Lung cancer

Last updated: May 6, 2022

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Lung cancer is the leading cause of cancer death in the US, accounting for almost a quarter of all cancer-related fatalities; 80–90% of cases can be attributed to smoking. Lung cancer is generally divided into two types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). SCLC is a single histological category and is characterized by its central location, rapid tumor growth, early metastasis, and association with numerous paraneoplastic syndromes. NSCLC accounts for ∼ 85% of all lung cancers and has multiple histological subtypes including adenocarcinoma and central squamous cell carcinoma. Patients with lung cancer are usually asymptomatic during the early stages of the disease. Lung cancer may be diagnosed after the incidental discovery of a pulmonary nodule on imaging. Late-stage disease can manifest with pulmonary symptoms, extrapulmonary symptoms, paraneoplastic syndromes (e.g., syndrome of inappropriate antidiuretic hormone secretion, hypercalcemia), and/or signs of metastatic disease. Patients with lung cancer frequently present with metastasis to the brain, liver, adrenal glands, and/or bones. Evaluation generally begins with CT imaging of the chest and the diagnosis is confirmed with a bronchoscopic or CT-guided biopsy. Patients with no evidence of distant metastases may be eligible for curative surgical resection (with or without adjunct chemotherapy) or radiation therapy. Unfortunately, most patients present with metastatic disease and are, therefore, not eligible for curative resection. These patients often receive palliative chemoradiotherapy. Prognosis is generally poor, with a 5-year survival rate below 20%.

Epidemiological data refers to the US, unless otherwise specified.

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

Classification of lung cancers [6][11]

WHO classification of lung cancers
Tumor type Location Characteristics Histology

Non-small cell lung cancer (NSCLC) [12]

Lung adenocarcinoma
  • Peripheral
  • Most common type of primary lung cancer
  • More common in women and nonsmokers
  • Associated with mutations in: [13]
  • Common finding: hypertrophic osteoarthropathy (digital clubbing)
  • Most common type of lung cancer that originates in pulmonary scars [10]
  • Prognosis is usually better than in other types of lung cancer
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

Squamous cell and Small cell lung cancer are both Sentrally located.

For squamous cell lung cancer, imagine a Squawking Parrot doing Karate in the Center of a Cave under a Bridge while Smoking: Squamous cell, PTHrP → hypercalcemia, Keratin pearls, Central location, Cavitation, intercellular Bridges, Smoking.

For small cell lung cancer, think of small blue KulChA flatbread In a Synapse: Kulchitsky cells, Chromogranin A, neuron-specific Enolase, Synaptophysin.

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.

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]

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

Approach [34][35][36][37]

Early diagnosis of lung cancer is challenging, as symptoms are usually mild and/or nonspecific until the disease is advanced. [37]

Initial studies

Common laboratory studies [34][35][39]

Imaging [37][39][41]

See also “Imaging for lung cancer staging.”

A normal x-ray does not rule out lung cancer, as 10–20% of patients with lung cancer will not have findings visible on x-ray. [37][45][46]

Consider an early chest CT for all patients with suspected lung cancer. [47]

Confirmation of diagnosis

Histopathological analysis of tissue biopsies is required to confirm the diagnosis of lung cancer; cytology may be confirmatory in select cases.

Obtain confirmation of metastatic disease with histopathological studies if feasible. [48]

Advanced studies

Since the majority of patients present with metastatic disease, a complete staging evaluation is required. Molecular testing can identify mutations and markers that help inform treatment selection.

Imaging for lung cancer staging [34][35][38][41]

Obtain cross-sectional imaging of the brain, chest, and abdomen. PET-CT is increasingly used for staging because of its high sensitivity for metastatic disease. See “Lung cancer staging” for interpretation. [34][35][38][41]

  • CT thorax and abdomen [34][35][38][41]
  • Brain imaging ; [34][35][41]
  • PET-CT [34][35][38]
    • Indicated for the assessment of thoracic and abdominal metastases in NSCLC; may be used in SCLC
    • Preferred method to assess bone metastases in all subtypes
    • May prevent unnecessary invasive procedures by demonstrating metastatic disease that was occult on other imaging [41][49][50]

PET-CT is the most sensitive imaging modality for detecting mediastinal metastases, lymph node involvement, and extrathoracic metastases including adrenal, liver, and bone. [34][35][38][41]

All metabolically active lesions suspicious for malignancy should undergo biopsy or excision for diagnostic confirmation.

Molecular diagnostics [38]

Molecular testing may provide guidance for the therapy of SCLC, but it is considered mandatory for patients with advanced or metastatic NSCLC as the presence of certain biomarkers modifies therapy. [51]

Staging of NSCLC [53][54]

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 SCLC is based on the extent of tumor spread within or beyond one hemithorax and includes two major stages: limited-stage and extensive-stage. 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%

Overview

  • Management is determined by the type of lung cancer and the stage at presentation.
  • If available, multidisciplinary tumor board involvement is recommended in the care of all patients with lung cancer. [38]
  • Early implementation of palliative care measures improves the patient's quality of life and may prolong survival. [46]

The majority of lung cancers are diagnosed at an advanced stage and treatment is largely palliative, not curative. [35]

Overview of the treatment of lung cancer [34][35][38]
Cancer type Tumor stage Treatment approach Typical treatment regimen
NSCLC

Stage I–IIA

No metastases
  • Curative
Stage IIB–IIIC
  • Preferred: surgical resection plus chemotherapy
  • Nonsurgical candidates (e.g., those with inoperable disease or significant comorbidities): chemotherapy plus radiation therapy; possibly adjuvant immunotherapy [51]

Stage IVA–B

Metastases
  • Palliative
SCLC Limited stage
  • Curative
  • Stage I–II and N0: Consider surgical resection. [34]
  • All patients
Extensive stage
  • Palliative

Although SCLC generally has a good initial response to chemotherapy, most patients have a recurrence within 6 months. [34]

Medical therapy

Radiation therapy

Radiation therapy is most commonly used in conjunction with chemotherapy in lung cancer, but it also has other indications in lung cancer management.

Surgical management [35]

Lung resection procedures [61][62]

Type of resection

Features Indication
Sublobar resection
  • Peripherally located tumors < 2–3 cm [35]
  • Patients unable to tolerate lobectomy [63]
Lobectomy
  • Anatomic resection of an entire pulmonary lobe
  • Accompanied by significant loss of postoperative lung function
  • Most tumors > 2–3 cm [63]
Pneumonectomy
  • Complete lung resection
  • High perioperative morbidity and mortality

Complications are common after surgery for lung cancer. Morbidity and mortality are higher for larger surgeries (e.g., pneumonectomy) and increase in patients with preexisting comorbidities. [64][65]

Definition

A solitary pulmonary nodule (SPN) is a single, well-defined lesion, ≤ 30 mm in diameter, that is completely located in the pulmonary parenchyma. [67]

Initial assessment

  • Perform a detailed clinical evaluation.
  • Review any previous imaging (if available) to evaluate for changes.
  • Obtain a thin-slice CT chest if not already available.
  • Identify nodule size, density (solid vs. subsolid), and other characteristics. [67]
  • Determine the risk of malignancy of a solitary pulmonary nodule.

A solitary pulmonary nodule identified on CXR in a patient with high-risk features (e.g., advanced age, smoking history) should be evaluated to rule out malignancy.

Risk of malignancy in solitary pulmonary nodules

The risk of malignancy can be determined by clinical evaluation and/or predictive modeling and helps guide management and follow-up. [67]

  • The most extensively validated model is the Mayo Clinic model in which 6 predictors of malignancy are combined in a logarithmic equation to calculate the risk. [42]
  • Risk categories
    • Low: < 5% (typically, patients with low-risk predictors)
    • Intermediate: 5–65% (typically, patients with a mixture of high-risk and low-risk predictors)
    • High: > 65% (typically, patients with high-risk predictors)
Predictors of malignancy risk in patients with SPNs [42][66][67]

Low-risk

High-risk

Patient history Age [66][67][68]
  • Young (e.g., < 35 years) [66]
  • Older (e.g., > 60 years) [68]
Smoking history
  • None
  • Heavy use (current or prior)
Prior cancer history
  • None
  • History of extrathoracic cancer
Nodule features Size [66][67]
  • Small (e.g., < 4 mm)
  • Large (e.g., > 8–10 mm)
Border
  • Smooth
  • Irregular (e.g., scalloped or spiculated)
Location
  • Middle or lower lobe
  • Upper lobe

Subsolid nodules are less common than solid nodules and are more likely to be malignant. [69]

Assume a solitary pulmonary nodule in a patient with current active cancer is metastatic until proven otherwise. [66]

Management

The following recommendations are consistent with the 2013 CHEST guidelines and the 2017 Fleischner Society guidelines on the evaluation and management of SPNs. [66][67]

  • Patients with any of the following characteristics should be excluded from this approach and require case-by-case management: [66]
    • Age < 35 years
    • Immunocompromise
    • Active known primary cancer
    • Symptomatic patients
  • Options typically include biopsy, further imaging, or long-term surveillance with serial imaging.

For any nodule followed by serial imaging, clear growth or a change in density should prompt evaluation for a biopsy and/or resection. [67]

Solid nodule > 8 mm

  • High risk: Obtain a surgical biopsy and start treatment based on the results.
  • Intermediate or low risk: Obtain a PET-CT scan.

Solid nodule ≤ 8 mm

  • Most patients are assessed with serial CT scans. [67]
  • Surveillance frequency is determined by the patient's malignancy risk and nodule size.
    • Intermediate or high risk
      • < 4 mm: Repeat CT at 12 months; if there is no change in size, no further follow-up is needed.
      • 4–6 mm: Repeat CT at 6–12 months and 18–24 months.
      • 6–8 mm: Repeat CT at 3–6 months, 9–12 months, and 18–24 months.
    • Low risk
      • < 4 mm: Surveillance is optional.
      • 4–6 mm: Repeat CT at 12 months; if there is no change in size, no further follow-up is needed.
      • 6–8 mm: Repeat CT at 6–12 months; if the size remains stable, repeat again at 18–24 months.

Solid lesions that decrease in size but do not completely resolve should be followed until no interval growth has been demonstrated over 2 years. [67]

Surveillance is optional for low-risk patients with a solitary pulmonary nodule < 4 mm in diameter. [67]

Subsolid pulmonary nodule

Assess with serial CT scans. Surveillance frequency is dictated by the appearance and size of the nodule.

  • Pure ground-glass opacification
    • ≤ 5 mm: no further evaluation
    • > 5 mm: annual CT for 3 years
    • > 10 mm: Consider CT at 3 months.
  • Partially solid appearance
    • ≤ 8 mm: Observe with serial CT.
    • > 8 mm: Repeat CT at 3 months; obtain PET-CT or biopsy if the nodule persists.

Differential diagnosis of pulmonary nodules [70]

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 [71]
  • More commonly multiple pulmonary nodules
Pulmonary neuroendocrine tumor
  • If centrally located, endobronchial nodule or perihilar mass [72]
  • If peripherally located, round or oval opacities
  • Size typically 2–5 cm
Benign lung tumors [73][74]
Infectious granulomas
  • Round, well-defined, calcified nodule
  • Most common cause of benign pulmonary nodules (∼ 80%) [76]
Inflammatory conditions
  • Multiple bilateral cavitating nodular lesions [77]
  • 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.

  • Overall 5‑year survival rate: approx. 20% [1]
  • SCLC [78]
    • 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%. [79]

Cessation of smoking

  • Can reduce the risk of developing lung cancer by up to 50% after 5–10 years [80][81]
  • After 15–20 years, the risk of lung cancer is the same as that of never smokers. [82]
  • See “Counseling on smoking cessation.”

Lung cancer screening [83]

The following recommendations are consistent with those of the US Preventive Services Task Force.

  • Annual screening with a low-dose CT scan in patients 50–80 years of age with ≥ 20 pack-year smoking history who have smoked within the past 15 years [83]
  • Discontinue screening if the patient:
    • Has abstained from smoking for 15 years
    • Develops a comorbidity that substantially limits their life expectancy
    • Expresses unwillingness to have curative lung surgery

In the US, lung cancer screening with low-dose CT chest is estimated to reduce lung cancer mortality by up to 20%. [83]

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