Correct Answer: D. Squamous cell carcinoma
Squamous cell carcinoma (SCC) of the lung is the classic presentation in this elderly male smoker with hypercalcemia and biopsy findings of large atypical cells with hyperchromasia. The discriminating feature is the paraneoplastic syndrome of hypercalcemia — SCC is the most common lung cancer associated with PTHrP (parathyroid hormone-related peptide) secretion, causing osteolytic hypercalcemia. The histological description of "large atypical cells with hyperchromasia" reflects the keratinizing squamous epithelium characteristic of SCC. SCC arises from the central airways (main/lobar bronchi) in smokers, presenting with chronic cough and airway obstruction. The combination of smoking history, central location, hypercalcemia, and squamous differentiation on biopsy makes SCC the diagnosis. Per Robbins pathology, SCC accounts for ~25–30% of lung cancers in India and remains the most common type in smokers, particularly in the Indian subcontinent where smoking prevalence is high. The weight loss and fatigue reflect advanced disease with paraneoplastic effects.
Why the other options are wrong
A. Large cell neuroendocrine tumor — Large cell neuroendocrine carcinoma (LCNEC) is rare (~3% of lung cancers) and presents with neuroendocrine markers (chromogranin, synaptophysin) on immunohistochemistry, not simple hyperchromasia. While it can cause hypercalcemia via PTHrP, it is not the most common paraneoplastic hypercalcemia lung cancer. The biopsy description lacks mention of neuroendocrine differentiation, making this a less likely diagnosis than SCC. B. Adenocarcinoma — Adenocarcinoma is now the most common lung cancer overall in India, but it is NOT associated with hypercalcemia — it causes hyponatremia via SIADH instead. Adenocarcinoma arises peripherally and shows glandular/mucin differentiation, not the keratinizing squamous pattern described. The hypercalcemia is a key discriminator that excludes adenocarcinoma as the diagnosis. C. Small cell carcinoma — Small cell carcinoma (SCLC) presents with small, round cells with scant cytoplasm and high mitotic rate — not 'large atypical cells.' SCLC causes SIADH-related hyponatremia and Cushing syndrome, not hypercalcemia. Although SCLC is aggressive and associated with smoking, the histological description and paraneoplastic syndrome (hypercalcemia) do not fit SCLC pathology.
High-Yield Facts
- Squamous cell carcinoma is the most common lung cancer associated with PTHrP-mediated hypercalcemia (osteolytic type).
- Central airway location (main/lobar bronchi) is typical for SCC; adenocarcinoma is peripheral.
- Keratinization and hyperchromasia on histology are hallmarks of squamous differentiation in lung SCC.
- Smoking is the dominant risk factor for SCC; it remains the most common lung cancer type in Indian smokers despite adenocarcinoma's rise overall.
- Paraneoplastic hypercalcemia in lung cancer: SCC (PTHrP) > LCNEC (PTHrP) >> adenocarcinoma (SIADH) or SCLC (SIADH).
Mnemonics
SCC Paraneoplastic: PTHCAL PTHrP → Hypercalcemia (osteolytic), Central location, Airway obstruction, Large keratinizing cells. Use when hypercalcemia + smoking + central lung mass is mentioned. Lung Cancer Paraneoplastic Syndromes SCC: PTHrP → hypercalcemia. SCLC: SIADH → hyponatremia, Cushing. Adenocarcinoma: SIADH → hyponatremia. LCNEC: PTHrP → hypercalcemia. Hypercalcemia = SCC or LCNEC; hyponatremia = SCLC or adenocarcinoma.
NBE Trap
NBE pairs "large atypical cells" with LCNEC to trap students unfamiliar with the paraneoplastic hypercalcemia–SCC link. The hypercalcemia is the key discriminator that rules out LCNEC and adenocarcinoma.
Clinical Pearl
In Indian smokers presenting with chronic cough and hypercalcemia, always suspect SCC first — it is the paraneoplastic hypercalcemia lung cancer. Serum PTHrP and 1,25-dihydroxyvitamin D levels confirm osteolytic hypercalcemia and guide management with bisphosphonates and hydration.
_Reference: Robbins & Cotran Pathologic Basis of Disease, Ch. 15 (Lung); Harrison's Principles of Internal Medicine, Ch. 85 (Lung Cancer)_