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Lung cancer

Last updated: January 11, 2021

Summary

Lung cancer is the leading cause of cancer death worldwide, with approx. 90% of cases being attributable to smoking. Lung cancer is often divided into two types: 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 accounts for approx. 85% of all diagnoses of lung cancer. Histologic subtypes of NSCLC include peripheral adenocarcinoma and central squamous cell carcinoma. Patients with lung cancer are usually asymptomatic during the early stages of the disease. Late-stage disease may manifest with pulmonary (e.g., dyspnea, cough, hemoptysis, chest pain) or extrapulmonary symptoms (e.g., weight loss, finger clubbing), paraneoplastic syndromes (e.g., SIADH in SCLC), or signs of metastatic disease. Lung cancer most commonly spreads to the brain, liver, adrenal glands, and/or bones. Solitary pulmonary nodules detected on chest x-ray should raise suspicion for lung cancer and should be further evaluated using a chest CT scan. Bronchoscopy or CT-guided biopsy confirms the diagnosis. Patients with no evidence of distant metastases can undergo surgical resection of one or more pulmonary lobes with or without chemotherapy. As most of the patients are inoperable at the time of diagnosis, chemoradiotherapy remains a common modality of lung cancer treatment. Prognosis is generally poor, with a 5-year survival rate below 20% even with a multimodal approach.

Epidemiology

Epidemiological data refers to the US, unless otherwise specified.

Etiology

Smokers exposed to asbestos have a significantly higher risk of developing lung cancer compared to smokers that are not.

Classification

WHO classification of lung cancers [6][11]

Tumor type Location Characteristics Histology

Non-small cell lung cancer (NSCLC) [12]
Lung adenocarcinoma
  • Peripheral
Lung squamous cell carcinoma (SCC)
  • Central
Large cell carcinoma
  • Peripheral
  • Undifferentiated
  • Large tumor cells
Lung neuroendocrine tumors
Small cell lung cancer (SCLC)
  • Central

Large cell neuroendocrine carcinoma
  • Peripheral
  • Generally, high-grade tumors
  • Poor clinical prognosis
Bronchial carcinoid tumor
  • Central/peripheral

“Step 2CK:” Smoking, Central, Chromogranin A, and Kulchitsky cells are the most important characteristics of small cell lung cancer.

“Step 3CK:” Smoking, Central, Cavitary, hyperCalcemia, and Keratin pearls are the most important characteristics of squamous cell lung cancer.

Variants of lung cancer

Pancoast tumor [20][21]

Lymphangitic carcinomatosis

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

Clinical features

Symptoms of lung cancer may be related to the local effects of the tumor in the lung or spread of disease beyond the chest. Lung cancer often only becomes symptomatic in late stages, generally affecting prognosis negatively.

Pulmonary symptoms [22]

Extrapulmonary symptoms [22]

Recurrent respiratory infections (e.g., pneumonia) in the same pulmonary region in patients ≥ 40 years old should always raise suspicion for lung cancer.

Symptoms of metastatic disease

“Lung cancer loves to BLAB:” the most common sites of metastasis from lung cancer are the Brain, Liver, Adrenals, and Bones.

Paraneoplastic syndromes of lung cancer [23]

NSCLC SCLC
Shared paraneoplastic features and syndromes
Unique paraneoplastic syndromes Endocrine
Other

Pathology

Non-small cell lung cancer [11]

Squamous cell carcinoma

Adenocarcinoma [14]

  • Characteristics
    • Glandular tumor
    • Mucin-producing cells (positive mucin staining)
  • Immunohistochemical makers: expression of napsin A and TTF-1
  • Historical terminology
    • Bronchioloalveolar carcinoma (BAC): obsolete term for well-differentiated, noninvasive adenocarcinomas that grow along the alveolar septa.
      • Today, adenocarcinomas of the lung are rather described on a spectrum of lepidic growth.
      • Lepidic growth: noninvasive tumor growth at intact alveoli.
      • BAC has been replaced by a variety of adenocarcinoma subtypes (see “Preinvasive subtypes” and “Invasive subtypes” below)
  • Preinvasive subtypes
    • Atypical adenomatous hyperplasia (AAH)
      • Atypical pneumocyte growth along alveolar walls without cytological features of carcinoma
      • Size: ≤ 5 mm
    • Pulmonary adenocarcinoma in situ (formerly BAC)
      • Small (≤ 3 cm) nodule with a lepidic growth pattern
      • Lacks any component of invasion
  • Invasive subtypes (classified according to the predominant histopathological growth pattern)
    • Minimally-invasive pulmonary adenocarcinoma (MIA)
      • Small (≤ 3 cm) tumor with a predominantly lepidic pattern
      • ≤ 5 mm of invasion
    • Lepidic-predominant adenocarcinoma (formerly nonmucinous BAC)
      • Tumor primarily shows intraalveolar growth
      • At least one focus of invasion > 5 mm
    • Mucinous-predominant adenocarcinoma (formerly mucinous BAC)
      • Goblet cell or columnar cell growth along alveolar septae
      • Multiple areas of invasion
  • Additional subtypes

Large cell carcinoma

  • Poorly differentiated, large polygonal tumor cells (abundant cytoplasm)
  • Prominent nucleoli
  • Lacks identifiable glandular, squamous, or neuroendocrine elements on microscopy or immunohistochemistry.
    • Definitive diagnosis cannot be made by biopsy, rather it can only be finalized from completely excised surgical specimens.

Neuroendocrine tumors [31]

Small cell lung cancer

Large cell neuroendocrine carcinoma

Bronchial carcinoid

Diagnostics

Workup of an incidental solitary pulmonary nodule [34]

  • Solitary pulmonary nodule: a small (≤ 30 mm), well-defined lesion in the pulmonary parenchyma with no lymph node enlargement
  • Diagnostic approach
    • Applies to individuals who are otherwise healthy, asymptomatic, > 35 years of age
    • Evaluation of high-risk groups via lung cancer screening is discussed in the “Prevention” section below.
  • Diagnostic steps
    • Obtain dedicated chest CT if nodule discovered on chest x-ray or other imaging modality.
    • Compare to previous x-rays or CT scans if available.
    • Perform malignancy risk assessment (based on CT findings and patient characteristics).
    • The decision to pursue serial imaging, PET/CT, biopsy, or surgical excision should be based on individualized patient factors:

Malignancy risk assessment for solitary pulmonary nodules [35][36][37][38]

Risk factor Low risk (< 5%) Intermediate risk (5–65%) High risk (> 65%)
Nodule size (mm) < 8 8–20 > 20

Patient age (years)

 < 40 40–60 > 60
Smoking status Never Current or past Current or past

Nodule location

 Lower/middle lobe Upper lobe Upper lobe
Nodule border Smooth Scalloped Spiculated

In patients aged > 40 years, any pulmonary nodule detected on chest x-ray should be considered lung cancer until proven otherwise.

Imaging [39]

Chest x-ray

CT chest

  • Every patient with suspected lung cancer should receive a dedicated chest CT (IV contrast preferable).
  • Allows for the delineation of the primary tumor and the assessment of mediastinal lymph node involvement
  • Relatively insensitive for detection of lymph node metastases [35]
  • Radiographic findings associated with increased risk of malignancy [37][42]
    • Irregular margins (i.e., scalloped or spiculated)
    • Large size (> 2 cm)
    • Upper lobe location
    • Absent calcifications
    • Air bronchograms
    • Subsolid nodule (e.g., ground-glass or part-solid) [43]

PET/CT [44]

Imaging for suspected metastatic disease

  • Site-specific imaging should be symptom- or CT-directed
  • Tissue confirmation of metastatic disease is strongly recommended for all patients.

Tissue biopsy [47]

Tissue biopsy is the confirmatory test required for the diagnosis of lung cancer.

Laboratory studies

Stages

Staging of NSCLC [49][50]

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

Management approach AJCC TNM Description

Curative
  • Stage IA
  • T1, N0, M0
  • Stage IB
  • T2a, N0, M0
  • Stage IIA
  • T2b, N0, M0
  • Stage IIB
  • T1-2, N1, M0
  • T3, N0, M0

Intermediate (curative)
  • Stage IIIA
  • T1-2, N2, M0
  • T3-4, N1, M0
  • T4, N0, M0
  • Stage IIIB
  • T1-2, N3, M0
  • T3-4, N2, M0
  • Stage IIIC
  • T3-4, N3, M0
Palliative
  • Stage IVA
  • T1-4, N0-3, M1a-b
  • Stage IVB
  • T1-4, N0-3, M1c
  • Any tumor size
  • Any nodal involvement
  • Multiple extrathoracic metastases (M1c)

As soon as distant metastases are detected, the cancer is classified as AJCC stage IV.

Staging of SCLC [31]

Staging of SLCS is based on the extent of tumor spread within or beyond one hemithorax and includes two major stages: limited stage (LS-SCLC) and extensive stage (ES-SCLS). The TNM staging system can be used as well.

Stage Classification Corresponding TNM Cancer spread Cancer stage at diagnosis
Curative
  • Limited stage
  • T1-2, N0-1
  • Approx. 30%
  • T3-4, N0-1
  • T1-4, N2-3
Palliative
  • Extensive stage
  • M1a-c
  • Approx. 70%

Differential diagnoses

Differential diagnosis of pulmonary nodules [51]

Differential diagnosis

 Examples Features
Primary lung cancer
  • Single central or peripheral nodule
  • Irregular margins and/or spicules
  • No calcifications or irregular calcifications
  • Size is typically > 2 cm
Lung metastases [52]
  • More commonly multiple pulmonary nodules
Pulmonary neuroendocrine tumor
  • If centrally located, endobronchial nodule or perihilar mass [53]
  • If peripherally located, round or oval opacities
  • Size typically 2–5 cm
Benign tumors [54][55]
Infectious granulomas
  • Round, well-defined, calcified nodule
  • Most common cause of benign pulmonary nodules (∼ 80%) [57]
Inflammatory conditions
  • Multiple bilateral cavitating nodular lesions [58]
  • Commonly associated with other systemic findings

Pulmonary nodules are more commonly metastases of other cancers than primary lung cancer.

The differential diagnoses listed here are not exhaustive.

Treatment

Surgical resection with or without chemotherapy is the standard of care for early-stage (e.g., stage I and stage IIA) lung cancers. Radiotherapy is the treatment of choice for patients with inoperable early-stage disease (either due to poor pulmonary reserve or medical comorbidities). Treatment of locally-advanced NSCLC and LS-SCLC (e.g., stage IIB–IIIC) requires a multimodal approach with chemotherapy, radiotherapy, surgical resection, and immunotherapy. Most cases of lung cancer are diagnosed at an advanced (i.e., metastatic) stage and are therefore treated palliatively with chemotherapy and immunotherapy. As it is used in nearly every stage of treatment, chemotherapy is the mainstay of lung cancer therapy.

Overview [31][49][59][60][61]

Cancer type Tumor stage Treatment approach Regimen
NSCLC

Stage I–IIA
  • Curative
  • Preferred treatment: surgical resection with or without adjuvant chemotherapy [62][63]
  • Surgically inoperable: stereotactic ablative radiotherapy (SABR)
Stage IIB–IIIC
  • If surgically resectable (see “Relative contraindications to surgery” in “Surgical management” below) [64]
  • If unresectable: concurrent chemoradiation followed by adjuvant immunotherapy

Stage IVA–B
  • Palliative
SCLC Limited stage
  • Curative
Extensive stage
  • Palliative
  • Standard treatment: chemotherapy or chemoimmunotherapy
  • PCI: only in patients with good response to initial systemic therapy

Although SCLC generally has a good initial response to chemotherapy, the rate of recurrence is high.

Therapeutic options

Medical therapy

Radiation therapy (including prophylactic cranial irradiation)

Surgical management

  • Indications: preferred local treatment modality for early-stage tumors and stage III tumors without nodal involvement [49]
  • Relative contraindications to surgery
    • N3 disease
    • Bulky N2 disease (> 3 cm)
    • Multiple N2 nodes
  • Complications [78]

Approx. 65% of patients with lung cancer are inoperable at the time of diagnosis.

Surgical procedures [49]

Pulmonary resection may be performed either as an open procedure or as video-assisted thoracoscopic surgery. See also “Preoperative pulmonary assessment” for workup in patients undergoing surgery.

Advantages and disadvantages of surgical procedures

Type of resection

 Definition Advantages Disadvantages
Lobectomy
  • Anatomic resection of a pulmonary lobe
  • Complete resection of the tumor with a wider safety margin
  • Can only be performed if the patient's FEV1 > 1.5 L and DLCO > 60% [79][80]
Sublobar resection
  • Only appropriate for small (i.e., 2–3 cm) tumors in the peripheral lung with at least one of the following:
    • Pure AIS histology
    • Nodule ≥ 50% ground-glass appearance on CT
    • Radiologic evidence of slow doubling-time (≥ 400 days)
Pneumonectomy
  • Complete lung resection
  • Useful for cancers that involve the hilum or main bronchi or that extend across a major fissure
  • High perioperative mortality
  • High incidence of pulmonary and cardiovascular complications
  • A lung-sparing anatomic resection (e.g., sleeve lobectomy) is preferred over pneumonectomy if margin-negative resection can be achieved. [81][82]

Prognosis

  • Overall 5‑year survival rate: approx. 20% [1]
  • SCLC [83]
    • Limited disease 5-year survival: 16% (median survival up to 20 months)
    • Extended disease 5-year survival: 3% (median survival up to 13 months)
  • NSCLC
    • Better prognosis
    • Depends primarily on the extent of disease and lymph node status
    • Locally confined stages (no lymph node involvement, no metastasis) have a 5-year survival rate of approx. 60–70%. [84]

Prevention

Cessation of smoking

  • Complete cessation is associated with a 40–50% reduction in risk for developing lung cancer after 5–10 years. [85][86]
  • Longer periods of abstinence lead to greater reductions in lung cancer risk. [87]
  • After approx. 15–20 years, the risk decreases to the corresponding level in nonsmokers. [88]

Lung cancer screening

  • Annual screening with low-dose CT imaging
    • Associated with a decrease in lung cancer-specific mortality [89][90]
    • Multiple oncology and thoracic societies have varying recommendations regarding the specifics of which patients should be screened. [91]
    • The U.S. Preventive Services Task Force (USPSTF) recommendation: patients aged 55–80 years with a history of smoking (≥ 30 pack-years) and who currently smoke or stopped within the past 15 years [92]

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