Neoplasia (Classification, Carcinogenesis, Tumor Markers, Paraneoplastic) MCQs

Pathology · 215 free questions with answers & explanations.

1. A 58-year-old man with small cell lung carcinoma develops proximal muscle weakness, hyporeflexia, and autonomic dysfunction. Electromyography shows augmentation of muscle action potential on repetitive nerve stimulation. Which antibody is most likely responsible for this paraneoplastic syndrome?
2. A molecular study of colorectal carcinoma reveals that tumor suppressor gene inactivation requires mutation of both alleles. This concept, originally proposed based on retinoblastoma genetics, is best described by which term?
3. A 45-year-old woman has a serum AFP level of 2800 ng/mL with a hepatic mass. Which feature of AFP in the context of tumor markers is most accurately described?
4. A 50-year-old smoker develops hypercalcemia, hyponatremia, and inappropriate ADH secretion. Imaging reveals a hilar lung mass. Which histological type is most commonly responsible for ADH-mediated paraneoplastic hyponatremia?
5. In the hallmarks of cancer framework, the ability of tumor cells to resist cell death despite DNA damage relates to which specific molecular alteration most commonly seen in human cancers?
6. A 55-year-old man with small-cell lung carcinoma presents with hyponatremia and concentrated urine. The paraneoplastic syndrome responsible involves ectopic secretion of which molecule?
7. The two-hit hypothesis of tumor suppressor gene inactivation requires that the second hit in hereditary retinoblastoma most commonly involves which mechanism?
8. Warburg effect, wherein tumor cells preferentially use aerobic glycolysis even in the presence of oxygen, primarily confers a survival advantage by:
9. A tumor marker elevated in both hepatocellular carcinoma and non-seminomatous germ cell tumors, and normally produced by the fetal yolk sac and liver, is:
10. Which of the following represents an epigenetic mechanism of carcinogenesis that silences tumor suppressor genes without altering the DNA sequence?
11. A 58-year-old man with a 35 pack-year smoking history develops hypercalcemia, weight loss, and a 3.5 cm hilar mass. Biopsy shows large polygonal cells with abundant pink cytoplasm, intercellular bridges, and keratin pearls. Which paraneoplastic mechanism best explains his hypercalcemia?
12. A molecular pathology report on a lung adenocarcinoma describes an exon 19 deletion in EGFR. The treating oncologist initiates first-line osimertinib. After 14 months, the patient progresses and repeat biopsy reveals a C797S mutation in EGFR exon 20 in trans with T790M. What is the mechanism of this acquired resistance?
13. A 42-year-old woman with endometrial carcinoma is found to have mismatch repair deficiency (dMMR) on immunohistochemistry showing loss of MSH2 and MSH6. This molecular subtype corresponds to which TCGA endometrial cancer classification?
14. A 65-year-old man is diagnosed with a well-differentiated pancreatic neuroendocrine tumor (PanNET). Pathology shows Ki-67 of 8% and 7 mitoses per 10 HPF. According to the 2022 WHO classification, this tumor is best classified as:
15. Calretinin, inhibin, and SF-1 are the most useful immunohistochemical markers for confirming a diagnosis of:
16. A 58-year-old man with a lung mass has elevated serum calcium (12.8 mg/dL) but no bone metastases on imaging. PTH-rP is elevated. The tumor histology shows cells with intercellular bridges and abundant pink cytoplasm. Which molecular alteration is MOST characteristic of this tumor type?
17. A research study examines telomerase activity in neoplasia. In normal somatic cells, telomerase is repressed, leading to telomere shortening with each division. In the context of carcinogenesis, which event most accurately describes the role of critically short telomeres BEFORE telomerase reactivation?
18. A 45-year-old woman is found to have elevated serum AFP and β-HCG. Imaging reveals a retroperitoneal mass. Biopsy shows primitive cells, syncytiotrophoblasts, and Schiller-Duval bodies. AFP is produced by which cell type in this tumor?
19. The concept of 'oncogene addiction' has important implications for targeted therapy. It refers to the phenomenon where a cancer cell:
20. A 62-year-old man with small cell lung carcinoma develops hyponatremia (Na+ 118 mEq/L), concentrated urine, and inappropriately elevated urine sodium. The paraneoplastic syndrome is mediated by ectopic secretion of:
21. A 55-year-old man with squamous cell carcinoma of the lung develops hypercalcemia despite no bone metastases on imaging. Serum PTH is suppressed but PTHrP is markedly elevated. Which downstream signaling pathway does PTHrP primarily activate to cause osteoclast-mediated bone resorption in this paraneoplastic setting?
22. Next-generation sequencing of a poorly differentiated carcinoma of unknown primary reveals an in-frame fusion of ETV6-NTRK3. This fusion gene is most characteristically associated with which tumor type that guides diagnosis?
23. A 62-year-old woman with small-cell lung carcinoma develops limbic encephalitis with anti-Hu antibodies. The anti-Hu (ANNA-1) target antigen is a nuclear RNA-binding protein. Which mechanism best explains why antibody-positive patients do not respond well to immunotherapy and have poor prognosis?
24. A tumor biopsy immunohistochemistry panel shows diffuse strong CK7 positivity, CK20 negativity, TTF-1 positivity, and napsin A positivity. This immunoprofile is most consistent with:
25. Promoter hypermethylation of RASSF1A gene in a non-small cell lung carcinoma silences a tumor suppressor that normally inhibits which oncogenic pathway?
26. A 58-year-old woman with ovarian cancer undergoes testing to guide PARP inhibitor eligibility. The tumor shows homologous recombination deficiency (HRD). Which molecular alteration is MOST directly responsible for this phenotype when inherited in the germline?
27. Immunohistochemistry on a mediastinal mass in a 25-year-old shows positivity for OCT3/4, SALL4, and CD30, but negativity for AFP and hCG. The most likely diagnosis is:
28. A tumor suppressor gene product normally sequesters E2F transcription factors by binding them through a 'pocket domain', thereby preventing S-phase entry. Loss of this protein's function is a hallmark of which type of carcinogenesis?
29. A patient is found to have elevated chromogranin A, synaptophysin-positive tumor cells, and a Ki-67 of 45%. According to current WHO 2022 classification, this neuroendocrine neoplasm would be graded as:
30. Which paraneoplastic syndrome is caused by ectopic secretion of parathyroid hormone-related peptide (PTHrP) and is classically associated with squamous cell carcinoma of the lung?
31. A 55-year-old man with non-small cell lung cancer develops hyponatremia (serum Na⁺ 118 mEq/L) with urinary sodium >20 mEq/L and urine osmolality >100 mOsm/kg in the absence of adrenal or thyroid dysfunction. Immunohistochemistry of the tumor shows expression of which hormone most directly responsible for this paraneoplastic syndrome?
32. A somatic gain-of-function mutation in codon 12 of the KRAS gene is found in 35% of colorectal cancers. This mutation impairs which intrinsic enzymatic activity of the Ras protein, leading to constitutive activation of downstream MAPK signaling?
33. Which of the following best describes the molecular mechanism by which loss of VHL tumor suppressor gene function leads to clear cell renal cell carcinoma?
34. A patient with a newly diagnosed gastrointestinal stromal tumor (GIST) undergoes molecular testing. Approximately 85% of GISTs harbor an activating mutation in which proto-oncogene, making imatinib mesylate the first-line targeted therapy?
35. Warburg effect is a metabolic hallmark of cancer cells in which glucose is preferentially metabolized to lactate even under aerobic conditions. This phenomenon provides a tumor cell growth advantage primarily by supplying:
36. A 55-year-old woman with a lung adenocarcinoma undergoes molecular profiling. The tumor harbors an EML4-ALK fusion. Which mechanism best explains why this fusion protein drives malignant transformation?
37. A biopsy from a retroperitoneal mass in a 40-year-old man shows a tumor with MDM2 gene amplification confirmed by FISH and CDK4 co-amplification. What is the most accurate diagnosis?
38. In Lynch syndrome, the mismatch repair (MMR) protein MSH2 is lost due to a germline mutation. Which downstream molecular consequence most directly accounts for the microsatellite instability (MSI-H) phenotype?
39. A paraneoplastic syndrome of hyponatremia, concentrated urine, and normal adrenal function is found in a patient with small-cell lung carcinoma. The ectopic product responsible for this syndrome is:
40. A 62-year-old man has a cecal adenocarcinoma with KRAS codon 12 mutation and no MLH1/MSH2 loss on IHC. Which is the most appropriate statement regarding targeted therapy selection?
41. A 58-year-old man with small cell lung carcinoma develops hyponatremia and elevated urine osmolality. Ectopic hormone production by the tumor is responsible. Which gene product directly mediates resistance to apoptosis in this neuroendocrine malignancy, making it particularly refractory to therapy despite initial chemosensitivity?
42. A 45-year-old woman has a gastric mass biopsy showing spindle cells with perinuclear vacuolization, positive for CD117 and DOG1, negative for CD34. Mutation analysis reveals a PDGFRA exon 18 D842V substitution. Which therapeutic agent is most likely to be ineffective for this tumor?
43. Transcriptional profiling of a breast tumor shows high expression of AURKA (Aurora kinase A), which phosphorylates BRCA1 at serine 308. The pathological consequence of AURKA-mediated BRCA1 inactivation specifically impairs which cell cycle checkpoint?
44. A paraneoplastic syndrome manifesting as subacute cerebellar degeneration is associated with anti-Yo antibodies (anti-PCA-1). The target antigen CDR2 is expressed by the tumor and cross-reacts with Purkinje cell antigens. Which primary malignancy most characteristically produces this paraneoplastic syndrome?
45. A researcher studying colorectal carcinogenesis finds that epigenetic silencing of MLH1 by promoter hypermethylation leads to microsatellite instability (MSI-H) without germline mutation. This sporadic mechanism is distinct from Lynch syndrome. In what percentage of sporadic MSI-H colorectal cancers is MLH1 silencing caused by BRAF V600E mutation-associated epigenetic reprogramming?
46. A 58-year-old man with non-small cell lung cancer develops hypercalcemia without bone metastases. PTH-related protein (PTHrP) is elevated. Which molecular pathway underlies PTHrP production in squamous cell carcinoma of the lung?
47. Telomerase reverse transcriptase (TERT) promoter mutations (C228T and C250T) are found in which of the following tumor types at the highest frequency (>70%)?
48. A tumor specimen stains positive for chromogranin A, synaptophysin, and Ki-67 index is measured at 22%. According to the WHO 2022 classification of neuroendocrine neoplasms, this tumor is best classified as:
49. CDH1 (E-cadherin) promoter methylation resulting in gene silencing is the initiating molecular event in which hereditary cancer syndrome?
50. Alpha-fetoprotein (AFP) is elevated in hepatocellular carcinoma. However, which of the following conditions produces the highest serum AFP levels, often exceeding 10,000 ng/mL?
51. A 58-year-old man with small-cell lung carcinoma develops hyponatremia with serum sodium of 118 mEq/L, urine osmolality 520 mOsm/kg and urine sodium of 65 mEq/L. The tumor cells express the same gene whose product is normally synthesized exclusively in the hypothalamus and posterior pituitary. Which of the following best describes the molecular mechanism responsible for this presentation?
52. A gain-of-function missense mutation in codon 12 of KRAS substitutes glycine with valine (G12V). Which of the following correctly describes why this mutation renders the Ras protein constitutively active?
53. In Wilms tumor (nephroblastoma), which molecular mechanism underlies loss of WT1 tumor suppressor function in the most common sporadic form?
54. Which tumor marker combination is most specific for monitoring treatment response in gestational choriocarcinoma, and what molecular property makes it uniquely elevated in this malignancy compared to normal pregnancy?
55. A 58-year-old man with a lung adenocarcinoma is found to have an EGFR exon 20 insertion mutation. Which of the following best explains why first-generation EGFR tyrosine kinase inhibitors (erlotinib/gefitinib) show limited efficacy against this mutation compared to exon 19 deletions?
56. Liquid biopsy from a patient with colorectal cancer detects a KRAS G12C mutation in circulating tumour DNA (ctDNA). Which of the following correctly describes the biochemical basis of why KRAS G12C mutations confer oncogenic activity?
57. A tumour shows microsatellite instability-high (MSI-H) status on PCR testing and loss of MLH1 expression on immunohistochemistry, but MLH1 gene sequencing shows no germline mutation. The most likely epigenetic mechanism responsible for this sporadic MSI-H colorectal cancer is:
58. A 45-year-old woman with ovarian high-grade serous carcinoma undergoes germline BRCA1 testing. BRCA1 is classified as a tumour suppressor gene that functions in homologous recombination repair. The 'BRCAness' phenotype in tumours with BRCA1/2 dysfunction makes them particularly sensitive to which class of drugs by causing synthetic lethality?
59. Warburg effect describes the preferential use of aerobic glycolysis by cancer cells even in the presence of oxygen. The oncometabolite 2-hydroxyglutarate (2-HG) produced in gliomas and AML with IDH1/2 mutations leads to malignant transformation primarily by:
60. A 58-year-old man with small cell lung carcinoma develops hyponatremia unresponsive to fluid restriction. Which molecular mechanism best explains the ectopic hormone production responsible for this syndrome?
61. A pathologist evaluates a colonic polyp showing dysplastic crypts surrounded by inflamed lamina propria that has NOT breached the muscularis mucosae. According to the WHO 2019 digestive tumor classification, how should this lesion be staged?
62. Fluorescence in situ hybridisation (FISH) of a salivary gland tumor reveals EWSR1-ATF1 gene fusion. Which tumor does this molecular finding most specifically diagnose?
63. A patient's tumor shows strong nuclear accumulation of beta-catenin on immunohistochemistry. This pattern is the molecular footprint of mutation in which pathway component?
64. A 45-year-old woman with MEN1 syndrome has a pancreatic neuroendocrine tumor. Which tumor suppressor gene on chromosome 11q13 is most likely mutated and is required for MEN1-associated tumor development according to Knudson's two-hit hypothesis?
65. A 58-year-old man with squamous cell carcinoma of the lung develops hypercalcemia, not explained by bone metastasis. Serum PTH-related protein (PTHrP) is markedly elevated. Which molecular mechanism best explains why squamous carcinomas — but not adenocarcinomas — characteristically produce PTHrP?
66. A pathologist receives a biopsy from a retroperitoneal mass. Histology shows intersecting fascicles of spindle cells with a herringbone pattern and frequent mitoses. IHC: desmin positive, myogenin negative, SMA negative, S100 negative. Molecular testing reveals a MDM2 gene amplification. What is the most likely diagnosis?
67. In the WHO 2022 Classification of Soft Tissue Tumours, NTRK-rearranged spindle cell neoplasms have been recognized as a distinct entity. Which statement about this entity is MOST accurate?
68. Paraneoplastic encephalomyelitis in a patient with small cell lung carcinoma is mediated by antibodies against Hu antigen (ANNA-1). The Hu proteins are RNA-binding proteins normally expressed only in neurons. Why does SCLC trigger anti-Hu autoimmunity?
69. Which epigenetic mechanism is specifically exploited by IDH1/IDH2 mutant gliomas and cholangiocarcinomas to drive carcinogenesis via production of an oncometabolite?
70. A 58-year-old man with squamous cell carcinoma of the lung develops hypercalcemia unrelated to bone metastasis. Immunohistochemistry of the tumor reveals cytoplasmic staining for a peptide that shares structural homology with the mid-region of parathyroid hormone. Which molecular mechanism best explains the hypercalcemia?
71. Molecular profiling of a colorectal carcinoma reveals high microsatellite instability (MSI-H) and loss of MLH1 protein expression by immunohistochemistry, but BRAF V600E mutation is absent and MLH1 promoter methylation is absent. Which germline syndrome is most likely?
72. A 45-year-old woman with breast carcinoma undergoes next-generation sequencing. The tumor shows PIK3CA mutation, PTEN loss, and HER2 amplification. The downstream kinase constitutively activated by loss of PTEN that is critical to HER2-driven proliferation is:
73. A 62-year-old man undergoes resection of a retroperitoneal mass. Histology shows spindle cells in a storiform pattern with thick hyalinized collagen bands and scattered plasma cells. IHC shows IgG4+ plasma cells > 50 per HPF with IgG4/IgG ratio > 40%. The WHO 2022 classification of soft tissue tumors would categorize this as:
74. The Warburg effect in cancer cells refers to preferential aerobic glycolysis over oxidative phosphorylation even in the presence of adequate oxygen. The oncometabolite that most directly promotes HIF-1alpha stabilization in the normoxic tumor microenvironment of IDH1-mutant gliomas is:
75. A 58-year-old man with small cell lung carcinoma develops hyponatremia and inappropriately concentrated urine. Immunohistochemistry of the tumor shows strong positivity for chromogranin A and synaptophysin. The paraneoplastic syndrome in this patient is mediated by ectopic secretion of which peptide?
76. On fluorescence in situ hybridization (FISH), a soft tissue tumor shows SS18-SSX fusion gene resulting from t(X;18)(p11;q11). This translocation is diagnostic of which neoplasm?
77. A tumor demonstrates simultaneous loss of heterozygosity (LOH) at 3p, 5q, 17p, and 18q. This pattern of chromosomal instability is most consistent with the development of which carcinoma via the chromosomal instability (CIN) pathway?
78. A woman with a history of BRCA1 germline mutation undergoes prophylactic bilateral salpingo-oophorectomy. The pathologist finds a microscopic focus of high-grade serous carcinoma in the fimbriated end of the fallopian tube. This finding supports which current concept about ovarian high-grade serous carcinoma?
79. A 45-year-old patient with a medullary thyroid carcinoma is found to have a RET proto-oncogene mutation. Which mechanism best describes how the mutant RET protein drives neoplastic transformation?
80. A 55-year-old man presents with hypercalcemia without bony metastases. His tumor is found to secrete a protein that binds to both PTH and PTH-related receptors. Immunohistochemistry of the resected lung mass shows cells positive for chromogranin A, synaptophysin, and a proliferation index (Ki-67) of 22%. Which WHO 2021 classification grade applies to this tumor?
81. Tumor cells that demonstrate autocrine VEGF signaling with co-expression of VEGF and its receptor VEGFR-2 on the same cell represent which mechanism of escape from normal growth control?
82. A 48-year-old woman has a serum CA-125 of 890 U/mL and a pelvic mass. Pathology shows papillary clusters with psammoma bodies and serous differentiation. The BRCA1 promoter is found methylated on somatic testing. Which statement best describes the molecular consequence of this finding?
83. Which paraneoplastic syndrome is most characteristically associated with anti-Hu antibodies directed against neuronal nuclear antigen ANNA-1, typically in the setting of small cell lung carcinoma?
84. In the cancer stem cell (CSC) hypothesis, which surface marker combination is used to prospectively isolate CSCs from human breast cancer specimens?
85. A 55-year-old man with a renal cell carcinoma develops erythrocytosis. Ectopic production of which cytokine by the tumor is responsible?
86. The E6 oncoprotein of high-risk HPV strains promotes cervical carcinogenesis primarily by:
87. Warburg effect in tumor cells refers to preferential use of aerobic glycolysis. The molecular driver most responsible is upregulation of which enzyme isoform?
88. A pathology report describes a tumor showing 'loss of heterozygosity at 17p13.1'. This finding implicates loss of function of which tumor suppressor?
89. Anti-Ri antibody (ANNA-2) is a paraneoplastic antibody most characteristically associated with which tumor?
90. A 58-year-old man with squamous cell carcinoma of the lung develops hypercalcemia. Biopsy of the tumor reveals strong immunopositivity for PTHrP. Which mechanism best explains the hypercalcemia in this case?
91. During carcinogenesis, a proto-oncogene is converted to an oncogene by a chromosomal translocation that places the coding sequence under control of a highly active promoter. This mechanism is BEST exemplified by which translocation-tumor pair?
92. A 45-year-old woman is found to have a medullary thyroid carcinoma. Genetic testing reveals a germline gain-of-function mutation in the RET proto-oncogene. This mutation is associated with which hereditary syndrome and additional tumor risk?
93. A tumor suppressor gene product normally promotes ubiquitin-mediated degradation of HIF-1alpha under normoxic conditions. Loss of this gene leads to constitutive HIF-1alpha activity, angiogenesis, and clear cell carcinoma. Which gene is this?
94. Which tumor marker is MOST specifically elevated in granulosa cell tumor of the ovary and can be used for monitoring recurrence?
95. A 58-year-old woman with a known small cell lung carcinoma develops hyponatremia with concentrated urine and normal renal, adrenal, and thyroid function. The paraneoplastic syndrome responsible is mediated by ectopic secretion of which peptide?
96. In oncogenesis, the RET proto-oncogene is characteristically mutated (point mutation or rearrangement) in all of the following EXCEPT:
97. Which mechanism best explains why cells with a mutant p53 protein (dominant-negative mutation) are more oncogenic than cells that simply lose one p53 allele?
98. Elevated serum AFP with low free β-hCG in an adult male with a testicular mass most strongly suggests which histological type?
99. Which of the following epigenetic mechanisms is PRIMARILY responsible for silencing of tumour suppressor genes in cancer, without altering the underlying DNA sequence?
100. A 55-year-old man with squamous cell carcinoma of the lung develops hypercalcemia (serum calcium 13.2 mg/dL) with a suppressed PTH. Which mediator is MOST responsible for this paraneoplastic hypercalcemia?
101. The RB1 tumor suppressor gene product pRb normally restrains the cell cycle by binding and inhibiting which transcription factor?
102. Warburg effect in tumor cells refers to preferential use of which metabolic pathway even in the presence of adequate oxygen?
103. A 40-year-old woman has a medullary thyroid carcinoma. Her serum calcitonin is markedly elevated and she is found to have a germline RET proto-oncogene mutation. This mutation is BEST classified as which type of gain-of-function alteration?
104. Which of the following tumor suppressor genes demonstrates 'loss of heterozygosity' as its second hit in familial adenomatous polyposis?
105. A 58-year-old man with small cell carcinoma of the lung develops proximal muscle weakness and absent deep tendon reflexes that improve with exercise. Immunofluorescence shows antibodies against presynaptic voltage-gated calcium channels. This paraneoplastic syndrome is best classified as:
106. A 45-year-old woman with ovarian adenocarcinoma develops cerebellar ataxia. Serum anti-Yo (anti-Purkinje cell) antibodies are detected. The pathological target of these antibodies in paraneoplastic cerebellar degeneration is:
107. In the two-hit hypothesis of tumour suppressor gene inactivation, the 'first hit' in hereditary retinoblastoma is characterised by:
108. A 65-year-old man with hepatocellular carcinoma has markedly elevated serum alpha-fetoprotein (AFP). AFP re-expression in HCC results primarily from:
109. Which of the following carcinogens exerts its effect primarily via formation of a covalent adduct with guanine residues in DNA, without requiring prior metabolic activation?
110. A 58-year-old man with small cell lung carcinoma develops hyponatremia with urine osmolality higher than serum osmolality. Which paraneoplastic mechanism is responsible?
111. A 45-year-old woman has an ovarian tumor with serum CA-125 of 980 U/mL and peritoneal implants. Histology shows psammoma bodies with papillary fronds lined by high-grade columnar cells. Which carcinogenesis pathway does this tumor follow?
112. Oncogene amplification in neuroblastoma is detected by FISH showing double minutes and homogeneously staining regions (HSRs). Which gene is amplified?
113. A patient with thymoma develops pure red cell aplasia. The autoantibody responsible targets which erythroid precursor surface molecule?
114. The Warburg effect in cancer cells describes aerobic glycolysis producing lactate even in the presence of adequate oxygen. The primary advantage of this metabolic reprogramming is:
115. A 58-year-old man with squamous cell carcinoma of the lung develops hypercalcemia (serum calcium 13.2 mg/dL) without bone metastases. The most likely mediator responsible for this paraneoplastic hypercalcemia is:
116. Which of the following best describes the function of the RB1 (retinoblastoma) protein in normal cell cycle regulation?
117. A tumor that arises from pluripotent cells containing tissues from all three germ layers is classified as:
118. The Warburg effect in tumor metabolism refers to:
119. A 45-year-old man is found to have elevated serum alpha-fetoprotein (AFP). Which of the following is the LEAST likely cause?
120. A 58-year-old man with squamous cell carcinoma of the lung develops hypercalcemia (serum calcium 13.2 mg/dL) without bone metastases. The mediator responsible for this paraneoplastic hypercalcemia is:
121. Which statement best describes the function of the RB1 (retinoblastoma) protein in normal cell cycle regulation?
122. A 45-year-old man is found to have elevated serum alpha-fetoprotein (AFP). Which of the following is the LEAST likely source?
123. Which oncogene product is a constitutively active GTPase caused by a point mutation that prevents intrinsic GTP hydrolysis, perpetuating downstream MAPK signaling?
124. A 58-year-old man with squamous cell carcinoma of the lung develops hypercalcemia despite the absence of bone metastases. Serum PTH is undetectable. Which molecule secreted by the tumor is most directly responsible?
125. In a multistep colorectal carcinogenesis model, the APC gene mutation is the initiating event. APC protein normally functions by:
126. A 45-year-old woman with endometrial carcinoma is found to have a germline mutation causing loss of MLH1. The mechanism of tumorigenesis is best described as:
127. Tumor angiogenesis is primarily driven by hypoxia-induced upregulation of VEGF. The transcription factor that directly activates VEGF gene expression under hypoxic conditions is:
128. A 62-year-old man with a testicular non-seminomatous germ cell tumor has markedly elevated AFP and beta-hCG. After orchiectomy and chemotherapy, AFP remains elevated while beta-hCG normalizes. The persistently elevated AFP most likely indicates:
129. Cancer-associated fibroblasts (CAFs) in the tumor microenvironment promote tumor progression primarily by secreting:
130. A 55-year-old man with small cell lung carcinoma develops bilateral proximal leg weakness worse with ambulation but improving with repetitive use. Deep tendon reflexes are absent. This paraneoplastic syndrome is caused by IgG antibodies targeting:
131. The Knudson 'two-hit' hypothesis was originally described for retinoblastoma. In the hereditary form, the first hit is:
132. Epigenetic silencing of tumor suppressor genes through promoter CpG island hypermethylation is a key mechanism in carcinogenesis. The enzyme catalyzing addition of methyl groups to cytosine residues in CpG dinucleotides is:
133. A 70-year-old man with prostate cancer develops confusion, polydipsia, and serum sodium of 122 mEq/L. His urine osmolality is 680 mOsm/kg and serum osmolality is 260 mOsm/kg. Cortisol and thyroid function are normal. This paraneoplastic syndrome is caused by ectopic secretion of:
134. A 58-year-old man with squamous cell carcinoma of the lung develops hypercalcemia with a serum calcium of 13.2 mg/dL, a low PTH, and an elevated PTH-related protein (PTHrP). This paraneoplastic hypercalcemia is primarily mediated by PTHrP acting on which receptor?
135. A pathologist examining a tumor specimen notes marked variation in nuclear size and shape, numerous atypical mitoses with tripolar spindles, and loss of cellular polarity. These features collectively define which component of tumor grading?
136. The Knudson two-hit hypothesis for tumor suppressor gene inactivation was originally proposed based on statistical analysis of which childhood tumor?
137. A 45-year-old woman presents with flushing, diarrhea, and right heart valvular lesions. Urine 5-HIAA is markedly elevated. The responsible tumor most commonly arises in which location?
138. Which oncogene product functions as a constitutively active GTPase due to a point mutation that impairs its intrinsic GTPase activity, locking it in the active GTP-bound state?
139. A 58-year-old man with small cell lung carcinoma develops hyponatremia, decreased serum osmolality, and concentrated urine. Which paraneoplastic mechanism best explains this finding?
140. Which of the following molecular alterations in cancer represents a gain-of-function mutation that constitutively activates a downstream signaling cascade without receptor engagement?
141. Alpha-fetoprotein (AFP) is elevated in hepatocellular carcinoma. Which other malignant tumor characteristically produces AFP as a tumor marker?
142. A tumor is described as having irregular islands of epithelial cells embedded in a dense fibrous stroma, making it hard to the touch. This histological pattern is best described as:
143. Lambert-Eaton myasthenic syndrome occurring as a paraneoplastic manifestation of small cell lung carcinoma involves antibodies directed against which target?
144. A 58-year-old man with small cell lung carcinoma develops hyponatremia and concentrated urine despite normal renal function. Which paraneoplastic mechanism best explains this?
145. The multi-hit model of carcinogenesis is best exemplified by which of the following hereditary tumor syndromes?
146. A tumor shows microsatellite instability (MSI-H) on molecular testing. Which DNA repair pathway is most likely defective?
147. A 45-year-old woman has a medullary thyroid carcinoma. Serum calcitonin is markedly elevated. Which tumor marker should also be measured to screen for concurrent pheochromocytoma in a possible MEN2A syndrome?
148. A 58-year-old man with small cell lung carcinoma develops hyponatremia, concentrated urine with urine osmolality 620 mOsm/kg, and serum osmolality 265 mOsm/kg. Brain MRI is normal. Which ectopic peptide best explains this paraneoplastic syndrome?
149. A 45-year-old woman has a 2 cm thyroid nodule. FNA shows follicular neoplasm. The pathologist notes a capsule but no capsular or vascular invasion on histology. What is the correct classification?
150. The Knudson two-hit hypothesis of tumor suppressor gene inactivation is best illustrated by which pair of clinical scenarios?
151. A 62-year-old man with hepatocellular carcinoma has serum AFP of 850 ng/mL. Which molecular mechanism most directly drives AFP re-expression in HCC?
152. A surgical pathologist examines a resected colonic polyp. Histology shows full-thickness dysplasia, budding of glands, and single-cell infiltration into the muscularis mucosae but NOT into the submucosa. This is classified as:
153. Warburg effect in cancer cells refers to:
154. During metastasis, cancer cells undergo epithelial-to-mesenchymal transition (EMT). Which transcription factor is MOST associated with EMT and causes repression of E-cadherin?
155. A 60-year-old woman with small cell lung cancer develops proximal muscle weakness with augmented strength after brief exercise and positive anti-VGCC antibodies. This paraneoplastic syndrome is:
156. A 50-year-old man undergoes liver biopsy for a hepatic mass in cirrhosis. Histology shows nuclear pleomorphism and atypical mitoses. Which single feature on reticulin stain MOST reliably distinguishes HCC from a large regenerative nodule?
157. A 58-year-old woman with newly diagnosed small cell lung carcinoma develops hyponatremia with serum sodium of 122 mEq/L, urine osmolality 600 mOsm/kg, and urine sodium 45 mEq/L. Which paraneoplastic mechanism is responsible?
158. Loss-of-function mutations in BRCA1 and BRCA2 predispose to breast and ovarian cancer. Both proteins share a common molecular function that explains this predisposition. What is this shared function?
159. A 70-year-old man with pancreatic adenocarcinoma develops sudden onset migratory thrombophlebitis in multiple extremities. This paraneoplastic phenomenon is called:
160. A tumor immunohistochemistry panel shows: CK7+, CK20−, TTF-1+, Napsin A+. Which primary malignancy does this pattern most consistently identify?
161. Which oncogene mechanism best describes the action of BCL-2 in follicular lymphoma, where it is overexpressed due to the t(14;18) translocation?
162. A 58-year-old man with small cell lung carcinoma develops hyponatremia with urine osmolality > plasma osmolality. Which paraneoplastic mechanism is responsible?
163. The multi-step carcinogenesis model requires sequential acquisition of which combination of hallmark capabilities, as described in the Hanahan & Weinberg framework?
164. A patient with medullary thyroid carcinoma has elevated serum calcitonin. Which additional tumor marker, if elevated, suggests co-existing pheochromocytoma in MEN 2A?
165. Which mechanism best explains how a loss-of-function mutation in a tumor suppressor gene requires both alleles to be inactivated before neoplastic transformation (Knudson's two-hit hypothesis)?
166. Alpha-fetoprotein (AFP) is a useful tumor marker. In which condition is an ELEVATED serum AFP NOT expected?
167. A 62-year-old man with squamous cell carcinoma of the lung presents with muscle weakness, proximal more than distal, and autonomic dysfunction. Electromyography shows facilitation of muscle action potentials with repetitive stimulation. The paraneoplastic syndrome is caused by antibodies directed against which target?
168. During carcinogenesis, a point mutation in codon 12 of the KRAS gene results in substitution of glycine by valine. The key functional consequence of this mutation is:
169. A 55-year-old woman has a uterine mass. Serum CA-125 is markedly elevated. Which histological type of ovarian tumor characteristically produces this marker?
170. The two-hit hypothesis of tumor suppressor gene inactivation was first proposed based on observations in patients with retinoblastoma. In a child with hereditary retinoblastoma, which statement best describes the genetic events?
171. Alpha-fetoprotein (AFP) is a useful serum tumor marker. In which of the following conditions is AFP elevation LEAST expected?
172. Microsatellite instability (MSI) results from defects in the mismatch repair (MMR) system. In colorectal cancer, which gene is most frequently silenced by epigenetic promoter methylation (as opposed to germline mutation in Lynch syndrome) to cause sporadic MSI-high colorectal cancer?
173. Angiogenesis is essential for tumor growth beyond 1–2 mm. The principal pro-angiogenic factor secreted by tumor cells that binds VEGFR-2 on endothelial cells to promote new vessel sprouting is:
174. Epithelial-to-mesenchymal transition (EMT) is a key step in cancer invasion and metastasis. Which transcription factor is a canonical inducer of EMT, causing downregulation of E-cadherin and upregulation of vimentin and N-cadherin?
175. A 58-year-old man with small cell lung carcinoma develops hyponatremia with inappropriately elevated urine osmolality. Immunostaining of the tumor would most likely show positivity for which peptide responsible for this paraneoplastic syndrome?
176. Which of the following best explains why tumor cells with mutated RAS oncogene have constitutive proliferative signalling even in the absence of growth factor receptor activation?
177. A 45-year-old woman with ovarian teratoma develops sub-acute cerebellar degeneration. Serum anti-Yo (anti-PCA-1) antibodies are detected. What is the target antigen of these antibodies in cerebellar Purkinje cells?
178. Which characteristic of a neoplasm distinguishes a high-grade dysplasia (carcinoma in situ) from invasive carcinoma on histology?
179. Tumor angiogenesis is driven primarily by hypoxia-induced transcription factor HIF-1α upregulating VEGF. Which enzyme degrades HIF-1α under normoxic conditions, targeting it for proteasomal destruction via the VHL E3 ubiquitin ligase complex?
180. A 58-year-old man with small cell lung carcinoma develops hyponatremia and inappropriately concentrated urine. The paraneoplastic syndrome is caused by ectopic secretion of which substance?
181. In the Knudson two-hit hypothesis applied to retinoblastoma, the hereditary form differs from the sporadic form in that:
182. Alpha-fetoprotein (AFP) is a clinically useful tumor marker for which combination of tumors?
183. A tumor shows loss of heterozygosity at chromosome 17p13. This mutation most likely inactivates which tumor suppressor gene, and what is its normal function?
184. A carcinoma is described as well-differentiated and grade 1 histologically, yet the patient has lymph node metastases (stage III). This scenario illustrates that:
185. A 58-year-old man with small cell lung carcinoma develops proximal muscle weakness and absent deep tendon reflexes that improve with repeated activity. Antibodies against which antigen are responsible for this paraneoplastic syndrome?
186. Which of the following best describes the role of promoters in chemical carcinogenesis?
187. A 67-year-old woman with known ovarian serous carcinoma has serum CA-125 levels measured serially. Which statement best describes the utility of CA-125 in this context?
188. The Warburg effect in cancer cells refers to which metabolic phenomenon?
189. A 45-year-old woman is found to have a germline mutation in the BRCA1 gene. Which of the following molecular functions does BRCA1 primarily serve?
190. The RET proto-oncogene encodes a receptor tyrosine kinase. Germline gain-of-function mutations in RET are most characteristically associated with which hereditary syndrome?
191. A 55-year-old smoker with small-cell lung carcinoma develops hyponatremia (serum Na 118 mEq/L) with inappropriately elevated urine osmolality. The mediator responsible for this paraneoplastic syndrome is:
192. Which of the following best describes the mechanism by which Warburg effect provides a survival advantage to tumor cells?
193. A tumor expressing strong nuclear positivity for beta-catenin on immunohistochemistry most likely harbors a mutation in which signaling pathway component?
194. Which tumor marker is specifically elevated in hepatocellular carcinoma arising on a background of hereditary tyrosinemia type I, and also serves as a neonatal screening marker?
195. A 55-year-old man undergoes resection of a colonic mass. Histopathology shows a well-differentiated adenocarcinoma invading through the muscularis propria into the pericolorectal fat, with 3 of 18 regional lymph nodes positive for metastatic carcinoma. No distant metastases are identified. According to TNM staging, what is the stage of this tumor?
196. A 62-year-old man presents with progressive hoarseness. Laryngoscopy reveals a friable exophytic mass on the true vocal cord. Biopsy shows dysplastic squamous epithelium with full-thickness loss of normal polarity, numerous mitoses including atypical forms, but the basement membrane is intact. What is the most accurate diagnosis?
197. A 9-year-old boy presents with a rapidly enlarging jaw mass. Biopsy shows a sheet of medium-sized lymphoid cells with round nuclei, dispersed chromatin, multiple small nucleoli, and a very high mitotic rate. The background contains scattered macrophages with phagocytosed apoptotic debris, imparting a 'starry sky' appearance. Immunophenotyping shows CD10+, CD20+, BCL-2−, and 100% Ki-67 positivity. Which chromosomal translocation is MOST characteristic of this tumor?
198. A pathologist reviews a resected breast mass and reports 'comedonecrosis' within dilated ducts. The duct lumens are filled with highly atypical epithelial cells with central areas of necrotic debris and calcification. The basement membrane of the ducts remains intact. What is the correct diagnosis, and what grade does this pattern signify?
199. A 62-year-old male smoker develops a small cell carcinoma of the lung. He presents with hyponatremia, concentrated urine with elevated urine sodium, and euvolemia. The most likely underlying mechanism is:
200. A 55-year-old woman has a 3 cm breast mass. Biopsy shows infiltrating ductal carcinoma. Immunohistochemistry reveals: ER−, PR−, HER2−. FISH confirms HER2 non-amplification. The tumor's aggressive behavior compared to hormone-receptor positive subtypes is best explained by:
201. Carcinoembryonic antigen (CEA) is elevated in a patient recovering from a resected sigmoid colon adenocarcinoma. A rising post-operative CEA level is best interpreted as:
202. RB1 acts as the 'guardian of the cell cycle.' A retinoblastoma develops in a child with germline RB1 mutation. When the second allele is somatically inactivated, pRb loss promotes entry into S-phase by:
203. A 48-year-old man with hepatitis C-related cirrhosis is found to have a 3 cm hypervascular hepatic mass on CT with arterial enhancement and portal washout. Serum AFP is 1,200 ng/mL. Which statement about this tumor marker is MOST accurate?
204. Tumor grade reflects histological differentiation, while tumor stage reflects anatomical extent. In which of the following malignancies does GRADE carry independent prognostic significance that directly determines treatment intensity, even at the same pathological stage?
205. A 40-year-old woman with a familial syndrome develops multiple osteomas, epidermoid cysts, supernumerary teeth, and is found on colonoscopy to have hundreds of colonic polyps. Genetic testing reveals an APC gene truncating mutation. The APC protein normally functions by:
206. The Warburg effect, observed in most solid tumors, refers to the preference for aerobic glycolysis over oxidative phosphorylation even in adequate oxygen. The PRIMARY advantage conferred to tumor cells by this metabolic reprogramming is:
207. During metastasis, tumor cells must intravasate, survive in circulation, and extravasate at distant sites. The step that is rate-limiting and requires tumor cells to remodel the basement membrane involves secretion of which enzyme class?
208. A 32-year-old woman with café-au-lait spots, axillary freckling, and multiple cutaneous neurofibromas is found to carry a germline NF1 mutation. The protein neurofibromin encoded by NF1 functions as a:
209. Warburg effect refers to aerobic glycolysis preferentially used by cancer cells even in the presence of oxygen. Which key oncoproteins drive upregulation of hexokinase II and glycolytic enzymes to enable the Warburg effect?
210. Which of the following tumour suppressor gene mechanisms results in haploinsufficiency rather than requiring the classic two-hit hypothesis to promote tumorigenesis?
211. Microsatellite instability (MSI-H) in colorectal cancer, classically seen in Lynch syndrome, results from defective mismatch repair (MMR). How does MSI-H status influence cancer immunotherapy response?
212. CpG island hypermethylation of promoter regions is a common epigenetic mechanism in cancer. When the MLH1 promoter is hypermethylated in sporadic colorectal cancer, the result is:
213. During neutrophil transmigration (diapedesis), the final step involving migration through the basement membrane is mediated by:
214. A patient with chronic granulomatous disease (CGD) suffers recurrent infections with catalase-positive organisms (S. aureus, Aspergillus). The molecular defect involves:
215. Which of the following inflammatory mediators is synthesized de novo and acts through nuclear factor-kappa B (NF-kB) activation rather than being preformed in granules?