carcinoma of the lung

Introduction

lung cancer is predominantly lung carcinoma

Classification

(WHO 2004) see lung neoplasm

Etiology

(risk factors)

• exposure to:
  • tobacco smoke (direct or indirect)
    • after smoking cessation, risk of lung carcinoma decreases for about 15 years, then remains twice that of people who never smoked
    • 15% of patients with non-small cell lung cancer are non-smokers or have a minimal smoking history
  • radon, asbestos, polycyclic aromatic hydrocarbons
  • arsenic (glass workers, smelters, pesticides)
  • coal dust (coke oven, road work, roofers)
  • diesel exhaust
  • chromium (leather, ceramic, metal)
  • vinyl chloride
  • chloromethyl ether (small cell carcinoma)
• chronic lung injury
  • chronic obstructive pulmonary disease (COPD)
  • pulmonary fibrosis
• genetic factors
• vitamin A deficiency ?
• supplementation of folic acid 0.8 mg, vit B12 0.4 mg & vit B6 40 mg QD
  • increases risk of cancer
  • increases risk of dying of cancer
  • increases all cause mortality
  • hazzard ratio 1.2-1.4, number needed to harm 40-90
  • vit B6 not associated with significant effects
  • editorialist proposes folic acid as culprit
• use of vitamin B6 (> 20 mg QD) & vitamin B12 (> 55 ug QD) as individual supplements, but not from multivitamins, associated with a 30-40% increase in lung cancer risk among men, but not women
• hormone replacement therapy may increase risk
• higher free T4 may be associated with increased risk
• physical fitness in midlife associated with reduced risk of lung cancer after age 65 (RR=0.5)
• ACE inhibitor associated with increases risk relative to ARB (RR=1.1 after 5 years, 1.3 after 10 years)

Epidemiology

• most common malignant disease & most common cause of cancer related death in the USA 1998
  • 75% of patients with lung cancer die from the cancer
• male:female ratio 1.13:1
• 87% related to smoking
• most patients are > 50 years of age
• 9% of elderly men hospitalized with pneumonia will be diagnosed with lung cancer (median time to diagnosis = 300 days)

Pathology

(lung cancers)

• small cell carcinoma (18%)
  • occurs almost exclusively in smokers
  • invariably metastatic on presentation
• lung squamous cell carcinoma (29%)
  • tends to occur more centrally
• lung adenocarcinoma (32%)
  • most common type in non-smokers
  • tends to occur more peripherally
• lung bronchoalveolar carcinoma (lung adenocarcinoma, 3%)
  • low-grade carcinoma frequently presenting as patchy infiltrate
• lung large cell carcinoma (9%)
• lung bronchial carcinoid (1%)
• mesothelioma
• lung mucoepidermoid carcinoma (0.1%)
• lung adenoid cystic carcinoma (< 0.1%)
• metastases
  • lymph node metastases (83% local, 29% distant)
  • liver metastases (73%)
  • ipsilateral or contralateral lung metastases (8%)
  • bone metastases (56%)
  • brain metastases (37%)
  • adrenal metastases (35%)
  • kidney metastases (16%)

Genetics

• increased expression of SERINC3, NPBWR1
• POSTN expressed at tumor periphery
• loss of PDCD4 expression
• overexpression of PIN1
• linked with chromosome region 15q25, a region containing several genes, including 3 that encode nicotinic acetylcholine receptor subunits (CHRNA3, CHRNA5 & CHRNB4)
• defects in EGFR are more common in never-smokers than in smokers & response to EGFR inhibitors is better
• KRAS, TP53, BRAF, JAK2, JAK3, & mismatch repair gene mutations are more common in smokers than never-smokers
• ROS1 & ALK fusions
• defects in DLEC1 are a cause of lung cancer
  • DLEC1 silencing due to promoter methylation & aberrant transcription are implicated in the development of lung cancer
• chromosomal deletion involving UHRF2 is found in multiple kinds of malignancies
• other implicated genes: ACRBP, TPX2, STXBP5L, WFDC2, SAGE1, CHRDL2, FOXA1, IGF2BP1, ANLN, DUS2L, PRAF2, RASSF2, TBRG1, ARID4B, STIL, KKLC1, FMR1NB, MIRH1, BAGE1, BAGE2, BAGE3, BAGE4, BAGE5, TUSC5, MINA, NME1, GUSB, PHF19, ARHGAP27, XRRA1, PLCL1, LCA10, PRKCDBP, CLCA2, SEZ6L2, TP53, TP63, BRS3, SLC39A6, SLC22A18, EREG, BRAF, STK11, MYO18B, LIMD1, GNL3, CSNK2A3

Clinical manifestations

• only 5% of patients are asymptomatic
  • ~75% of lung cancers causing symptoms are at an advanced stage
• cough is most frequent symptom
  • more common in squamous & small cell carcinomas
• hemoptysis occurs in 35-50% of patients
  • more common in squamous & small cell carcinomas, carcinoid & endobronchial metastases
• wheezing due to intraluminal or extrinsic tumor compression
• dyspnea is dependent on
  • extent of tumor
  • COPD
  • degree of bronchial obstruction
• peristent chest pain
  • metastases to ribs
  • local extension of tumor
  • involvement of parietal pleural
• hoarseness (laryngeal nerve involvement)
• weight loss, loss of appetitite
• recurrent pneumonia or other respiratory tract infections
  • post-obstructive pneumonia
• fatigue
• superior vena cava syndrome
• Horner's syndrome with Pancoast tumor
• shoulder pain, shoulder & arm weakness (brachial plexopathy) may occur in association with Horner's syndrome with Pancoast tumors (Pancoast syndrome)
• paralyzed hemidiaphragm (phrenic nerve involvement)
• pleural effusion
• digital clubbing
• manifestations of distant metastases
  • fever
  • obstructive pneumonitis
  • non-thoracic skeletal pain
  • central nervous system symptoms
    • headache
    • focal neurologic symptoms
    • seizures
    • spinal cord compression generally manifests as pain followed by weakness
  • abdominal pain
  • hepatomegaly
  • lymphadenopathy
  • bone pain & bone fracture
  • skin nodules
• paraneoplastic manifestations
  • cachexia, anorexia, weight loss, nausea, vomiting
  • marantic endocarditis
  • thromboembolism
  • fever
  • disseminated intravascular coagulation (DIC)
  • dysproteinemia
  • acanthosis nigricans (adenocarcinoma)
  • epidermolysis bullosa (squamous cell carcinoma)
  • nephrotic syndrome
  • paraneoplastic encephalomyelitis
    • confusion
    • rapidly progressive dementia
    • seizures
  • paraneoplastic sensory neuropathy
    • paresthesias
    • sensory ataxia
    • multimodal sensory loss
  • SIADH
  • Lambert-Eaton myasthenic syndrome

Laboratory

• laboratory studies for paraneoplastic manifestations
  • complete blood count (CBC)
    • erythrocytosis
    • leukocytosis
    • lymphocytopenia
    • eosinophilia
    • thrombocytosis
    • leukemoid reaction
  • serum chemistries
    • serum sodium: hyponatremia secondary to SIADH
    • serum calcium: hypercalcemia of malignancy
• sputum cytology less sensitive than chest X-ray
• laboratory findings associated with distant metastasis
  • serum alkaline phosphatase may be elevated with bone involvement
  • complete blood count:
    • anemia, leukopenia, thrombocytopenia
  • serum lactate dehydrogenase may be elevated
• molecular diagnostic testing
  • EGFR gene mutation (non-small cell lung carcinoma)
  • lung cancer 8-protein signature (CPT)
• see ARUP consult

Diagnostic procedures

• diagnosis & staging of lung cancer should be done simultaneously to limit invasive testing
  • needle aspiration of suspicious peripheral lymph node
• bronchoscopy
  • transbronchial biopsy
    • needle aspiration rather than biopsy of mediastinal lymph node diagnostic
  • staging & assessing resectability
  • laser treatment for large airway disease
  • brachytherapy
• transthoracic needle aspiration
  • 85-90% yield
  • incidence of pneumothorax is 25%
  • needle aspiration rather than biopsy of lymph node diagnostic
• thoracentesis with indwelling pleural catheter if pleural effusion
  • pleurodesis as indicated
• mediastinoscopy
  • ultrasound-guided needle aspiration through the trachea or esophagus may be an alternative to mediatinoscopy
• pulmonary function testing
  • many patients with lung cancer have COPD

Radiology

• chest X-ray for mass lesion
  • compare to previous X-ray(s)
  • a solid lung nodule that has been stable for 2 years is unlikely to be cancer
  • biopsy with histopathology necessary for confirmation
• computed tomography
  • assessing extent of disease
  • examining hila & mediastinum
  • metastases to adrenal gland
  • next procedure after chest X-ray to characterize lung masses &/or lymphadenopathy to guide appropriate diagnostic procedure
• MRI to resolve uncertainties on CT
  • apical neoplasms
  • chest wall or mediastinal vascular invasion
  • adrenal "incidentaloma" versus metastases
    • adrenal adenomas generally contain some fat
• positron emission tomography (PET) with [18]-fluorodeoxyglucose to look for area of hypermetabolism
  • more sensitive than CT
  • useful for staging of lung cancer
  • useful for ruling out regional lymph node metastases
    • lymph node metastases needs confirmation by biopsy
• bone scan to assess bony metastases

Staging

see staging of lung cancer

Complications

• the main driving emergency department (ED) visits for elderly with metastatic lung cancer is the cancer burden itself
  • therapy-related events account for only 10% of ED visits
• neuronal autoantibodies in > 1/3 of patients with lung cancer
  • 45% of patients with SCLC & 33% of patients with NSCLC
  • neuronal autoantibodies associated with cognitive impairment
    • with NSCLC, immunoglobin A autoantibodies targeting the NMDA receptor increased risk of verbal memory impairment (RR=183)
• thoracic radiation therapy for pulmonary airway obstruction, superior vena cava syndrome, or spinal cord metastases (after surgical decompression)

Management

• staging, see staging of lung cancer
• early palliative care consult for metastatic lung cancer
  • concurrent chemotherapy & palliative care can improve quality of life & increase life expectancy 20%
• surgical resection for non-small cell cancer, stage I & II
• some stage IIIA carcinomas are resectable
• stage IIIB & IV & small cell carcinoma are inoperable
• chemotherapy for stage III & IV lung cancer with or without adjuvant radiation therapy
  • chemotherapy is palliative for metastatic disease (non-small cell lung cancers)
  • chemotherapy plus radiation for small cell carcinoma
• adjuvant radiation for resected stage II & IIIA cancers
  • does not improve survival
  • does reduce local recurrence
• palliative radiation therapy
  • brain metastases
  • spinal cord compression
  • weight-bearing lytic bony lesions
  • symptomatic local lesions
    • nerve paralysis
    • obstructed airway
    • hemoptysis
  • CT-guided, percutaneous radiofrequency ablation may induce complete response in patients with unresectable malignancies
• management of other medical conditions & supportive care during chemotherapy
• aerobic exercise & tai chi can improve sleep quality in patients with advanced lung cancer
  • tai chi is the more effective of the 2
• do not treat patients with poor performance status with chemotherapy, regardless of age
• smoking cessation improves survival
• entrance into a clinical trial if eligible
• also see management of non-small cell carcinoma & management section of non-small cell carcinoma

See lung neoplasm for WHO classification of pulmonary neoplasms.

See lung carcinoma for further information.

Prognosis:

• non-small cell carcinoma
  • stage 1: overall survival 50%, 1 year survival 80%
  • stage 2: overall survival <20%
  • stage 3: overall survival <10%
• small cell carcinoma
  • median survival < 12 months
  • 5-year survival for limited disease is 15-20%
  • 5-year survival for extensive disease is 1-5%
• overall 5-year survival for all lung cancers is 14%
• stage at presentation & perfomance status are the 2 most important prognostic indicators

Screening: see screening for lung cancer

Prevention:

• not smoking & smoking cessation (most important)
• phytoestrogens appear to be protective
• vitamin A (or beta-carotene), vitamin E of no benefit

Comparative biology

• inhalation of IL-12 messenger RNA, encapsulated within extracellular vesicles, is preferentially taken up by cancer cells of mice with lung tumours
  • these extracellular vesicles promote IGN-gamma mediated immune activation, systemic immunity & immune memory resulting in tumor suppression & resistance to tumor rechallenges

More general terms

• lung cancer
• carcinoma

More specific terms

• adenocarcinoma of the lung
• adenoid cystic carcinoma, lung
• adenosquamous carcinoma, lung
• bronchogenic carcinoma
• large cell carcinoma, lung
• mucoepidermoid carcinoma, lung
• non-small cell carcinoma of the lung (NSCLC)
• small cell carcinoma of the lung (SCLC, oat cell carcinoma)
• squamous cell carcinoma, lung

Additional terms

• lung cancer genotyping
• lung cancer pathogensis - genetic & pathways
• mediastinal neoplasm
• pleural neoplasm
• pulmonary metastases
• screening for lung cancer
• staging of lung cancer

Patient information

lung cancer patient information

Database

• OMIM: https://mirror.omim.org/entry/211980
• OMIM: https://mirror.omim.org/entry/612052