lung%20cancer
LUNG CANCER
Lung cancer is having a malignant tumor in the lungs especially in the cells lining air passages.
Primary tumor-related signs and symptoms are cough, dyspnea, hemoptysis, and chest discomfort.
Signs and symptoms due to intrathoracic spread may involve the nerves (hoarseness, dyspnea, muscle wasting of upper limb, Horner's syndrome), chest wall and pleura (chest pain, dyspnea) and vascular structures (facial swelling, dilated neck veins, cardiac tamponade) & viscera (dsyphagia).
The signs and symptoms due to metastatic spread are bone pain with or without pleuritic pain, neurologic symptoms, limb weakness, unsteady gait, cervical lymphadenopathy, and skin nodules.

Staging

Staging of Non-Small Cell Lung Cancer (NSCLC)
  • Clinical staging is established initially from history, physical exam, pathologic findings, chest, upper abdomen, & adrenal computed tomography (CT) scan, complete blood count with platelet count, & chemistry profile of the patient
    • Pathologic mediastinal lymph node evaluation may be done through mediastinoscopy, mediastinotomy, endobronchial ultrasound (EBUS), endoscopic ultrasound (EUS), endobronchial ultrasound-guided fine needle aspiration (EBUS-FNA), endoscopic ultrasound-guided-fine needle aspiration (EUS-FNA), or CT-guided biopsy
    • Supraclavicular lymph node metastasis in non-small cell lung cancer (NSCLC) may be staged using CT, PET-CT scan, or neck ultrasound fine needle aspiration (FNA)
    • Fluoro-D-glucose-positron emission tomography computed tomography (FDG PET-CT) scanning is recommended for detection of distant metastases in non-small cell lung cancer (NSCLC)

Revised Tumor, Nodes & Metastases (TNM) System (7th Edition)

  • Proposed by the International Association for the Study of Lung Cancer (IASLC) & adopted by the American Joint Committee on Cancer (AJCC) & Union Internationale Contre le Cancer
  • Determines if the patient would benefit from surgical resection & may predict patient’s survival
  • Currently recommended to classify both non-small cell lung cancer (NSCLC) & small cell lung cancer (SCLC)

Tumor Evaluation

  • Evaluates the degree of spread of the primary tumor

Tx

  • Tumor size cannot be assessed or tumor proven by presence of malignant cells in sputum or bronchial washings but not visualized by imaging techniques or bronchoscopy

T0

  • No evidence of primary tumor

Tis

  • Carcinoma in situ

T1

  • Tumor size ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, involves the lobar bronchus

T1a(mi)

  • Minimally invasive adenocarcinoma

T1a

  • Superficial spreading tumor; Tumor size ≤1 cm in greatest dimension

T1b

  • Tumor size >1 cm but ≤2 cm in greatest dimension

T1c

  • Tumor size >2 cm but ≤3 cm in greatest dimension

T2

  • Tumor size >3 cm but ≤5 cm or tumor with any of the following features:
    • Involves main bronchus with atelectasis extending to the hilar region
    • Invades the visceral pleura

T2a

  • Tumor size >3 cm but ≤4 cm in greatest dimension

T2b

  • Tumor size >4 cm but ≤5 cm in greatest dimension

T3

  • Tumor size is >5 cm but ≤7 cm in greatest dimension or tumor directly involving any of the following: chest wall, pericardium, phrenic nerve or separate nodules in the same lobe

T4

  • Tumor size is >7 cm in greatest dimension w/ invasion of these relevant structures: mediastinum, heart, great vessels, trachea, diaphragm, recurrent laryngeal nerve, esophagus, vertebral body and carina, or separate tumor nodules in different ipsilateral lobe

Regional Lymph Node (LN) Evaluation

  • Evaluation of extent of nodal involvement
    • Mediastinal lymph node involvement usually makes surgical resection inappropriate

Nx

  • Regional LN cannot be assessed

N0

  • No regional LN metastasis

N1

  • Metastases in ipsilateral pulmonary or hilar LN

N1a

  • Involvement of single-station N1

N1b

  • Involvement of multiple-station N1

N2

  • Metastases in ipsilateral mediastinal or subcarinal lymph node

N2a1

  • Single-station N2 without involvement of N1

N2a2

  • Single-station N2 with involvement of N1

N2b

  • Involvement of multiple-station N2

N3

  • Involvement of N3 lymph node; Metastases in contralateral mediastinal lymph node and/or contralateral hilar lymph node, or ipsilateral or contralateral scalene lymph node, or supraclavicular lymph node

Evaluation of Distant Metastasis

M0

  • No distant metastasis

M1a

  • Malignant pleural or pericardial effusion or presence of separate nodules in the contralateral lobe

M1b

  • Single extrathoracic metastasis

M1c

  • Multiple extrathoracic metastasis in ≥1 organ

Staging

Occult carcinoma

  • TX N0 M0

Stage 0

  • Tis N0 M0

Stage IA1

  • T1mi N0 M0; T1a N0 M0

Stage IA2

  • T1b N0 M0

Stage IA3

  • T1c N0 M0

Stage IB

  • T2a N0 M0

Stage IIA

  • T2b N0 M0

Stage IIB

  • T1a,b N1 M0
  • T2a,b N1 M0
  • T3 N0 M0

Stage IIIA

  • T1a,b,c N2 M0; T2a,b N2 M0
  • T3 N1 M0
  • T4 N0,1 M0

Stage IIIB

  • T4 N1 M0
  • T3 N2 M0; T4 N2 M0

Stage IIIC

  • T3 N3 M0; T4 N3 M0

Stage IVA

  • Any T Any N M1a; Any T Any N M1b

Stage IVB

  • Any T Any N M1c

Residual Tumor After Treatment

R0

  • No identifiable tumor remaining, surgical margins are negative

R1

  • Microscopically positive margins but without visible tumor remaining

R2

  • Remaining tumor is grossly visible or palpable

Staging of Small Cell Lung Cancer (SCLC)
  • Full staging of small cell lung cancer (SCLC) should include history, physical exam, computed tomography (CT) scan of the chest, liver, adrenal glands, magnetic resonance imaging (MRI) or computed tomography (CT) scan of the head, chest, liver or adrenals, & a bone scan if positron emission tomography (PET) scan is obtained
    • Bone marrow aspirate for biopsy is advised in patients with nucleated red blood cells on peripheral blood smear, neutropenia, thrombocytopenia & no evidence of other metastasis
    • Chest X-ray & positron emission tomography (PET) scan may be optional part of initial evaluation
  • The updated TNM system (8th ed) by International Association for the Study of Lung Cancer (IASLC) may be used for staging small cell lung cancer (SCLC)
  • Staging should not delay the start of treatment for >1 week because small cell lung cancer (SCLC) is a very aggressive disease, with faster doubling time, higher growth fraction, & earlier development of metastasis

Limited Disease (LD)

  • Confined to the primarily affected hemithorax, mediastinum or supraclavicular nodes
  • Equivalent to stages I to III of the TNM system except T3-4 with multiple lung nodules that do not fit or are too extensive in a tolerable radiation field
  • Pulmonary function tests, bone imaging, & mediastinal staging via mediastinoscopy, mediastinotomy, endobronchial/esophageal ultrasound-guided biopsy & video-assisted thoracoscopy may be performed prior to initial treatment
    • Mediastinal staging may not be performed if patient decides against surgical resection

Extensive Disease (ED)

  • Metastases found beyond the supraclavicular areas, in contralateral chest or at distant sites
  • Same as stage IV of the TNM system or T3-4 with multiple lung nodules that do not fit in a tolerable radiation field

Assessment

  • Identify comorbidities (ie heart, kidney, liver problems)
  • Assess performance status (PS)
    • Usually utilizes the grading system developed by the Eastern Cooperative Oncology Group (ECOG) to determine disease progression, effect of disease to the patient, prognosis & suitability of the treatment employed
      • Grade 0 - Fully active; no restriction
      • Grade 1 - With restrictions to strenuous activity but can do light work
      • Grade 2 - Capable of self-care but not other activity
      • Grade 3 - Performs limited self-care & stays in bed or chair for >50% of waking hrs
      • Grade 4 - Disabled; restricted to bed or chair
      • Grade 5 - Dead
  • Evaluate pulmonary function
    • Spirometry is recommended to patients being considered for lung surgery
    • May indicate increased risk of perioperative death & cardiopulmonary complication with standard lung surgery (ie FEV1 <40%, carbon monoxide diffusion capacity <40%, max O2 uptake <10 mL/kg/min, arterial O2 sat <90%)
  • Identify histologic subtype
    • Immunohistochemical staining is used to differentiate primary pulmonary adenocarcinoma from the following: squamous cell carcinoma, large cell carcinoma, metastatic carcinoma, and malignant mesothelioma
      • It is also used to determine if there is neuroendocrine differentiation
  • Squamous cell carcinomas are often TTF-1 negative & p63 positive, whereas adenocarcinomas are usually TTF-1 positive
  • Predictive biomarkers (eg EGFR, ALK) are molecules that is indicative of therapeutic efficacy; that is, there is an interaction between the biomolecule & therapy on patient outcome
Risk Status Assessment
High Risk
  • Patients 55-74 years old with smoking history of ≥30 pack years & has already stopped smoking for <15 years or
  • Patients ≥50 years old with smoking history of ≥20 pack years & with other risk factors aside from second hand smoking
Moderate Risk 
  • Patients ≥50 years old with smoking history of ≥20 pack years or exposure to second hand smoking but without additional risk factors
Low Risk
  • Patients <50 years old &/or with smoking history of <20 pack years
Physical Examination
  • The 2 important factors that predict the survival of patients following treatment are weightloss & performance status
  • Patients who lost <10% of their pre-treatment weight & are mobile have better chances of survival
Laboratory Tests
  • Should include electrolytes, liver function tests (LFTs), calcium, lactate dehydrogenase (LDH), blood urea nitrogen (BUN), creatinine 

History

Patients should be asked for the presence or absence of:

  • Dizziness or headache - to rule out brain metastasis
  • Bone or joint pain - to rule out bone metastasis
  • Other head or neck symptoms - to rule out other tumors

Laboratory Tests

Sputum Cytology
  • Due to poorly controlled sample collection, diagnostic yield tends to be low
  • Should be reserved for patients in whom bronchoscopy or fine needle aspiration biopsy (FNAB) is contraindicated

Fine Needle Aspiration Biopsy (FNAB)

  • Recommended confirmatory test for solitary extrathoracic site suspected to be a metastatic lesion
  • May be done blindly but preferably guided by computed tomography (CT), magnetic resonance imaging (MRI), fluoroscopy or ultrasound
    • Computed tomography-guided fine needle aspiration/percutaneous core biopsy - 86-94% sensitive, 41-100% specific, 83-93% accurate for peripheral pulmonary lesions

Histologic Diagnosis

  • Cell size is the major distinguishing factor of NSCLC and SCLC
  • The 2 most common types of lung cancer are:
    • Non-small cell lung cancer (NSCLC)
      • A slow-growing type of epithelial lung cancer that accounts for approximately 85% of all lung cancers (most common)
      • Classic features such as keratin pearls and gland formation differentiates NSCLC from SCLC
    • Small cell lung cancer (SCLC) 
      • A fast-growing cancer that forms in the tissues of the lungs that easily spreads to other parts of the body (aggressive and rare type)
      • Accounts for about 15% of all reported cases of lung cancer
      • Cell size is twice the size of the lymphocytes
      • Other features that distinguishes SCLC from NSCLC are hyperchromatic appearance, high nuclear to cytoplasmic ratio, cohesive sheets of small blue cells w/ rosette formation, cell fragility and crush artifact w/ necrosis 
  • Three main subtypes of NSCLC: 
    • Adenocarcinoma
      • Cancer that begins in the glandular or secretory cells
      • Comprises 40% of the NSCLC
      • May develop in patients who do not smoke
    • Squamous cell carcinoma
      • Cancer that forms in the squamous cells
      • Centrally located and can be found in larger bronchi
      • Comprises 25-30% of the NSCLC
    • Poorly differentiated or large cell carcinoma
      • Comprises 10-15% of the NSCLC
  • World Health Organization (WHO)/International Association for the Study of Lung Cancer (IASLC)
    • Squamous cell carcinoma
      • Papillary
      • Clear cell 
      • Small cell
      • Basiloid
    • Adenocarcinoma
      • Acinar
      • Papillary
      • Bronchioalveolar carcinoma (nonmucinous, mucinous, mixed mucinous and nonmucinous or indeterminate cell type)
      • Solid adenocarcinoma w/ mucin
      • Adenocarcinoma w/ mixed subtypes
      • Variants [well-differentiated fetal adenocarcinoma, mucinous (colloid) adenocarcinoma, mucinous cystadenocarcinoma, signet ring adenocarcinoma and clear cell adenocarcinoma] 
    • Large cell carcinoma
      • Variants [large cell neuroendocrine carcinoma (LCNEC), combined LCNEC, basiloid carcinoma, lymphoephithelioma-like carcinoma, clear cell carcinoma, large cell carcinoma w/ rhabdoid phenotype
    • Adenosquamous carcinoma
    • Carcinomas w/ pleomorphic, sarcomatoid or sarcomatous elements
      • Carcinomas w/ spindle and/or giant cells
      • Spindle cell carcinoma
      • Giant cell carcinoma
      • Carcinosarcoma
      • Pulmonary blastoma
    • Carcinoid tumor 
      • Typical carcinoid
      • Atypical carcinoid 
    • Carcinomas of salivary gland type
      • Mucoepidermoid carcinoma
      • Adenoid cystic carcinoma 
      • Others
    • Unclassified carcinoma

Imaging

Noninvasive Imaging Procedures

Chest X-ray

  • Should be performed in all patients in whom lung cancer is suspected but should not be used alone as a screening tool
  • Not enough sensitivity to determine lymph node involvement
  • Usual findings in lung cancer include:
    • Solitary pulmonary nodule
    • Pulmonary or hilar mass
    • Poorly resolving pneumonia
    • Pleural effusion

Chest Computed Tomography (CT) Scan

  • Defines size, location & characteristics of pulmonary mass
  • Determines presence of lymphadenopathy
  • Allows evaluation of surrounding structures
  • May be used to evaluate presence of pleural effusion
  • Low-dose computed tomography is the recommended screening tool to detect lung cancer
    • Standard imaging procedure for determining metastasis 
    • May lower lung cancer-specific mortality by 20%

Positron Emission Tomography (PET) Scan

  • Determines normal from neoplastic tissues even as small as 1 cm
  • May be performed in patients with solitary lung lesions
  • Can increase accuracy of staging patients with small cell lung cancer
  • Positive results are due to: 
    • Infection or inflammation
    • Absence of lung cancer with localized infection
    • Presence of lung cancer with post-obstructive infection 
    • Presence of lung cancer with inflammation in the node, parenchyma & pleura
  • False-negative results are due to:
    • Small nodule 
    • Non-solid nodule or ground-glass opacity (GGO)
    • Adenocarcinoma in situ 
    • Carcinoid tumor
  • Better than computed tomography scan for mediastinal staging in non-small cell lung cancer; however, it is not reliable in identifying brain & urinary tract metastases

PET/CT Scan

  • May be done to assess distant metastases (eg bone metastasis) & guide mediastinal evaluation in patients with small cell lung cancer limited-stage disease & benign lung lesions presenting as a solitary nodule
    • Superior to positron emission tomography scan alone & to other standard imaging but inferior in detecting metastases to the brain
  • Improves target accuracy of radiation therapy in patients with significant atelectasis & in patients with contraindication to IV CT contrast

Fluorodeoxyglucose-Positron Emission Tomography (FDG-PET) Scan

  • Used to diagnose lung cancer tumors that are as small as 1 cm
  • Has a very high accuracy

Brain Magnetic Resonance Imaging (MRI) Scan

  • More preferred than CT scan in identifying brain metastasis 
  • Should be obtained in all patients
Bronchoscopy
  • Used for diagnosing & staging central & peripheral lung lesions
    • May be used as a confirmatory test for suspected central lesions
  • Electromagnetic guidance for bronchoscopy increases bronchoscopy sensitivity (60%), specificity (91%), & accuracy (67%) for peripheral lesions.

Endobronchial or Esophageal Ultrasound-guided Biopsy [transesophageal endoscopic ultrasound-guided FNA (EUS-FNA) or endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA)]

  • Minimally invasive technique used for mediastinal staging, as compared to mediastinoscopy
    • Studies have shown that endobronchial ultrasound-guided transbronchial needle aspiration achieved similar results for the mediastinal staging of lung cancer hence may possibly replace mediastinoscopy in patients with potentially resectable non-small cell lung cancer
      • Diagnostic yield of 80% for peripheral lesions; 82-94% sensitive for central lesions
      • Has low rates of nondiagnostic & false-negative biopsy findings, may be done in small subcentimeter nodes, & can confirm radiographically positive mediastinum
      • Allows access to the hilar & interlobar lymph nodes which can not be reached by mediastinoscopy
    • Video-assisted thoracoscopy is another minimally invasive technique used in mediastinal staging
  • Endobronchial ultrasound or endoscopic ultrasound are done as part of pretreatment evaluation in patients with stage I-IIIA (T4 extension, N0-1; T3, N1)
    • May be preferred over mediastinoscopy in sampling mediastinal lymph nodes, reserving mediastinoscopy & mediastinal lymph node dissection until the planned surgical resection

Mediastinoscopy

  • Gold standard procedure for evaluating mediastinal nodes
    • Recommended in patients with peripheral T2a, central T1ab, or T2 lesions with negative PET/CT scan

Screening

  • Several recommendations have emerged for screening of lung cancer, including those by the American Association for Thoracic Surgery, the National Comprehensive Cancer Network (NCCN), and the United States Preventive Services Task Force (USPSTF)
  • No recommendations have been endorsed in Europe yet but the European Society of Radiology (ESR) and the European Respiratory Society (ERS) recommends that lung cancer screening may be conducted within clinical trials or routine clinical practice with multidisciplinary medical centers
  • It is recommended that all screening and follow-up CT scans should be performed at a dose of 100-120 kVp and 40-60 mAs or less 
Recommendations for Patients with Lung Nodules on Initial Screening Using Low-Dose Computed Tomography (LDCT)
  • Solid nodules
    • For solid nodule ≤5 mm, annual screening low-dose computed tomography (LDCT) is recommended until the patient is no longer a candidate for definitive treatment
    • For solid nodule 6-7 mm, low-dose computed tomography (LDCT) should be done in 6 months
    • For solid nodule 8-14 mm, low-dose computed tomography (LDCT) should be done in 3 months or PET/CT scan is considered
    • For solid nodule ≥15 mm, chest CT with or without contrast and/or PET/CT scan is recommended
    • For solid endobronchial nodule, low-dose computed tomography (LDCT) should be done in 1 month (immediately after vigorous coughing)
  • Part-solid nodules
    • For ≤5 mm part-solid nodule, an annual screening low-dose computed tomography (LDCT) is recommended until the patient is no longer a candidate for a definitive treatment
    • For ≥6 mm part-solid nodule with ≤5 mm solid component, low-dose computed tomography (LDCT) should be done in 6 months
    • For ≥6 mm part-solid nodule with 6-7 mm solid component, low-dose computed tomography (LDCT) should be done in 3 months or PET/CT scan may be considered
    • For part-solid nodule with ≥8 mm solid component, chest CT scan w/ or without contrast and/or PET/CT scan is recommended
  • Non-solid nodules
    • For ≤19 mm non-solid nodule, annual screening low-dose computed tomography (LDCT) is recommended until the patient is no longer a candidate for a definitive treatment
    • For ≥20 mm non-solid nodule, low-dose computed tomography (LDCT) should be done in 6 months
Recommendations for Annual Screening Using Low-Dose Computed Tomography (LDCT)
  • New nodules
    • For suspected infection or inflammation, low-dose computed tomography (LDCT) should be done in 1-3 months
    • For suspected infection or inflammation that is resolving, low-dose computed tomography (LDCT) should be repeated in 3-6 months until it reaches resolution or stability
    • For patients with suspected infection or inflammation that has been resolved, annual low-dose computed tomography (LDCT) is recommended
    • For patients with suspected infection or inflammation that is persistent or the nodule is enlarging and those without suspected inflammation or infection, please see recommendations on solid/part-solid/non-solid nodules on follow-up below
  • Solid nodules
    • For ≤7 mm solid nodule that is unchanged on follow-up, an annual low-dose computed tomography (LDCT) is recommended  
    • For 8-14 mm solid nodule that is unchanged on follow-up, low-dose computed tomography (LDCT) should be done in 6 months, if still unchanged after 6 months then, an annual low-dose computed tomography (LDCT) is recommended 
    • For ≥15 mm solid that is unchanged on follow-up, an low-dose computed tomography (LDCT) in 6 months or PET/CT scan is recommended
    • For unchanged findings in a year, an annual low-dose computed tomography (LDCT) is still recommended
    • For ≤3 mm new solid nodule on follow-up, annual low-dose computed tomography (LDCT) is recommended 
    • For 4-5 mm new solid nodule on follow-up, low-dose computed tomography (LDCT) should be done in 6 months
    • For 6-7 mm new solid nodule on follow-up, low-dose computed tomography (LDCT) should be done in 3 months
    • For ≥8 mm new solid nodule on follow-up, chest CT scan with or without contrast and/or PET/CT scan is recommended
    • For ≤7 mm growing nodule on follow-up, low-dose computed tomography (LDCT) should be done in 3 months
    • For ≥8 mm growing nodule on follow-up, chest CT scan with or without contrast and/or PET/CT scan is recommended
  • Part-solid nodules
    • For ≤5 mm part-solid nodule that is unchanged on follow-up, & ≥6 mm part-solid nodule & with 6-7 mm solid component, annual low-dose computed tomography (LDCT) is also recommended
    • For ≥6 mm part-solid nodule & with ≥8 mm solid component, low-dose computed tomography (LDCT) in 6 months or PET/CT scan is recommended
      • If the part-solid nodule is unchanged, then an annual low-dose computed tomography (LDCT) is recommended
    • For new part-solid nodule that is <6 mm on follow-up, low-dose computed tomography (LDCT) should be done in 6 months
    • For new or growing part-solid nodule that is ≥6 mm in size with a growing <4 mm solid component on follow-up, low-dose computed tomography (LDCT) should be done in 3 months
    • For new or growing part-solid nodule with ≥4 mm solid component, chest CT scan with or without contrast and/or PET/CT scan is recommended
  • Non-solid nodules
    • For ≤19 mm new & stable non-solid nodule, annual low-dose computed tomography (LDCT) is recommended 
    • For ≥20 mm new NS nodule, annual low-dose computed tomography (LDCT) or biopsy or surgical excision is recommended
    • For ≥20 mm stable NS nodule, low-dose computed tomography (LDCT) should be done in 6 months 
    • For ≤19 mm growing NS nodule, low-dose computed tomography (LDCT) should be done in 6 months
    • For ≥20 mm growing NS nodule, low-dose computed tomography (LDCT) should be done in 6 months or biopsy or surgical excision
  • Multiple NS nodules
    • For pure NS nodules, measure the largest nodule
    • For dominant nodules with part-solid component, measure the largest nodule
  • For patients without lung nodules on low-dose computed tomography (LDCT), an annual screening with low-dose computed tomography (LDCT) is recommended
    • Should be done until the patient is no longer a candidate for definitive treatment 
  • A follow-up low-dose computed tomography (LDCT) in 1-3 months is recommended for patients with multiple nodules or other findings suggestive of possible occult infection or inflammation
  • Bronchoscopy should be done in patients w/ solid endobronchial nodule on low-dose computed tomography (LDCT) screening
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