Pathology Flashcards

A 58-year-old man undergoes nephrectomy for a renal mass. Histology reveals tumor cells with abundant clear cytoplasm arranged in nests separated by a delicate vascular network. Immunohistochemistry shows positivity for CD10, vimentin, and carbonic anhydrase IX (CAIX), but negativity for CK7 and TFE3. A deletion in which chromosomal region is most characteristic of this tumor type?

Answer: Deletion of chromosome 3p (VHL locus)

The described tumor is clear cell renal cell carcinoma (ccRCC), the most common renal malignancy. The characteristic molecular alteration is loss of heterozygosity at chromosome 3p25, where the VHL (von Hippel-Lindau) tumor suppressor gene resides. VHL inactivation leads to constitutive HIF activation and downstream upregrowth of VEGF and PDGF. CAIX positivity reflects HIF-driven transcription. TFE3 translocation at Xp11 characterizes Xp11 translocation RCC, a separate entity with TFE3 positivity. WT1 deletion is associated with Wilms tumor. Monosomy 1 is seen in chromophobe RCC along with monosomies of chromosomes 2, 6, 10, 13, and 17.

Autopsy of a 72-year-old woman with a history of longstanding systemic lupus erythematosus reveals sterile verrucous endocarditis affecting both surfaces of the mitral valve leaflets. Which of the following best characterizes the pathogenesis of this finding?

Answer: Immune complex deposition and antiphospholipid antibody-mediated microthrombosis on valve surfaces

Libman-Sacks endocarditis, the sterile verrucous endocarditis of SLE, is pathognomonic for this condition and uniquely affects both surfaces (atrial AND ventricular) of the mitral valve leaflets — unlike rheumatic fever vegetations which are limited to the line of closure. The mechanism involves immune complex deposition and antiphospholipid antibodies (which cause microthrombosis) producing small, irregular, warty vegetations. These can embolize but are not infective. Myxomatous degeneration (mitral valve prolapse) leads to regurgitation and late risk of infective endocarditis, not Libman-Sacks lesions. Viral valvulitis is not a recognized mechanism.

A 45-year-old woman presents with episodic severe headaches, diaphoresis, and hypertension. Urine metanephrines are markedly elevated. Surgical resection of a right adrenal mass is performed. Histologically, the tumor shows a 'Zellballen' (nest) pattern with sustentacular cells at the periphery, and is positive for chromogranin A, synaptophysin, and S-100 (sustentacular cells). Which of the following histological features is the MOST reliable indicator of malignant behavior in this tumor?

Answer: Presence of capsular and vascular invasion with metastasis to non-chromaffin tissue

Pheochromocytoma is notorious for being one of the few tumors where malignancy CANNOT be reliably determined by histological features alone — even capsular invasion, necrosis, high mitotic rate, and pleomorphism can be seen in benign lesions. The ONLY absolute criterion for malignancy in pheochromocytoma is the presence of metastasis to sites that normally lack chromaffin tissue (e.g., lymph nodes, liver, lung, bone). PASS (Pheochromocytoma of the Adrenal Gland Scaled Score) uses multiple histologic parameters, but none are individually definitive. This distinguishes pheochromocytoma from most other endocrine tumors and is a classic board-level concept.

A 3-year-old boy presents with a flank mass, hematuria, and hypertension. Imaging reveals a large intrarenal mass. Nephrectomy is performed. Histology shows a triphasic pattern with blastemal, stromal, and epithelial components. Which of the following genetic alterations confers the WORST prognosis and is associated with diffuse anaplasia in this tumor?

Answer: TP53 mutation

This is Wilms tumor (nephroblastoma). Diffuse anaplasia — defined by markedly enlarged, multipolar polyploid mitotic figures and nuclear enlargement (≥3× normal) with hyperchromasia in ≥10% of the tumor or any anaplasia outside the primary site — is the single most important adverse histologic feature. Diffuse anaplasia correlates strongly with TP53 mutations, which develop during tumor progression and confer resistance to chemotherapy, significantly worsening prognosis. WT1 mutations are associated with Denys-Drash syndrome and bilateral Wilms tumors but do not specifically drive anaplasia. IGF2 overexpression (Beckwith-Wiedemann) and CTNNB1 mutations are associated with increased tumor risk but not directly with anaplastic histology.

A 66-year-old male smoker presents with hemoptysis and weight loss. Bronchoscopic biopsy of a central airway lesion reveals large polygonal cells with abundant pink granular cytoplasm, distinct cell borders, intercellular bridges, and individual cell keratinization. The tumor is strongly positive for p40 and CK5/6, and negative for TTF-1 and napsin A. Which paraneoplastic syndrome is MOST specifically associated with this histologic subtype of lung cancer?

Answer: Hypercalcemia due to PTHrP secretion

The tumor described is squamous cell carcinoma of the lung (p40+, CK5/6+, TTF-1−, napsin A−, with intercellular bridges and keratinization). Squamous cell carcinoma is the histologic subtype most specifically associated with hypercalcemia of malignancy mediated by PTHrP (parathyroid hormone-related protein) secretion — a humoral mechanism distinct from bony metastases. SIADH is classically associated with small cell lung carcinoma (SCLC). Ectopic ACTH (Cushing) is also primarily an SCLC/carcinoid association. Lambert-Eaton myasthenic syndrome results from autoantibodies against voltage-gated calcium channels and is almost exclusively seen with SCLC.

A liver biopsy from a 52-year-old woman with autoimmune hepatitis shows interface hepatitis, lymphoplasmacytic infiltrate, and prominent hepatocyte 'rosette' formation. Despite immunosuppression, she develops cirrhosis and a 3 cm hepatocellular carcinoma. Molecular analysis of the HCC reveals a mutation causing constitutive nuclear accumulation of β-catenin. Which of the following BEST explains the direct downstream oncogenic consequence of this mutation?

Answer: Transcriptional activation of cyclin D1 and c-Myc via TCF/LEF complexes

CTNNB1 (β-catenin) mutations prevent phosphorylation by the APC/Axin/GSK-3β destruction complex, allowing β-catenin to accumulate in the nucleus. There, it complexes with TCF/LEF transcription factors to drive expression of pro-proliferative target genes including cyclin D1 (cell cycle entry) and c-Myc (global transcriptional amplifier) — this is the canonical Wnt pathway oncogenic output. CTNNB1-mutant HCCs have a distinct transcriptional profile and tend to be well-differentiated with cholestatic features. MDM2 upregulation is the mechanism by which HDM2 amplification suppresses p53, not β-catenin. RAS-MAPK bypass is characteristic of KRAS or BRAF mutations. CDKN2A silencing occurs via epigenetic mechanisms unrelated to β-catenin.