Lung cancer

Lung cancer is the leading cause of cancer death worldwide with around 70% of cases attributable to smoking. Lung cancer is classified into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). SCLC is characterized by its central location, rapid tumor growth, early metastases, and association with numerous paraneoplastic syndromes. NSCLC comprises a number of cancer types, including peripheral adenocarcinoma and central squamous cell carcinoma. Symptoms such as dyspnea, cough, hemoptysis, and chest pain typically develop in advanced stages of disease. New onset cough or pneumonia constitute warning signs, particularly in smokers. Over 50% of patients have metastases at the time of diagnosis, most commonly in the brain, liver, adrenal glands, or bones. Solitary pulmonary nodules detected on chest x-ray should be compared to previous chest x-rays, if available, or evaluated in a chest CT scan. Bronchoscopy or CT-guided biopsy confirm the diagnosis. Chemotherapy is the mainstay of treatment. Surgical resection of one or more pulmonary lobes is only possible in early stages of lung cancer. Approx. 65% of patients are inoperable at the time of diagnosis because of tumor metastases or poor pulmonary function. Radiation therapy is indicated in nonsurgical candidates, as an adjunct to chemotherapy, or for palliative management of metastastic disease. Even with a multimodal approach, the 5-year survival rate is 17%.

• Incidence: : second most common carcinoma ; leading cause of cancer death (worldwide)
• Peak incidence: 50–70 years
• Sex: ♂ > ♀ (∼ 3:1)
  • Adenocarcinoma is an exception: ♂ < ♀ (∼ 1:6)

References:^[1][2][3]

Epidemiological data refers to the US, unless otherwise specified.

• Risk factors
  • Nicotine: smoking causes approx. 90% of lung cancers
  • Occupational and environmental exposure to carcinogens: passive smoking; , asbestos, arsenic, radon, uranium , chromium, nickel, fumes from industry, and traffic
  • Family history (genetic predisposition)
  • Scar tissue in the lungs (e.g., pulmonary fibrosis, history of tuberculosis)
• Idiopathic: particularly adenocarcinoma

References:^[4][1][2][5]

Tumor type		Frequency	Localization	Characteristics
Small cell lung cancer (SCLC)		∼ 15%	Central	Strong correlation with cigarette smoking Pulmonary neuroendocrine tumor; associated with several paraneoplastic syndromes Very aggressive ; early metastases Associated mutations: l-myc
Non-small cell lung cancer (NSCLC) approx. 85%	Adenocarcinoma	∼ 40%	Peripheral	Most common type of lung cancer overall and in women Most common lung cancer in non-smokers Associated mutations: EGFR , ALK , and KRAS Distant metastases are common Noninvasive subtype: bronchioloalveolar carcinoma
	Squamous cell carcinoma (SCC)	20–25%	Central airways	Strong association with smoking! Cavitary lesions are common Direct spread to hilar lymph nodes ↑ Parathyroid hormone-related protein (PTHrP) leads to hypercalcemia (See Hypercalcemia of malignancy) [6]
	Large cell carcinoma	5–10%	Peripheral	Late metastases Poor prognosis

References:^{[7][4][8][1][2][3][9][10][11][12]}

Symptoms commonly only develop in advanced stages of the disease.

Pulmonary symptoms

• Cough (chronic or recently developed)
• Hemoptysis
• Progressive dyspnea
• Chest pain

Recurring common colds in patients ≥ 40 years should always raise the suspicion of lung cancer!

Extrapulmonary symptoms

• Constitutional symptoms (weight loss, fever, weakness)
• Clubbing of the fingers and toes
• Signs or symptoms of tumor infiltration or compression of neighboring structures
  • Superior vena cava syndrome (SVC syndrome): Compression of the superior vena cava impairs the venous backflow to the right atrium, resulting in venous congestion in the head, neck, and upper extremities.
    • Feeling of fullness in the head
    • Dyspnea
    • Edema of the upper extremities and face
    • Prominent venous pattern on the chest, face, and upper extremities
  • Paralysis of the recurrent laryngeal nerve: hoarseness
  • Paralysis of the phrenic nerve: results in diaphragmatic elevation and dyspnea
  • Malignant pleural effusion: dullness on percussion, reduced breath sounds on the affected side
  • Dysphagia
  • Postobstructive pneumonia (See secondary pneumonia)

Paraneoplastic syndromes

NSCLC	SCLC
General paraneoplastic manifestations: cachexia, increased risk of thrombosis (and lung embolism!) Dermatomyositis Hypoglycemia: insulin-like-factor secretion Acanthosis nigricans See also paraneoplastic syndromes.
Endocrine Hypercalcemia of malignancy (squamous cell carcinoma) Gynecomastia (large cell carcinoma) Other Hypertrophic osteoarthropathy (also known as Pierre-Marie-Bamberger disease) Clubbing of the fingers and toes (Hippocratic fingers) Swelling and pain in joints and long bones Hypercoagulability and thrombophlebitis migrans (adenocarcinoma) Nonbacterial verrucous endocarditis (adenocarcinoma)	Endocrine Cushing syndrome Syndrome of inappropriate antidiuretic hormone secretion (SIADH) Neurologic Lambert-Eaton syndrome (similar clinical features as myasthenia gravis) Paraneoplastic cerebellar degeneration Peripheral neuropathy

Symptoms of metastatic disease

• Early lymphogenic and hematogenic metastasis (particularly in SCLC)
  • Brain: headaches; , behavioral changes, seizures; , focal motoric deficits (see also brain metastases)
  • Liver: nausea, jaundice, ascites (see also metastatic liver disease)
  • Adrenal gland: usually asymptomatic
  • Bones: bone pain

Approx. 50% of patients with NSCLC and 60–70% of patients with SCLC have metastatic disease at the time of presentation!

References:^{[4][8][1][2][3][5][13][14][15]}

Pancoast tumor

• A peripheral lung carcinoma (predominantly NSCLC) that is located in the superior sulcus of the lung; often involves the cervical sympathetic nerves and brachial plexus.
• Symptoms of Pancoast syndrome
  • Severe, localized pain in the axilla and shoulder
  • Horner syndrome
  • Atrophy of arm and hand muscles
  • Edema of the arm, facial swelling, morning headaches
• Cough; , hemoptysis, dyspnea , SVC syndrome, and recurrent laryngeal nerve compression are uncommon and are associated with advanced disease (poor prognosis).

Bronchioloalveolar carcinoma

• Noninvasive subtype of adenocarcinoma (also known as adenocarcinoma in situ)
• Chest x-ray findings
  • Early disease: solitary peripheral nodule
  • Advanced disease: diffuse consolidation that can resemble pneumonia

Lymphangitic carcinomatosis

• Spread of cancer cells along lymphatic vessels
• Radiologically, a streaky-reticular pattern may be observed.

References:^{[4][8][3][9][16]}

Staging of NSCLC

The staging of NSCLC is based on the UICC TNM staging system. This classification defines four stages from I to IV, corresponding to cancer spread.

UICC stages	TNM	Brief description
Stage IA	T1	Tumor size ≤ 7 cm No lymph node involvement beyond the ipsilateral hilar nodes No mediastinal invasion No metastases
Stage IB	T2a
Stage IIA	T2b, N0 or T1, N1
Stage IIB	T3, N0 or T2b, N1
Stage IIIA	Up to T4, N1 or T3, N2	Tumor size > 7 cm Mediastinal lymph node involvement and/or regional spread No mediastinal invasion or metastases
Stage IIIB	T4, N2 or N3	Mediastinal invasion Distant nodes and/or distant metastases
Stage IV	M1

As soon as distant metastases are detected, the cancer is classified as UICC stage IV!

Staging of SCLC

The SCLC staging mostly depends on whether the tumor is limited to one hemithorax or has spread beyond the hemithorax (according to the Veterans Administration Lung Study Group). Alternatively, the TNM classification may be used.

Classification	Cancer spread	Corresponding TNM	Cancer stage at diagnosis
Very limited disease	Confined to one hemithorax	T1-2, N0-1	approx. 5%
Limited disease		T3-4, N0-1 or T1-4, N2-3	approx. 20%
Extensive disease	Beyond one hemithorax Contralateral supraclavicular or hilar lymph node involvement Malignant pericardial or pleural effusion Distant metastasis	M1	approx. 75%

References:^[8][17]

Approach to suspected lung cancer and workup of a solitary pulmonary nodule

1. Chest x-ray and comparison to previous images if available
2. CT imaging for further evaluation indicated if
   • New lesion detected on chest x-ray
   • Changes (e.g., enlargement) compared to previous chest x-ray
   • No previous CXR is available
3. Assessment of lesion size and probability of malignancy (based on CT findings and patient characteristics)
   • Increased probability of malignancy
     • History of smoking
     • Patient age > 40 years
     • Other known risk factors (e.g., positive family history, asbestos exposure)

Solid lesion size	Probability of malignancy	Next step
< 4 mm	Low	No follow-up needed
	High	Follow-up CT at 12 months
4–6 mm	Low	Follow-up CT at 12 months
	High	Follow-up CT at 6–12 months
6–8 mm	Low	Follow-up CT at 6–12 months
	High	Follow-up CT at 3–6 months
≥ 8 mm	Low or high	PET and/or biopsy

In patients aged > 40 years, any pulmonary nodule detected on CXR is considered lung cancer unless proven otherwise!

Chest x-ray

• Findings
  • Solitary nodule
  • Indirect signs: atelectasis, postobstructive pneumonia, pleural effusion (particularly unilateral), mediastinal widening, cavitary lesions

CT imaging

• Signs of malignancy
  • Solid lesion ≥ 8 mm
  • Irregular margins
  • Spicules
  • No or irregular calcifications

Positron emission tomography (PET)

• More accurate than CT at differentiating between benign and malignant nodules
• Performed prior to biopsy; if the CT imaging is inconclusive, particularly for patients with a high probability of malignancy

Bronchoscopy and biopsy

• Confirmatory test
• Procedures
  • Bronchoscopy with transbronchial biopsy: central nodules
  • CT-guided transthoracic biopsy: peripheral nodules
  • Thoracoscopy: if bronchoschopy or CT-guided biopsy are inconclusive, or in small peripheral nodules
  • Mediastinoscopy: to biopsy mediastinal nodes or masses

Staging of diagnosed lung cancer

• CT scan (chest, liver, adrenal glands) to evaluate
  • Nodules: localization, size, margins, calcifications
  • Regional spread (hilar lymph nodes, mediastinal invasion, pleural effusions)
  • Distant metastasis (hepatic lesions, adrenal gland mass)
• Blood tests: CBC, serum chemistry (calcium, alkaline phosphatase, liver function test, kidney function test)
  • Tumor markers
    • Neuron‑specific enolase (NSE): tumor marker for SCLC
    • CYFRA 21-1: tumor marker for lung cancer, regardless of histological properties (although it is particularly useful for NSCLCs)

Tumor markers do not play a role in the diagnosis of lung cancer. Even for evaluating disease progression, they are of limited importance!

• Further radiographic imaging
  • Abdominal ultrasound and CT: assesses lymph node involvement and extent of metastatic disease
  • Skeletal scintigraphy: detects bone metastases
  • Cranial MRI: detects CNS metastases
  • Whole body PET-CT: best method for detection of occult disease
• Preoperative evaluation for thoracic surgery

References:^{[8][1][2][18][19][20][21][22]}

Small cell lung cancer

• Kulchitsky cells: Small, dark blue neuroendocrine cells with hyperchromatic nuclei and scarce cytoplasm.
  • Hyperchromatic nuclei (salt and pepper appearance) is a marker for rapid growth and high metabolic activity
• Rapid growth pattern
• Immunohistochemistry: expression of chromogranin A, neuron-specific enolase, synaptophysin, CK18, and CK7

Non-small cell lung cancer

• Squamous cell carcinoma
  • Solid, epithelial tumor
  • Subtypes: keratinizing, nonkeratinizing, basaloid
  • Histology: intercellular bridges (desmosomes), keratin pearls
  • Immunohistochemistry: expression of cytokeratin subtypes CK5 and CK6
• Adenocarcinoma
  • Glandular tumor
  • Mucin-producing cells (positive mucin staining)
  • Subtypes of adenocarcinomas are classified according to the growth pattern (e.g., lepidic ;, papillary, acinar, solid)
    • Preinvasive lesions
      • Atypical adenomatous hyperplasia
      • Adenocarcinoma in situ (≤ 3 cm); : tumor cells with a lepidic growth pattern showing no evidence of invasion of the stroma, lymphatic, vascular or pleural tissue
    • Invasive adenocarcinoma
      • Minimally invasive adenocarcinoma (≤ 3 cm lepidic predominant adenocarcinoma, invasion ≤ 5 mm)
      • Invasive lepidic predominant (formerly: mucinous bronchioloalveolar carcinoma)
      • Acinar adenocarcinoma
      • Papillary adenocarcinoma
      • Additional subtypes
  • Detection of EGFR mutations and ALK translocations (immunohistochemistry or FISH)
  • Immunohistochemistry: expression of napsin A and TTF-1
• Large cell carcinoma
  • Poorly differentiated, pleomorphic giant cells
  • Can secrete β-hCG

References:^{[4][22][9][10]}

Differential diagnosis of pulmonary nodules

	Conditions	Features
Primary lung cancer	SCLC/NSCLC	Central or peripheral nodule Irregular margins and/or spicules Tumor size typically > 2 cm No calcifications or irregular calcifications
Lung metastases	Breast cancer Colorectal cancer Renal cell carcinoma Prostate cancer Bladder cancer Melanoma	More commonly multiple pulmonary nodules Nodule size typically > 1 cm
Pulmonary neuroendocrine tumor	Carcinoid bronchial carcinoma	Round or oval opacities Size typically 2–5 cm Hilar or perihilar mass
Benign tumors	Hamartomas	“Popcorn” calcifications Round, well-circumscribed nodules, lobulated by respiratory epithelium Histology findings Disorganized connective and epithelial tissue: predominantly cartilage that may undergo calcification or osseous changes Fat, fibromyxoid tissue, sometimes smooth muscle Size typically 1–3 cm 90% are peripheral, 10% are endobronchial
Infectious granulomas	Tuberculosis Nontuberculous mycobacteria Histoplasmosis	Round, well-defined, calcified nodule
Inflammatory conditions	Sarcoidosis Granulomatosis with polyangiitis (Wegener granulomatosis)	Multiple bilateral cavitating nodular lesions

Pulmonary nodules are more commonly metastases of other cancers rather than primary lung cancer!
References:^{[4][8][23][19][24][25]}

The differential diagnoses listed here are not exhaustive.

While early stages of lung cancer are treated with a curative approach, the majority of cases are diagnosed in advanced stages and can therefore only be treated palliatively. Surgery is often not possible due to distant metastases or because the patient has poor pulmonary reserve. In such cases, chemotherapy is the mainstay of treatment; radiation therapy is also frequently necessary. An individual treatment approach is usually determined by an interdisciplinary tumor board and discussed with the patient.

Overview

Tumor stage (see “Stages” above)		Treatment approach	Regimen
NSCLC	Stage I and II	Curative	Surgical resection ± adjuvant chemotherapy for stage IB and II (radiation therapy is only required if the resection margins are not tumor free) If surgery is not possible: radiation therapy + polychemotherapy
	Stage IIIA		Polychemotherapy + radiation therapy Consider surgery if tumor size decreases significantly after initial treatment Prophylactic cranial irradiation does not improve survival
	Stage IIIB and IV	Palliative	Polychemotherapy ± targeted therapy Alternative: symptom-oriented palliative support Radiation therapy may be considered for management of metastases and complications (e.g., bone pain, brain metastasis, SVC syndrome)
	Pancoast tumors up to stage IIIB	Curative	Neoadjuvant radiation therapy + polychemotherapy Surgery
SCLC	Limited disease (20%) T1-2, N0-1, T3-4, N0-1, T1-4, N2-3	Curative	Polychemotherapy + radiation therapy Usually unresectable; consider surgery in patients with very small, resectable lesions Prophylactic cranial irradiation in patients who respond to initial chemotherapy treatment
	Extensive disease (75%)	Palliative	Polychemotherapy Radiation therapy if the patient responds well to initial chemotherapy Prophylactic cranial irradiation if the patient responds to the initial chemotherapy treatment

SCLCs initially respond very well to chemotherapy, but remission only lasts for a short period! Only in very rare cases can patients be healed by surgery!

Therapeutic options

• Medical therapy
  • Polychemotherapy (mainstay of treatment), e.g.,
    • SCC: cisplatin and vinorelbine
    • SCLC: cisplatin and etoposide
  • Targeted therapy
    • EGFR inhibitors (e.g., gefitinib) in advanced-stage NSCLC that is EGFR-positive
    • ALK tyrosine kinase inhibitors (e.g., crizotinib) in advanced-stage NSCLC that is ALK-positive
  • Management of concurrent symptoms/conditions (e.g., pain, electrolyte imbalances due to paraneoplastic syndromes, dysphagia, cachexia, COPD)
• Radiation therapy includes prophylactic cranial irradiation and stereotactic body RT
• Surgical management: see preoperative pulmonary assessment
  • Procedures: open surgery or video-assisted thoracoscopic surgery
    • Lobectomy (standard approach): resection of one lobe
      • If FEV1 > 1.5 L and DLCO > 60%: lobectomy can be tolerated
    • Sublobar resection: wedge resection or segmentectomy for patients who cannot tolerate lobectomy
      • Advantages: lower perioperative mortality than lobectomy; preserved lung function
      • Disadvantages: only possible for small, localized tumors
    • Pneumonectomy: complete lung resection in the case of a central tumor
    • Systematic lymph node dissection
  • Complications
    • Displacement of the heart towards the operated side
    • Bronchial stump insufficiency
      • Severe complication of lung resection
      • Invariably leads to effusions; risk of pleural empyema
    • Pneumothorax (possibly tension pneumothorax)
    • Postoperative hemorrhage → hemothorax
    • Chylothorax (damage to the thoracic duct)
    • Atelectasis
    • Pneumonia
    • Acute cor pulmonale

Approx. 65% of lung cancer cases are inoperable at the time of diagnosis!
References:^{[2][19][17][26][27][28][29][30][31]}