):216-23.

The pathogenesis of lung cancer is like other cancers, beginning with

carcinogen-induced initiation events, followed by a long period of promotion
and progression in a multistep process. Cigarette smoke both initiates and
promotes carcinogenesis. The initiation event happens early on, as evidenced by
similar genetic mutations between current and former smokers (e.g. 3p deletion,
p53 mutations). Smoking thus causes a “field effect” on the lung epithelium,
providing a large population of initiated cells and increasing the chance of
transformation. Continued smoke exposure allows additional mutations to
accumulate due to promotion by chronic irritation and promoters in cigarette smoke
(e.g. nicotine, phenol, formaldehyde). The time delay between smoking onset and
cancer onset is typically long, requiring 20-25 years for cancer formation. Cancer
risk decreases after smoking cessation, but existing initiated cells may progress if
another carcinogen carries on the process.

SCLC and NSCLC are treated differently because they (i) originate from different
cells, (ii) undergo different pathogenesis processes, and (iii) accumulate different
genetic mutations. SCLC often harbours mutations in MYC, BCL2, c-KIT, p53, and
RB, while NSCLC often has mutations in EGFR, KRAS, CD44, and p16. These are all
either tumour suppressor genes or oncogenes. See Cancer genetics and Cancer
biology chapters for a description of how mutations like these can cause cancer.
Classification of invasive lung
cancer
Semin Roentgenol. 2011 Jul;46(3):178-86.
Clin Chest Med. 2002 Mar;23(1):65-81, viii.

Lung cancer diagnosis is established by biopsy of tumours found on imaging

(chest X-ray or CT). The pathological types are divided into SCLC and NSCLC.
NSCLC is further divided into the types below:

Lung cancer Location in the lung Features

type

Adenocarcinoma Peripheral Most common type of lung cancer in

(38%) nonsmokers and morecommon in
women
Arises from small airway epithelial
and type II alveolar cells
Should test for EGFR mutation for
possible targeted therapy
Sometimes appear at site of scarring
Tend to form glands and secrete
mucin

Squamous cell ⅔ central Strongly associated with cigarette

carcinoma (20%) smoking
⅓ peripheral
Arises from large (proximal) airway
epithelial cells
Tend to create obstruction and cause
distal atelectasis
Intrathoracic spread rather than
distant metastasis; therefore, best
prognosis
Small-cell lung Central Strongest smoking association
carcinoma (endobronchial) Arises from pulmonary
(SCLC) (14%) neuroendocrine cells, which are
Neuroendocrine
responsible for making
cells are
neurotransmitters, growth factors,
located at
and vasoactive substances
bifurcation of
Causes paraneoplastic syndrome:
small airways
commonly secrete ADH (SIADH) or
ACTH (ectopic Cushing syndrome)
Rapid growth and early distant
metastasis (brain, liver, bone),
leading to the worst prognosis

Large cell Peripheral Behave similar to adenocarcinomas

carcinoma (3- but the lesions formed tend to be
5%) somewhat larger

Pathophysiology and clinical

features
Cancer. 1985 Oct 15;56(8):2107-11.
Chest. 2007 Sep;132(3 Suppl):149S-160S.
Clin Oncol (R Coll Radiol). 2002 Oct;14(5):338-51.

The symptoms produced by the primary tumour depend on its location (i.e., central
vs peripheral). Central tumours generally produce symptoms of cough, dyspnea,
atelectasis, postobstructive pneumonia, wheezing, and hemoptysis; whereas,
peripheral tumours, in addition to causing cough and dyspnea, can lead to pleural
effusion and severe pain as a result of infiltration of parietal pleura and the chest
wall.

Symptoms Mechanism and pathophysiology

Primary lung lesion symptoms

Cough (50-70%) Presence of a mass irritates the cough receptors in

the airway
More common in squamous cell carcinoma andSCLC
(more commonly found in the central airways)
Obstruction from central airway could also lead to
post-obstructive pneumonia and distal atelectasis

Weight loss (46%) Cancer induced lipolysis and proteolysis leads to loss
of adipose and skeletal muscle. Protein synthesis is
also reduced via a number of mechanisms.
Curr Opin Gastroenterol. 2010 Mar;26(2):146-51.

Hemoptysis (25-50%) Tumour in the central airway

Blood vessels resulting from tumour-induced
angiogenesis are leaky and tortuous, predisposing
them to easy rupture and causing hemoptysis

Dyspnea (25%) Extrinsic or intraluminal airway obstruction

Activation of mechanoreceptors and chemoreceptors
in lungs due to cachexia or hypoxemia/acidosis
J Pain Symptom Manage. 1997 Apr;13(4):220-32.
See also Mediastinal involvement

Chest pain (20%) Tumour involving pleural surface causing pleuritic

chest pain
See also Mediastinal involvement

Mediastinal involvement

Superior vena cava Obstruction of superior vena cava by the tumour

syndrome More common in SCLC (central tumour)
 2-4% of lung cancer patients develop it at some point
See Oncologic emergencies chapter

Pericardial effusion Tumours can at times infiltrate into the pericardium or

press on the heart causing pericardial effusion
See Oncologic emergencies chapter

Pleural effusion Benign pleural effusion may be due to lymphatic

obstruction, post-obstructive pneumonitis, or
Chest pain
atelectasis
Dyspnea
Malignant pleural effusion occurs when malignant
cells are present in pleural fluid

Dysphagia Enlargement of the subcarinal lymph nodes

compressing on the middle third of the esophagus

Pancoast tumour Tumour originates in the apical portion of the lung

(superior sulcus Occurs in 5% of non-small cell lung cancer
tumour) Invasion of brachial plexus causes pain and muscle
wasting of arm and hand
Shoulder or arm
Invasion of superior cervical sympathetic ganglion
pain
leads to Horner syndrome:
Weakness,
Loss of sympathetic control of Muller muscle
atrophy,
that elevates the upper eyelid leads to partial
numbness of
ptosis
ipsilateral hand
Loss of sympathetic drive of iris dilator muscle
Horner syndrome
leads to miosis (excessive constriction of the
Ptosis
pupil)
Miosis
Anhidrosis (lack of sweating) caused by
Anhidrosis
impingement of sweat gland fibres arising from

N Engl J cervical sympathetic ganglion

Med. 1997 Nov

Phrenic nerve involvement can lead to unilateral
6;337(19):1370-6.
diaphragm paralysis
Recurrent pharyngeal nerve involvement can lead to
 voice hoarseness

Paraneoplastic syndromes: symptoms in cancer patients not attributable to

tumour compression or invasion

Mayo Clin Proc. 2010 Sep;85(9):838-54.

Ectopic Cushing Ectopic secretion of adrenocorticotrophic

syndrome hormone (ACTH) → adrenal cortisol secretion
→ weight gain, hypertension, hypokalemia, muscle
See Adrenal
weakness
cortex chapter in
Most common form of ectopic secretion in lung
Endocrinology
cancer, especially SCLC

Syndrome of Ectopic secretion of ADH → retain free water in

inappropriate collecting ducts
antidiuretic hormone Euvolemic hyponatremia and concentrated urine
production (SIADH) Mild symptoms include headache and
weakness, severe symptoms include altered mental
See
status, seizures, respiratory depression, and death
Hyponatremia in
Common in SCLC
Nephrology for
details

Hypercalcemia Increased secretion of PTHrP → acts like parathyroid

hormone to increase bone resorption and renal
calcium reabsorption → hypercalcemia
Associated with squamous cell carcinoma
See Oncologic emergencies chapter

Hypertrophic Associated with NSCLC, especially the

osteoarthropathy and adenocarcinoma type
digital clubbing Periosteal proliferation of the tubular bones
characterized by (i) painful symmetrical arthritis of
 the ankles, knees, wrists and elbows, and (ii) digital
clubbing.
Mechanism is due to secretion of various factors
including VEGF, PDGF, and prostaglandin E2.

Distant metastasis

Metastatic sites Frequently asymptomatic however 33% of patient

include brain, bone, presents with symptoms relating to distal metastasis
liver and adrenal See Oncological emergencies and Metastasis
glands chapters for details.

Treatment
Lung Cancer: the diagnosis and treatment of lung cancer (National Institute for
Health and Clinical Excellence, 2011)

Smoking cessation
Smoking increases the risk of pulmonary complications after surgery
Three main interventions exist in addition to counselling and support:
Nicotine replacement therapy (NRT): can be purchased in many forms
including gum and transdermal patch; all forms increases rate of quitting
by 50-70%.
Cochrane Database Syst Rev. 2008 Jan 23;(1):CD000146.
Antidepressants: bupropion and nortriptyline are as effective as NRT;
other antidepressants such as selective serotonin reuptake inhibitors
(SSRI) are not effective.
Cochrane Database Syst Rev. 2007 Jan 24;(1):CD000031.
Nicotine receptor partial agonist: varenicline is more effective than
bupropion and NRT.
Cochrane Database Syst Rev. 2012 Apr 18;4:CD006103.
Surgery
Surgical resection of the tumour and some normal tissue around it.
First line of choice for NSCLC who are medically fit to undergo surgery.

Radiation therapy
Indicated for patients with stage I, II, III NSCLC.
See Introduction to neoplasia for definition of TMN staging.
In lung cancer, stages I, II, and III describe various sizes of primary
tumour and lymph node involvement without distant metastasis. Any
distant metastasis is automatically stage IV.
Also used in combination with surgery for NSCLC and with
chemotherapy for SCLC.

Chemotherapy
First line of treatment for SCLC, which are often disseminated upon clinical
presentation.
Also indicated for patients with more advanced stage of NSCLC (to improve
survival, disease control or for palliative care).
First line therapy for NSCLC with EGFR mutations involves targeted therapies.
Epidermal growth factor receptor (EGFR): epidermal growth factor
(EGF) stimulates cell proliferation by binding the EGFR and causing
tyrosine kinase activation of effectors. NSCLC often harbour EGFR
mutations that make the receptor more active, signalling downstream
effectors to increase cell proliferation. Two classes of drugs target this
particular aberrant protein: EGFR tyrosine kinase inhibitors (erlotinib
and gefitinib) and monoclonal antibody targeted at EGFR (cetuximab).
Both classes of drugs are usually effective initially in tumours with EGFR
mutations, but relapse often occurs due to accumulation of other
mutations.
Palliative care
Advanced disease may be present at the diagnosis. Given the poor prognosis,
the goals of lung cancer therapy may be switched from curative to palliative.
Palliative care aims to improve the quality of life and reduce suffering for
patients rather than to prolong life.
Studies have shown that early palliative care actually prolongs life in lung
cancer patients (by 2.7 months in a study with metastatic NSCLC patients). It
also reduces patient suffering, healthcare costs, unnecessary treatment, and
impart greater patient and family satisfaction.
N Engl J Med. 2010 Aug 19;363(8):733-42.

Posted December 27, 2012 in Oncology, Respirology

by Ke Wu

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