Lung cancer

Epidemiology

• NSLC typically occurs 50-70 years old
• Most frequent cause of death from cancer in Western countries in both genders

Risk factors

• Cigarette smoking (unequivocally most important)
• Other environmental factors
  • Environmental radon gas exposure
  • Asbestos
  • Arsenic
  • Chromium
  • Nickel
  • Organic chemicals
  • Iatrogenic radiation exposure
  • Air pollution
  • Secondary pollution from smokers
• Personal or family history of lung cancer
• Personal history of lung disease

Histopathology

• Subtypes
  • Adenocarcinoma
    • Malignant epithelial tumours with glandular differentiation or mucin production
    • Cuboidal to columnar cells with adequate to abundant pink or vacuolated cytoplasm, and some evidence of gland formation
    • Growth patterns: (can have one pattern or a mixture of patterns)
      • 'Lepidic' describes non-invasive growth of tumour cells along intact alveolar septae

	Definition
Preinvasive glandular proliferations
Atypical adenomatous hyperplasia	Proliferation of atypical pneumocytes or Clara cells along alveolar walls, with cytology that falls short of carcinoma and is ≤5 mm.
Adenocarcinoma in situ (AIS)	Malignant epithelial cells growing along intact alveolar walls (lepidic pattern) with no evidence of invasion, measuring ≤3 cm.
Invasive adenocarcinoma subtypes
Minimally invasive	Lepidic growth present in the majority of the tumor, but with ≤5 mm of invasion. Tumors are generally ≤3 cm.
Lepidic	Lepidic growth present in the majority of the tumor, but with at least one focus of invasion that is >5 mm.
Acinar	Tumors cells form gland-like spaces (acini), sometimes with cribriform architecture. Typically associated with desmoplastic stromal response.
Papillary	Tumor cells coat papillae with central fibrovascular core.
Micropapillary	Tumor cells coat papillae but do not have a fibrovascular core. Tumor cells seem to float in alveolar spaces.
Solid	Tumors lack recognizable glandular features or papillae. The cells grow in solid-appearing sheets. Mucin generally present with special stains. Also, typically express pneumocytic differentiation by immunoperoxidase studies, eg, TTF-1.
Invasive mucinous	Tumor cells have goblet cell morphology or columnar cells with abundant mucin. Many of the cells grow along intact alveolar septae, but will also show areas of invasion. Most of these tumors were formerly known as mucinous bronchioloalveolar carcinomas.
Colloid	Malignant cells are associated with abundant extracellular mucin. Tumor cells may be hard to find and may also be found floating in the mucin.
Fetal	The overall low appearance of the tumor resembles fetal lung. The tumors resemble endometrioid adenocarcinoma.
Enteric-like	The tumors resemble those arising in the colorectum. Central necrosis is typically present in the tumor cell nests.
Signet ring and clear cell features	Both of these patterns may be seen as components of other tumor types, most commonly solid forms and are no longer considered as stand-alone diagnoses.

• • • Accounts for 45% of all lung cancers
    • 75% of adenocarcinomas are peripherally located
    • Tends to metastasise earlier than SCC, and spreads frequently to CNS
    • Solitary focus of adenocarcinoma in situ or minimally invasive adenocarcinoma is treated similar to invasive adenocarcinoma (anatomic resection)
    • Multifocal adenocarcinoma in situ requires treating the worst lesions and surveillance of the others, with lung preservation as the aim
  • Squamous cell carcinoma
    • Malignant epithelial tumour showing keratinisation and/or intercellular bridges that arises from bronchial epithelium
    • >90% of SCC occur in smokers
    • 66% are centrally located and tend to expand against the bronchus, causing extrinsic compression
    • Prone to undergo central necrosis and cavitation
    • Tends to metastasise later than adenocarcinoma
    • May be more readily detected on sputum cytology than adenocarcinoma
  • Large cell undifferentiated carcinoma
    • Diagnosed when specific cytological features of SCC or adenocarcinoma or neuroendocrine differentiation are lacking
    • Tends to occur peripherally and metastasise early
  • Neuroendocrine tumours of the lung
    • Arise from cells derived from the embryologic neural crest - Kulchitsky cells - in the bronchial epithelium
    • Subtypes
      • Small cell carcinoma
        • Extremely rare in never-smokers
        • Centrally located
        • Spread early to mediastinal lymph nodes and distant sites including BM and brain
        • Generally treat with CRT
        • Consider prophylactic cranial irradiation
        • Complete responses occur in about 30% of patients, but 5 year survival is 5%
        • Consider for resection if disease is <3cm, no nodal mets and no extrathoracic mets) followed by adjuvant CRT
        • Needs FDG PET, brain imaging and mediastinoscopy for staging - mediastinal mets is a contraindication to surgery
      • Large cell neuroendocrine carcinomas
      • Typical carcinoids (lower grade)
      • Atypical carcinoids (more aggressive, metastasise to liver, bone and adrenals)
    • Typical carcinoids are indolent while small cell carcinoma and large cell neuroendocrine tumour are highly aggressive
    • Peripheral carcinoids are usually asymptomatic, while more central ones can cause obstruction
    • Carcinoid syndrome is uncommon and occurs with large tumours or extensive metastatic disease
    • Mostly found in lobar bronchi (75%)
    • Usually diagnosed on bronchoscopy, with a sessile appearance
    • Aim for anatomic complete resection with lobectomy, although endobronchial polypectomy has been performed for polypoid tumours if surgery is contraindicated
• Driver mutations
  • EGFR (mutated epidermal growth factor receptor) - confers favourable prognosis
  • ALK (anaplastic lymphoma kinase translocation) - can be treated with ALK TKIs, which significantly prolong progress-free survival
  • ROS1 rearrangements - allow treatment with TKIs
• All lung cancers commonly metastasise to pulmonary and mediastinal lymph nodes, but haematogenous spread can occur to adrenal glands, brain, lung and bone (osteolytic). Extra-thoracic mets may occur without nodal or mediastinal disease.

Screening

• Guidelines recommend screening with annual low-dose CT if:
  • 55-74 year old with >30 pack year history
  • >50 year old with >20 pack year history but other factors making them high-risk for lung cancer

Symptoms

• Generally asymptomatic until late
• Symptoms are caused by physical impact of tumour growth within the lung parenchyma
  • Pain
  • Haemoptysis
  • Obstructive pneumonia
  • Dyspnoea
  • Chest wall pain

Presentation and initial evaluation

• Cardiorespiratory symptoms
• Check cervical and supraclavicular lymph nodes (suggests N3 disease)
• Check for paraneoplastic syndromes
  • Small cell cancer frequently causes neurologic syndromes
  • Other cancers may cause hypertrophic osteoarthropathy
• Pancoast syndrome: shoulder and arm pain, Horner syndrome (miosis, ptosis, anhidrosis, enophthalmos) and occasionally paraesthesias in ulnar distribution of the hand
  • Caused by local extension of cancer at the apex of the lung into the thoracic inlet
  • Much more common in NSCLC than SCLC or benign disease
  • Pain from C8 and T1 nerve roots
  • Typically, ribs 1, 2, and 3 are involved and require resection; the bony spine and intra-foraminal spaces can also be involved
  • Need MRI to determine resectability
  • Probably need neoadjuvant chemoradiotherapy

Work-up

• Solitary pulmonary nodules - see separate topic
• Evaluation of T stage
  • CXR/CT is generally adequate
  • MRI can provide further information on depth of invasion
  • Bronchoscopy if pneumonectomy or bronchoplastic resection is planned for a central tumour, to assess resectability
• Evaluation of N stage
  • CT (axial transverse diameter >1cm)
  • If positive nodes are identified, nodal tissue must be examined with EBUS, cervical mediastinoscopy, EUS, or VATS
  • Suspicious nodes elsewhere can have FNA or core
  • FDG PET (negative predictive value for mediastinal lymph nodes is 85-95%, more accurate in smaller primary tumours, more accurate in larger lymph nodes)
  • Mediastinoscopy
    • Indicated in otherwise operable NSCLC with enlarged paratracheal or subcarinal nodes
    • Especially if the cancer is proximal, pneumonectomy is planned, or the patient is high-risk for resection
    • Biopsy bilateral paratracheal and subcarinal nodes
    • Provides access to levels 2, 4, 5, 6, and 7
  • EBUS
    • Provides access to nodal stations 2, 4, 7, 10, and 11
  • EUS via oesophagus
    • Provides access to nodal stations 2, 4, 7, 8, and 9
  • VATS
    • Provides access to nodal stations 4, 7, 8, 9, and 10 bilaterally and 5 or 6 on the left
• Evaluation of M stage
  • Pleural effusion needs to be sampled - malignant effusions are contraindications to resection (M1a), but many effusions are simply reactive
    • If multiple cytological examinations are negative for tumour and fluid is non-bloody, and not an exudate, it can be excluded from staging
  • Brain imaging, generally with CT
    • Indications for MRI (to pick up occult brain metastases)
      • Stage I or II cancer with new neurologic symptoms
      • All patients with stage III or IV cancer
      • Small cell carcinoma
      • Superior sulcus tumours (Pancoast tumour)
  • PET for metastases

Staging:

• Use TNM system for most
• Small cell cancer can be staged with either TNM system or as limited stage (restricted to an ipsilateral hemithorax within a single radiation port) or extensive stage (obvious metastatic disease)
• Refer to lymph node station map under 'anatomy'
• TNM 8th edition for lung cancer:

T: Primary tumor
Tx	Primary tumor cannot be assessed or tumor proven by presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy
T0	No evidence of primary tumor
Tis	Carcinoma in situ
T1	Tumor ≤3 cm in greatest dimension surrounded by lung or visceral pleura without bronchoscopic evidence of invasion more proximal than the lobar bronchus (ie, not in the main bronchus)*
T1a(mi)	Minimally invasive adenocarcinoma¶
T1a	Tumor ≤1 cm in greatest dimension*
T1b	Tumor >1 cm but ≤2 cm in greatest dimension*
T1c	Tumor >2 cm but ≤3 cm in greatest dimension*
T2	Tumor >3 cm but ≤5 cm or tumor with any of the following features:Δ Involves main bronchus regardless of distance from the carina but without involvement of the carina Invades visceral pleura Associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung
T2a	Tumor >3 cm but ≤4 cm in greatest dimension
T2b	Tumor >4 cm but ≤5 cm in greatest dimension
T3	Tumor >5 cm but ≤7 cm in greatest dimension or associated with separate tumor nodule(s) in the same lobe as the primary tumor or directly invades any of the following structures: chest wall (including the parietal pleura and superior sulcus tumors), phrenic nerve, parietal pericardium
T4	Tumor >7 cm in greatest dimension or associated with separate tumor nodule(s) in a different ipsilateral lobe than that of the primary tumor or invades any of the following structures: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, and carina
N: Regional lymph node involvement
Nx	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension
N2	Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)
N3	Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s)
M: Distant metastasis
M0	No distant metastasis
M1	Distant metastasis present
M1a	Separate tumor nodule(s) in a contralateral lobe; tumor with pleural or pericardial nodule(s) or malignant pleural or pericardial effusion◊
M1b	Single extrathoracic metastasis§ (including a single non-regional lymph node)
M1c	Multiple extrathoracic metastases in one or more organs
Stage groupings
Occult carcinoma	TX	N0	M0
Stage 0	Tis	N0	M0
Stage IA1	T1a(mi)	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 to c	N1	M0
	T2a	N1	M0
	T2b	N1	M0
	T3	N0	M0
Stage IIIA	T1a to c	N2	M0
	T2a to b	N2	M0
	T3	N1	M0
	T4	N0	M0
	T4	N1	M0
Stage IIIB	T1a to c	N3	M0
	T2a to b	N3	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

Treatment overview:

• Resect when the local disease can be controlled, the patient can tolerate the procedure, and the anticipated morbidity and mortality are reasonable.
• Stage I and II disease: anatomic resection of the lobe with complete sampling of mediastinal lymph nodes, aiming to achieve complete resection of the tumour and its intra-lobar draining lymph nodes. Consider sub-lobar anatomic resections for small and peripheral tumours, however wedge resection is inferior to anatomic resection and should only be performed when more extensive surgery cannot be tolerated by the patient. In non-surgical candidates, stereotactic body radiation therapy (SBRT) has good early local control rates (90% at 3 years).
• Stage IIIA: mostly too advanced for resection, however can be considered, generally in patients with small tumours with low metastatic burden to ipsilateral mediastinum, or larger tumours that do not involve mediastinal lymph nodes. Likely to need neoadjuvant or adjuvant chemoradiotherapy to control micro-metastases.
• Stage IIIB and IV: Usually incurable. Chemoradiation, with surgery reserved for palliation. Immunotherapy can now target specific driver mutations.

Neoadjuvant chemotherapy

• Indications: stage IB or higher operable NSCLC
• Induction chemoradiotherapy can be considered for patients with resectable stage IIIA NSCLC

Surgery

• Situations where segmentectomy may be appropriate:
  • Peripheral small tumours with low metabolic activity on PET (stage I cancers)
  • In this situation, retrospective analysis shows similar results between lobectomy and segmentectomy
• Patients with NSCLC invading into chest wall may have resection with lobectomy and en-bloc chest wall resection
• Contraindications to resection:
  • SVC syndrome
  • Tumour invasion across the mediastinum into the main pulmonary artery
  • N3 nodal metastases
  • Malignant pleural or pericardial disease
  • Extra-thoracic metastases
• Features that make resection very difficult:
  • Involvement of trachea, atrium, great vessels, or other mediastinal or vertebral structures
  • Trache-oesophageal fistula (palliate with stent)
• Mediastinal lymph node sampling
  • Minimum requirements (American College of Surgeons Oncology Group)
    • Right-sided cancers: 2R, 4R, 7, 8, and 9
    • Left-sided cancers: 4L, 5, 6, 7, 8, and 9
• Mediastinal lymphadenectomy
  • Right: 2R, 4R, 7, 8, and 9
  • Left: 4L, 5, 6, 7, 8, and 9

Adjuvant chemotherapy

• Indications: stage IB and IIB

Prognosis

• Stage-specific
• Early-stage - 5 year survival 54%
• Locally advanced or metastatic - 26% 1 year, 4% five year