Lung cancer

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.

• Incidence ^[1][2]
  • Second most common cancer
  • Leading cause of cancer death worldwide
• Age: peak incidence at 65–75 years ^[1]
• Sex ^[1]
  • ♂ > ♀
    • Except for adenocarcinoma, which is more common in women ^[3]
    • Declining incidence in men
    • Mortality rates for men and women are converging ^[4]

Epidemiological data refers to the US, unless otherwise specified.

• Tobacco smoking ^[5][6][7]
  • Associated with the development of approx. 90% of lung cancers
  • Weaker association with lung adenocarcinoma
• Occupational and environmental exposure to carcinogens ^[6]
  • Passive smoking
  • Radon (2^nd leading cause of lung cancer) and uranium (radioactively decays into radon) ^[8]
  • Asbestos ^[9]
  • Occupational carcinogens (e.g., arsenic, chromium, nickel, beryllium, silica)
  • Environmental air pollution
• Family history (genetic predisposition)
• Other risk factors: pulmonary scarring, previous radiation, pulmonary fibrosis, chronic infections (e.g., tuberculosis, HIV) ^[10]

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

WHO classification of lung cancers ^[6][11]

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]

• An apical lung carcinoma
• Located in the superior sulcus of the lung (superior sulcus tumor)
• Predominantly NSCLC
• May lead to the development of Pancoast syndrome: a constellation of symptoms secondary to the mass effect of the tumor on surrounding structures
  • Cervical sympathetic ganglion (stellate ganglion): Horner syndrome (ipsilateral miosis, ptosis, and anhidrosis)
  • Brachial plexus
    • Localized pain in the axilla and shoulder (plexus neuralgia)
    • Upper limb motor and sensory deficits (e.g., hand muscle weakness and atrophy)
  • Recurrent laryngeal nerve: hoarseness
  • Brachiocephalic vein
    • Unilateral edema of the arm
    • Facial swelling
  • Phrenic nerve: paralysis of the hemidiaphragm (visible as elevated hemidiaphragm on chest x-ray)

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]

• Cough, hemoptysis
• Progressive dyspnea
• Wheezing
• Chest pain

Extrapulmonary symptoms ^[22]

• Constitutional symptoms (weight loss, fever, weakness)
• Signs and symptoms of tumor infiltration and/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.
  • Hoarseness: paralysis of the recurrent laryngeal nerve ^[22]
  • Dyspnea and diaphragmatic elevation: paralysis of the phrenic nerve
  • Dullness on percussion, reduced breath sounds: malignant pleural effusion on the affected side
  • Postobstructive pneumonia (see “Secondary pneumonia”)
  • Dysphagia: esophageal compression

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

• Over half of all patients diagnosed with lung cancer have metastatic disease at the time of presentation. ^[1]
• The symptoms of metastatic disease are site-specific
  • Brain: headaches, seizures, focal motor deficits, behavioral changes (see “Brain metastases”)
  • Liver; : typically asymptomatic, but may manifest with nausea, jaundice, ascites (see “Metastatic liver disease”)
  • Adrenal gland: typically asymptomatic
  • Bones: bone pain, elevated serum alkaline phosphatase and calcium

“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

• Characteristics
  • Solid, epithelial tumor
  • Intercellular bridges (desmosomes)
  • Keratin pearls
• Immunohistochemical markers: expression of p40, p63, CK5, or CK6 ^[30]
• Subtypes
  • Keratinizing
  • Nonkeratinizing
  • Basaloid
  • Carcinoma in situ

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
  • Acinar
  • Papillary
  • Solid
  • Colloid
  • Fetal
  • Enteric

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

• Characteristics
  • High number of mitotic figures ^[32]
  • Kulchitsky cells
    • Small, dark blue neuroendocrine cells
    • Hyperchromatic nuclei (salt and pepper appearance)
    • Scarce cytoplasm
• Immunohistochemical markers
  • Chromogranin A
  • Neuron-specific enolase
  • Synaptophysin
  • CD56 ^[33]

Large cell neuroendocrine carcinoma

• Cell characteristics
  • Large cells with abundant eosinophilic cytoplasm organized in trabecular or palisading patterns
  • Coarse and granular nuclear chromatin
  • Prominent necrosis
  • High number of mitotic figures ^[32]
• Immunohistochemical markers
  • Chromogranin A
  • Synaptophysin

Bronchial carcinoid

• Typical (low-grade) carcinoid subtype
  • Polygonal cells arranged in organoid, trabecular, or insular patterns
  • Fine chromatin with small nucleoli
  • Few mitotic figures ^[32]
• Atypical (intermediate-grade) carcinoid subtype
  • Similar to typical carcinoid subtype
  • Diagnosis requires the additional presence of either necrosis or a higher number of mitotic figures ^[32]
• Immunohistochemical markers
  • Chromogranin A
  • Synaptophysin
  • CD56

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:
    • Clinical probability of lung cancer
    • Surgical risk
    • Biopsy risk
    • Patient adherence to follow up
    • Probability of other diagnoses
    • Patient's desires and preferences

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

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

• Less sensitive than chest CT ^[40]
• Indirect signs of malignancy
  • Atelectasis
  • Postobstructive pneumonia
  • Pleural effusion (particularly unilateral)
  • Mediastinal widening
  • Cavitary lesions
• Adenocarcinoma in situ (previously BAC): characteristically shows hazy infiltrates (as seen in pneumonia) ^[41]
• Squamous cell carcinoma: may manifest as a cavitating lesion with air-fluid levels

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]

• Useful for detecting occult lymph node involvement and extrathoracic metastases
• More sensitive than CT for detecting mediastinal metastasis ^[35][45]
• Metabolically active lesions suspicious for malignancy should always undergo biopsy or excision for diagnostic confirmation.
• False positives common in:
  • Inflammatory lesions
  • Infections
  • Granulomatous disease
• False negatives seen in:
  • Small lymph node size (< 1 cm)
  • Micrometastasis

Imaging for suspected metastatic disease

• Site-specific imaging should be symptom- or CT-directed
  • Brain: gadolinium-enhanced MRI
  • Extrathoracic metastasis (bone, adrenal, liver): PET/CT is more accurate than CT alone or bone scans. ^[46]
• 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.

• Nonsurgical procedures
  • Bronchoscopy with transbronchial biopsy: central nodules
  • CT-guided transthoracic biopsy: peripheral nodules
• Surgical procedures
  • Mediastinoscopy: used to biopsy mediastinal lymph nodes or masses
  • Video-assisted thoracoscopy: used when previous procedures yield no diagnostic results or tumor is inaccessible
  • Anterior mediastinotomy: used to sample specific mediastinum lymph nodes (e.g., paraaortic and subaortic)

Laboratory studies

• Complete blood count
  • Anemia
  • Thrombocytopenia
  • Neutropenia
• Serum chemistry
  • Hypercalcemia
  • High alkaline phosphatase
  • Abnormal liver function test
• Molecular testing
  • Recommended in all patients with metastatic NSCLC (especially in patients with adenocarcinoma and never-smokers) ^[48]
  • Next-generation sequencing (entire genome) or real-time polymerase chain reaction (specific mutations)
    • Epidermal growth factor receptor (EGFR) mutations
    • Anaplastic lymphoma kinase (ALK) fusions
    • c-ROS oncogene 1 (ROS1) rearrangements
    • Other: e.g., MET exon-14-skipping mutation, RET rearrangement, BRAF V600E
• Programmed death-ligand 1 (PD-L1) testing: recommended in patients with metastatic NSCLC ^[49]
  • PD-L1 is a coregulatory molecule expressed on tumor cells that inhibits T-cell mediated death.
  • Cytotoxic T cells express PD-1 (a negative regulator) that binds PD-L1.
  • Immune checkpoint inhibitors (ICIs) block the PD-L1/PD-1 interaction, improving the antitumor effect of endogenous T-cells.
  • Immunohistochemical staining for PD-L1 is used to identify disease most likely to respond to ICIs (see “Treatment” below).

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.

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.

Differential diagnosis of pulmonary nodules ^[51]

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

The differential diagnoses listed here are not exhaustive.

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]}

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

Therapeutic options

Medical therapy

• Polychemotherapy (mainstay of treatment)
  • NSCLC: cisplatin-based (e.g., cisplatin, pemetrexed)
  • SCLC: cisplatin and etoposide
• Targeted therapy (for advanced-stage NSCLC)
  • NSCLC that is EGFR-positive: EGFR inhibitors (e.g., osimertinib, gefitinib, erlotinib)
  • NSCLC that is ALK-positive: ALK tyrosine kinase inhibitors (e.g., crizotinib)
• Immunotherapy
  • Locally-advanced NSCLC: durvalumab administered after chemoradiotherapy ^[65]
  • Metastatic NSCLC
    • Pembrolizumab alone if PD-L1 ≥ 50% ^[66]
    • Prembrolizumab with chemotherapy if PD-L1 < 50% ^[67]
  • ES-SCLC: atezolizumab with chemotherapy ^[68]
• Supportive care: management of concurrent symptoms/conditions (e.g., pain, electrolyte imbalances due to paraneoplastic syndromes, dysphagia, cachexia, COPD)

Radiation therapy (including prophylactic cranial irradiation)

• Early stage NSCLC: SBRT for medically inoperable patients or those who refuse surgery ^[69][70]
• Locally advanced NSCLC: concurrent chemoradiotherapy recommended for all patients with inoperable stage II and stage III disease ^[65][71]
• Diffusely metastatic NSCLC: palliative treatment (e.g., to relieve pain, bleeding, bronchial obstruction)
• Oligometastatic NSCLC: In well-selected patients with a limited number of metastases (typically 3–5), definitive radiation may prolong overall survival. ^[72][73]
• LS-SCLC: concurrent chemoradiotherapy with or without PCI ^[74][75]
• ES-SCLC: PCI decreases the incidence of brain metastases but does not improve survival. ^[76][77]

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]
  • Pneumonia
  • Atelectasis
  • Chylothorax
  • Postoperative hemorrhage leading to hemothorax
  • Pneumothorax
  • Bronchial stump insufficiency
    • Severe complication of lung resection
    • Invariably leads to effusions → risk of pleural empyema
  • Mediastinal shift towards the operated side and elevation of the hemidiaphragm

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.

• 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]

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
    • Indicated in patients aged 50–80 years with a history of smoking (≥ 20 pack-years) within the past 15 years
    • Screening should be discontinued if the patient quit smoking more than 15 years ago or has a health problem that lowers the life expectancy or limits their ability or willingness to have curative lung surgery.

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