Lung%20cancer Diagnosis

Diagnosis of a patient will depend on:

• Size of the tumor
• Location of the tumor
• Presence of mediastinal or distant disease
• Presence of pulmonary pathology and/or other comorbidities
• Experience and expertise of the healthcare personnel

• Clinical staging is established initially from history, physical exam, pathologic findings, chest, upper abdomen, and adrenal computed tomography (CT) scan, complete blood count with platelet count, and 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 NSCLC may be staged using CT, PET-CT scan, or neck ultrasound fine needle aspiration (FNA)
  • Brain magnetic resonance imaging (MRI) and fluoro-D-glucose-positron emission tomography computed tomography (FDG PET-CT) scanning are recommended for detection of distant metastases in NSCLC

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

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

• Full staging of SCLC should include history, physical exam, computed tomography (CT) scan of the chest and/or abdomen,, magnetic resonance imaging (MRI) or CT scan of the head and a bone scan from the base of skull to mid-thigh if positron emission tomography (PET) scan is not obtained and limited stage is suspected
  
  • Bone marrow aspirate for biopsy is advised in patients with nucleated red blood cells on peripheral blood smear, neutropenia, thrombocytopenia and no evidence of other metastasis
  • Chest X-ray and PET scan may be optional part of initial evaluation

• The updated TNM system (8th edition) by International Association for the Study of Lung Cancer (IASLC) may be used for staging SCLC
• Staging should not delay the start of treatment for >1 week because SCLC is a very aggressive disease, with faster doubling time, higher growth fraction, and 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, and mediastinal staging via mediastinoscopy, mediastinotomy, endobronchial/esophageal ultrasound-guided biopsy and 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

• 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 and 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 and stays in bed or chair for >50% of waking hours
    • 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 and 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 and genetic alterations/mutations
  
  • Immunohistochemical staining is used to identify gene rearrangements and mutations and fusions, and 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

• Other assays being used include next-generation sequencing (NGS), real-time polymerase chain reaction (PCR), Sanger sequencing and fluorescence in situ (FISH) analysis     
• Predictive biomarkers (eg EGFR, ALK, ROS1, BRAF V600E, KRAS, NTRK, PD-L1, MET, RET, ERBB2, tumors mutational burden) are molecules that is indicative of genetic mutations and rearrangements and protein overexpression that are used as therapeutic targets
  • T790M testing should be done in patients with EGFR mutation with possible resistance to initial treatment

• Patients 55-77 years old with smoking history of ≥30 pack years or have already stopped smoking for <15 years or
• A patient ≥50 years old with smoking history of ≥20 pack years who is a current or previous smoker and with ≥1 additional risk factors aside from second hand smoking
• Family history in never-smoker patients, especially those with 1st-degree relatives with lung cancer, based on the TALENT (Taiwan Lung Cancer Screening for Never Smoker Trial) study

• Patients ≥50 years old with smoking history of ≥20 pack years or exposure to second hand smoking but without additional risk factors

• Patients <50 years old and/or with smoking history of <20 pack years

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

• To accompany invasive procedure if possible

• 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

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 with rosette formation, cell fragility and crush artifact with 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 showing keratinization and/or intercellular bridges
    • 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

Immunohistochemistry (IHC)

• Aids in distinguishing primary lung cancer from secondary metastases and in the determination of the specific subtype of NSCLC and SCLC
• IHC stains used include: Thyroid transcription factor 1 (TTF1), napsin A, p40, p63
  • Adenocarcinoma: TTF1, napsin A
  • Squamous cell carcinoma: p40, p63
  • NSCLC-NOS: If neither TTF1 nor p40 are positive
  • SCLC: Insulinoma-associated protein 1 (INSM1), CD56/NCAM, synaptophysin, chromogranin A

• Epithelial tumors
  • Squamous cell carcinoma
    
    • Papillary
    • Clear cell 
    • Small cell
    • Basiloid
  • Adenocarcinoma
    • Lepidic, acinar, papillary, micropapillary, invasive mucinous (mixed invasive mucinous, nonmucinous), colloid, fetal, enteric, solid adenocarcinoma, minimally invasive (nonmucinous, mucinous), preinvasive lesions [atypical adenomatous hyperplasia, adenocarcinoma in situ (mucinous, nonmucinous)]
  • Pulmonary neuroendocrine tumors
    • Carcinoid tumors (typical carcinoid, atypical carcinoid)
    • Small cell lung carcinoma (combined small cell neuroendocrine carcinoma)
    • Large cell neuroendocrine carcinoma (LCNEC) (combined LCNEC)
  • Large cell carcinoma
  • Adenosquamous carcinoma
  • Sarcomatoid carcinomas (pleomorphic, spindle cell, giant cell, carcinosarcoma, pulmonary blastoma)
  • Other and unclassified carcinomas (lymphoepithelioma-like, NUT carcinoma)
  • Preinvasive lesion (diffuse idiopathic pulmonary neuroendocrine cell hyperplasia)
  • Salivary gland-type tumors (mucoepidermoid, adenoid cystic, epithelial-myoepithelial, pleomorphic)
  • Papillomas [squamous cell (exophytic, inverted), glandular, mixed squamous and glandular]
  • Adenomas (sclerosing pneumocytoma, alveolar, papillary, mucinous cystadenoma, mucous gland)
• Mesenchymal tumors
  • Pulmonary hamartoma, chondroma, PEComatous (lymphangioleiomyomatosis, PEComa benign - clear cell tumor, PEComa malignant), congenital peribronchial myofibroblastic tumor, diffuse pulmonary lymphangiomatosis, inflammatory myofibroblastic tumor, epithelioid hemangioendothelioma, pleuropulmonary blastoma, synovial sarcoma, pulmonary artery intimal sarcoma, pulmonary myxoid sarcoma with EWSR1–CREB1 translocation, myoepithelial (myoepithelioma, myoepithelial carcinoma)
• Lymphohistiocytic tumors
  • Extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT lymphoma), diffuse large cell lymphoma, lymphomatoid granulomatosis, intravascular large B cell lymphoma, pulmonary Langerhans cell histiocytosis, Erdheim-Chester disease)
• Tumors of ectopic origin
  • Germ cell tumors (teratoma mature/immature), intrapulmonary thymoma, melanoma, meningioma, NOS
• Metastatic tumors

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, and pleural effusion

Chest Computed Tomography (CT) Scan

• Defines size, location and characteristics of pulmonary mass (for staging purposes)
• Determines presence of lymphadenopathy
• Allows evaluation of surrounding structures
• May be used to evaluate presence of pleural effusion
• Standard imaging procedure for determining metastasis
• Low-dose computed tomography (LDCT) is the recommended screening tool to detect lung cancer among defined high-risk population
  • May lower lung cancer-specific mortality by 20%
• Multidetector CT may be considered for very small benign or malignant lung nodules

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
• 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 and 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 and urinary tract metastases

PET/CT Scan

• May be done to assess distant metastases (eg bone metastasis) and guide mediastinal evaluation
  
  • Superior to positron emission tomography scan alone and to other standard imaging but inferior in detecting metastases to the brain

• Improves target accuracy of radiation therapy in patients with significant atelectasis and in patients with contraindication to IV CT contrast
• If PET/CT scan is not available then bone scan may be used as an alternative in identifying bone metastasis
• Fluorodeoxyglucose (FDG)-PET-CT scan is useful for the evaluation of solitary lung nodules, intra-thoracic pathological LN and distant metastases

Brain Magnetic Resonance Imaging (MRI) Scan

• More preferred than CT scan in identifying brain metastasis
  

Bone Scan

• For survey of bone metastasis; although may be less sensitive in cases of purely lytic bone metastases 

Invasive Procedures

• The least invasive technique that renders the highest yield should be chosen

• Used for diagnosing and staging central and peripheral lung lesions
  • May be used as a confirmatory test for suspected central lesions
  • A required procedure prior to surgical resection

• Sampling can be done through transbronchial needle aspiration, transbronchial lung biopsy, transbronchial cryobiopsy, bronchial brushing or bronchial washing
• Electromagnetic guidance for bronchoscopy increases bronchoscopy sensitivity (60%), specificity (91%), and accuracy (67%) for peripheral lesions.

Fine Needle Aspiration Biopsy (FNAB)

• May be considered as a confirmatory test for solitary extrathoracic site suspected to be a metastatic lesion and peripheral primary lung 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

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
    
    • Has low rates of nondiagnostic and false-negative biopsy findings, may be done in small subcentimeter nodes, and can confirm radiographically-positive mediastinum
    • Allows access to the hilar and 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 and mediastinal lymph node dissection until the planned surgical resection

Mediastinoscopy

• Gold standard preoperative procedure for evaluating mediastinal nodes
  
  • Recommended in patients with peripheral T2a, central T1ab, or T2 lesions with negative PET/CT scan
• A preoperative mediastinoscopy should be considered in patients found negative for malignancy in endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) but clinically positive in PET-CT scan or when intraoperative cytology or frozen section analysis is not available

Pleural Procedure (Pleural Biopsy, Pleural Effusion Cytology, Pleuroscopy)

• Can be done if there are pleural effusions or abnormalities (eg solid masses, nodules, thickening) which are suspicious for malignant involvement of the pleura
• Pleuroscopy allows direct visualization of the pleural surfaces, complete drainage of the pleural fluid if present and take biopsies from involved and uninvolved parts of the pleura

Surgical Excisional Biopsy

• Gold standard for diagnosis of pulmonary nodule
  • Curative in some cases of pulmonary nodule
• Diagnostic wedge resection by video-assisted thoracoscopic surgery (VATS) is the preferred procedure for pulmonary nodules suspicious of malignancy
  • Can directly visualize the lesion and the involvement of the surrounding structures (eg lymph nodes, vessels, pleura) which allows for rapid intraoperative diagnosis, staging and therapy

• Several recommendations have emerged for screening of lung cancer, including those by the American Association for Thoracic Surgery, the National Comprehensive Cancer Network (NCCN), the United States Preventive Services Task Force (USPSTF), the European Society of Radiology (ESR) and the European Respiratory Society (ERS)
• NCCN, ESR and ERS recommend that lung cancer screening be conducted within clinical trials or routine clinical practice with multidisciplinary medical centers, to include individuals 55-80 years old, with smoking history of ≥30 pack years, current smoker, or those who have quit smoking within the last 15 years
• Individuals with comorbidities precluding curative therapy and without consent to undergo curative therapy 

• National Lung Screening trial (NLST): 1st US-based randomized controlled lung screening trial for current smokers or who used to consume >30 pack-years with ages of 55-74 years
• European NEderlands-Leuvens Screening ONderzoek (NELSON) trial: 2nd largest screening trial and the largest European randomized controlled trial in Europe used to assess patient risk based on age and smoking history 

• Solid nodule
  
  • For solid nodule <6 mm, annual LDCT is recommended until patient has been excluded for definitive treatment
  • For single solid nodule ≥6-<8 mm, LDCT should be fulfilled at 6 months
  • For an ≥8-<15 mm solid nodule, LDCT should be considered at 3 months; may also consider PET/CT
  • Patients with ≥15 mm solid tumor, chest CT with contrast and/or PET/CT is recommended
    • LDCT after 3 months should be considered in patients with low risk for lung cancer
    • Biopsy or surgical excision is recommended for patients at high risk for lung cancer
  • For patients with solid endobronchial nodule, LDCT ≤1 month is recommended, followed by bronchoscopy if without resolution

• Part-solid nodule
  
  • For part-solid nodule <6 mm, annual LDCT is recommended until patient has been excluded for definitive treatment
  • LDCT after 6 months is recommended for patients with ≥6 mm part-solid nodule with solid component <6 mm
    • If with ≥6-<8 mm solid component, LDCT is recommended 3 months after initial screening or may also consider PET/CT
  • Patients with part-solid nodule with solid component of ≥8 mm, chest CT with contrast and/or PET/CT is recommended
    • If highly suspicious for lung cancer, biopsy or surgical resection should be considered
    • LDCT after 3 months is recommended for patients at low risk for lung cancer
Non-solid nodule

• Annual LDCT is recommended for non-solid nodules <20 mm until patient has been excluded for definitive treatment
• LDCT 6 months after initial screening is recommended for patients with ≥20 mm non-solid nodule

• New nodule
  
  • For suspected infection or inflammation, LDCT should be done in 1-3 months
  • For suspected infection or inflammation that is resolving, 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 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 nodule
  
  • For <8 mm solid nodule that is unchanged on follow-up, an annual LDCT is recommended  
  • For ≥8-<15 mm solid nodule that is unchanged on follow-up, LDCT should be done in 6 months, if still unchanged after 6 months then, an annual LDCT is recommended 
  • For ≥15 mm solid unchanged on follow-up, a LDCT in 6 months or PET/CT scan is recommended
  • For unchanged findings in a year or for <4 mm new solid nodule on follow-up, an annual LDCT is still recommended
  • For 4-<6 mm new solid nodule on follow-up, LDCT should be done in 6 months
  • For 6-<8 mm new solid nodule on follow-up, LDCT should be done in 3 months
  • For ≥8 mm new solid nodule on follow-up, chest CT scan with contrast and/or PET/CT scan is recommended 
  • For ≤7 mm growing nodule on follow-up, LDCT should be done in 3 months
  • For ≥8 mm growing nodule on follow-up, chest CT scan with contrast and/or PET/CT scan is recommended
  • Based on patient risk: 
    • If with low risk for lung cancer, LDCT after 3 months is recommended
    • LDCT in 3 months for ≥8 mm solid nodule on chest CT with contrast and/or PET/CT for patients at low risk for lung cancer
    • Biopsy or surgical resection is recommended for patients at high risk for lung cancer

• Part-solid nodule
  
  • For <6 mm part-solid nodule that is unchanged on follow-up LDCT, and ≥6 mm part-solid nodule and with <6 mm solid component, annual LDCT is also recommended
  • For ≥6 mm part-solid nodule and with ≥6-<8 mm solid component, LDCT in 6 months or PET/CT scan is recommended
    • If with low risk for lung cancer, LDCT after 6 months is recommended
    • Biopsy or surgical resection is recommended for patients at high risk for lung cancer
  • If the part-solid nodule is unchanged, then an annual LDCT is recommended
  • For new part-solid nodule that is <6 mm on follow-up, 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, LDCT should be done in 3 months
  • For new or growing part-solid nodule with ≥4 mm solid component, chest CT scan with contrast and/or PET/CT scan is recommended
    • If with low risk for lung cancer, LDCT after 3 months is recommended
    • Biopsy or surgical resection is recommended for patients at high risk for lung cancer

• Non-solid (NS) nodule
  
  • For <20 mm new and stable NS nodule, annual LDCT is recommended 
  • For ≥20 mm new and stable NS nodule, LDCT should be done in 6 months, then annually once stable
  • For <20 mm growing NS nodule, LDCT should be done in 6 months
  • For ≥20 mm growing NS nodule, LDCT should be done in 6 months or may consider biopsy or surgical excision

• Multiple NS nodules
  
  • For pure NS nodules, measure the largest nodule and manage based on size as a NS or part-solid nodule
  • For dominant nodules with part-solid component, measure the largest nodule and manage based on size as a part-solid or solid nodule; all part-solid nodules ≥6 mm should be identified and solid areas should be measured

• For patients at high risk for lung cancer without lung malignancy on LDCT, biopsy or surgical excision, an annual screening with LDCT is recommended
  • Should be done until the patient is no longer a candidate for definitive treatment 
• A follow-up LDCT in 1-3 months is recommended for patients with multiple nodules or other findings suggestive of possible occult infection or inflammation