Karsinoma Paru

01Pathophysiology

Lung cancer arises from the cumulative genetic damage to bronchial and alveolar epithelial cells, most commonly driven by carcinogens found in cigarette smoke. These carcinogens (polycyclic aromatic hydrocarbons, nitrosamines) cause DNA adduct formation, point mutations, and eventual inactivation of tumor suppressor genes such as TP53 and RB1, along with activation of oncogenes such as KRAS, EGFR, and ALK rearrangements. The type of mutation often dictates the histologic subtype and, critically for exam purposes, the treatment approach.

Non-Small Cell Lung Cancer encompasses three major subtypes. Adenocarcinoma is the most common overall subtype and the most common lung cancer in non-smokers and women. It arises from mucin-secreting glandular cells in the lung periphery, which is why it classically presents as a peripheral lung nodule on imaging rather than a central hilar mass. Its peripheral location also explains why it is less likely to cause early obstructive symptoms like hemoptysis and more likely to be found incidentally. Squamous cell carcinoma arises from the bronchial epithelium centrally, driven by a metaplasia-dysplasia-carcinoma sequence in response to chronic irritation from smoking. Because of its central location, it commonly causes endobronchial obstruction, leading to post-obstructive pneumonia, hemoptysis, and cavitary lesions on imaging. It is strongly associated with hypercalcemia through production of parathyroid hormone-related peptide (PTHrP). Large cell carcinoma is a poorly differentiated tumor diagnosed by exclusion (lacks the glandular, squamous, or neuroendocrine features of other subtypes) and tends to present as a large peripheral mass with rapid growth and early metastasis.

Small Cell Lung Cancer (SCLC), historically called "oat cell carcinoma" due to its small, round, blue cell morphology, is a neuroendocrine tumor with an extremely aggressive course. It is almost exclusively seen in smokers. SCLC has the highest growth rate and earliest metastatic potential of all lung cancers, which is why the majority of patients present with extensive-stage disease. Its neuroendocrine origin explains its strong association with paraneoplastic syndromes: ectopic ACTH production (leading to Cushing syndrome), SIADH (causing hyponatremia), and Lambert-Eaton myasthenic syndrome (antibodies against presynaptic voltage-gated calcium channels causing proximal muscle weakness that improves with repeated use, the opposite of myasthenia gravis).

Pancoast tumors (superior sulcus tumors) deserve special attention. These are tumors arising at the lung apex that invade the brachial plexus (C8-T1, causing shoulder/arm pain and hand muscle wasting), the stellate ganglion (causing Horner syndrome: ipsilateral ptosis, miosis, anhidrosis), and sometimes the subclavian vessels. The classic vignette describes a smoker with shoulder pain radiating down the arm, hand weakness, and ipsilateral Horner syndrome.

SVC syndrome occurs when a tumor (most often right-sided lung cancer or lymphoma) compresses or invades the superior vena cava, causing impaired venous return from the head and upper extremities. The classic presentation includes facial plethora, upper extremity edema, jugular venous distension, and prominent collateral veins on the chest wall. SCLC is the most common lung cancer subtype to cause SVC syndrome because of its tendency for bulky mediastinal lymphadenopathy.

02Classification and Clinical Manifestation

Histologic Classification and Associations

Staging Systems

Common Metastatic Sites and Their Presentations

03Diagnostic Workup

The workup begins with the chest X-ray, which remains the best initial test when a patient presents with concerning respiratory symptoms and a significant smoking history. On CXR, the examiner may describe a solitary pulmonary nodule (a lesion less than 3 cm, often called a "coin lesion"), a hilar or perihilar mass, unilateral pleural effusion, or post-obstructive atelectasis. Any of these findings in a patient with risk factors should prompt further evaluation.

The next step is a CT scan of the chest with intravenous contrast. CT provides detailed characterization of the lesion: size, density, border morphology, and relationship to mediastinal structures. Features that suggest malignancy include spiculated (irregular) borders, a size greater than 3 cm (which reclassifies it as a "mass" rather than a "nodule"), absence of calcification, and growth on serial imaging. CT also evaluates for mediastinal lymphadenopathy and hepatic or adrenal metastases.

The gold standard for diagnosis is tissue biopsy with histopathologic examination. The method of biopsy depends on tumor location. Central lesions are best approached with flexible bronchoscopy (with endobronchial biopsy or transbronchial needle aspiration). Peripheral lesions not accessible by bronchoscopy require CT-guided percutaneous transthoracic needle biopsy. For patients with pleural effusion, thoracentesis with cytology can be diagnostic. Beyond histologic subtype, all NSCLC specimens should be tested for molecular biomarkers (EGFR mutations, ALK rearrangements, ROS1, BRAF, PD-L1 expression) because these directly determine eligibility for targeted therapy and immunotherapy.

PET-CT is used for systemic staging once the diagnosis is established. It detects distant metastases (bone, adrenal, contralateral lung) that would upstage the disease and change management from curative to palliative. A standardized uptake value (SUV) greater than 2.5 raises concern for malignancy in a detected lesion.

Brain MRI is performed routinely for SCLC (given its high propensity for brain metastasis) and for Stage III-IV NSCLC.

For surgical candidates, pulmonary function testing is required to confirm the patient can tolerate resection. The key metric is predicted postoperative FEV1: a value greater than 0.8 L (or greater than 40% of predicted) generally indicates the patient can tolerate lobectomy.

Lung Cancer Screening

An important exam topic is the low-dose CT (LDCT) screening recommendation. Current guidelines recommend annual LDCT for individuals aged 50 to 80 years with a 20 pack-year or greater smoking history who currently smoke or have quit within the past 15 years. This is based on the National Lung Screening Trial (NLST), which demonstrated a 20% reduction in lung cancer mortality with LDCT screening compared to standard chest X-ray. CXR is not recommended as a screening tool.

04Management and Treatment

NSCLC Early Stage (I-II):
The cornerstone of curative treatment is surgical resection. Lobectomy (removal of an entire lobe) is the preferred procedure, as it has lower local recurrence rates compared to sublobar resection. Patients who are not surgical candidates due to comorbidities or poor pulmonary reserve may receive stereotactic body radiation therapy (SBRT) as a definitive alternative with curative intent. Following surgery for Stage II disease, adjuvant chemotherapy with a cisplatin-based doublet (typically cisplatin + vinorelbine, 4 cycles) improves overall survival. Adjuvant osimertinib is now recommended for resected EGFR-mutant Stage IB-IIIA NSCLC following standard adjuvant chemotherapy.

NSCLC Locally Advanced (Stage III):
Stage IIIA disease is a complex decision point. Patients with potentially resectable disease may receive neoadjuvant chemoradiation followed by surgery or definitive concurrent chemoradiation. For unresectable Stage III NSCLC, the standard is concurrent platinum-based chemotherapy with thoracic radiation, followed by durvalumab (a PD-L1 inhibitor) as consolidation immunotherapy for up to 12 months in patients whose disease has not progressed. This consolidation step is very high-yield for exams.

NSCLC Metastatic (Stage IV):
Treatment is guided by molecular profiling. For patients with actionable driver mutations:

• EGFR mutation positive: First-line osimertinib 80 mg orally once daily (a third-generation EGFR tyrosine kinase inhibitor). This is the preferred agent due to its CNS penetration and superior progression-free survival.

• ALK rearrangement positive: First-line alectinib 600 mg orally twice daily. Alectinib has largely replaced crizotinib as the preferred first-line ALK inhibitor due to improved CNS activity.

• No actionable mutation, PD-L1 >= 50%: Pembrolizumab monotherapy 200 mg IV every 3 weeks.

• No actionable mutation, PD-L1 < 50%: Pembrolizumab + platinum-based doublet chemotherapy.

SCLC Limited Stage:
The standard regimen is cisplatin (60-80 mg/m² IV on day 1) + etoposide (100-120 mg/m² IV on days 1 through 3), repeated every 21 days for 4 cycles, administered concurrently with thoracic radiation therapy. Radiation should begin early (within the first 2 cycles of chemotherapy). In patients who achieve a complete or partial response, prophylactic cranial irradiation (PCI) is offered because SCLC has a very high rate of brain metastasis. PCI has been shown to improve overall survival.

SCLC Extensive Stage:
The current standard is carboplatin (AUC 5 on day 1) + etoposide (100 mg/m² on days 1 through 3) + atezolizumab (1200 mg IV on day 1), every 21 days for 4 cycles, followed by atezolizumab maintenance until disease progression. The addition of immunotherapy (atezolizumab or durvalumab) to chemotherapy is a relatively recent advance and a testable update.

Important Contraindication: Bevacizumab (an anti-VEGF agent sometimes used in NSCLC) is contraindicated in squamous cell carcinoma due to the risk of fatal pulmonary hemorrhage from cavitary, centrally located tumors invading major vessels.

05Differential Diagnosis and Distractors

06Traps and High-Yield Pearls

The most common way students lose points on lung cancer questions is by confusing the histologic subtype associations. Vignette writers rely on you knowing that adenocarcinoma is peripheral and most common in non-smokers, while squamous cell carcinoma is central and causes hypercalcemia, and small cell is central with paraneoplastic syndromes (SIADH, ectopic ACTH, Lambert-Eaton). If you see a non-smoking woman with a peripheral lung nodule, the answer is adenocarcinoma, not squamous cell, regardless of how "classic" the rest of the vignette looks.

A frequent trap involves paraneoplastic syndromes. When a vignette presents hyponatremia (SIADH) or proximal muscle weakness that improves with use (Lambert-Eaton), the answer is SCLC. When the vignette describes hypercalcemia with a central cavitary mass, the answer is squamous cell carcinoma. Students who do not anchor these associations to the correct subtype will pick the wrong answer.

Another tested concept is the distinction between Lambert-Eaton and myasthenia gravis. Both cause weakness, but Lambert-Eaton causes proximal weakness that improves with repeated muscle use (antibodies against presynaptic calcium channels), while myasthenia gravis causes weakness that worsens with use (antibodies against postsynaptic acetylcholine receptors) and preferentially affects ocular and bulbar muscles. If the vignette mentions a smoker, think Lambert-Eaton and SCLC.

Students also get tripped up on the Pancoast tumor vignette. The "gotcha" is that the question may not mention the word "lung." Instead, it describes shoulder pain radiating down the medial arm (C8-T1 brachial plexus invasion) plus Horner syndrome (ptosis, miosis, anhidrosis), and the student must recognize this as an apical lung tumor, not a musculoskeletal or neurological condition.

For screening, remember that low-dose CT is the only recommended screening modality (not CXR, not sputum cytology). The age range is 50 to 80, with at least 20 pack-years, and the patient must be a current smoker or have quit within the last 15 years.

Finally, a management trap: students may select surgery for SCLC. Surgery has almost no role in SCLC because the disease is nearly always disseminated at diagnosis. The answer for SCLC is always chemotherapy-based (cisplatin + etoposide, with or without radiation depending on stage). The only narrow exception is a very rare, truly solitary Stage I SCLC nodule, which is almost never the tested scenario.

The core competency being tested across lung cancer questions is your ability to match histologic subtype to clinical presentation, paraneoplastic syndrome, imaging pattern, and treatment strategy in a single integrated framework, rather than treating each piece of information in isolation.