How lung cancer is tested on Step 1

Expect a smoker with a lung mass plus a lab abnormality or neurologic sign, and a question about the tumor type, histology, or mechanism of the paraneoplastic syndrome.

workspace_premium Central vs peripheral

Squamous and Small cell are Sentral (central) and strongly smoking-related. Adenocarcinoma and large cell carcinoma tend to be peripheral.

Histologic types

Small cell lung cancer behaves differently enough that it is staged and treated separately from the non–small cell group.

Lung cancerAdenocarcinomaPeripheral;EGFR, ALK, KRASSquamouscellCentral;keratin, PTHrPLarge cellPeripheral;undifferentiatedSmall cellCentral;neuroendocrineCarcinoidCentral; lowgrade
Lung cancer types. Non–small cell types together make up about 85% of cases.
TypeLocationHistologyAssociations
AdenocarcinomaPeripheralGlands, mucin; lepidic spread in situNonsmokers, women; EGFR, ALK, ROS1 targets; hypertrophic osteoarthropathy
Squamous cellCentralKeratin pearls, intercellular bridgesSmoking; PTHrP hypercalcemia; cavitation
Small cellCentralSmall blue cells, scant cytoplasm; chromogranin, synaptophysin, NSESmoking; SIADH, ACTH, Lambert-Eaton; early metastasis
Large cellPeripheralLarge pleomorphic cells, no glands or keratinSmoking; poor prognosis
Bronchial carcinoidCentralNests of uniform cells; chromograninNot smoking-related; can obstruct airway

Small cell carcinoma is usually metastatic at diagnosis, so surgery is rarely an option.

Paraneoplastic syndromes

Tumors can secrete hormones or trigger antibodies that act far from the tumor.

SyndromeMediatorTumorClue
HypercalcemiaPTH-related peptideSquamous cellConfusion, constipation; low PTH
SIADHADHSmall cellEuvolemic hyponatremia, concentrated urine
Cushing syndromeACTHSmall cell (also carcinoid)Hypokalemia, hyperglycemia, hyperpigmentation
Lambert-Eaton syndromeAntibodies to presynaptic Ca²⁺ channelsSmall cellProximal weakness improving with use; ↓ reflexes
Paraneoplastic encephalomyelitis, sensory neuronopathyAnti-Hu antibodiesSmall cellMemory changes, ataxia, numbness (anti-Yo, by contrast, is linked to ovarian and breast cancer)
Hypertrophic osteoarthropathyUnclear (VEGF, PDGF)AdenocarcinomaClubbing, periostitis

In Lambert-Eaton, repeated stimulation increases strength (unlike myasthenia gravis).

Local complications and molecular targets

Tumors near critical structures cause recognizable syndromes.

SyndromePancoast tumorHorner syndromeSuperior vena cava syndromeRecurrent laryngeal nerve palsyPhrenic nerve palsyCause and findingApical tumor invades brachial plexus —shoulder and arm painSympathetic chain: ptosis, miosis,anhidrosisFacial and arm swelling, distended neckveinsHoarseness (left nerve loops under theaorta)Elevated hemidiaphragm, dyspneavs
Local complications. SVC syndrome is most often caused by lung cancer (small cell is the type most prone to it) or lymphoma.
BiopsyConfirmadenocarcinomaMoleculartestingEGFR, ALK,ROS1, KRAS,PD-L1EGFRmutationOsimertinibALKfusionAlectinib,crizotinibHighPD-L1Pembrolizumab
Targeted therapy. EGFR mutations and ALK rearrangements are most common in never-smokers with adenocarcinoma.

Clinical application

Paraneoplastic labs often identify the tumor type.

functions Worked example — the confused smoker

A 63-year-old with a 50 pack-year history is confused. Serum sodium is 119 mEq/L; he is clinically euvolemic; urine osmolality is 610 mOsm/kg. Chest CT shows a large central hilar mass with mediastinal nodes. What is the likely tumor and mechanism?

  1. Euvolemic hyponatremia with concentrated urine indicates SIADH.
  2. A central mass in a heavy smoker suggests squamous or small cell carcinoma.
  3. Ectopic ADH secretion is characteristic of small cell carcinoma.
  4. Bulky mediastinal nodes fit early spread.

Answer. Small cell lung carcinoma secreting ADH. Treat with fluid restriction (and hypertonic saline if severe) plus platinum–etoposide chemotherapy with immunotherapy.