Pulmonary Nodules and Lung Cancer

DDX: Cough (General)

acute cough→u3 wks

• clinical dx

• viral URI

• considerations:
  -PNA
  -acute bronchitis
  -asthma
  -COPD exacerbation

subacute cough→3-8 wks

• post-viral cough

chronic cough→8+ wks
with the abscence of red flags:
common causes:

• upper airway cough syndrome (UACS)
  -PND
  -allergic rhinitis
  -sinus sx

• asthma

• non-asthmatic eosinophilic bronchitis (NAEB)

• gastroesophageal reflux dx (GERD)

• ACEi-induced cough

• smoking-related chronic bronchitis/COPD

DDX: Cough Red Flags

hemoptysis

unexplained wt loss/fever/night sweats

persistent/worsening dyspnea

recurrent PNA

significant smoking hx

other lung cancer RFs

persistent cough/concerning assoicated sxs→malignancy

DDX: Hemoptysis

PP: expectoration of blood originating from the lower respiratory tract below the vocal folds
-indicator for lung cancer

true hemoptysis vs pseudohemoptysis

• URT bleeding
  -nose
  -mouth
  -pharynx

• GI bleeding (hematemesis)

assess severity+clinical severity:
-asphyxiation from blood obstructing the airways→immediate danger (not blood loss salone)

non-life threatening

• blood-streaked sputum

• limited bleeding without respiratory

• hemodynamic compromise

life-threatening (“massive”)
causes/threatens:

• airway obstruction

• respiratory failure

• hemodynamic stability

• traditional volume thresholds→100-600 mL/24h

• stabilization+hemorrhage control>dx workup

Solitary Pulmonary Nodule

PP/CM: rounded/irregular opacity within the lung parenchyma
-up to 3 cm in diameter (3+cm→pulmonary mass)

E:

neoplastic

• benign→hamartoma
  -cartilage
  -muscle
  -fat
  -bone

• malignant→primary lung cancer/metastatic dx

infectious

• granuloma from prior infxn
  -TB
  -histoplasosis

• active fungal/mycobacterial infxn

inflammatory

• rheumatoid nodule

• other inflammatory/granulomatous conditions

DX→CXR

TX:
observation
biopsy
surgical resection

• ID nodules with high malignancy probability

• benign dx→avoid invasive procedures

• consider pt’s unique clinical situation

Solitary Pulmonary Nodule Malignancy Probability

clinical presentation

• asx→incidental finding

• clinically concerning sxs
  -unexplained wt loss
  -hemoptysis

RF

• increases with age

• current/previous tobacco use

• prior malignancy

• FHx of lung cancer

DX

• most important step→review old imaging studies+compare

• estimate growth

• size

• appearance

Solitary Pulmonary Nodule CXR: Ground Glass Nodule

hazy opacity+preserved underlying vascular markings

often grows slowly

may represent

• inflammation

• infxn

• early adenocarcinoma-spectrum lesion

Solitary Pulmonary Nodule CXR: Part-Solid Nodule

contains both ground-glass+solid components

increasing size/development of a solid component→raises concern for malignancy

Solitary Pulmonary Nodule: Low vs Mid vs High Malignancy Probability DX+TX

low malignancy probability (u5%)

I: u40 y/o
lesions stable 2+ yrs
benign calcification

• watchful waiting

• CT surveilance when indicated (no immediate biopsy)

• monitor for changes:
  -size
  -growth
  -morphology

• follow appropriate nodule surveilance guidelines

intermediate malignancy probability (6-65%)

• solid+8+mm→PET/CT

• tissue dx
  -CT-guided transthoracic needle biopsy
  -navigational bronchoscopy+biopsy
  -select pts→surgical biopsy

• management
  -imaging
  -estimated risk
  -lesion accessibiltiy
  -pt factors

high malignancy probability (60+%)

• refer for multidisciplinary evaluation+appropriate cancer staging

• select pts→no pre-op biopsy→surgical resection+dx

• non-surgical tx

PET/CT Scan

positron emission tomography/computed tomography

function

• combines functional (PET)+anatomic (CT) imaging

• uses radioactive fluorodeoxyglucose (FDG)
  -glucose analog

• metabolically active tissues→increased FDG uptake

• standardized uptake value (SUV)
  -measures relative tracer uptake

I:

• solid pulmonary modules

• evaluate regional lymph nodes+distant metastases for staging

• guides biopsy location+tx planning

limitations

false positives:

• infxn

• inflammation

• increased FDG uptake

false negatives:

• small nodules (u8-10mm)

• ground-glass lesions

• certain low-metabolid tumors (carcinoid)

• not reliable for brain cancer metastasis

• does not replace tissue dx

PET/CT Scan: SUVmax+Probability of malignancy

SUVmax→measure of FDG uptake

• higher SUV values→increased suspicion for malignancy
  -historically: 2.5+ (no specific cutoff)

• use with other RFs:
  -CT morphology
  -nodule size+growth

PET-negative doesn’t mean cancer negative
PET-positive doesn’t confirm cancer
-tells us where metabolic activity is increased→not where cancer is present

Video-Assisted Thoracoscopic Surgery (VATS)

nodulectomy usually via wedge resection

send to pathology→frozen section

positive→lobectomy

negative→no further resection necessary

Bronchogenic Carcinoma RFs

tobacco→cigarettes

environmental+occupational exposures

• non-smokers→radon gas

• asbestos

• occuptional carcinogens
  -arsenic
  -chromium
  -nickel
  -silica
  -diesel exhaust

• air pollution

• prior chest radiation

pt-related

• increasing age

• FHx of lung cancer

• personal history of lung cancer→preventable

• chronic lung dx
  -COPD
  -PF

Bronchogenic Carcinoma E/Types+Dx

average age at dx→approximately 70 y/o

leading cause of cancer-related death in US

non-small cell lung cancer (NSCLC)

• m/c subtype→adenocarcinoma
  -non-invasive→adenocarcinoma in-situ

• SCC

• large cell carcinoma

small cell lung cancer (SCLC)

• neuroendocrine caricinoma

• aggressive

DX→molecular testing

I: NSCLC tumors→looking for molecular alterations

• EGFR

• ALK

• ROS1

• BRAF

• KRAS

• MET

• RET

• HER2

• PD-L1 expression→may help guide immunotherapy selection

Non-Small Cell Lung Cancer (NSCLC): Adenocarcinoma

most common lung cancer subtype (~40%)
-women
-non-smokers

from gland/mucin-producing epithelial cells
-type 2 pnuemocyte
-club-cell differentiation

located in peripheral lung→nodule/mass

may cause pleural retraction/”puckering” from associated firbosis

molecular alterations (EGFR/ALK/KRAS/etc.)→may guide targeted tx

Non-Small Cell Lung Cancer (NSCLC): Adenocarcinoma-In-Situ (AIS)

small+localized+noninvasive adenocarcinoma

chest CT→persistent ground-glass nodule

lepidic growth: tumor cells grow on alveolar walls without invading underlying tissue

no stromal/vascular/pleural invasion

P: complete surgical resection→excellent

Non-Small Cell Lung Cancer (NSCLC): Squamous Cell Carcinoma (SCC)

25% of lung cancers
-cigarette smokers

arises from bronchial epithelial cells→endobronchial mass→airway obstruction→hemoptysis/recurrent PNA/post-obstructive PNA
-centrally located
-near larger bronchi
-associated with hypercalcemia

larger tumors→central necrosis+cavitation

Non-Small Cell Lung Cancer (NSCLC): Large Cell Carcinoma

rare→2-3% of lung cancer

poorly/undifferentiated malignant epithelial tumor

lacks ID’able glandular/squamous differentiation

morphology+immunohistochemistry (IHC)→r/o potentially other cancers

aggressive→rapid growth+early metastasis potential

Small Cell Lung Cancer (SCLC)

10-15% of lung cancers
-cigarette smoking

neuroendocrine carcinoma
-high-grade
-poorly-differentiated
-arises centrally near major bronchi→causes airway narrowing/obstruction

hematogenous dissemination→rapid growth+early metastatic spread→high recurrence risk
-often metastatic at dx

early dissemination→no surgery→systemic tx needed

associated with paraneoplastic syndromes:

• SIADH→hyponatremia

• ectopic ACTH→cushing syndrome

• lambert-eaton myasthenic syndrome

Bronchial Carcinoid Tumors

PP: well-differentiated neuroendocrine tumors

E: rare (1-2% of lung malignant cancers)

typical carcinoid

• low-grade

• slow-growing

• favorable prognosis

atypical carcinoid

• intermediate-grade

• more aggressive

• greater metastatic potential

CM:
m/c→central/endobronchial→vascular+polypoid endobronchial masses
-may occur peripherally→asx→incidental finding

• cough

• hemoptysis

• focal wheezing

• airway obstruction

• recurrent post-obstructive PNA

DX:
chest CT
tissue biopsy
staging→TNM classification

TX:
localized→surgeical resection+regional lymph node evaluation
advanced/unresectable→specialized systemic therapies

P: better than SCLC

Bronchogenic Carcinoma CM

CM:

most pts (~75%)→sxs at dx

early stage lung cancer→asx+incidental/DX discovery

sxs depend on

• location of primary tumor

• extent of local spread

• presence of metastases

• paraneoplastic syndromes

subjective (pt reports)

• decreased appetite

• wt loss

• cough

• dyspnea

• hemotpysis

• pain

• hoarseness

• neuro sx→metastasis
  -headache
  -syncope
  -seizures
  -extremity weakness
  -AMS

objective (PE)

• wt loss

• hoarseness

• lymphadenopathy

• clubbing

• large tumor/PE→abnormal breath sounds

• large tumor/PE→dullness to chest percussion

• metastasis→bony tenderness

• metastasis→soft tissue mass

• focal neuro sxs

• post-obstructive PNA

• intrinsic/extrinsic/mixed stenosis

• SVC syndrome

• pancoast syndrome

• paraneoplastic syndromes

• hypercalcemia

• cushing sx

• syndrome of inappropriate antidiuretic hormone (SIADH)

• lambert-eaton myasthenic syndrome (LEMS)

Bronchogenic Carcinoma: Post-Obstructive Pneumoina

tumor obstructs/compresses a bronchus→impairs normal airway clearance

mucus+secretions accumulate distal to the line of obstruction

retained secretions→predispose to bx infxn+PNA

Bronchogenic Carcinoma: Hoarseness

recurrent laryngeal N paralysis→vocal cord dysfxn

Bronchogenic Carcinoma: Superior Vena Cava (SVC) Syndrome

PP: compression/invasion/thrombosis of SVC→obstructs venous return from head/neck/UEs/upper chest

E: lung cancer→central tumors
lymphoma

CM: face+neck+UE swelling
jugular venous distention (JVD)
dilated+superficial chest wall veins
dyspnea
cough
head fullness
worsening sxs→lying flat+bending forward

DX: contrast-enhanced chest CT
CT venography
cancer→tissue biopsy

TX:
rapid sx relief (emergency)→endovascular stenting

• severe airway compromise

• laryngeal edema

• neurologic deterioration/AMS

underlying malignancy→chemotherapy±radiation

Bronchogenic Carcinoma: Pancoast syndrome

apical lung malignancy→invades thoracic inlet

E: lower brachial plexus (C8-T1)
cervical sympathetic chain/stellate ganglion

CM: severe shoulder pain→radiates to scapula+axilla+medial/ulnar aspect of arm/hand
weakness+atrophy of intrinsic hand muscles

sympathetic N impairment→horner sx

• ptosis→drooping eyelid

• myosis→constricted pupil

• anhidrosis→decreased sweating

Bronchogenic Carcinoma: Paraneoplastic Syndrome

PP: disorders associated with malignancy that are not caused by direct tumor invasion/compression/metastasis

E: hormonal effects
immune-mediated effects

CM: hypercalcemia
cushing’s syndrome
symptom of inappropirate antidiuretic hormone (SIADH)
lambert-eaton myasthenic syndrome (LEMS)
anemia
hypercoagulability
thombocytosis

clinical significance

• particularly associated with small cell lung cancer (SCLC)

• may develop before dx of cancer

• can cause urgent+potentially life-threatening complications
  -severe hyponatremia
  -hypercalcemia

• tx may resolve syndrome even without cancer cure

Bronchogenic Carcinoma: Hypercalcemia

PP: tumor cells secrete parathyroid hormone-related protein (PTHrP)→PTHrP acts on PTH receptors→sxs:
-increased osteoclast-mediated bone resoprtion→calcium released into bloodstream
-increased renal tubular calcium reabsorption→decreased urinary calcium excretion

E: SCC

CM: “bones stones groans and psychiatric overtones”
fatigue
confusion
increased thirst
N+V
constipation
bone pain
kidney Stones

severe

• cardiac arrhythmia

• kidney failure

• coma

TX: underlying malignancy→IV hydration+IV biphosphonate/denosumab

Bronchogenic Carcinoma: Cushing Syndrome

PP: ACTH secreted independently of normal pituitary regulation (ectopic ACTH production)→ACTH stimulates adrenal cortex→production of excess cortisol→hypercortisolism
-normal ACTH secretion→anterior pituitary gland

E: small cell lung cancer (SCLC)

CM: new-onset HTN
profound hypokalemia
hyperglycemia
MSK weakness
may not have classic appearance→may develop severe metabolic abnormalities beforehand

Bronchogenic Carcinoma: Syndrome of Inappropriate Antidiuretic Hormone (SIADH)

PP: ectopic ADH/vasopressin production→ADH increases water reabsorption by the kidneys→excess water retention→dilution of serum sodium→dilutional hyponatremia
-normal ADH/vasopressin production→hypothalamus→released by posterior pituitary gland

E: small cell lung cancer (SCLC)

CM: clinically euvolemia (without obvious edema)

mild

• nausea

• headache

• fatigue

• muscle cramps

moderate-severe

• confusion

• AMS

• seizures

• coma

Lambert-Eaton Myasthenic Syndrome (LEMS)

PP: autoantibodies attack calcium channels at motor nerve terminals→impaired release of acetylcholine (ACh) from nerve terminalis

E: small cell lung cancer (SCLC)
autoimmune disorder→affects presynaptic neuromuscular injection

CM:

• proximal muscle weakness
  -LEs→difficulty climbing stairs/rising from a chair
  -similar to myasthenia gravis

• decreased/absent deep tendon reflexes

• repeated use→temporary improvement
  -MG→worsens with repeated use

• autonomic dysfxn
  -dry mouth
  -constipation
  -erectile dysfxn

• ptosis
  -less common than in MG

• diplopia
  -less common than in MG

Bronchogenic Carcinoma Dx (General)

imaging

• CXR

• chest CT

• PET/CT

confirmation→tissue biopsy/cytology

• requires malignant cells on tissue biopsy/cytology for definitive/confirmative dx

• serum tumor markers→not sufficiently sensitive/specifc for dx

• need adequate material/enough tissue for:
  -histology
  -immunochemistry
  -molecular testing

• choose the safest+least-invasive procedure

• determine cancer stage at same time

Bronchogenic Carcinoma Dx: Tissue Biopsy Options

biopsy options→based on tumor location

central/endobronchial lesions

• bronchoscopy+endobronchial biopsy/brushing/washings

peripheral lung lesions

• CT-guided transthoracic needle biopsy (TTNB)

• guided bronchoscopy
  -navigational
  -robotic-assisted

• less-invasive techniques non-dx→surgical biopsy

suspected lymph node involvement

• EBUS-guided transbronchial needle aspiration (EBUS-TBNA)

• EUS-guided needle sampling of selected mediastinal nodes

• ultrasound-guided biopsy of accessible supraclavicular lymph nodes

suspected pleural/distant metastases

• pleural effusion (PE)→thoracentesis+cytology

• biopsy of an accessible metastatic site

surgical DX

• VATS

• robotic-assisted thoracoscopic biopsy/resection

• endosonographic sampling inadequeate→mediastinoscopy

Bronchogenic Carcinoma Dx: Staging

TNM

T→local growth+invasion

N→lymphatic spread

M→distant metastases

• brain

• bone

• liver

• adrenal glands

SCLC:

• limited (30%)→tumor only in UL hemithroax

• extensive (70%)→tumor extends beyond hemithorax

NSCLC:

• TNM

• stages HV

Hx+PE

• red flag sxs

• weight loss

• exclude obvious metastatic dx
  -lymphadenopathy
  -focal neurologic defects
  -bone pain

labs

• CBC→anemia

• tx planning→electrolytes+renal fxn

• calcium

• organ fxn+nutritional status→liver tests+albumin

imaging

• CT
  -size/shape/location of primary tumor
  -ID of PE

• PET
  -ID metabolically active mediastinal LN
  -ID distant sites
  -does not evaluate brain

• brain MRI+contrast
  -all SCLC pts
  -NSCLC→stage 2+
  -any concerning sxs

mediastinal lymph nodes

• u1 cm+no FDG uptake+no distant metastasis→surgical resection

• 1+cm+±FDG uptake/potential metastasis→confirm/edclude malignancy in those areas
  -endobronchial US
  -TBNA

Bronchogenic Carcinoma Tx Definitions

local therapy→txs cancer in a specific area

• surgery

• radiation

systemic therapy→txs cancer throughout body

• chemotherapy

• targeted therapy

• immunotherapy

neoadjuvant→tx given before surgery

• tx systemic micro metastatic dx

• improve surgical outcomes

adjuvant→tx given after surgery

• reduce risk of recurrence

palliative

• relief of thoracic sxs

• improve quality of life at any stage of cancer with other txs

Bronchogenic Carcinoma Tx

stage 1-2: localized dx

• 1st line→surgery

• no surgery→stereotactic body radation therapy (SBRT)

• select pts→neoadjuvant/adjuvant chemo/immuno/targeted therapy

stage 3: locally advanced dx
requires a multidisciplinary tx approach

• resectable→surgery+systemic tx±radiation

• unresectable→concurrent chemoradiation→immuno/targeted therapy

• cure may still be possible

stage 4: metastatic dx

• 1st line→systemic therapy
  -targeted therapy
  -immunotherapy+/chemotherapy

• sx control→radiation/surgery

• early integration of palliative care

overall 5-yr survival rate (all stages combined)→approximately 32%

Bronchogenic Carcinoma Tx: Surgical Resection Considerations

surgical resection→offers best chance of cure

considerations

• is complete surgical resection technically feasible

• if yes→is pt able to tolerate surgery with acceptable morbidity+mortality chance

Bronchogenic Carcinoma TX: Preoperative Evaluation+Tests

I→pts with underlying dxs→increases risk of perioperative complciations+postoperative respiratory insufficiency

• COPD

• CV dx

• reduced fxnal capacity

pulmonary fxn testing (PFTs)

• FEV1→measures airflow+ventilatory fxn

• DLCO→measures lung’s ability to transfer gas into bloodstream

• required for all pts considering lung resection

postoperative lung fxn prediction

based on:

• ppoFEV1

• ppoDLCO

• preoperative fxn

• amount of lung tissue removed

• lower predicted values→greater risk of complications
  -60+%→lower risk
  -40-59%→moderate risk
  u40%→high risk

Bronchogenic Carcinoma: Non-Small Cell Lung Carcinoma (NSCLC) Tx

surgical resection

• lobectomy

• wedge resection

• segmentectomy

• lymph node biopsy+evaluation

surgical approach options

• thoracotomy

• video-assisted thoracoscopic surgery (VATS)

• robotic-assisted thoracoscopic surgery (RATS)

Bronchogenic Carcinoma: Small Cell Lung Cancer (SCLC) Tx

limited-stage

• concurrent chemo (platinum+etoposide)+thoracic radiation

• no dx progression→consolidation immunotherapy (durvalumab)

• generally given with cure intentions

extensive-stage

• platinum+etoposide+atezolizumab/durvalumab

• select pts→maintenance systemic therapy

• prolong survival+control sxs

prognosis+recurrence

• rapid-growing+aggressive cancer+early metastatic potential

• responds well to initial chemo+radiation

• high recurrence rate

• new txs→offer additional options after recurrence

overall 5-yr survival rate (alls tages combined)→approximately 10%

Malignant Mesothelioma

PP: mesothelial cell malignancy
-pleura (80%)
-peritoneum (20%)
-longer latency period→20-50 yrs post-exposure

RF: asbestos exposure
older adults
men
smoking→not a RF

E:
subtypes

• m/c→epitheliod
  -best prognosis

• sarcomatoid
  -more aggressive
  -worst prognosis

• biphasic
  -contains both epitheloid+sacromatoid components

CM: gradually progressive dyspnea
angina/chest discomfort
weight loss
fatigue
recurrent UL pleural effusion (PE)

DX: staging→PET/CT

chest CT+IV contrast

• UL nodular/irregular pleural thickening

• PE

• may progress→pleural rind invading adjacent structures

tissue biopsy

• 1st line→thoracoscopic (VATS) pleural biopsy

• image-guided core biopsy

• confirmation→histology+immunochemistry

TX:

1st line→systemic therapy

• unresectable 1st line→nivolumab+ipilimumab

• pembrolizumab+platinum/pemetrexed

• platinum+pemetrexed

select pts→surgery

• early-stage+predominantly epithelioid dx

• specialized centers→lung-sparing pleurectomy/decortication

• extrapleural pneumonectomy→rare→high mortality

sx management/palliative care

• recurrent sx effusions→thoracentesis/indwelling pneural catheter/pleurodesis

• sx dx (pain)→radiation

• early supportive+palliative care

P: generally poor
varies with stage/histology/fxnal status+tx
overall 5-yr relative survival (all stages combined)→approximately 15%

Lung Cancer Screening+Pack Years

United States Preventative Services Task Force (USPTF)

I: asx pts
50-80 y/o+20 pack yr smoking hx+currently smoke/quit in last 15 yrs

• discuss potential benefits/limitations/harms

• refer to a center with experience/expertise in lung cancer screening

• smoking cessation interventions

american cancer society (2023)
same recommendation except no 15-yr smoking cessation cutoff

pack years

numer of years you have smoked x average number of packs per day=pack years

Assessing Readiness to Quit Smoking

5 A’s model

Ask about tobacco use

Advise to quit

Assess willingness to try quitting

Assist in quit attempt

Arrange follow up

Smoking Cessation Methods

behavioral counseling

• brief provider advice+motivational counseling

• individual/group counseling

• telephone quitlines
  -1-800-QUIT-NOW

• digital tools:
  -text messaging
  -apps
  -online programs

pharmacotherapy

nicotine replacement therapy (NRT):

• patch

• gum lozenge

• inhaler

• nasal spray

combination NRT:

patch+gum/lozenge=more effective

1st-line mx→varenicline (chantix):

• highly effective

• partial nicotinic acetylcholine receptor agonist

alternative 1st-line mx→bupropion SR (zyban):

• inhibits norepinephrine+dopamine uptake

combination behavioral counseling+pharacotherapy=most effective