Lung Tumors

Internal Medicine - Pneumology Lecture #3 General Medicine ELP

Assoc. Prof. Robert Vyšehradský, M.D., PhD. Clinicic of Pneumology & Phthisiology

Simplified Classification of Lung Tumors

• Epithelial tumors – Adenocarcinoma

– Squamous cell carcinoma

– Neuroendocrine tumors • Small cell carcinoma

• Carcinoid (typical, atypical, tumourlets)

– Large cell carcinoma

– Adenosquamous carcinoma

– Sarcomatoid carcinomas

– Salivary gland-type tumors • Papillomas

• Adenomas

• Mesenchymal tumors – Hamartoma – Chondroma – Perivascular epithelioid cell

tumors • Lymphangioleiomyomatosis

– Sarcomas • Lymphohistiocytic tumors

– Lymphomas – Lymphomatoid

granulomatosis – Pulmonary Langerhans cell

histiocytosis • Tumors of ectopic origin • Metastatic tumors

Lung Cancer

• the most common cancer in men

• the third most common cancer in women

• one of the most aggressive cancers

• 5-year overall survival of 10–15%

Burdens of Lung Cancer Estimated world cancer incidence proportions, 2012

Lung 17%

Prostate 15%

Colorectum 10% Stomach

9%

Liver 7%

Bladder 4%

Oesophagus 4%

NHL 3%

Kidney 3%

Other 28%

Men

Breast 25%

Colorectum 9%

Lung 9%

Cervix uteri 8%

Stomach 5%

Corpus uteri 5%

Ovary 4%

Thyroid 3%

Liver 3%

Other 29%

Women

Epidemiology

• 1.8 mil. new cases annually = 13% of total cancer incidence

• 1.6 mil. deaths annually = 20% of total cancer mortality

Global distribution of estimated age-standardized incidence rates (ASR) per 100 000, 2012. men women

Epidemiology - trends Age-standardized incidence rates per 100 000 by year in selected populations, 1975–2012. men women

Etiology

Exogenous risk factors • tobacco smoking – 90%

• arsenic, metals, fibres, dusts

• organic compounds (painters, rubber industry)

• radon

• household combustion of coal

• β-carotene supplements, fruits and foods containing carotenoids

Exogenous risk factors 2

Factor Relative risk

Environmental tobacco smoke 1.2

Asbestos (risk proportional to dose) 1.0–5.0

Radon gas (granite rock) 1.2

Diesel fumes (occupational) 1.3

Silicosis 2.5–3.2

Family history (especially women) <50 yr 2–4

Gender (women at greater risk) 1.2–1.7

COPD 2.7–5.0

Radon Level World

Endogenous risk factors

• 5p15

• 6p21

• 15q25 (14% attributable risk)

genes regulating NACCHr and telomerase production

Micromorphological types

SCLC 15-20%

Adeno 40-50%

Squamous 25-40%

Large cell 3-5%

NOS <5%

NSCLC 80-85%

Driver mutations

mutation molecularly targeted drug

Adenocarcinoma EGFR, HER2 (ERBB2), KRAS, ALK, BRAF, PIK3CA, and ROS1

available

Small cell carcinoma

TP53 and RB1 (100%) no

Squamous cell carcinoma

without specific molecular abnormalities but 50% have genetic alterations that are potential molecular targets: TP53, CDKN2A (P16), PTEN, PIK3CA, KEAP1, and MLL2

in development

Driver mutations in adenocarcinoma smokers vs nonsmokers

smokers never-smokers

EGFR mutation 14% 38%

ALK translocation 2% 12%

Clinical symptoms Vague, non-specific, late onset

Symptoms and signs Range of frequency (%) Cough 8–75 Weight loss 0–68 Dyspnoea 3–60 Chest pain 20–49 Haemoptysis 6–35 Bone pain 6–25 Clubbing 0–20 Fever 0–20 Weakness 0–10 Superior cava vein sy. 0–4 Dysphagia 0–2 Wheezing and stridor 0–2

Physical findings

• Non-specific!

• Signs of complications (airways obstruction, pneumonia, pleural effusion, lung collapse).

• General cancer symptoms (cachexia, anemia...)

• Signs of extrathoracic spread (extrathoracic lymphadenomegaly, Bernard-Horner sy., SCV sy., intracranial hypertension, neurological symptoms, hepatomegaly, bone fracture, skin metastasis).

• Paraneoplastic syndromes.

Paraneoplastic syndromes Secreted peptide or hormone

Mechanism Clinical presentation

Vasopressin antidiuretic hormone, ADH)

Low serum sodium

Weakness, blackouts

Adrenocorticotrophin (ACTH)

High cortisol Cushing’s syndrome

Atrial natriuretic peptide (ANP)

Low serum sodium

Weakness, blackouts

Granulocyte colony stimulating factor (G-CSF)

High WBC Asymptomatic

Paraneoplastic encephalomyelitis /sensory neuropathy

Anti-Hu antibodies

Sensory neuropathy, cerebellar ataxia, pseudo-obstruction

Lambert Eaton myasthenic syndrome (LEMS)

Voltage-gated calcium channel antibodies

Proximal muscle weakness, autonomic symptoms

Physical findings

Work-up

• Micromorphology

• Staging

• Biomarkers

• Assessment of fitness for surgery

• Investigation for CHT, RT

Micromorphology • Bronchoscopy: Narrow Band Imaging (NBI),

brushig, forceps biopsy, perbronchial needle aspiration, kryobiopsy, endobronchial ultrasound (EBUS).

• Perthoracic needle biopsy (CT-guided, ultrasound-guided).

• Sputum cytology.

• Pleural fluid cytology.

• Surgical biopsy (resection).

• Distant metastasis biopsy.

• Liquid biopsy?

Staging procedures

T – Bronchoscopy: localization in the bronchial tree. – CT: size, localization, involvement of the adjacent

structures.

– CT: localization and size of intrathoracic LN – EBUS: micromorphology – Mediastinoscopy/thoracoscopy: micromorphology – PET/CT – specificity of 85%

N

Abdominal ultrasound + according to symptoms

M

NSCLC

Abdominal ultrasound Bone scintigraphy Brain imaging? + according to symptoms

NSCLC

Simplified TNM

T

Tis In situ carcinoma

T1 ≤3 cm, no more proximal than the lobar bronchus

T2 >3 cm ≤7 cm or: involves main bronchus, ≥2 cm distal to the carina; visceral pleura; atelectasis or obstructive pneumonitis

T3 >7 cm or invades: parietal pleura, chest wall, diaphragm, phrenic nerve, mediastinal pleura, pericardium; main bronchus <2 cm distal to the carina; nodule in the same lobe

T4 any size + mediastinal organs, vertebral body, carina, nodule(s) in a ipsilateral lobe

N

N0 No regional lymph nodes

N1 Ipsilateral peribronchial and/or hilar LN

N2 Ipsilateral mediastinal and/or subcarinal LN

N3 Contralateral mediastinal or hilar, scalene, or supraclav. LN

M M0 No distant metastasis

M1 Distant metastasis

Simplified staging Occult TX N0 M0

0 Tis N0 M0

IA T1 N0 M0

IB T2a N0 M0

IIA T2b N0 M0

T1-2a N1 M0

IIB T2b N1 M0

T3 N0 M0

IIIA T1-3 N2 M0

T3-4 N1 M0

T4 N0-1 M0

IIIB T1-3 N3 M0

T4 N2-3 M0

IV Any T Any N M1

Lung cancer metastasis distribution autopsy data

Biomarkers

• SCCAg

• CYFRA21-1

• CEA

• NSE

Operability assessment

• Resecability – CT scan

– screening for distant metastasis (PET/CT? 20% of metastasis not detecable by CT).

• Operability: – overall status performance,

– comorbidities,

– lung function (spirometry, BGA, lung diffusion capacity, ergospirometry),

– cardiovascular ability (echocardiography, possibly ergometry, coronarography).

Investigation for CHT, RT

• BUN, creatinine clearance, CBC, liver enzymes

• EGFR, ALK, ROS1,

Treatment NSCLC

I, II N0 lobectomy

+ evaluation of LN

II N1(p)

IIIa N2a lobectomy, pneumonectomy

+ complete homolateral lymphadenectomy

IIIa N2b neoadjuvant

CHT

lobectomy + complete homolateral

lymphadenectomy

lobectomy, pneumonectomy + complete homolateral

lymphadenectomy ERT

ERT

concomitantCHT Pt+ERT

ERT

IIIb

induction CHT Pt

induction CHT Pt

ERT

IV CHT Pt+

biological treatment

adjuvant CHT

adjuvant CHT

adjuvant CHT

Treatment SCLC

LD

ED

lobectomy/pneumonectomy + complete

lymphadenectomy

concomitant CHT Pt+Etoposide, CAV

+ ERT

CHT Pt+Etoposide, CAV

adjuvant CHT

ERT

prophylactic brain irradiation

neoadjuvant CHT

T1,2 N0,1

Molecular targeted therapies Gene Histological type Therapy

EGFR mutation

Advanced adenocarcinoma

EGFR tyrosine kinase inhibitor Erlotinib, gefitinib

ALK fusion Adenocarcinoma Crizotinib

ROS1 fusion Advanced adenocarcinoma

Crizotinib

HER2 Adenocarcinoma Afatinib (BIBW 2992)

PI3KCA NSCLC Trastuzumab, PI3K inhibitor

BRAF NSCLC Sorafenib?

MET NSCLC Phase 2: rilotumumab (AMG 102), MetMAb

RAS Adenocarcinoma PI3K + MEK inhibitors

Immunotherapy

• checkpoint inhibitors - “taking the brakes off” the immune system: – PD-1/PD-L1 checkpoint inhibitors: nivolumab,

pembrolizumab, atezolizumab, durvalumab, (NSCLC) – CTLA-4 checkpoint inhibitors : ipilimumab, Ipilimumab

• monoclonal antibodies: bevacizumab, ramucirumab • therapeutic vaccines: to elicit an immune response

against tumor-specific antigens (MAGE-3 – 42%; NY-ESO-1 – 30%; p53 – 50%; survivin, MUC1).

• adoptive cell therapy: T cells removed from a patient, genetically modified or treated with chemicals to enhance their activity, and then re-introduced into the patient.

Supportive Care

• nausea

• pain

• fatigue

• shortness of breath

• cough

• nourishment

• emotional and spiritual problems

Prevention

• Low-dose CT

• Healthy individuals aged 55–79 years with at least a 30 pack-year history of smoking and who have smoked within the past 15 years

• Mortality reduction by 20%.

• Smoking cessation.

Smoking cessation

• 70% of smokers want to quit!

• Quit programmes cost € 890 per life-year saved (1998 data); lung cancer CHT is 25 times as expensive.

• Simple advice by a doctor = quit rate of 1–3%.

• Nicotine replacement = quit rate of 6–8%.

• Bupropion – improvement by 36%.

‘quitting smoking is the easiest thing in the world to do; I have done it several times.’

Prognosis

• Lung cancer accounts for 13% of all cancers and 20% of all cancer deaths.

• 5-year survival of 10–15%.

• 80% diagnosed with metastatic disease.

• >50% distant metastases.

Overall and five-year survival and median survival by stage for NSCLC

The impact of small-cell lung cancer (SCLC) treatment on survival