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Facharzt FMH Pathologie - independent subject foundations study materials
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Facharzt FMH Pathologie - independent subject foundations practice questions

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Question 1Digestive, hepatic and pancreatic tissue interpretation

A diagnostic biopsy of an advanced gastric adenocarcinoma is submitted for predictive biomarker assessment to determine eligibility for targeted trastuzumab therapy. Immunohistochemistry for HER2 (clone 4B5) is performed. Which of the following staining patterns on a biopsy specimen meets the standard diagnostic criteria for HER2-positive (IHC 3+) status in gastric cancer?

  1. Weak-to-moderate complete membranous staining in >=10% of tumor cells.
  2. Strong circumferential membranous staining in >50% of tumor cells only, with incomplete staining interpreted as negative.
  3. Nuclear immunoreactivity for HER2 in >20% of viable malignant cells.
  4. Strong complete, basolateral, or lateral membranous staining in a cluster of at least 5 contiguous tumor cells, regardless of the overall percentage. Correct answer.

Explanation

Due to the frequent histologic heterogeneity and glandular polarity in gastric cancer, the ASCO/CAP and European guidelines define HER2 IHC 3+ in gastric endoscopic biopsy specimens as a cluster of at least 5 contiguous viable tumor cells displaying strong (intense) complete, basolateral, or lateral ('U-shaped') membranous reactivity. Unlike breast cancer, circumferential (complete circular) staining is not mandatory because gastric glandular cells often stain only along the basolateral membranes. Biopsy specimens with IHC 3+ qualify directly for trastuzumab therapy without mandatory FISH reflex.

Question 2Digestive, hepatic and pancreatic tissue interpretation

A 34-year-old man presents with chronic malabsorptive diarrhea and iron deficiency anemia. Duodenal biopsies show marked intraepithelial lymphocytosis (>35 intraepithelial lymphocytes per 100 enterocytes), pronounced crypt hyperplasia with increased mitotic figures, and subtotal (marked) blunting and flattening of the intestinal villi. How is this lesion categorized according to the Marsh-Oberhuber classification of celiac disease?

  1. Marsh 1 (Infiltrative lesion).
  2. Marsh 3b (Destructive lesion with subtotal villous atrophy). Correct answer.
  3. Marsh 0 (Pre-infiltrative normal mucosa).
  4. Marsh 2 (Hyperplastic lesion without villous flattening).

Explanation

Under the Marsh-Oberhuber classification for gluten-sensitive enteropathy (celiac disease), Marsh 3 represents the destructive stage combining intraepithelial lymphocytosis (>25 IELs/100 enterocytes), crypt hyperplasia, and villous atrophy. Marsh 3 is further subclassified into Marsh 3a (partial villous atrophy), Marsh 3b (subtotal villous atrophy with markedly blunted, stubby villi), and Marsh 3c (total villous atrophy with flat mucosa).

Question 3Digestive, hepatic and pancreatic tissue interpretation

A 44-year-old man undergoes resection of a right-sided ascending colon adenocarcinoma. Immunohistochemistry for DNA mismatch repair (MMR) proteins reveals complete loss of nuclear expression for MLH1 and PMS2 within the tumor cells, with preserved nuclear staining in internal non-neoplastic stromal and lymphoid cells. Nuclear expression of MSH2 and MSH6 is completely retained. To differentiate between a sporadic MSI-H carcinoma and Lynch syndrome, which molecular test should be performed next?

  1. Sequencing of APC and TP53 genes to evaluate chromosomal instability.
  2. BRAF V600E mutation testing and/or MLH1 promoter hypermethylation analysis. Correct answer.
  3. Testing for KRAS and NRAS exon 2-4 mutations to guide anti-EGFR antibody selection.
  4. FISH analysis for ERBB2 (HER2) gene amplification.

Explanation

Concurrent loss of MLH1 and PMS2 expression is the most common MMR deficiency pattern in colorectal carcinoma. Approximately 80-85% of MLH1/PMS2-deficient cases are sporadic and caused by somatic epigenetic hypermethylation of the MLH1 promoter, which strongly correlates with somatic BRAF V600E mutations. The presence of a BRAF V600E mutation or MLH1 promoter hypermethylation effectively rules out Lynch syndrome, whereas the absence of both warrants germline genetic testing for Lynch syndrome.

Question 4Digestive, hepatic and pancreatic tissue interpretation

In an adequately assessed pancreatic lesion, which listed set of histological clues can support invasion in the relevant differential with chronic pancreatitis, interpreted together with the full architecture rather than as three individually infallible rules?

  1. Presence of chronic lymphoplasmacytic inflammation surrounding lobular units.
  2. Ducts with more than 4:1 variation in nuclear size, 'naked glands' immediately adjacent to muscular arteries, or perineural invasion. Correct answer.
  3. Mild ductal dilation with inspissated proteinaceous secretions.
  4. Preservation of lobular architecture with uniform spacing between adjacent pancreatic ducts.

Explanation

Histological hallmarks that unequivocally establish invasive pancreatic ductal adenocarcinoma (PDAC) on biopsy and frozen section include: marked variation in nuclear size (>4:1 ratio between adjacent cells in the same duct), irregular nuclear contours with chromatin clearing, incomplete/abortive lumen formation, 'naked glands' directly abutting muscularized arterial walls without intervening stroma, and perineural invasion. In chronic pancreatitis, ducts retain a lobular architecture, display smooth round nuclei with <4:1 size variation, and are accompanied by preserved duct spacing and periductal condensation of stroma.

Question 5Breast, gynecologic and genitourinary morphology

A 56-year-old woman has a 1.6 cm breast mass. Core biopsy shows invasive carcinoma growing in single-file linear cords with targetoid arrangement around residual ducts. E-cadherin immunostain is negative. The most likely diagnosis is:

  1. Invasive ductal carcinoma, NST
  2. Invasive lobular carcinoma Correct answer.
  3. Tubular carcinoma
  4. Mucinous carcinoma

Explanation

Invasive lobular carcinoma (ILC) classically grows as single-file linear cords and targetoid (concentric) patterns around uninvolved ducts, with loss of E-cadherin from CDH1 alteration. ~85% of ILC is E-cadherin negative; the remainder show aberrant cytoplasmic dot-like staining. ILC is typically ER+/PR+ and HER2-negative with lower mitotic rate than NST.

Question 6Breast, gynecologic and genitourinary morphology

On core needle biopsy of a breast lesion, low-grade nuclei form cribriform and micropapillary architecture confined within duct walls. p63 and calponin highlight an intact peripheral myoepithelial layer; there is no stromal invasion. The diagnosis is:

  1. Invasive ductal carcinoma, well-differentiated
  2. Atypical ductal hyperplasia
  3. Ductal carcinoma in situ, low grade Correct answer.
  4. Lobular carcinoma in situ

Explanation

Low-grade DCIS shows monotonous low-grade nuclei in cribriform or micropapillary patterns with an intact myoepithelial layer (p63+/calponin+/SMM-HC+). ADH has identical cytology but is limited (<2 mm or ≤2 membrane-bound spaces). LCIS is discohesive with E-cadherin loss. Invasion would breach the myoepithelial layer.

Question 7Breast, gynecologic and genitourinary morphology

Per ASCO/CAP 2023 HER2 testing guidelines, which IHC score requires reflex in situ hybridization to determine HER2 amplification status?

  1. 0
  2. 1+
  3. 2+ Correct answer.
  4. 3+

Explanation

HER2 IHC 2+ (equivocal) requires reflex dual-probe ISH (HER2/CEP17) to resolve amplification status. 0 and 1+ are HER2-negative for traditional therapy (though 1+ and 2+/ISH-negative now qualify as HER2-low for trastuzumab-deruxtecan after DESTINY-Breast04). 3+ is HER2-positive without ISH needed.

Question 8Breast, gynecologic and genitourinary morphology

A 14-year-old girl has a well-circumscribed mobile breast mass. Histology shows biphasic stromal and epithelial proliferation with intracanalicular and pericanalicular patterns. Stromal mitoses are rare and there is no stromal overgrowth. The diagnosis is:

  1. Fibroadenoma Correct answer.
  2. Phyllodes tumor, malignant
  3. Tubular adenoma
  4. Invasive lobular carcinoma

Explanation

Fibroadenoma is the most common benign breast tumor in adolescents - well-circumscribed, biphasic with intracanalicular and/or pericanalicular architecture and bland stroma with rare mitoses. Phyllodes tumors show leaf-like architecture, stromal hypercellularity, and elevated mitoses (benign <2.5/mm², borderline 2.5-5, malignant >5/mm² with stromal overgrowth).

Question 9Breast, gynecologic and genitourinary morphology

A triple-negative (ER-/PR-/HER2-) breast carcinoma in a 38-year-old woman with a basal-like phenotype (CK5/6+, EGFR+) and pushing borders with central necrosis is most strongly associated with which germline mutation?

  1. BRCA1 Correct answer.
  2. CDH1
  3. PTEN
  4. STK11

Explanation

BRCA1-associated breast cancers are classically high-grade, triple-negative, with basal-like phenotype (CK5/6+, EGFR+) and pushing borders with central necrosis and lymphocytic infiltrate. BRCA2 tumors are usually ER+. CDH1 → hereditary diffuse gastric cancer and lobular carcinoma. PTEN (Cowden) → mixed pattern. STK11 → Peutz-Jeghers.

Question 10Breast, gynecologic and genitourinary morphology

Paget disease of the nipple shows large pale intraepidermal cells with prominent nucleoli. Which immunoprofile most reliably distinguishes Paget cells from melanoma in pagetoid spread?

  1. S100+, Melan-A+
  2. CK7+, HER2+ Correct answer.
  3. p63+, CK5/6+
  4. CD20+, PAX5+

Explanation

Paget cells are CK7+ and typically HER2+ glandular cells in the epidermis, usually with underlying DCIS or invasive carcinoma. Melanoma in pagetoid spread is S100+/Melan-A+/HMB45+. p63/CK5/6 favors squamous (Bowen). HER2 positivity distinguishes Paget from melanoma and Bowen disease.

Question 11Breast, gynecologic and genitourinary morphology

Per ASCO/CAP preanalytic standards for breast biomarker testing (ER/PR/HER2), formalin fixation in 10% NBF should be:

  1. 1 to 4 hours
  2. 6 to 72 hours Correct answer.
  3. At least 7 days
  4. Variable, no minimum

Explanation

ASCO/CAP standards mandate cold ischemia ≤1 hour and 10% neutral buffered formalin fixation for 6-72 hours for breast biomarkers. Under-fixation (<6 hr) and over-fixation (>72 hr) both compromise antigenicity and are reasons to reject the specimen. Cold ischemia >1 hour also requires re-biopsy/re-resection consideration.

Question 12Breast, gynecologic and genitourinary morphology

Oncotype DX is most useful for guiding adjuvant chemotherapy in which breast cancer subtype?

  1. ER+, HER2-, node-negative early-stage breast cancer Correct answer.
  2. Triple-negative breast cancer
  3. HER2-amplified breast cancer
  4. Inflammatory breast cancer

Explanation

Oncotype DX 21-gene Recurrence Score (RS) is validated for ER+, HER2-, node-negative early-stage breast cancer. The TAILORx trial showed RS 0-25 do not benefit from chemotherapy in this group (women >50). RS guides chemotherapy decisions for ER+/HER2- disease - not for TNBC, HER2+, or inflammatory subtypes.

Question 13Breast, gynecologic and genitourinary morphology

On a sentinel lymph node from a breast carcinoma resection, a focus measures 0.4 mm. Per AJCC 8 staging, this is classified as:

  1. Isolated tumor cells (ITC, pN0(i+))
  2. Micrometastasis (pN1mi) Correct answer.
  3. Macrometastasis (pN1)
  4. Negative (pN0)

Explanation

AJCC 8 nodal staging for breast: Isolated tumor cells (ITC) ≤0.2 mm or <200 cells = pN0(i+); micrometastasis >0.2 mm to ≤2 mm = pN1mi; macrometastasis >2 mm = pN1. A 0.4 mm focus falls within micrometastasis (pN1mi).

Question 14Breast, gynecologic and genitourinary morphology

A renal mass nephrectomy from a 55-year-old shows clear-cell tumor with delicate vasculature. NGS shows VHL inactivation. The diagnosis is:

  1. Clear cell renal cell carcinoma Correct answer.
  2. Chromophobe renal cell carcinoma
  3. Papillary renal cell carcinoma type 2
  4. Translocation (MiT-family) RCC

Explanation

Clear cell RCC is the most common adult RCC, characterized by clear cytoplasm (lipid/glycogen), delicate chicken-wire vasculature, and VHL gene alterations on chromosome 3p (3p25-26). Chromophobe shows perinuclear halos and CK7 diffuse. Papillary RCC has fibrovascular cores and AMACR+. MiT-family (Xp11) RCC shows TFE3+/TFEB+.

Question 15Breast, gynecologic and genitourinary morphology

A prostate needle biopsy shows infiltrative single glands and small cribriform glands. AMACR is positive in tumor cells; basal cells are absent on p63 and HMW-CK. The Gleason score is 4+3=7 (Grade Group 3). What proportion of pattern 4 is required for Grade Group 3?

  1. Pattern 4 < pattern 3 by volume
  2. Pattern 4 ≥ pattern 3 by volume Correct answer.
  3. Pattern 5 component required
  4. Pattern 3 only

Explanation

ISUP/WHO Grade Groups: GG1 = 3+3=6; GG2 = 3+4=7 (pattern 4 < pattern 3); GG3 = 4+3=7 (pattern 4 ≥ pattern 3 by volume); GG4 = 8 (4+4, 3+5, 5+3); GG5 = 9-10. AMACR (P504S) is positive in adenocarcinoma; basal cells (p63, HMW-CK 34βE12) are absent in invasive carcinoma but retained in benign glands and HGPIN.

Question 16Breast, gynecologic and genitourinary morphology

A bladder resection contains invasive high-grade urothelial carcinoma in lamina propria, but detrusor muscle is not represented. Which listed minimum invasion category is established in the sampled tissue, without excluding unsampled deeper disease?

  1. pTa
  2. pT1 Correct answer.
  3. pT2
  4. pTX

Explanation

The observed lamina-propria invasion establishes at least pT1 in the sampled material. Because muscularis propria is not represented, the specimen does not exclude deeper invasion elsewhere. Reporting the sampling limitation is clinically important and differs from claiming that the entire tumor is definitively confined to the lamina propria.

Question 17Breast, gynecologic and genitourinary morphology

A testicular mass in a 28-year-old shows nests of polygonal cells with clear cytoplasm and prominent nucleoli, separated by fibrous septa containing lymphocytes. Tumor cells are OCT3/4+, SALL4+, CD117+, and SOX17+; CD30 and AFP negative. Diagnosis:

  1. Embryonal carcinoma
  2. Seminoma Correct answer.
  3. Yolk sac tumor
  4. Choriocarcinoma

Explanation

Seminoma classically shows polygonal clear cells with prominent nucleoli in nests separated by lymphocyte-rich fibrous septa. Markers: OCT3/4+, SALL4+, CD117 (KIT)+, SOX17+, PLAP+; CD30/AFP negative. Embryonal carcinoma is CD30+/OCT3/4+. Yolk sac is AFP+/glypican-3+ with Schiller-Duval bodies. Choriocarcinoma shows syncytiotrophoblast/cytotrophoblast and beta-hCG.

Question 18Breast, gynecologic and genitourinary morphology

An endometrial biopsy from a 62-year-old shows endometrioid carcinoma. Molecular workup: POLE exonuclease domain pathogenic mutation, MMR proteins intact, p53 wild-type pattern. Per ProMisE/TCGA classification this is:

  1. POLE ultramutated (excellent prognosis) Correct answer.
  2. MMR-deficient (intermediate prognosis)
  3. p53-abnormal (worst prognosis)
  4. No specific molecular profile (NSMP)

Explanation

TCGA/ProMisE classifies endometrial carcinoma into: POLE ultramutated (excellent prognosis, ~5-10%, even in high-grade tumors); MMR-deficient (~30%, intermediate); p53-abnormal (~15%, worst); NSMP/copy-number low (~50%, intermediate). POLE testing is now standard-of-care reporting alongside MMR IHC and p53 IHC per WHO 2020.

Question 19Breast, gynecologic and genitourinary morphology

A cervical biopsy shows full-thickness atypia of the squamous epithelium with mitoses extending to the surface and diffuse strong p16 block-positive staining. The diagnosis is:

  1. LSIL (CIN 1)
  2. HSIL (CIN 2-3) Correct answer.
  3. Atrophy with reactive change
  4. Invasive squamous cell carcinoma

Explanation

HSIL (CIN 2-3) shows full-thickness atypia with mitoses to surface and is reliably marked by diffuse strong block-positive p16 staining (surrogate for HR-HPV E7 transcription via Rb degradation). LSIL (CIN 1) is patchy or negative for p16. Invasion would breach the basement membrane with paradoxical maturation.

Question 20Breast, gynecologic and genitourinary morphology

An eligible advanced high-grade serous ovarian cancer with a pathogenic BRCA1 variant has responded to the qualifying platinum treatment. Which listed maintenance class can have a role in this supplied molecular and response context?

  1. PARP inhibitor maintenance therapy Correct answer.
  2. Trastuzumab (anti-HER2)
  3. Imatinib (anti-KIT)
  4. Crizotinib (anti-ALK)

Explanation

High-grade serous ovarian carcinoma with BRCA1/2 alteration or HRD-positive (homologous recombination deficiency) responds to PARP inhibitors (olaparib, niraparib, rucaparib) - synthetic lethality. p53 is mutated in >95% of HGSOC (aberrant pattern: strong/diffuse or complete null). Trastuzumab/imatinib/crizotinib are not standard for HGSOC.

Question 21Breast, gynecologic and genitourinary morphology

Products of conception from a first-trimester loss show hydropic chorionic villi with circumferential trophoblast proliferation. p57 immunostain is negative in cytotrophoblast and villous stromal cells. The diagnosis is:

  1. Complete hydatidiform mole Correct answer.
  2. Partial hydatidiform mole
  3. Hydropic abortus
  4. Choriocarcinoma

Explanation

p57 (paternally imprinted, maternally expressed) is NEGATIVE in cytotrophoblast and villous stroma of complete moles (androgenetic, paternal-only DNA). p57 is POSITIVE in partial mole (triploid with maternal contribution) and hydropic abortus (biparental). Complete moles have ~15-20% risk of persistent GTD requiring surveillance with serum hCG.

Question 22Breast, gynecologic and genitourinary morphology

An endocervical adenocarcinoma is diffusely positive for p16 (block pattern) and HPV in situ hybridization is positive for high-risk HPV. Per IECC/WHO 2020 this is classified as:

  1. HPV-associated endocervical adenocarcinoma Correct answer.
  2. Gastric-type endocervical adenocarcinoma (HPV-independent)
  3. Mesonephric adenocarcinoma
  4. Clear cell carcinoma

Explanation

The IECC and WHO 2020 separate HPV-associated endocervical adenocarcinoma (HPV+, p16 block, better prognosis) from HPV-independent types: gastric-type (worst prognosis, MUC6+, often p53-abnormal), clear cell, and mesonephric (GATA3+/CD10+/TTF-1+). HPV-independent types are not preventable by HPV vaccination.

Question 23Breast, gynecologic and genitourinary morphology

A renal mass in a 42-year-old has nests of polygonal cells with finely granular eosinophilic cytoplasm and perinuclear halos. CK7 is diffusely positive; CD117 (KIT) is positive. The diagnosis is:

  1. Clear cell renal cell carcinoma
  2. Chromophobe renal cell carcinoma Correct answer.
  3. Oncocytoma
  4. Papillary RCC

Explanation

Chromophobe RCC shows polygonal cells with reticulated cytoplasm and prominent perinuclear halos with raisinoid nuclei. CK7 is diffusely positive (vs oncocytoma which is patchy/negative for CK7). Both chromophobe and oncocytoma are CD117+. Hale colloidal iron is diffusely positive in chromophobe.

Question 24Breast, gynecologic and genitourinary morphology

On a cervical Pap (LBC) the cytopathologist identifies superficial and intermediate squamous cells with mildly enlarged nuclei (~3x normal), slight irregularity, but no koilocytosis. The Bethesda category is:

  1. NILM
  2. ASC-US Correct answer.
  3. LSIL
  4. HSIL

Explanation

ASC-US (atypical squamous cells of undetermined significance) is reserved for changes that fall short of LSIL - slightly enlarged nuclei (up to 3x intermediate cell nucleus), mild irregularity, without definite koilocytosis or LSIL features. ASC-US triage is HR-HPV reflex testing for women ≥25 years per ASCCP.

Question 25Breast, gynecologic and genitourinary morphology

An adequately cellular urine specimen contains numerous well-preserved atypical urothelial cells with the supplied high nuclear-to-cytoplasmic ratio, marked hyperchromasia, irregular membranes and coarse chromatin. Which listed high-grade category is supported in the relevant Paris framework?

  1. Negative for HGUC
  2. Atypical urothelial cells (AUC)
  3. Suspicious for HGUC
  4. High-grade urothelial carcinoma (HGUC) Correct answer.

Explanation

Paris System for Reporting Urinary Cytology (TPS 2.0) HGUC requires at least 5-10 abnormal cells with N:C ratio ≥0.7, hyperchromasia, irregular nuclear membranes, and coarse chromatin. ROM ~90%. AUC and 'suspicious for HGUC' are intermediate categories with quantitative criteria for cell number and degree of atypia.

Question 26Breast, gynecologic and genitourinary morphology

A placenta from a preterm delivery shows acute neutrophilic infiltrate of the chorion and amnion (chorioamnionitis). Per the Amsterdam Placental Workshop Group consensus, the maternal inflammatory response is graded by:

  1. Stage and grade based on extent and intensity of neutrophils in chorion-amnion-decidua Correct answer.
  2. Number of villi per high-power field
  3. Trophoblast proliferation index
  4. Decidual fibrin only

Explanation

Amsterdam Placental Workshop Group consensus (2016) grades acute chorioamnionitis as maternal inflammatory response (MIR, neutrophils from mother in chorion-decidua) and fetal inflammatory response (FIR, neutrophils from fetus in umbilical cord/chorionic plate vessels). MIR/FIR each have stages (1-3, location-based) and grades (1-2, intensity). Higher MIR/FIR correlates with neonatal sepsis, cerebral palsy, and BPD.

Question 27Pulmonary, pleural, soft-tissue and bone pathology

A 2.8 cm resected peripheral lung adenocarcinoma is histologically subtyped according to the WHO 5th edition / IASLC classification. Microscopic evaluation demonstrates 60% acinar pattern, 15% papillary pattern, and 25% micropapillary pattern (composed of small discohesive papillary tufts lacking fibrovascular cores floating within alveolar spaces). How should this lung adenocarcinoma be graded according to the modern IASLC grading system?

  1. Grade 3 (Poorly differentiated); because it contains >=20% of a high-grade pattern (micropapillary). Correct answer.
  2. Grade 1 (Well-differentiated); because acinar and papillary patterns predominate over solid sheets.
  3. Grade 2 (Moderately differentiated); because acinar pattern is the single predominant pattern.
  4. Ungraded; lung adenocarcinoma grading is not clinically recommended.

Explanation

According to the modern IASLC / WHO 5th edition grading system for invasive pulmonary adenocarcinoma, tumors are categorized into three prognostic grades: Grade 1 (well-differentiated: lepidic-predominant with <20% high-grade pattern); Grade 2 (moderately differentiated: acinar- or papillary-predominant with <20% high-grade pattern); and Grade 3 (poorly differentiated: any tumor harboring >=20% high-grade patterns, which comprise micropapillary, solid, or complex cribriform glands). Because this tumor contains 25% micropapillary architecture (>=20%), it is classified as Grade 3 (poorly differentiated), which predicts a higher risk of recurrence and nodal metastasis.

Question 28Pulmonary, pleural, soft-tissue and bone pathology

A CT-guided core needle biopsy of an unclassifiable 3.0 cm solid pulmonary mass in a 65-year-old heavy smoker demonstrates sheets of poorly differentiated malignant polygonal epithelial cells without clear glandular lumina, mucin production, or obvious keratinization. To establish a definitive diagnosis while rigorously conserving tissue for comprehensive Next-Generation Sequencing (NGS), which minimal two-marker immunohistochemical panel is recommended by CAP, IASLC, and ESMO guidelines?

  1. Cytokeratin 7 (CK7) and Cytokeratin 20 (CK20).
  2. TTF-1 (thyroid transcription factor-1) and p40 (DeltaNp63). Correct answer.
  3. Synaptophysin and Chromogranin A.
  4. Vimentin and S100.

Explanation

According to the CAP/IASLC/AMP and ESMO guidelines for non-small cell lung cancer (NSCLC) on small biopsies and cytology specimens, tissue conservation for downstream molecular biomarker testing is paramount. A minimalist two-marker panel consisting of TTF-1 (adenocarcinoma marker) and p40 (squamous cell carcinoma marker) accurately subtypes >90% of poorly differentiated NSCLCs. p40 (DeltaNp63) offers superior specificity over p63 because p63 can be falsely positive in up to 30% of pulmonary adenocarcinomas, whereas p40 is virtually 100% specific for squamous differentiation.

Question 29Pulmonary, pleural, soft-tissue and bone pathology

For an appropriate lung-cancer assessment using a validated ALK D5F3 assay, which listed statement describes the recognized role of immunohistochemistry relative to FISH, with assay validation and local requirements still relevant?

  1. ALK rearrangements are commonly co-mutated with EGFR exon 19 deletions in >50% of cases.
  2. Standard first-line therapy for ALK-rearranged NSCLC consists of anti-PD-1 monotherapy due to high tumor mutational burden.
  3. ALK translocations predict primary intrinsic resistance to all tyrosine kinase inhibitors.
  4. Standardized Ventana ALK (D5F3) immunohistochemistry is validated across Europe as an equivalent standalone diagnostic assay without mandatory FISH confirmation. Correct answer.

Explanation

ALK gene rearrangements (most commonly EML4::ALK fusions arising from an inversion on chromosome 2p) occur in 4-6% of non-small cell lung cancers, predominantly in younger non-smokers. According to ESMO and CAP/IASLC/AMP guidelines, standardized, validated ALK immunohistochemistry (such as the Ventana D5F3 assay with amplification) has near-100% concordance with break-apart FISH and is officially approved as an equivalent standalone diagnostic test for prescribing targeted ALK tyrosine kinase inhibitors (e.g., alectinib, brigatinib, lorlatinib). ALK fusions are mutually exclusive with EGFR, ROS1, and KRAS driver mutations.

Question 30Skin, head and neck, thyroid and nervous-system interpretation

An FNA of a parotid mass shows basaloid cells with hyaline matrix material in cribriform architecture and reticulated stroma. Most likely diagnosis per Milan System:

  1. Pleomorphic adenoma
  2. Adenoid cystic carcinoma Correct answer.
  3. Warthin tumor
  4. Mucoepidermoid carcinoma

Explanation

Adenoid cystic carcinoma shows basaloid cells around hyaline globules in cribriform architecture (Swiss-cheese pattern) with MYB-NFIB fusion. Pleomorphic adenoma shows fibrillary/myxoid/chondroid matrix and PLAG1 alteration. Warthin shows oncocytes + lymphocytes. Mucoepidermoid (MAML2) shows mucous, intermediate, and squamoid cells.

Question 31Skin, head and neck, thyroid and nervous-system interpretation

A 65-year-old smoker has a 2.8 cm pigmented melanoma on the back. Histology: nodular melanoma, Breslow 2.6 mm, with ulceration. Per AJCC 8 melanoma staging, the pT stage is:

  1. pT2a
  2. pT2b
  3. pT3a
  4. pT3b Correct answer.

Explanation

AJCC 8 melanoma pT: pT1 ≤1 mm; pT2 >1.0-2.0 mm; pT3 >2.0-4.0 mm; pT4 >4.0 mm. Each stratified 'a' (no ulceration) vs 'b' (with ulceration). 2.6 mm with ulceration = pT3b. Mitotic rate is no longer required for pT1 staging in AJCC 8.

Question 32Skin, head and neck, thyroid and nervous-system interpretation

An adult diffuse glioma has confirmed IDH mutation and validated whole-arm 1p/19q codeletion in the appropriate integrated assessment. Which listed CNS5 category fits?

  1. Glioblastoma, IDH-wildtype
  2. Astrocytoma, IDH-mutant
  3. Oligodendroglioma, IDH-mutant and 1p/19q-codeleted Correct answer.
  4. Diffuse midline glioma, H3 K27-altered

Explanation

WHO CNS5 (2021) defines oligodendroglioma as a diffuse glioma with IDH mutation AND 1p/19q codeletion (CIC and FUBP1 frequently mutated). Astrocytoma IDH-mutant lacks 1p/19q codeletion. Glioblastoma IDH-wildtype is IDH-negative (and has TERT, EGFR amp, +7/-10). Diffuse midline glioma H3 K27 is pediatric/midline.

Question 33Skin, head and neck, thyroid and nervous-system interpretation

A childhood cerebellar tumor has confirmed WNT-pathway activation with the relevant CTNNB1 and chromosome findings in an integrated medulloblastoma assessment. Which listed molecular group and typical relative prognosis fit, without guaranteeing an individual outcome?

  1. WNT-activated medulloblastoma - best prognosis Correct answer.
  2. SHH-activated medulloblastoma - variable
  3. Group 3 medulloblastoma - worst prognosis with MYC amp
  4. Group 4 medulloblastoma - intermediate

Explanation

WHO CNS5 medulloblastoma molecular groups: WNT-activated (~10%, monosomy 6, CTNNB1 nuclear staining, best prognosis ~95% 5-yr survival); SHH-activated (TP53-wildtype vs -mutant, intermediate); Group 3 (often MYC amplified, worst); Group 4 (most common, intermediate). Treatment is being de-escalated for WNT-activated tumors in current trials.

Question 34Marrow and lymph-node pathological diagnosis

A 68-year-old man with new fatigue has CBC: Hgb 9 g/dL, MCV 72 fL (low), RDW 18%. Iron studies show ferritin 8 ng/mL, low TSAT, low serum iron, elevated TIBC. The most likely cause is:

  1. Beta-thalassemia trait
  2. Iron deficiency anemia Correct answer.
  3. Anemia of chronic disease
  4. Sideroblastic anemia

Explanation

Iron deficiency anemia: microcytic (low MCV), elevated RDW (anisopoikilocytosis), low ferritin (<15 ng/mL diagnostic), low TSAT, and elevated TIBC. Mentzer index >13 (MCV/RBC count) favors iron deficiency over thalassemia trait. Thalassemia trait has normal/high RBC count, normal RDW, and normal ferritin. ACD has high ferritin and low TIBC.

Question 35Marrow and lymph-node pathological diagnosis

A 32-year-old woman presents with thrombocytopenia (platelets 12k), microangiopathic hemolytic anemia with schistocytes, fever, neurologic changes, and renal dysfunction. ADAMTS13 activity is <10%. The most appropriate immediate treatment is:

  1. Platelet transfusion
  2. Therapeutic plasma exchange (TPE) ± caplacizumab Correct answer.
  3. IVIG
  4. Eculizumab

Explanation

TTP (ADAMTS13 <10%, with anti-ADAMTS13 inhibitor) is treated emergently with therapeutic plasma exchange (replaces functional ADAMTS13) plus glucocorticoids and caplacizumab (anti-vWF nanobody, HERCULES trial). Platelet transfusion is contraindicated unless life-threatening bleeding. Eculizumab treats aHUS/PNH.

Question 36Marrow and lymph-node pathological diagnosis

A 70-year-old develops thrombocytopenia 7 days after starting unfractionated heparin for DVT. Platelet count drops from 250k to 60k (>50% drop). 4Ts score is 6 (high). The most appropriate next step is:

  1. Continue heparin and transfuse platelets
  2. Stop all heparin, send PF4/heparin ELISA, switch to argatroban Correct answer.
  3. Order a heparin challenge test
  4. Switch from unfractionated to low molecular weight heparin

Explanation

HIT diagnosis: 4Ts ≥4 (intermediate) or ≥6 (high) → STOP all heparin including flushes immediately, switch to non-heparin anticoagulant (argatroban, bivalirudin, or fondaparinux), and confirm with PF4/heparin ELISA → SRA (gold standard). Do NOT transfuse platelets unless life-threatening bleeding (thrombosis, not bleeding, is the primary risk).

Question 37Marrow and lymph-node pathological diagnosis

A bone marrow biopsy from a 55-year-old with pancytopenia shows hypercellular marrow with abnormal promyelocytes (faggot cells with bundles of Auer rods). Cytogenetics shows t(15;17). The molecular finding and treatment of choice are:

  1. BCR-ABL1; imatinib
  2. PML-RARA; ATRA + arsenic trioxide Correct answer.
  3. RUNX1-RUNX1T1; cytarabine + daunorubicin
  4. NPM1 mutation; venetoclax

Explanation

Acute promyelocytic leukemia (APL, AML-M3) has t(15;17) PML-RARA fusion. Treated with ATRA (all-trans retinoic acid) + arsenic trioxide (ATO) - induction without standard chemotherapy in low/intermediate-risk per APL0406. Differentiation syndrome (cytokine release) is a major early complication. CBF leukemias (inv(16)/t(8;21)) get cytarabine-based induction.

Question 38Marrow and lymph-node pathological diagnosis

A 60-year-old has leukocytosis 80k with left-shifted granulocytes including basophilia and eosinophilia. Bone marrow shows myeloid hyperplasia with all stages of maturation. FISH shows BCR-ABL1 fusion (Philadelphia chromosome). The first-line treatment is:

  1. Hydroxyurea
  2. Imatinib (or other BCR-ABL TKI) Correct answer.
  3. Allogeneic stem cell transplant
  4. Interferon-alpha

Explanation

Chronic myeloid leukemia (CML) has t(9;22) BCR-ABL1 fusion (Philadelphia chromosome), p210 in CML. First-line treatment is BCR-ABL TKI (imatinib, dasatinib, nilotinib, bosutinib). Monitor with quantitative BCR-ABL transcript (IS, log reduction). Allo-SCT is reserved for TKI failure or blast crisis.

Question 39Marrow and lymph-node pathological diagnosis

A patient with elevated platelets (>500k), splenomegaly, and erythromelalgia has a JAK2 V617F mutation on PCR. Bone marrow shows megakaryocytic hyperplasia with hyperlobated forms. The diagnosis is:

  1. Polycythemia vera
  2. Essential thrombocythemia Correct answer.
  3. Primary myelofibrosis
  4. Reactive thrombocytosis

Explanation

Essential thrombocythemia (ET) - sustained platelets ≥450k, megakaryocyte hyperplasia with mature/hyperlobated forms, JAK2 V617F (~55%), CALR (~25%, exon 9), or MPL (~3%). Polycythemia vera shows elevated Hgb/Hct with JAK2 (>95% V617F) and reduced erythropoietin. Primary MF has fibrosis, leukoerythroblastosis, and tear-drop cells.

Question 40Marrow and lymph-node pathological diagnosis

A 67-year-old with bone pain has SPEP showing a monoclonal IgG kappa spike (4.5 g/dL). Marrow plasma cells 35%. Calcium 11.2, creatinine 2.1, Hgb 9.5, lytic lesions on imaging. The diagnosis per IMWG is:

  1. MGUS
  2. Smoldering multiple myeloma
  3. Symptomatic multiple myeloma (CRAB criteria) Correct answer.
  4. Solitary plasmacytoma

Explanation

IMWG criteria for symptomatic multiple myeloma: ≥10% clonal marrow plasma cells (or biopsy-proven plasmacytoma) PLUS one or more myeloma-defining events: CRAB (hyperCalcemia, Renal insufficiency, Anemia, Bone lesions) or SLiM (Sixty% plasma cells, Light chain ratio ≥100, MRI lesions). This patient meets multiple CRAB.

Question 41Marrow and lymph-node pathological diagnosis

A peripheral blood flow cytometry from a 65-year-old with lymphocytosis shows monomorphic small B cells positive for CD5, CD19, CD20 (dim), CD23, kappa light chain (dim). The diagnosis is:

  1. Mantle cell lymphoma
  2. Chronic lymphocytic leukemia / SLL Correct answer.
  3. Marginal zone lymphoma
  4. Hairy cell leukemia

Explanation

CLL/SLL classic immunophenotype: CD5+, CD23+, CD19+, CD20 dim, surface immunoglobulin dim (kappa or lambda light chain restricted). Mantle cell lymphoma is CD5+/CD23-/cyclin D1+ with t(11;14). Marginal zone is CD5-/CD23-. Hairy cell is CD20 bright/CD11c+/CD25+/CD103+/annexin A1+ with BRAF V600E.

Question 42Marrow and lymph-node pathological diagnosis

Coagulation studies from a postoperative bleeding patient show: PT prolonged, aPTT prolonged, mixing study corrects both. Fibrinogen normal. Platelets normal. The most likely cause is:

  1. Lupus anticoagulant
  2. Vitamin K deficiency or warfarin effect Correct answer.
  3. Factor VIII inhibitor
  4. DIC

Explanation

Both PT and aPTT prolonged with correction on mixing study indicates factor deficiency (not inhibitor). Vitamin K deficiency / warfarin affects factors II, VII, IX, X (and proteins C/S) - prolongs both PT (more sensitive due to factor VII) and aPTT. Lupus anticoagulant fails to correct on mixing. DIC has low fibrinogen, low platelets, elevated D-dimer.

Question 43Marrow and lymph-node pathological diagnosis

A lymph node biopsy shows large neoplastic cells in a polymorphous background of lymphocytes, plasma cells, eosinophils, and neutrophils. The large cells are CD30+, CD15+, PAX5 dim+, CD45-. The diagnosis is:

  1. Diffuse large B-cell lymphoma
  2. Anaplastic large cell lymphoma
  3. Classic Hodgkin lymphoma Correct answer.
  4. Nodular lymphocyte-predominant Hodgkin lymphoma

Explanation

Classic Hodgkin lymphoma (cHL) - Reed-Sternberg cells in a mixed inflammatory background. RS cells are CD30+, CD15+ (~75%), PAX5 dim+, CD20 -/dim, CD45-, MUM1+. NLPHL has L&H 'popcorn' cells that are CD20+/CD45+/PAX5+/BCL6+/CD30-/CD15-. ALCL is CD30+/ALK+ (T-cell).

Question 44Marrow and lymph-node pathological diagnosis

A patient with B-cell ALL has bone marrow showing CD19+, TdT+, CD10+ (CALLA+), CD20-, CD34+ blasts. Cytogenetics shows t(9;22) BCR-ABL1. The most appropriate addition to chemotherapy is:

  1. Imatinib (TKI) Correct answer.
  2. Rituximab
  3. Brentuximab
  4. Trastuzumab

Explanation

Ph+ B-ALL (t(9;22), p190 fusion) is treated with chemotherapy plus a BCR-ABL TKI (imatinib, dasatinib, ponatinib) - markedly improves outcomes. Pediatric Ph+ ALL was historically the worst-prognosis subtype before TKI integration. Rituximab is for CD20+ B-ALL, brentuximab for CD30+, trastuzumab for HER2+.

Question 45Marrow and lymph-node pathological diagnosis

Schistocytes >2% on peripheral smear, low platelets, low haptoglobin, elevated LDH, and elevated indirect bilirubin in a postpartum woman with hypertension. The differential includes TTP, HELLP, DIC, and aHUS. Which test best differentiates TTP from these?

  1. ADAMTS13 activity (<10% confirms TTP) Correct answer.
  2. Fibrinogen level
  3. D-dimer
  4. Coombs test

Explanation

In the appropriate thrombotic-microangiopathy presentation, severe ADAMTS13 deficiency strongly supports TTP and guides the relevant urgent pathway. Interpret the assay with clinical findings, timing and the complete differential rather than treat every isolated low value as an adequate stand-alone diagnosis.

Question 46Marrow and lymph-node pathological diagnosis

A 3-year-old has hepatosplenomegaly and pancytopenia. Bone marrow shows infiltration by lymphoblasts that are TdT+, CD10+, CD19+, CD79a+. Cytogenetics: hyperdiploidy (>50 chromosomes). The diagnosis and prognosis are:

  1. B-ALL with hyperdiploidy - favorable prognosis Correct answer.
  2. T-ALL with NOTCH1 mutation - intermediate prognosis
  3. Burkitt leukemia/lymphoma - favorable
  4. B-ALL with hypodiploidy - poor prognosis

Explanation

B-ALL with hyperdiploidy (51-65 chromosomes, especially +4, +10, +17) is the most favorable cytogenetic subgroup in childhood B-ALL. Hypodiploidy (<45) and Ph+ (BCR-ABL1, KMT2A rearrangement) are unfavorable. ETV6-RUNX1 t(12;21) is also favorable. T-ALL is treated similarly but distinct biology.

Question 47Cytological method, molecular assays, quality and autopsy

A molecular pathology laboratory is validating comprehensive Next-Generation Sequencing (NGS) panels for predictive biomarker testing in non-small cell lung cancer (NSCLC) and solid tumors. Which of the following technical principles correctly describes the comparative utility of DNA-based versus RNA-based NGS sequencing for oncogenic alterations?

  1. DNA-based NGS is superior to RNA-based NGS for detecting gene fusions involving large, highly repetitive, intronic breakpoint regions (such as ALK, ROS1, RET, and NTRK1-3).
  2. RNA-based NGS sequencing directly interrogates spliced mature mRNA transcripts, allowing reliable detection of known and novel gene fusion partners regardless of large intronic breakpoints, whereas DNA-based NGS is optimal for single nucleotide variants (SNVs), small indels, and copy number variations. Correct answer.
  3. RNA sequencing cannot detect fusion transcripts if the fusion partner gene is unknown.
  4. DNA sequencing is completely incapable of detecting point mutations in formalin-fixed paraffin-embedded (FFPE) tissue.

Explanation

RNA-based sequencing can be useful for expressed fusion detection because it evaluates spliced transcripts and can avoid some large-intron coverage limitations of DNA panels. DNA methods are important for relevant sequence and copy-number alterations. Performance depends on RNA quality, panel design, expression, coverage and validation; neither approach guarantees detection of every possible event.

Question 48Cytological method, molecular assays, quality and autopsy

A liquid-based Pap test must contain a minimum of how many well-visualized squamous cells to meet Bethesda adequacy criteria?

  1. 1,000
  2. 5,000 Correct answer.
  3. 8,000-12,000
  4. 50,000

Explanation

LBP adequacy requires a minimum of 5,000 well-visualized squamous cells (Bethesda). Conventional Pap smears require 8,000-12,000 well-visualized squamous cells. Inadequacy is reported as 'unsatisfactory for evaluation' with a specific reason (low cellularity, obscuring blood/inflammation, etc.). ASCCP 2020 uses adequacy to trigger repeat testing intervals.

Question 49Cytological method, molecular assays, quality and autopsy

A CSF cytology from a patient with leptomeningeal spread of breast carcinoma is best worked up with which IHC panel?

  1. GATA3, ER, mammaglobin on cell block Correct answer.
  2. TTF-1 and napsin only
  3. Synaptophysin and chromogranin only
  4. WT-1 and calretinin only

Explanation

GATA3 is a highly sensitive breast and urothelial marker. Combined with ER (estrogen receptor) and mammaglobin (or GCDFP-15), the panel confirms metastatic breast adenocarcinoma. CSF cell blocks enable IHC workup of malignant cells. TTF-1/napsin would suggest lung; WT-1/calretinin mesothelial/ovarian serous; synaptophysin neuroendocrine.

Question 50Cytological method, molecular assays, quality and autopsy

An advanced lung adenocarcinoma requires a validated predictive biomarker assessment on adequate material. Which listed combined molecular and immunohistochemical panel includes relevant targets and immune-marker assessment rather than treating PD-L1 as a DNA-sequencing result?

  1. Only HER2 testing
  2. EGFR, ALK, ROS1, BRAF, KRAS, NTRK, MET, RET, HER2, and PD-L1 (22C3 or SP263) on cell block or biopsy Correct answer.
  3. Only BRCA testing
  4. Only microsatellite instability testing

Explanation

Relevant lung-cancer predictive assessment can combine validated sequence, fusion and expression tests according to the actual indication. PD-L1 is assessed by an appropriate immunohistochemical method and is not itself an NGS mutation result. Panel design, tissue adequacy, assay validation and current disease-specific eligibility govern interpretation.