• Clinical science

Lung cancer

Abstract

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%.

Epidemiology

  • 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.

Etiology

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

Classification

Tumor type Frequency Localization Characteristics
Small cell lung cancer (SCLC) ∼ 15% Central

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
  • 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
Large cell carcinoma 5–10% Peripheral

References:[6][4][7][1][2][3][8][9][10][11]

Clinical features

Symptoms commonly only develop in advanced stages of the disease.

Pulmonary symptoms

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

Extrapulmonary symptoms

Paraneoplastic syndromes

NSCLC SCLC

Symptoms of metastatic disease

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

References:[4][7][1][2][3][5][12][13][14]

Subtypes and variants

Pancoast tumor

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][7][3][8][15]

Stages

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

M1 approx. 75%

References:[7][16]

Diagnostics

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

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

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

References:[7][1][2][17][18][19][20][21]

Pathology

Small cell lung cancer

Non-small cell lung cancer

  • Squamous cell carcinoma
  • 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][21][8][9]

Differential diagnoses

Differential diagnosis of pulmonary nodules

Conditions Features
Pulmonary lung cancer
  • Central or peripheral nodule
  • Irregular margins and/or spicules
  • Tumor size typically > 2 cm
  • No calcifications or irregular calcifications
Lung metastases
  • More commonly multiple pulmonary nodules
  • Nodule size typically > 1 cm
Pulmonary neuroendocrine tumor
  • Round or oval opacities
  • Size typically 2–5 cm
  • Hilar or perihilar mass
Benign tumors
  • “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 Round, well-defined, calcified nodule
Inflammatory conditions Multiple bilateral cavitating nodular lesions

Pulmonary nodules are more commonly metastases of other cancers rather than primary lung cancer!
References:[4][7][22][18][23][24]

The differential diagnoses listed here are not exhaustive.

Treatment

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

Approx. 65% of lung cancer cases are inoperable at the time of diagnosis!
References:[2][18][16][25][26][27][28][29][30]

Prognosis

  • Overall 5‑year survival rate: approx. 17%
  • SCLC
    • Limited disease 5-year survival: 12–15%
    • Extended disease 5-year survival: 2% (median survival 8–13 months)
  • NSCLC: better prognosis, depends primarily on extent of disease and lymph node status
    • Locally confined stages (no lymph node involvement, no metastasis) have a survival rate of up to 60–70%.

References:[2][29][5]

Prevention

  • Cessation of smoking
    • After cessation, the risk of lung cancer reduces by half within 5–10 years. After approx. 15–20 years, the risk decreases to the corresponding level in nonsmokers.
  • Screening with low-dose CT imaging in patients aged 55–74 years (USPSTF recommends 55–80 years) with either:
    • A history of smoking (≥ 30 pack years) and continue smoking or stopped within 15 years
    • Or a history of smoking (≥ 20 pack years) and another risk factor for lung cancer (see “Etiology” above)

References:[31]