Pathology Board Questions

A completely excised tubular adenoma with high-grade dysplasia but no submucosal invasion (pTis) is adequately treated by polypectomy alone, provided the margin is clear. Current guidelines recommend surveillance colonoscopy within 3 years due to the high-grade dysplasia. Segmental colectomy would be indicated if there were submucosal invasion with adverse features (positive margin, lymphovascular invasion, poorly differentiated component).

The combination of elevated ALP, positive AMA, and histological florid duct lesion with granulomatous bile duct destruction is pathognomonic for primary biliary cholangitis (PBC, formerly primary biliary cirrhosis). PSC shows concentric "onion-skin" periductal fibrosis. Autoimmune hepatitis predominantly affects hepatocytes (interface hepatitis) rather than bile ducts. Drug-induced injury can mimic many patterns but the AMA positivity points specifically to PBC.

This is a gastric GIST. Risk stratification for GIST uses the modified NIH criteria considering tumour size, mitotic rate, and site. A gastric GIST of 5 cm with >5 mitoses/5 mm² falls into the high-risk category. DOG1 and CD117 positivity with negative desmin and S100 confirms GIST over leiomyoma (desmin+) and schwannoma (S100+). High-risk gastric GISTs have significant metastatic potential and typically warrant adjuvant imatinib therapy.

Solid pseudopapillary neoplasm (SPN) classically presents in young women as a large solid and cystic pancreatic mass. The hallmark histology is pseudopapillary architecture with hyalinised fibrovascular cores. Nuclear β-catenin (due to CTNNB1 mutation) and progesterone receptor positivity are characteristic IHC findings. PanNETs show synaptophysin/chromogranin positivity. Acinar cell carcinoma shows trypsin/chymotrypsin positivity. MCN has ovarian-type stroma.

In ulcerative colitis, a DALM with concurrent flat dysplasia in the surrounding mucosa indicates a field change with high risk of synchronous or metachronous carcinoma. The combination of a raised dysplastic lesion, flat dysplasia elsewhere, and p53 overexpression (suggesting TP53 mutation, a late event in the IBD-dysplasia-carcinoma sequence) constitutes a strong indication for proctocolectomy. Isolated, well-circumscribed polyps (adenoma-like DALMs) without surrounding flat dysplasia may be managed endoscopically, but multifocal dysplasia changes the calculus.

The combination of malignant squamous cell features (hyperchromatic nuclei, irregular membranes, high N:C ratio) with orangeophilic (keratinising) cytoplasm AND tumour diathesis (necrotic debris, old blood) indicates invasive squamous cell carcinoma. HSIL shows similar nuclear abnormalities but without tumour diathesis or keratinisation. LSIL shows koilocytes with relatively low N:C ratio. The tumour diathesis is the critical distinguishing feature.

The combination of papillary architecture, nuclear grooves, intranuclear pseudoinclusions, powdery chromatin, and psammoma bodies is diagnostic of papillary thyroid carcinoma. This warrants Bethesda VI (Malignant) classification. Bethesda V (Suspicious) would be used when some but not all features are present. The triad of nuclear grooves + pseudoinclusions + powdery chromatin is the classic "Orphan Annie eye" nuclear morphology of PTC.

The cytological features (glandular architecture, mucin vacuoles, prominent nucleoli) combined with TTF-1 positivity are diagnostic of pulmonary adenocarcinoma. Squamous cell carcinoma shows keratinisation, intercellular bridges, and is typically TTF-1 negative. Small cell carcinoma shows nuclear moulding, crush artefact, and salt-and-pepper chromatin. Mesothelioma typically shows calretinin+, WT1+, D2-40+ rather than TTF-1 positivity.

The IHC profile (CK7+, TTF-1+, calretinin−) points to metastatic pulmonary adenocarcinoma in pleural fluid. Calretinin negativity rules out mesothelioma (which is calretinin+, WT1+, D2-40+). Cell cannibalism is a feature of malignancy in effusion cytology. Metastatic breast carcinoma would be GATA3+ and typically TTF-1 negative (though rare TTF-1 positivity occurs in breast). The CK7+/CK20−/TTF-1+ profile is highly specific for lung primary.

Clear cell renal cell carcinoma (ccRCC) is characterised by clear cytoplasm, sinusoidal vasculature, and strong CAIX membranous positivity. VHL gene inactivation (3p25 deletion or mutation) is the hallmark genetic event, leading to HIF pathway activation. MET mutations are associated with papillary RCC type 1. TFE3 translocations define MiT family translocation RCC. Fumarate hydratase loss defines hereditary leiomyomatosis-associated RCC.

Well-formed individual discrete glands = Gleason pattern 3. The absence of basal cells (negative p63/CK5/6) with positive AMACR confirms malignancy over a benign mimic. Grade Group 1 (Gleason 3+3=6) has an excellent prognosis and is often managed with active surveillance. Gleason pattern 4 would show poorly formed, fused, or cribriform glands. The ISUP Grade Group system (1–5) is the current WHO-recommended reporting standard.

The combination of architectural disorganisation, scattered mitoses at all levels, loss of polarity, and full-thickness CK20 positivity (normal urothelium shows CK20 limited to umbrella cells) indicates high-grade urothelial carcinoma. Invasion into lamina propria makes it pT1. Aberrant p53 supports high-grade/aggressive biology. PUNLMP has minimal atypia. Low-grade has orderly cells with mild atypia. CIS is flat high-grade dysplasia without papillary architecture.

Classic seminoma shows sheets of large uniform cells with clear/watery cytoplasm, distinct cell borders ("fried egg" appearance), central nuclei with prominent nucleoli, and characteristic lymphocytic infiltrate. Seminoma has normal AFP (elevated AFP rules out pure seminoma), may have mildly elevated β-hCG (syncytiotrophoblastic giant cells), and elevated LDH. Embryonal carcinoma shows more pleomorphic, cohesive epithelioid cells with CD30 positivity. Yolk sac tumour elevates AFP.

Nottingham grading: Tubule formation >75% = score 1. Nuclear pleomorphism mild = score 1. Mitoses 4/10 HPF = score 1. Total = 3–5 = Grade 1. Grade 2 = total 6–7. Grade 3 = total 8–9. This is a fundamental surgical pathology grading system tested on every board exam. Grade 1 invasive breast carcinoma (usually Luminal A-like) has excellent prognosis.

ER−/PR−/HER2− = triple-negative breast cancer, which corresponds to the basal-like molecular subtype in most cases. BRCA1 mutations are strongly associated with triple-negative/basal-like breast cancers. High Ki-67 and high mitotic rate are typical. These tumours do not benefit from endocrine therapy or anti-HER2 therapy; treatment relies on chemotherapy and increasingly on immunotherapy (pembrolizumab) and PARP inhibitors (olaparib in BRCA-mutant disease).

Invasive lobular carcinoma (ILC) is characterised by small, discohesive, monomorphic cells infiltrating in single-file (Indian file) and targetoid (concentric periductal) patterns. Loss of E-cadherin expression (due to CDH1 mutation or methylation) is the molecular hallmark and key diagnostic IHC marker. Ductal NST shows cohesive nests/tubules and retains E-cadherin. Tubular carcinoma shows angulated open tubules. Classic (pleomorphic) medullary pattern shows syncytial growth with lymphocytic infiltrate.

Endometrial serous carcinoma (ESC) shows papillary architecture with slit-like spaces, high-grade nuclear atypia, and a characteristic IHC profile: p53 mutant pattern (diffuse strong overexpression due to missense TP53 mutation), ER/PR negative, and p16 block-positive (diffuse strong, due to TP53 pathway rather than HPV). This is a "p53-abnormal" carcinoma in the new molecular classification (TCGA). It is aggressive regardless of stage. Grade 3 endometrioid is ER+/PR+ in most cases.

Current evidence and WHO 5th Edition classification recognise that the majority of "ovarian" high-grade serous carcinomas (HGSC) actually originate from serous tubal intraepithelial carcinoma (STIC) in the fallopian tube fimbriae. The IHC profile (PAX8+, WT1+, p53 mutant, CK7+) is consistent with Müllerian/tubal origin. This paradigm shift has led to risk-reducing salpingo-oophorectomy in BRCA carriers and the routine examination of fallopian tubes (SEE-FIM protocol).

AJCC 8th Edition melanoma staging: pT2 = Breslow 1.01–2.0 mm. The "a" suffix indicates no ulceration. So 1.8 mm without ulceration = pT2a. Mitotic rate is no longer part of T-staging in AJCC 8th (it was in AJCC 7th for pT1b). pT1 = ≤1.0 mm, pT2 = 1.01–2.0 mm, pT3 = 2.01–4.0 mm, pT4 = >4.0 mm. "a" = no ulceration, "b" = ulceration present.

Dermatofibrosarcoma protuberans (DFSP) is a low-grade dermal sarcoma with a characteristic storiform growth pattern, CD34 positivity, and honeycomb infiltration of subcutaneous fat. The hallmark translocation t(17;22) produces a COL1A1-PDGFB fusion gene, resulting in autocrine PDGFB signalling. This is therapeutically relevant as imatinib (PDGFR inhibitor) is effective in unresectable/metastatic DFSP. Factor XIIIa is typically positive in benign dermatofibroma (the main differential).

Per WHO 5th Edition, lung adenocarcinoma is classified by the predominant architectural pattern (acinar at 60% here). However, the new IASLC grading system grades adenocarcinoma by the highest-grade pattern present: Grade 1 = lepidic predominant without high-grade patterns. Grade 2 = acinar or papillary predominant without high-grade patterns. Grade 3 = any amount of solid, micropapillary, or complex glandular pattern. This tumour is acinar predominant but Grade 3 due to the 30% solid component.

ALK-rearranged lung adenocarcinomas characteristically show solid growth with signet ring cell features and/or abundant intracellular mucin. They are more common in younger patients and non-smokers. EGFR-mutant adenocarcinomas are more commonly lepidic or papillary. ALK rearrangement is a predictive biomarker for crizotinib/alectinib/lorlatinib therapy. Detection methods include FISH (break-apart probe), IHC (ALK D5F3 clone), and NGS.

Reed-Sternberg cells (binucleated with owl-eye nucleoli) in a mixed inflammatory background (eosinophils, histiocytes, plasma cells, lymphocytes) is classic for mixed cellularity Hodgkin lymphoma. The IHC profile CD30+/CD15+/PAX5 dim/CD20−/CD45− is the hallmark of classic Hodgkin lymphoma (all subtypes). ALCL is CD30+ but ALK+ (in ALK-positive variant) and CD45+. DLBCL is CD20+, CD45+, PAX5 strong.

Hairy cell leukaemia (HCL) shows characteristic lymphocytes with cytoplasmic projections ("hairy cells"), round nuclei, and a specific immunophenotype: CD25+, CD103+, CD11c+, Annexin A1+ (the most specific marker). BRAF V600E mutation is present in virtually all classic HCL and is absent in the variant form and other small B-cell lymphomas. This is a targetable mutation (vemurafenib). CLL is CD5+/CD23+. MCL is CD5+/cyclin D1+. SMZL lacks CD103 and Annexin A1.

NIFTP was introduced in the 2017 revision and retained in WHO 5th Edition to reclassify non-invasive encapsulated follicular variant of PTC as a borderline/low-risk neoplasm. Criteria: encapsulated, follicular growth, PTC nuclear features, NO invasion, NO BRAF V600E. RAS mutation is characteristic (similar to follicular neoplasms). The reclassification reduces overtreatment — these lesions are managed with lobectomy alone without radioactive iodine.

The Weiss scoring system uses 9 histological criteria to differentiate adrenocortical adenoma from carcinoma. A score ≥3 indicates adrenocortical carcinoma. The 9 criteria are: high nuclear grade, >5 mitoses/50 HPF, atypical mitoses, ≤25% clear cells, diffuse architecture, necrosis, venous invasion, sinusoidal invasion, and capsular invasion. This tumour with 9/9 is unequivocally malignant. Note: some studies use a cut-off of ≥4 for carcinoma; the standard board answer is ≥3.

Ewing sarcoma is a small round blue cell tumour characterised by sheets of monomorphic cells with membranous CD99 positivity (highly sensitive but not specific), FLI-1 and NKX2-2 nuclear positivity, and EWSR1 rearrangement (most commonly EWSR1-FLI1 t(11;22)). Negative desmin/myogenin rules out rhabdomyosarcoma. Synovial sarcoma shows SS18-SSX fusion and biphasic or monophasic morphology. DSRCT shows EWSR1-WT1 fusion and a desmoplastic stroma.

WHO 2021 CNS classification uses an integrated diagnosis requiring both histological AND molecular features. IDH-mutant + ATRX loss + intact 1p/19q = astrocytoma, IDH-mutant (not oligodendroglioma, which requires 1p/19q codeletion). No microvascular proliferation, no necrosis, and no CDKN2A/B homozygous deletion → Grade 2 (not 3 or 4). Grade 3 would show brisk mitotic activity. Grade 4 requires microvascular proliferation, necrosis, OR CDKN2A/B homozygous deletion.