Pathology USMLE Practice Questions
Disease mechanisms, cellular injury, and tissue diagnosis.
5 free pathology practice questions
Pick an answer and check it. After each question you get the same explanation StepGenie students see: the stem decoded clue by clue, the reasoning chain with its infographic, why every wrong option is wrong, and the trap the question was built around. Step 1 questions test mechanism; Step 2 CK questions ask for the next step.
A researcher is investigating the mechanisms that allow breast cancer cells to metastasize. Neoplastic cells obtained from 30 patients with stage IV invasive ductal carcinoma of the breast are tagged with a fluorescent antibody and placed into a medium that mimics normal human tissue. After 2 weeks, microscopy demonstrates that the malignant cells have invaded through the surrounding matrix and have migrated away from the original site of insertion in a pattern consistent with hematogenous spread. Which of the following cellular properties is most likely responsible for this metastatic capability?
Correct answer · G
Release of matrix metalloproteinase
Decoding the stem
Step-by-step reasoning
Step 1 of 5
Metastasis requires several steps: loss of adhesion, attachment to ECM, degradation of basement membrane/ECM, and migration into vessels.
Step 2 of 5
The vignette specifically highlights that cells "invaded through the surrounding matrix"—this is the ECM and basement membrane barrier around tissues and vessels.
Step 3 of 5
To cross this barrier, tumor cells secrete matrix metalloproteinases (MMPs), which degrade type IV collagen and other ECM components.
Step 4 of 5
Once ECM is degraded, tumor cells can migrate along matrix components and enter blood vessels, leading to hematogenous spread as described.
Step 5 of 5
Therefore, the cellular property most directly responsible for this in vitro invasion and migration pattern is release of matrix metalloproteinase.
Why not the others?
A. Loss of cellular polarity
This option implies loss of normal apical-basal orientation seen in dysplasia and carcinoma in situ, which helps identify malignancy, BUT it does not directly mediate ECM degradation or hematogenous spread; it explains atypical architecture, not invasive migration through matrix.
B. Overexpression of E-cadherin
This option implies increased cell–cell adhesion, which tends to keep epithelial cells tightly attached, BUT invasive carcinomas usually downregulate E-cadherin to detach; overexpression would oppose, not promote, metastatic migration.
C. Upregulation of telomerase
This option implies cellular immortality and unlimited replicative potential, which supports tumor growth, BUT it does not explain the specific ability to invade through matrix and migrate away—those steps depend on adhesion changes and ECM degradation, not telomere maintenance.
D. Overexpression of HER2/neu
This option implies increased growth factor receptor signaling (a tyrosine kinase) leading to proliferation and a more aggressive clinical course, BUT the question focuses on physical invasion through matrix and hematogenous spread, which are directly mediated by ECM-degrading enzymes (MMPs), not just proliferative signaling.
E. Increase in N:C ratio
This option implies cytologic atypia (larger nuclei relative to cytoplasm), a hallmark of malignancy on microscopy, BUT it is a diagnostic feature, not a mechanistic driver of invasion or metastasis; it does not enable cells to penetrate ECM or migrate.
F. Presence of fibrous tissue capsule
This option implies a well-circumscribed, often benign or less invasive tumor with a pseudocapsule, BUT metastatic, highly invasive carcinomas typically lack a true fibrous capsule; having a capsule would hinder, not facilitate, invasion into surrounding matrix.
Exam trap
Many options describe general malignant features (↑N:C ratio, loss of polarity) or aggressiveness markers (HER2, telomerase). The stem, however, specifically emphasizes physical invasion through matrix and hematogenous migration, which requires you to recognize the mechanistic step of ECM degradation via matrix metalloproteinases, not just any marker of malignancy.
The bottom line
Metastatic carcinoma cells invade and spread by releasing matrix metalloproteinases, degrading basement membrane/extracellular matrix to allow migration and hematogenous dissemination.
A 65-year-old man comes to the physician with a 6-month history of progressive fatigue and abdominal discomfort. He also reports early satiety. Physical examination reveals pale mucous membranes and splenomegaly. Laboratory testing shows a hemoglobin concentration of 9.1 g/dL and a leukocyte count of 3,400/mm³. Peripheral blood smear demonstrates nucleated red blood cells and teardrop-shaped erythrocytes. Molecular analysis identifies a Janus kinase 2 (JAK2) gene mutation. Which of the following is the most likely underlying mechanism of this patient's condition?
Correct answer · C
Fibrosis in the bone marrow
Decoding the stem
Step-by-step reasoning
Step 1 of 7
JAK2 mutation → constitutive activation of tyrosine kinase signaling in myeloid precursors → myeloproliferative neoplasm.
Step 2 of 7
In primary myelofibrosis, megakaryocytes release excess growth factors (e.g., PDGF, TGF-β).
Step 3 of 7
These growth factors stimulate fibroblasts in the bone marrow, leading to progressive marrow fibrosis.
Step 4 of 7
Fibrosed marrow cannot produce sufficient blood cells → pancytopenia (anemia and leukopenia as seen in labs).
Step 5 of 7
To compensate, hematopoiesis shifts to extramedullary sites (especially spleen) → splenomegaly and early satiety from abdominal mass effect.
Step 6 of 7
Blood cells forced out through fibrotic marrow become misshapen, producing teardrop-shaped (dacrocyte) RBCs and nucleated RBCs in circulation.
Step 7 of 7
Thus, the core underlying mechanism is fibrosis of the bone marrow driven by a JAK2-mutated myeloproliferative process.
Why not the others?
A. Viral replication in lymphoid cells
This option implies infections like EBV (e.g., mononucleosis) or retroviruses causing lymphoid proliferation, which present with atypical lymphocytes and acute symptoms, BUT this patient has chronic cytopenias, teardrop cells, and JAK2 mutation—features of myelofibrosis, not a viral lymphoid process.
B. Lymphocytic infiltration of reticuloendothelial system
This suggests conditions like hairy cell leukemia or some lymphomas, which cause massive splenomegaly and cytopenias, BUT they show lymphoid cells with specific morphology/immunophenotype, not teardrop RBCs with a JAK2 mutation typical of a myeloproliferative neoplasm.
D. Translocation between chromosome 9 and 22
This option implies the BCR-ABL fusion (Philadelphia chromosome) seen in CML, which typically has marked leukocytosis with many myeloid precursors, not leukopenia with teardrop cells and a leukoerythroblastic smear due to marrow fibrosis.
E. Elevated levels of circulating hepcidin
This implies anemia of chronic disease (hepcidin-mediated iron sequestration and ↓ iron utilization), which causes microcytic or normocytic anemia, BUT it does not explain splenomegaly, JAK2 mutation, or teardrop-shaped RBCs indicating marrow fibrosis and extramedullary hematopoiesis.
Exam trap
Students may see JAK2 and reflexively pick the classic CML/Philadelphia translocation or a generic myeloproliferative answer. The key is integrating the smear (teardrop cells), splenomegaly, and cytopenias to recognize myelofibrosis, which specifically hinges on bone marrow fibrosis, not just any myeloproliferative change.
The bottom line
Primary myelofibrosis from JAK2 mutation causes bone marrow fibrosis → extramedullary hematopoiesis → splenomegaly and teardrop cells on smear.
A 62-year-old man is found unconscious on a park bench early one January morning when the ambient temperature is -4°C (25°F). He is barefoot and dressed only in sweatpants, a T-shirt, and a light coat. On arrival to the emergency department, his heart rate is 45/min, blood pressure is 100/70 mm Hg, respiratory rate is 10/min, and core body temperature is 30°C (85.5°F). His feet and palms are edematous with clear fluid-filled blisters; the overlying skin appears yellow and waxy. The patient does not respond to verbal stimuli. Which of the following cold-associated injuries is this patient most likely experiencing?
Correct answer · D
Frostbite
Decoding the stem
Step-by-step reasoning
Step 1 of 5
Prolonged exposure to subfreezing temperatures (−4°C) with inadequate clothing → risk of tissue temperature dropping below freezing.
Step 2 of 5
At subfreezing tissue temperatures, ice crystals form within cells and extracellular space, causing mechanical disruption and osmotic injury.
Step 3 of 5
Cold causes intense vasoconstriction and ischemia, further damaging tissue and predisposing to necrosis.
Step 4 of 5
Clinically, frozen tissue appears pale/yellow, waxy, and firm; with rewarming, clear or hemorrhagic blisters and edema develop.
Step 5 of 5
This patient’s waxy yellow skin and clear fluid-filled blisters on cold-exposed extremities match the classic description of frostbite, not milder functional cold injuries.
Why not the others?
A. Frostnip
This option implies reversible superficial cold injury with transient numbness/erythema, BUT it does not produce blisters or waxy, severely damaged skin as seen here.
B. Pernio
This option implies chilblains—painful, pruritic, erythematous or violaceous lesions from nonfreezing cold, BUT this patient has subfreezing exposure with blisters and waxy skin, indicating freezing injury.
C. Immersion foot
This option implies prolonged exposure to cold, wet conditions above freezing (e.g., sailors, soldiers), causing numb, pale, swollen feet, BUT not the waxy/yellow, blistering appearance of frozen tissue.
E. Trench foot
This option implies a similar nonfreezing cold-wet injury from long periods in wet boots (classically in soldiers), causing mottled, painful feet, BUT again lacks the clear blisters and waxy frozen appearance of frostbite.
Exam trap
Students may confuse frostnip (mild, reversible, no blisters) with frostbite. The presence of waxy skin and clear blisters signals true freezing injury (frostbite).
The bottom line
Frostbite causes freezing of tissues with ice-crystal formation, leading to waxy, yellow skin, clear blisters, and possible irreversible damage.
A 42-year-old man with HIV infection who has been inconsistently taking his antiretroviral medications presents with a 2-month history of malaise and unintentional 12-lb weight loss. Over the past 2 weeks, he has developed cough, night sweats, and subjective fevers. A chest radiograph shows a cavitary lesion in the left upper lobe, and an interferon-gamma release assay is positive. He is started on appropriate antimicrobial therapy. One month later, he returns for follow-up. Laboratory evaluation shows leukocytosis with a normal differential, anemia, thrombocytosis, and microcytosis. Peripheral blood smear demonstrates Pappenheimer bodies. Labs: - Leukocyte count: 11,000/mm^3 - Hemoglobin: 9.2 g/dL - Platelet count: 400,000/mm^3 - Mean corpuscular volume (MCV): 75 µm^3 Which of the following is the most accurate diagnostic test for this patient’s condition?
Correct answer · E
Prussian blue staining
Decoding the stem
Step-by-step reasoning
Step 1 of 5
Patient treated for tuberculosis will likely receive isoniazid, a drug that can cause sideroblastic anemia by inhibiting pyridoxine (vitamin B6)-dependent heme synthesis.
Step 2 of 5
One month later he has microcytic anemia with Pappenheimer bodies, which are iron-containing granules in RBCs seen with abnormal iron utilization (sideroblastic anemia).
Step 3 of 5
In sideroblastic anemia, iron is present in excess in mitochondria but cannot be properly incorporated into heme, causing ring sideroblasts in marrow and Pappenheimer bodies in blood.
Step 4 of 5
The most accurate confirmatory test for sideroblastic anemia is identifying iron-laden mitochondria in erythroid precursors with Prussian blue iron stain on bone marrow or blood smear.
Step 5 of 5
Therefore, Prussian blue staining is the most accurate diagnostic test for this patient’s condition.
Why not the others?
A. Genetic testing
This option implies a hereditary cause (eg, congenital sideroblastic anemia or thalassemias), which causes lifelong anemia, BUT this patient has new-onset anemia after TB treatment and clear acquired risk factors.
B. Hemoglobin electrophoresis
This option implies thalassemia or hemoglobinopathy, which cause abnormal Hb fractions and target cells, BUT the key finding here is Pappenheimer bodies indicating iron granules, not abnormal globin chains.
C. Iron studies
This option implies iron deficiency or anemia of chronic disease, which alter serum iron, ferritin, TIBC, BUT these do not explain Pappenheimer bodies, which specifically reflect iron-laden cells best confirmed by iron staining.
D. Methylmalonic acid level
This option implies vitamin B12 deficiency, which causes macrocytic anemia and neurologic changes, BUT the patient has microcytic anemia with iron granules, not a macrocytosis or neurologic findings.
Exam trap
Students may see microcytic anemia and reflexively choose iron studies for iron deficiency. The key discriminator is Pappenheimer bodies, which specifically point to sideroblastic anemia and require Prussian blue iron stain for confirmation.
The bottom line
Sideroblastic anemia from disordered iron utilization shows Pappenheimer bodies; confirm with Prussian blue stain for iron-containing granules.
A 22-year-old white woman presents with a 6-month history of lower abdominal pain and recurrent episodes of loose, bloody stools. For the past month, she has also experienced painful bowel movements. She reports an unintentional 10-kg (22-lb) weight loss over the last year. Her past medical history is notable for recent treatment of streptococcal pharyngitis. Family history is significant for a maternal grandfather who died of colon cancer at age 52. She does not smoke and drinks 3–5 beers on social occasions. She is 162 cm (5 ft 4 in) tall and weighs 52 kg (115 lb) with a BMI of 19.7 kg/m². Temperature is 37°C (98.6°F), pulse is 60/min, respirations are 13/min, and blood pressure is 110/70 mm Hg. Cardiopulmonary examination is unremarkable. Abdominal examination reveals a soft abdomen with tenderness to palpation in the left lower quadrant without guarding or rigidity. Rectal examination shows no masses. Laboratory studies show microcytic anemia, leukocytosis, thrombocytosis, and the following: Labs: - Hemoglobin: 10.4 g/dL - Leukocyte count: 10,800/mm³ - Platelet count: 450,000/mm³ - Sodium: 138 mEq/L - Chloride: 103 mEq/L - Potassium: 4.9 mEq/L - Bicarbonate (HCO₃⁻): 22 mEq/L - Blood urea nitrogen: 18 mg/dL - Creatinine: 0.6 mg/dL - Antinuclear antibodies: negative - Perinuclear antineutrophil cytoplasmic antibodies (p-ANCA): positive - Anti-Saccharomyces cerevisiae antibodies: negative A colonoscopy is scheduled for the next day. Which of the following findings is most likely to be present on colonoscopy in this patient?
Correct answer · C
Confluent inflammation of the colonic mucosa with edema, fibrin-covered ulcers, and loss of vascular pattern
Decoding the stem
Step-by-step reasoning
Step 1 of 6
Chronic bloody diarrhea, LLQ pain, weight loss, and anemia indicate a chronic inflammatory process in the colon rather than functional or acute infectious disease.
Step 2 of 6
LLQ pain and rectal symptoms suggest disease starting in the rectum/distal colon, which is characteristic of ulcerative colitis rather than patchy small bowel disease.
Step 3 of 6
Lab findings (microcytic anemia, leukocytosis, thrombocytosis) support chronic intestinal blood loss and systemic inflammation seen in IBD.
Step 4 of 6
Autoantibody profile: p-ANCA positive and ASCA negative strongly favors ulcerative colitis over Crohn disease (usually ASCA+).
Step 5 of 6
Ulcerative colitis causes continuous mucosal and submucosal inflammation starting in rectum with diffuse erythema, edema, friability, and superficial ulcers that may be fibrin-covered and obscure normal vascular pattern.
Step 6 of 6
Therefore, colonoscopy is most likely to show confluent inflammation of the colonic mucosa with edema, fibrin-covered ulcers, and loss of vascular pattern.
Why not the others?
A. Pseudomembranes overlying regions of colonic inflammation
This option implies C. difficile pseudomembranous colitis, which causes acute watery diarrhea often after antibiotic use, BUT this patient has chronic bloody diarrhea, weight loss, and IBD serologies, not an acute post-antibiotic illness.
B. Patchy inflammation of mucosa with cobblestone appearance and intervening areas of normal mucosa
This option implies Crohn disease with skip lesions and cobblestoning, which can cause non-bloody diarrhea and often involves terminal ileum, BUT this patient has p-ANCA+, ASCA–, LLQ-predominant symptoms, and a pattern more typical of ulcerative colitis.
D. Normal colonic mucosa
This option implies no significant inflammation or structural disease, which would not explain chronic bloody diarrhea, weight loss, anemia, and systemic inflammatory markers; colonoscopy in IBD is rarely normal during active disease.
E. Numerous polyps extending throughout the colon
This option implies familial adenomatous polyposis (FAP) or severe polyposis syndromes, which present with many adenomatous polyps and often a strong family history, BUT this patient’s presentation is inflammatory with bloody diarrhea and positive p-ANCA, not polyposis-related.
Exam trap
The presence of colon cancer in a grandparent may tempt you toward a polyposis or neoplastic answer, BUT the chronic bloody diarrhea, p-ANCA+, and LLQ pain point to ulcerative colitis with continuous mucosal inflammation, not diffuse polyps or acute pseudomembranes.
The bottom line
Ulcerative colitis: continuous colonic mucosal inflammation, bloody diarrhea, weight loss, positive p-ANCA; colonoscopy shows diffuse erythema, edema, friability, and superficial ulcers.
Source: StepGenie question bank. Questions are written by StepGenie, not taken from NBME or USMLE materials, and are chosen for this page by how students actually performed on them (first-attempt accuracy on StepGenie). Selection last refreshed September 5, 2026.
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Foundation in cellular adaptation, inflammation, neoplasia, and organ-specific pathology. Learn to recognize classic histological patterns and understand disease pathogenesis at the molecular level.
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Are the pathology practice questions on this page free?
Yes. The 5 questions above come from StepGenie's question bank and can be answered here without an account, with the full explanation shown after each one. From the link under the set you can try three more Pathology questions in the dashboard preview, also without an account; a free account is what lets you choose the system and keep going.