UWORLD Neoplasia

A 32-year-old woman comes to the office for evaluation of a breast lump. She noticed the lump a few months ago but thinks it might be getting larger. The patient has a history of right lower limb amputation at age 17 due to osteosarcoma. The patient's mother died of an adrenal tumor, and her younger sister died of leukemia. Examination of the left breast shows a 5-cm, firm immobile mass with irregular borders. Which of the following gene mutations is the most likely etiology for this patient's condition? APC BRCA1 NF2 TP53 RB1

A history of sarcoma, leukemia, adrenal, and breast cancer is suggestive of Li-Fraumeni syndrome. Cancers of the brain are also common. The syndrome is the result of an autosomal dominant mutation in TP53, a gene that codes for the tumor suppressor protein p53. Patients with this disorder are genetically predisposed to cancer development at a young age. Patients with Li-Fraumeni syndrome inherit one mutated allele of TP53, but somatic mutation of the second allele is needed for tumor development (2-hit hypothesis). p53 plays an essential role in maintaining the integrity of the human genome by causing cells with mutant DNA to arrest in the G1/S stage of the cell cycle until the damage is repaired. Normally, cells with irreversible DNA damage are not allowed to divide and proceed to apoptosis. Without a functioning p53 protein, the defective cells divide unchecked and become cancerous. (Choice A) The adenomatous polyposis coli (APC) gene mutation is found in patients with familial polyposis syndromes, sporadic colon cancer, and melanomas. APC is responsible for maintaining low levels of β-catenin (oncogenic protein) and for intercellular adhesion. (Choice B) Mutation of the BRCA1 tumor suppressor gene increases the risk for breast and ovarian cancers, and it is the most common hereditary breast cancer. This mutation is not associated with sarcomas, leukemia, or brain tumors. (Choice C) NF2 is a tumor suppressor gene. Mutation of NF2 increases the risk for developing neurofibromatosis type 2. Patients present with bilateral acoustic neuromas (schwannomas of the cerebellopontine angle). Symptoms include bilateral hearing loss, vertigo, and tinnitus. (Choice E) RB1 is a tumor suppressor gene that codes for the Rb protein, which regulates the G1-S checkpoint of the cell cycle. Mutation of RB1 predisposes to the development of retinoblastomas and osteosarcomas, but not breast cancer or leukemia. The 2-hit hypothesis has been proposed to account for hereditary retinoblastoma. Educational objective: Li-Fraumeni syndrome is caused by an autosomal dominant mutation in the tumor suppressor gene TP53. Leukemia, sarcomas, and tumors of the breast, brain, and adrenal cortex are most common.

Name women's cancers from highest to lowest incidence. Cancer 1 has highest incidence, second highest mortality. Cancer 2 has second highest incidence, and highest mortality. Cancer 3 has lowest incidence and mortality

According to 2019 estimates, the most common cancers (excluding basal and squamous cell skin cancer) in women by order of incidence are breast, lung, and colorectal cancer. In terms of mortality, lung cancer claims the most lives, followed by breast and colorectal cancer.

A researcher studying the cell cycle observes a sudden increase in the activity of several enzymes, including dihydrofolate reductase and DNA polymerase. Which of the following processes most immediately precedes the observed increase in enzyme activity? Caspase enzyme cleavage GDP binding to Ras protein p27 protein upregulation Protein kinase A phosphorylation Retinoblastoma protein phosphorylation

An increase in the activity of enzymes responsible for DNA synthesis (eg, dihydrofolate reductase, DNA polymerase) signifies that the cell is in the S phase of the cell cycle. Immediately prior to the S phase is the G1/S checkpoint, in which the cell ensures DNA integrity. Cells with damaged DNA are not allowed to enter the S phase to limit propagation of mutations. Retinoblastoma (Rb) protein is a regulator of the G1/S phase transition. The Rb protein has two forms, active (dephosphorylated) or inactive (phosphorylated). When the cell is stimulated by growth factors, activation of cyclin D, cyclin E, and the corresponding cyclin kinases (CDK 4 and 2) occurs and the Rb protein is phosphorylated (rendering it inactive). Phosphorylated Rb releases the E2F transcription factor, which allows progression through the G1/S checkpoint. After the cell divides, Rb protein is dephosphorylated (active) and remains so until the cell is ready to enter S phase again. In terminally differentiated cells, the Rb protein stays in the dephosphorylated (active) state bound to E2F transcription factors, resulting in inhibited transcription of genes necessary for G1/S transition. Therefore, active Rb protein stops the cell from dividing and allows the cell to enter a quiescent (G0) phase. (Choice A) Caspases are cysteine proteases, enzymes essential for apoptosis. Caspases are not associated with the G1/S transition in the cell cycle. (Choice B) Ras protein is a component of the MAP-kinase signal transduction system. It transmits growth signals from cell surface receptors into the nucleus, leading to the transcription of cyclin D complexes. Although involved in cell cycle progression, Ras protein signaling would occur before phosphorylation of RB protein and would not immediately precede the S phase. (Choice C) The p27 protein is a cell cycle inhibitor. It acts during the G1 phase by inhibiting cyclin-dependent kinases. Normal tissues (composed primarily of differentiated cells) contain high levels of p27, and malignant tissues contain very low levels of p27. Upregulation of p27 would stop the cell cycle. (Choice D) Protein kinase A is a component of the cAMP signaling system. It is not associated with the G1/S transition in the cell cycle. Educational objective: Dihydrofolate reductase and DNA polymerase are enzymes involved in DNA synthesis, which occurs during the S phase of the cell cycle. The Rb protein, in its active (dephosphorylated) form, regulates cell cycle progression by preventing the transition from the G1 phase to the S phase. Phosphorylation of the Rb protein inactivates it, allowing cells to progress through the G1/S checkpoint and proliferate.

A 60-year-old man undergoes lymph node biopsy due to persistent cervical lymphadenopathy. Histologic examination reveals a population of small lymphoid cells arranged in a follicular pattern. The cells demonstrate overexpression of the BCL2 gene. The protein encoded by this gene normally inhibits which of the following processes? Cytochrome c release DNA mismatch accumulation Nuclear transcription RAS-induced signal transduction Telomere shortening

Apoptosis (ie, programmed cell death) is a strictly controlled method of cell death that allows for the degradation and removal of cells without evoking an inflammatory response. BCL2 protein functions as an inhibitor of the intrinsic (ie, mitochondrial) apoptotic pathway. Apoptosis involves triggering a cascade of proteolytic caspase enzymes. In the mitochondrial pathway, caspase activation occurs via the movement of cytochrome c protein from the mitochondrial intermembrane space to the cytoplasm. The BCL2 protein family regulates the ability of cytochrome c to permeate the mitochondrial outer membrane. This protein family includes both proapoptotic members (eg, BAX, BAK), which increase the permeability of the membrane via pore formation, and antiapoptotic members (eg, BCL2, BCL-XL), which preserve membrane integrity and prevent the release of cytochrome c. The characteristic cytogenetic abnormality associated with follicular lymphoma, a mature B-cell lymphoma, is a translocation involving the BCL2 gene on chromosome 18 and the immunoglobulin heavy-chain gene on chromosome 14 [t(14;18)]. This results in overexpression of BCL2 protein, which allows the neoplastic cells to evade apoptosis. (Choice B) Mutations of genes responsible for DNA mismatch repair (eg, MSH2) can be seen in disorders such as hereditary nonpolyposis colon cancer (ie, Lynch syndrome). This condition is characterized by a familial predisposition to colon cancer and other visceral malignancies (eg, endometrial cancer). (Choice C) Retinoblastoma (Rb) is a tumor suppressor protein that regulates cell cycle progression. When active, Rb binds E2F transcription factors, prevents transcription, and blocks progression through the G1/S checkpoint. (Choice D) RAS protein is a component of the mitogen-activated protein (MAP) kinase pathway, a signaling system that regulates cell proliferation via transmission of stimuli from the cell surface receptor to the nucleus. Neurofibromin, encoded by the NF1 gene, is a tumor suppressor protein that inhibits RAS function. (Choice E) Telomeres are DNA sequences found at the ends of chromosomes that are shortened with cellular division, eventually leading to growth arrest. Telomerase is an RNA-dependent DNA polymerase that prevents shortening of telomeres. The majority of cancer cells show increased telomerase activity, thereby avoiding growth arrest and facilitating continuous cell proliferation. Educational objective: BCL2 protein inhibits apoptosis by blocking the release of proapoptotic factors (eg, cytochrome c protein) from the mitochondria. BCL2 is overexpressed in follicular lymphoma secondary to the t(14;18) translocation involving BCL2 and immunoglobulin heavy-chain genes.

What cancer in women has the highest mortality rate?

Between 1950 and 2000, rising rates of tobacco use resulted in an increase in female lung cancer incidence and mortality. Lung cancer is currently the most common cause of cancer death in both women and men in the United States.

A 72-year-old man comes to the office due to progressive weakness, fatigue, anorexia, and a 10-kg (22-lb) weight loss over the past 4 months. He says that food doesn't taste as good as it once did, and he feels full after eating only a small amount. The patient has had a morning cough for the past several years and had streaks of blood in his sputum 2 weeks ago. He has a 50-pack-year smoking history. On examination, the patient appears frail with a sunken face and bitemporal wasting. His arms are thin with notable muscle wasting. Lung examination reveals wheezing on the right side. Chest x-ray reveals an irregular right perihilar mass. Which of the following is most likely contributing to this patient's muscle wasting? Calcium channel autoantibody Interferon-alpha Interleukin-3 Transforming growth factor-beta Tumor necrosis factor-alpha Vasopressin

Cachexia is a syndrome that encompasses anorexia, malaise, anemia, weight loss, and generalized wasting due to underlying systemic disease. Cachexia in this patient is likely a manifestation of the lung neoplasm revealed on his chest x-ray. Tumor necrosis factor-α (TNF-α) is a cytokine that causes necrosis of some tumors in vitro and produces symptoms of cachexia in experimental animals. TNF-α is also called cachectin and is considered a main mediator of paraneoplastic cachexia (along with interleukin [IL]-1β, and IL-6). TNF-α is produced by macrophages in response to infection as well as by some neoplastic cells. Its role in cachexia is explained by its influence on the hypothalamus, leading to appetite suppression. It also increases basal metabolic rate. In bacterial infections, TNF-α produces fever (along with IL-1), mediates many of the symptoms of septic shock, and causes hepatic release of acute-phase reactants (eg, C-reactive protein and fibrinogen). (Choice A) Eaton-Lambert syndrome is a paraneoplastic condition that manifests as progressive, symmetric proximal muscle weakness (rather than wasting) along with ocular and autonomic symptoms. It is due to autoantibodies to voltage-gated calcium channels. (Choice B) Interferon-α is synthesized by leukocytes and has antiviral as well as anti-tumor activity. (Choice C) IL-3 is produced by activated CD4+ TH cells. It stimulates growth and differentiation of myeloid cells. (Choice D) The main function of transforming growth factor-β is inhibition of the inflammatory response. It decreases T cell proliferation and cytokine production. (Choice F) Production of vasopressin by some tumors (eg, small cell lung cancer) results in the syndrome of inappropriate antidiuretic hormone secretion. Educational objective: Tumor necrosis factor-α is thought to mediate paraneoplastic cachexia in humans by suppressing appetite and increasing basal metabolic rate.

A 54-year-old man comes to the office due to a neck mass that has been slowly growing over the past 3 months. The mass is not painful. The patient has had no associated fever or chills but has lost weight. He has no chronic medical conditions and takes no daily medications. He has smoked a pack of cigarettes per day for the last 30 years and has used alcohol occasionally. Physical examination reveals a 2-cm, hard, left-sided supraclavicular lymph node. Biopsy of the lymph node reveals anaplastic cells that are diffusely positive for cytokeratin immunohistochemical stain. Which of the following is the most likely origin of the cells detected on the biopsy? Endothelial cells Epithelial cells Fibroblasts Lymphocytes Melanocytes Muscle cells

Cytokeratins are proteins that form the intermediate filaments (IFs) in epithelial cells. IFs are stable fibers that extend across the cell cytoplasm and connect to anchoring proteins (eg, desmosomes, hemidesmosomes) in the plasma membrane, therefore supplying cells with structural support to withstand mechanical forces. The proteins that compose IFs vary based on tissue type. Detecting antigens that are specific to certain tissues can help characterize the origin of neoplastic cells in undifferentiated tumors (ie, anaplastic tumor cells that do not morphologically resemble their cell of origin). For this reason, immunohistochemical stains targeting IF proteins are often used to classify tumors. Positivity for cytokeratinstain suggests that a tumor has epithelial origin (eg, carcinoma). Other IF proteins that can be targeted to determine a tumor's cell of origin include the following: Desmin: Muscle cell origin (Choice F) Glial fibrillary acidic protein: Glial origin Neurofilament: Neuronal origin Vimentin: Mesenchymal (eg, fibroblast) origin (Choice C) (Choice A) Tumors of endothelial origin (eg, angiosarcoma) are typically positive for CD31 (ie, platelet endothelial cell adhesion molecule-1 [PECAM1]), which participates in leukocyte transmigration, and von Willebrand factor, which binds platelets. (Choice D) Lymphoid neoplasms (eg, lymphoma) frequently express CD45, a glycoprotein found on most hematopoietic cells. Lymphomas can be further classified based on expression of B-cell markers (eg, CD20) or T-cell markers (eg, CD3). (Choice E) Melanocytic neoplasms (eg, melanoma) typically express S100 (protein in cells of neural crest origin), SOX10 (transcription factor in cells of neural crest origin), and HMB-45 (marker of premelanosomes). Educational objective:The proteins that compose intermediate filaments (IFs) vary based on tissue type. Cytokeratins are a type of IF protein found in epithelial cells. Positive staining for cytokeratin in tumor cells suggests that a tumor has epithelial origin (eg, carcinoma).

A 36-year-old woman comes to the office after she noticed some lumps under her arm while getting dressed. She says she feels fine and has no other symptoms. Her medical history is significant for hypothyroidism. Family history is negative. On physical examination, her body mass index is 24 kg/m2. Breast examination shows nontender left axillary lymphadenopathy. The patient is sent for an ultrasound-guided biopsy. Microscopy of the tissue specimen shows clumps of cells that have positive immunohistochemical staining for cytokeratin. These cells most likely belong to which of the following lineages? Epithelial Lymphoid Mesenchymal Myeloid Neuroendocrine

Cytokeratins are proteins that help form the keratin-containing intermediate filaments that make up the cytoskeleton of almost all epithelial cells. Keratin proteins are highly abundant in exposed stratified squamous epithelium such as the epidermis and oral mucosa and are less abundant but still present in simple epithelium such as that found in the liver, gut, and pancreas. As a result, cytokeratin is a commonly used immunohistochemical marker for epithelial-derived tumors, such as breast cancer. Keratin is also the major protein component of hair and nails. Keratin is composed of large amounts of alanine and glycine that, because of their small structure, are able to coil tightly and form large numbers of hydrogen bonds. In addition, keratin contains a significant amount of the sulfur-containing amino acid cysteine, and formation of disulfide bonds between cysteine residues gives additional rigidity and toughness to the protein. (Choice B) CD20 is a marker used to identify B lymphocytes, and CD3 is used to identify T lymphocytes. (Choice C) Vimentin is an intermediate filament present in mesenchymal tissue and can be used to detect sarcomas. (Choice D) Myeloperoxidase is a peroxidase enzyme that can be used as a marker for myeloid cells such as those in acute myeloid leukemia. (Choice E) Chromogranin A and synaptophysin are markers used for neuroendocrine tumors. Educational objective: Cytokeratin is a commonly used immunohistochemical marker of epithelial cell carcinomas.

Rats subjected to chronic inhalation exposure of formaldehyde develop nasal squamous cell carcinomas. Decreased activity of which of the following genes is likely to be found on cytogenetic studies of the tumor cells? brc-abl Ras Erb-B2 p53 N-myc

Decreased activity of a tumor suppressor gene would predispose to neoplasms. Of the choices listed, p53 is the only tumor suppressor gene. In normal individuals, p53 regulates cell proliferation. It acts during phase G1 of the cell cycle to detect abnormalities of the cellular genome. If there is damaged DNA, p53 will prevent the cell from progressing to mitosis, causing the cell to be arrested in the G1 phase. If the DNA can be repaired, the cell will subsequently be allowed to divide, but if the damage is so severe that repair is impossible, the cell will proceed instead to apoptosis. p53 is nicknamed "the molecular policeman" because of its important role in guarding the integrity of genetic material. (Choice A) The bcr-abl fusion gene is a product of translocation of genetic material from chromosome 9 to chromosome 22 [t(9;22)]. It codes for a protein with tyrosine kinase activity. The bcr-abl translocation is the Philadelphia chromosome found in chronic myelogenous leukemia. (Choice B) The ras proto-oncogene codes a protein that participates in signal transduction (MAP-kinase associated pathway). Over-expression of this gene leads to increased sensitivity of cells to mitogenic stimuli. This mutation occurs in a large number of cancers. (Choice C) The Erb-B2 gene encodes a protein with tyrosine kinase activity related to the epidermal growth factor receptor. Over-expression of this proto-oncogene is associated with breast and ovarian cancers. (Choice E) Expression of the N-myc proto-oncogene is amplified in neuroblastoma. Educational Objective: p53 is a tumor suppressor gene that controls cell division and apoptosis. It is inactivated in many tumors.

A 68-year-old man comes to the office due to an enlarging mole on his right forearm. The patient is a retired farmer and received a significant amount of sun exposure over the course of his life. On examination, he has a black-brown macular lesion on the dorsum of his right forearm measuring approximately 1 cm in diameter with an irregular border. Excisional biopsy is performed and histopathology reveals malignant melanoma. Immunohistochemical analysis indicates that the malignant cells have decreased integrin expression. These cells are most likely to exhibit poor adhesion to which of the following components of the extracellular matrix? Actin Fibronectin Hyaluronic acid Keratan sulfate Keratin

Diagram on UWORLD: 1872 Cellular adhesion is the means by which one cell binds to another cell, surface, or matrix. The integrins are a family of transmembrane protein receptors that interact with the extracellular matrix by binding to specific proteins, including collagen, fibronectin, and laminin. Other adhesion molecule classes include the cadherins, selectins, and Ig superfamily members. Fibronectins are large glycoproteins produced by fibroblasts and some epithelial cells. Fibronectin binds to integrins, matrix collagen, and glycosaminoglycans, serving as a mediator of cell adhesion and migration. Differential expression of integrin subtypes affects adhesion properties of individual cells, and correlates with malignant behavior in a number of tumors, including melanoma. (Choices A and E) The intracellular domains of the integrins interact with a number of structural proteins, including microfilaments (actin) within the cytoplasm and intermediate filaments (keratin). However, the extracellular domains do not interact with these structures. (Choices C and D) Hyaluronic acid is a glycosaminoglycan that contributes to water retention in the extracellular matrix, and determines the stiffness of the matrix. Keratan sulfate is a glycosaminoglycan in the extracellular matrix that may play a role in maintaining type I collagen fibril organization in a number of tissues (eg, cornea). However, neither of these is a ligand for integrins. Educational objective: Adhesion of cells to the extracellular matrix involves integrin-mediated binding to fibronectin, collagen, and laminin. Differential expression of integrin subtypes affects adhesion properties of individual cells, and has been found to correlate with malignant behavior in a number of tumors.

A 61-year-old man comes to the office due to 4 months of easy fatigability, anorexia, and a 4.5-kg (10-lb) unintentional weight loss. His stool occult blood testing is positive, and laboratory studies show microcytic hypochromic anemia. Colonoscopy reveals a 6-cm (2.4-in) mass in the descending colon. Biopsy samples obtained during the procedure are consistent with adenocarcinoma. A subsequent CT scan of the abdomen shows multiple metastatic liver lesions. Therapy with monoclonal antibodies that bind to epidermal growth factor receptors on the malignant cells is considered. An activating mutation in which of the following will most likely make this therapy ineffective? Adenomatous polposis coli protein KRAS protein p53 protein Platelet-derived growth factor Vascular endothelial growth factor

Epidermal growth factor receptor (EGFR) is stimulated in a paracrine or autocrine fashion by its ligands, leading to the downstream activation of KRAS, a membrane-bound GTP-binding protein that stimulates cellular growth and proliferation. Many cancers (eg, colorectal, pancreas) leverage this system to drive unchecked cellular growth by overexpressing EGFR and its ligands or by developing constitutive activating mutations in the KRAS proto-oncogene. The EGFR signaling system can be targeted for cancer treatment through the use of monoclonal antibodies (eg, cetuximab, panitumumab) that block EGFR, leading to reduced KRAS stimulation and decreased cellular growth. However, this treatment is only effective for tumors with wild-type (normal) KRAS. Tumors with KRAS-activating mutations are resistant to anti-EGFR agents as they have a constitutive activation of a downstream signal that is independent of EGFR stimulation or blockade. Prior to the use of anti-EGFR agents, genetic testing of tumor tissue is performed to see if KRAS is wild-type (eligible for treatment) or mutated (noneligible). (Choice A) Adenomatous polyposis coli is a tumor suppressor protein that helps degrade beta-catenin, preventing uncontrolled cell growth. Inherited inactivating gene mutations are responsible for familial adenomatous polyposis. (Choice C) p53 is a tumor suppressor protein involved in DNA repair, apoptosis, and cell cycle control; mutations or deletions are present in a large percentage of human tumors. (Choice D) Platelet-derived growth factor stimulates formation of new blood vessels and proliferation of fibroblasts and smooth muscle cells by binding to a receptor tyrosine kinase; mutations resulting in overexpression encourage tumor growth by promoting uncontrolled angiogenesis. (Choice E) Vascular endothelial growth factor (VEGF) is the dominant growth factor involved in angiogenesis and lymph vessel development. Overexpression of VEGF promotes tumor vascularization, facilitating the growth and metastasis of cancers. Educational objective: Activating mutations of the KRAS gene lead to constitutive activation of the epidermal growth factor receptor (EGFR) pathway, promoting increased cell proliferation and growth. Tumors harboring these mutations are resistant to treatment with anti-EGFR drugs (eg, cetuximab, panitumumab).

A 47-year-old woman, gravida 2 para 2, comes to the office after noticing a pea-sized lump in her right breast while taking a shower. Her medical history is significant for 3 pack-years of cigarette use during her 20s. She underwent infertility treatment and in vitro fertilization for both of her pregnancies. The patient has no family history of breast or ovarian cancer. A clinical breast examination confirms the presence of a firm, fixed nodule in the right breast with a small patch of overlying puckered skin. Mammogram findings are highly suspicious for malignancy, and a needle biopsy reveals infiltrating ductal carcinoma. A right mastectomy and axillary lymph node dissection are scheduled. Overexpression of which of the following markers is most likely to be associated with aggressive disease in this patient? BCL-2 Estrogen receptor HER2 Mutated p53 Progesterone receptor

Human epidermal growth factor receptor 2 (HER2, also called ERBB2) is a member of the epidermal growth factor receptor family. It is overexpressed in 20%-30% of breast cancers. HER2 is a transmembrane glycoprotein with tyrosine kinase activity that acts to increase cell proliferation. It is present in diminutive amounts in normal breast and ovarian cells. In breast cancer, HER2 overexpression (positivity) is associated with poorly differentiated, rapidly growing tumors. Clinically, HER2 status is used to predict therapeutic response to anti-HER2 monoclonal antibodies (eg, trastuzumab). (Choice A) Overexpression of the anti-apoptotic BCL-2 protein is classically observed in follicular lymphomas, but it also occurs in a variety of other malignancies, including breast cancer. Unlike in lymphomas, increased expression of BCL-2 in breast cancer is associated with a favorable prognosis. (Choices B and E) Breast cancers that express high levels of estrogen and/or progesterone receptors are typically associated with improved outcomes. Activation of these receptors acts as a stimulus for tumor growth. Therefore, anti-estrogen therapy (eg, aromatase inhibitors, tamoxifen) is used to treat hormone receptor-positive breast cancer. (Choice D) Overexpression of a mutated form of p53 is found in many human cancers, including breast cancers. However, the degree of protein expression does not correlate well with clinical outcomes. Rather, the effects on prognosis are more dependent on the specific mutation (eg, nonsense, gain of function). Educational objective: Estrogen- or progesterone-receptor positivity in breast cancer indicates expected sensitivity to tamoxifen and aromatase inhibitor treatment. HER2 overexpression in breast cancer suggests a more aggressive tumor that typically responds to therapy with the anti-HER2 monoclonal antibody trastuzumab.

A 28-year-old woman comes to the office after finding a lump in her right breast. Her mother died from ovarian cancer at age 34 and her maternal aunt died from breast cancer at age 32. After an appropriate workup, the patient is diagnosed with breast cancer. This patient most likely inherited a mutation in a gene normally responsible for which of the following processes? Angiogenesis Apoptosis suppression DNA repair Intercellular adhesion Signal transduction

Most breast cancer cases occur sporadically in women age >50. Hereditary breast cancer should be suspected in patients diagnosed at a young age, patients with ≥2 primary breast and/or ovarian cancers, and individuals with multiple family members affected by early-onset breast or ovarian cancer. Most cases of hereditary breast and ovarian cancer are associated with mutations in the tumor suppressor genes BRCA1 and BRCA2. Tumor suppressor genes are involved in multiple processes, including: DNA repair Cellular differentiation Checkpoint control of the cell cycle Transcription factor regulation BRCA1 and BRCA2 are involved in repair of double-stranded DNA breaks. Mutations in BRCA1 and BRCA2 result in genetic instability, predisposing cells to an increased risk of malignant transformation. Both BRCA mutations are inherited in an autosomal dominant manner with variable penetrance. Affected women have a 70%-80% lifetime risk for developing breast cancer. Moreover, their lifetime risk of developing ovarian cancer is also increased by up to 40%, although the BRCA2 gene is less likely to lead to ovarian cancer. (Choice A) Angiogenesis is an essential factor in the growth of tumors due to their rapid rate of division and high metabolic demands. Although they stimulate angiogenesis by increasing production of substances such as vascular endothelial growth factor, tumors frequently outgrow their blood supply and become necrotic in the center. (Choice B) Apoptosis refers to programmed cell death in response to irreparably damaged DNA or misfolded proteins. Malignant cells in chronic lymphocytic lymphoma upregulate the protooncogene BCL2, which stabilizes the mitochondrial membrane, thereby preventing cytochrome C leakage, caspase activation, and apoptotic death. (Choice D) Intercellular adhesion is impaired in the majority of malignant tumors, which allows portions of the tumor to break off and metastasize. Adhesion molecules such as E-cadherin are also responsible for transduction of growth signals important for normal tissue growth and regeneration; disruption of intercellular adhesion signaling can promote unchecked cellular proliferation. (Choice E) A large number of malignancies are associated with aberrant signal transduction. For example, overexpression of HER2 (a receptor tyrosine kinase involved in growth signal transduction) causes the development of certain types of aggressive breast cancer. Unlike BRCA1 and BRCA2, HER2 mutations are acquired, not inherited. Educational objective: Hereditary breast cancer is most commonly associated with mutations in BRCA1 and BRCA2. These tumor suppressor genes are involved in DNA repair, and their mutations increase the risk of developing breast and ovarian cancer.

A 35-year-old woman, gravida 1 para 0, at 20 weeks gestation comes to the office for a routine prenatal visit and fetal anatomy ultrasound. The ultrasound reveals several abnormalities. An amniocentesis is performed and a fetal karyotype analysis is ordered; the results are shown in the image below (image shows trisomy 21) This fetus is at greatest risk for developing which of the following conditions after birth? Acute lymphoblastic leukemia Aplastic anemia Chronic myelogenous leukemia Germ cell tumor Retinoblastima Rhabdomyosarcoma

This karyotype shows trisomy 21 (47, XY, +21), which is diagnostic for Down syndrome. This condition usually results from meiotic nondisjunction in the ovum, with advanced maternal age (age ≥35) as a risk factor. Prenatal diagnosis is often suspected based on associated ultrasound findings, including a thickened nuchal fold, cardiac septal defects, and/or gastrointestinal abnormalities (eg, duodenal atresia). Down syndrome is the most common genetic cause of intellectual disability. In addition, Down syndrome significantly increases the risk of childhood hematologic malignancies, including acute lymphoblastic leukemia (most common leukemia in patients with Down syndrome) and acute megakaryoblastic leukemia. The pathogenesis of the increased leukemia risk is uncertain, but may involve increased chromosome 21 gene expression promoting overall genomic instability. (Choice B) Patients with Fanconi anemia, not Down syndrome, develop bone marrow failure (aplastic anemia) due to an inherited mutation that causes defective DNA repair. Karyotype analysis would be normal in this condition. (Choice C) Chronic myelogenous leukemia is commonly associated with a reciprocal translocation between the long arms of chromosomes 9 and 22 (ie, Philadelphia chromosome). This translocation fuses the BCR gene on chromosome 22 to the ABL gene on chromosome 9, resulting in formation of the oncogenic BCR-ABL fusion gene. Unlike this case, karyotype analysis would show elongation of chromosome 9 and shortening of chromosome 22. (Choice D) Turner syndrome (45, XO) and Klinefelter syndrome (47, XXY) increase the risk of ovarian germ cell tumors and extragonadal germ cell tumors, respectively. This patient's karyotype is inconsistent with these diagnoses, and germ cell tumors are not increased in patients with Down syndrome. (Choices E and F) Incidence of retinoblastoma, which is associated with a retinoblastoma (RB1) gene mutation, and rhabdomyosarcoma is not increased in patients with Down syndrome. Educational objective: Trisomy 21 (which is diagnostic for Down syndrome) is detectable by cytogenetic karyotype analysis. Patients are at increased risk of developing hematologic malignancies, including acute lymphoblastic leukemia and acute megakaryoblastic leukemia.

A 55-year-old Caucasian male is found on colonoscopy to have a solitary mass in his sigmoid colon. Biopsy is consistent with colon cancer, and surgery is scheduled. Which of the following features would carry the worst prognosis in this patient? Presence of clinical symptoms Tumor penetration into the muscularis propria Poor differentiation of tumor cells High degree of tumor cell aneuploidy High numbers of mitotic figures

The extent of tumor expansion is characterized by the stage of a tumor. The degree of tumor differentiation (from well-differentiated to anaplastic) is referred to as the grade. Tumor stage is the most important criteria for determining prognosis. If the tumor is confined to the mucosa (stage A), the patient has 90%+ chance of 5-year survival. If it involves the muscular layer, 5-year survival rate is 70-80%. Lymph node involvement (stage C) and distant metastasis (stage D) have poor prognosis. (Choice A) Colon adenocarcinomas tend to be asymptomatic at early stages, which is why screening colonoscopies are so important. By the time symptoms appear, tumor size is substantial. Clinical manifestations, however, do not correlate as well with prognosis as the stage of an adenocarcinoma does. (Choices C, D and E) Tumor cell differentiation, degree of aneuploidy, and number of mitotic figures determines the grade of the tumor. Remember that stage is more important than grade in determining the prognosis of colon cancer. Educational Objective: Prognosis of colorectal adenocarcinoma is directly related to the stage of the tumor (not to the grade!).

23-year-old man comes to the emergency department due to 4 days of cramping abdominal pain. He has been feeling weak for the past 2 weeks. He tried over-the-counter antacids without relief. He is an industrial laborer with no significant medical history or known allergies. The patient's parents have hypertension, and his siblings are healthy. Temperature is 37.1 C (98.8 F). Physical examination is unremarkable. The patient's peripheral blood smear is shown on the image below. Picture shows microcytic, hypochromatic and basophilic stippling on erythrocytes. Which of the following is the most likely cause of this patient's symptoms? Acute intermittent porphyria Acute leukemia Atrophic gastritis Metal poisoning Non-Hodgkin lymphoma Poor nutrition

This patient likely has lead poisoning. In the United States, lead poisoning (plumbism) is typically a pediatric condition that results from children ingesting lead-containing paint chips. However, lead poisoning can also occur in adults. Affected individuals are usually miners or industrial workers (especially those in battery manufacturing) who inhale particulate lead while working. Adults with lead poisoning present with weakness, abdominal pain, and constipation. In severe cases, there may be neurologic manifestations (eg, headache, cognitive symptoms, peripheral neuropathy). On physical examination, patients may have blue "lead lines" at the junction of the teeth and gingivae. The classic diagnostic finding on peripheral blood smear is coarse basophilic stippling on a background of hypochromic microcytic anemia. Basophilic stippling results from the abnormal degradation of ribosomal RNA (due to lead-induced inhibition of a nucleotidase). The hypochromic microcytic anemia results from inhibition of δ-aminolevulinate dehydratase (δ-ALA dehydratase) and the resultant reduced incorporation of iron into heme. The net effect of these defects is decreased hemoglobin synthesis. (Choice A) Acute intermittent porphyria can cause attacks of abdominal pain (without abdominal tenderness) due to autonomic neuropathy. Erythropoiesis is not affected, and the peripheral blood smear is normal. (Choice B) Myeloblasts containing cytoplasmic Auer rods on peripheral blood smear are a characteristic finding of acute myelogenous leukemia. (Choice C) The autoimmune destruction of gastric parietal cells and/or intrinsic factor cause atrophic (autoimmune) gastritis, which can lead to pernicious anemia due to vitamin B12 malabsorption. (Choice E) Non-Hodgkin lymphoma can invade the bone marrow, causing myelophthisic anemia. A peripheral blood smear would show leukoerythroblastosis (immature granulocytes and nucleated teardrop-shaped erythrocytes). (Choice F) Malnutrition may lead to folate deficiency or, more rarely, vitamin B12 deficiency. Deficiencies of either vitamin cause megaloblastic anemia, with hypersegmented neutrophils and large erythrocytes on peripheral blood smear. Educational objective: Coarse erythrocyte basophilic stippling and microcytic hypochromic anemia are common peripheral blood smear findings in lead poisoning. High-risk groups include young children ingesting paint chips and industrial workers inhaling particulate lead.

A 52-year-old man comes to the office due to a progressively enlarging neck mass, fatigue, and weight loss over the past 2 months. Physical examination shows enlarged, firm, and nontender cervical lymph nodes. The patient also has enlarged tonsils, bilateral axillary lymphadenopathy, and splenomegaly. Excisional lymph node biopsy reveals diffuse sheets of atypical, large B cells that have replaced the normal tissue architecture. In situ hybridization of the tissue specimen is positive for Epstein-Barr virus. Which of the following risk factors is most strongly associated with development of this patient's condition? Advanced HIV infection Aspirin and NSAID use Cigarette smoke Radiation exposure Socioeconomic status

This patient likely has non-Hodgkin lymphoma (NHL). Depending on the subtype, NHL may present with a rapidly progressive mass, lymphadenopathy, splenomegaly, and B symptoms (eg, night sweats, weight loss). Diagnosis is typically made with excisional lymph node biopsy, which usually demonstrates a loss of normal tissue architecture with expansion of abnormal lymphocytes (most often B cells, as in this patient with large, atypical B cells). Lymphoma is frequently associated with Epstein-Barr virus (EBV), a ubiquitous herpesvirus that primarily infects B lymphocytes and causes persistent latent infections. Although viral reactivation is uncommon, the latent EBV genome still transcribes viral gene products that can result in malignant transformation of infected cells. EBV is particularly associated with nasopharyngeal carcinoma, Hodgkin lymphoma, and some forms of NHL (eg, Burkitt lymphoma). Educational objective: Patients with HIV have much higher rates of lymphoma than the general population. Many cases are due to underlying Epstein-Barr virus infection, which acts synergistically with HIV to promote uncontrolled B lymphocyte proliferation.

A 62-year-old man is evaluated for worsening cough, shortness of breath, and episodic hemoptysis over the past 6 months. The patient has also had a 15-kg (33-lb) weight loss over the same period without any change in his diet or activity level. He has a 50-pack-year smoking history and does not use alcohol or illicit drugs. BMI is 18 kg/m2. The patient appears cachectic with temporal wasting and generalized loss of muscle mass. Chest x-ray reveals a large lung mass with mediastinal lymphadenopathy and pleural effusion. Which of the following cellular processes is most likely responsible for this patient's muscle loss? Covalent attachment of ubiquitin to muscle proteins Plasma membrane rupture with leakage of cellular contents Plasma membrane instability due to defective dystrophin Progressive shortening of chromosomal telomeres Reprogramming of undifferentiated mesenchymal cells

This patient who has a 50-pack-year smoking history and a mediastinal mass likely has muscle atrophy due to cancer-related cachexia. Cachexia is a hypermetabolic state driven by elevated pro-inflammatory cytokines (eg, tumor necrosis factor-alpha, interleukin-6), which stimulate the ubiquitin-proteasome pathway to degrade skeletal muscle proteins (eg, actin, myosin). The ubiquitin-proteasome pathway is the major eukaryotic mechanism for selective proteolysis (the destruction of targeted proteins). The addition of ubiquitin multimers to a target protein marks it for rapid destruction by the proteasome, whereby the protein is unfolded within the proteasome core and chopped into small oligopeptides. These oligopeptides can be further degraded by cytosolic peptidases into individual amino acids. Other proteolytic pathways play a less prominent role in the degradation of muscle tissue. Lysosomes, membrane-bound organelles that contain proteases and other digestive enzymes, are primarily tasked with breaking down extracellular components that are brought into the cell via endocytosis and with slowly recycling obsolete cytosolic organelles and debris. (Choice B) Necrosis is characterized by cellular injury and premature death due to external factors such as infection, toxin, or trauma. It is often characterized by irreparable damage to the cellular membrane with subsequent leakage of cellular contents. (Choice C) Both Duchenne and Becker muscular dystrophies are caused by X-linked mutations to the dystrophin gene. Dystrophin provides mechanical stability to muscle cells during contraction. Mutations are associated with membrane tears that allow calcium to enter the cell and cause myofiber damage. (Choice D) Telomeres are DNA-protein structures at the end of chromosomes that shorten with each cell division. When telomeres shorten beyond a certain point, the cell undergoes apoptosis or senescence. (Choice E) Reprogramming of undifferentiated mesenchymal cells (eg, connective tissue) is a form of metaplasia. Metaplasia is characterized by the substitution of one differentiated cell type for another differentiated cell type not normally found in that tissue (eg, bone formation in muscle tissue after muscle injury). Educational objective: The ubiquitin-proteasome pathway mediates targeted protein degradation, which allows for rapid disposal of unneeded intracellular proteins. In cancer-related cachexia, high levels of pro-inflammatory cytokines lead to increased ubiquitination of sarcomeric muscle proteins, which in turn leads to extensive skeletal muscle loss.

A 23-year-old man comes to the office due to a left-sided jaw mass that has rapidly enlarged over the past several weeks. The patient is an immigrant from East Africa. He has no known medical problems and takes no medications. Temperature is 37.1 C (98.8 F). Physical examination shows a large left-sided tumor on his jaw with associated lymphadenopathy but no erythema or warmth. The rest of the examination is unremarkable. HIV testing is negative. The lesion is biopsied, and numerous mitotic figures and apoptotic bodies are observed on histopathologic examination. Which of the following genetic features is most likely to be present in the abnormal tissue? BCL2 overexpression BCR-ABL1 fusion BRAF mutation MYC overexpression RET mutation

This patient with a rapidly enlarging jaw mass likely has endemic (ie, African-type) Burkitt lymphoma, of which jaw involvement is a characteristic feature. Burkitt lymphoma is a mature B-cell malignancy associated with overexpression of the MYC protooncogene, which encodes a transcription factor that regulates cell growth. Approximately 80% of Burkitt lymphoma cases are associated with translocation of MYC on chromosome 8 to the immunoglobulin heavy chain region of chromosome 14 [t(8;14)]. This translocation leads to MYC overexpression and uncontrolled tumor cell growth, resulting in rapid mass enlargement. Histologically, Burkitt lymphoma is characterized by a sea of medium-sized, basophilic (ie, blue) lymphoid cells with numerous mitotic figures (indicating brisk proliferation) and apoptotic bodies. Scattered tingible body macrophages, which digest the apoptotic debris, create the characteristic "starry sky" appearance. Although very aggressive, Burkitt lymphoma responds well to short-term, intensive, high-dose chemotherapy. (Choice A) In follicular lymphoma, t(14;18) results in overexpression of the BCL2 gene, which encodes an antiapoptotic protein. Follicular lymphoma causes generalized lymphadenopathy and tends to affect the elderly. A rapidly enlarging jaw mass would be very unusual. (Choice B) The BCR-ABL1 fusion gene, the characteristic abnormality seen in chronic myeloid leukemia (CML), produces a constitutively active tyrosine kinase that results in uncontrolled proliferation of granulocytes. Patients with CML typically have nonspecific symptoms (eg, fatigue) and leukocytosis, not a rapidly enlarging jaw mass. (Choice C) The BRAF protooncogene encodes a protein kinase in the mitogen-activated protein kinase (MAPK) signaling pathway. Activating BRAF point mutations lead to cell proliferation and are associated with hairy cell leukemia (eg, splenomegaly, cytopenia) and melanoma. (Choice E) The RET protooncogene encodes a receptor tyrosine kinase involved in cell growth, and mutations can result in constitutive activation. RET mutations are associated with medullary thyroid carcinoma and multiple endocrine neoplasia type 2. Educational objective: Burkitt lymphoma is usually associated with translocations of the MYC gene on chromosome 8 to the immunoglobulin heavy chain region of chromosome 14 [t(8;14)], resulting in MYC overexpression. It presents with a rapidly growing mass (eg, jaw) and is histologically characterized by a "starry sky" appearance, with numerous mitotic figures and apoptotic bodies.

A 73-year-old man comes to the office due to blood in his urine. He has noted bright red blood at the end of micturition on several occasions but has had no urinary frequency or pain with urination. The patient has a history of hypertension and chronic bronchitis. He has smoked a pack of cigarettes daily for 30 years. Temperature is 37 C (98.6 F). Abdominal, external genital, and rectal examinations are unremarkable. Urinalysis shows hematuria. Urine cytology is positive for malignant cells. Cystoscopy is planned for visualization and biopsy of suspected urinary tract cancer. Which of the following features would be most suggestive of a poor prognosis? High-grade intraepithelial lesion Involvement of the muscularis propria layer Location at the anterior bladder wall Papillary morphology Tumor size >2cm

This patient with a significant smoking history has developed painless gross hematuria, which raises suspicion for bladder cancer. Urothelial (transitional cell) carcinomas arising from the transitional epithelium lining the bladder (ie, urothelium) are the most common type of bladder cancer; squamous cell and adenocarcinomas may occur but are significantly less common. Urothelial cancer typically grows as an erythematous papillary, nodular, or sessile mass and is easily diagnosed on cystoscopy. Microscopy may show cells resembling normal bladder epithelium but with irregular architecture, pleomorphism, hyperchromatic nuclei, and atypical mitoses. Tumor stage is the most important factor for determining prognosis in urothelial carcinoma and is based on the depth of invasion into the bladder wall and the degree of spread to other tissues. Tumor penetration through the lamina propria into the muscularis propria layer (indicating stage T2 or higher in the Tumor, Node, Metastasis [TNM] system) carries an unfavorable prognosis. (Choice A) Tumor grade, or the degree of cellular abnormality, also influences prognosis but to a lesser extent than staging. High-grade intraepithelial lesions (eg, urothelial carcinoma in situ), despite their high degree of cellular abnormality, have a relatively favorable prognosis as they have not yet invaded the basement membrane. (Choice C) Urothelial tumors at the bladder neck may have an elevated risk of recurrence, but, in general, tumor location within the bladder has only a minor effect on prognosis. (Choice D) Tumors with papillary morphology are more likely to extend into the bladder lumen rather than penetrate into the bladder wall. However, these tumors can become invasive, and papillary morphology itself does not directly influence prognosis. (Choice E) Larger tumors are associated with worse prognosis; however, depth of tumor invasion is a much more important prognostic factor than tumor size. Educational objective: Urothelial (transitional cell) carcinoma is the most common type of bladder cancer. Tumor stage is the most important factor for determining prognosis and is based on the depth of invasion into the bladder wall and the degree of regional (eg, lymph nodes) and metastatic spread. Tumor invasion into the muscularis propria layer of the bladder wall carries an unfavorable prognosis.

A 24-year-old recent Russian immigrant describes a long history of weight loss, night sweats and nagging cough. Imaging and biopsy of his lungs reveal numerous apical granulomas with central caseous necrosis. Surrounding the necrotic areas are large cells with abundant pale cytoplasm. Which of the following surface markers is most specific for those cells? CD4 CD7 CD8 CD14 CD20

This patient's history of night sweats, weight loss, and cough with the finding of apical pulmonary granulomas showing caseous necrosis is highly suggestive of active tuberculosis. The caseating granulomas of tuberculosis consist of large epithelioid macrophages with pale pink granular cytoplasm surrounding a central region of necrotic debris. The most specific cell surface marker of the monocyte-macrophage cell lineage is CD14, which binds to bacterial lipopolysaccharide. The caseating granulomas of tuberculosis are almost always surrounded by large epithelioid macrophages with pale pink granular cytoplasm. CD14 is a surface marker specific to the monocyte-macrophage cell lineage.

A 4-year-old girl is brought to the clinic due to an inward deviated right eye. Examination shows a pale red reflex in the right eye relative to the left eye. Dilated funduscopic examination reveals a well-circumscribed white mass within the retina. Genetic analysis shows a germline mutation in the patient's cells leading to development of the mass. Which of the following is the most likely function of the protein affected by this patient's gene mutation? Activation of receptor tyrosine kinase Conversion of GTP to GDP Opposition of p53 activity Prevention of the G1/S cell cycle transition Repair of damaged DNA

This patient's pale red reflex and well-circumscribed white mass within the retina are indicative of retinoblastoma. Retinoblastoma is an intraocular tumor caused by inactivating mutations affecting the RB1tumor suppressor gene with subsequent dysregulation of the cell cycle. The cell cycle consists of the following stages: Gap phase 0 (G0 phase) is a resting stage in which the cell cycle is suspended. Interphase is the stage in which the cell prepares for division. Interphase is subdivided into the G1 phase (synthesis of RNA, protein, lipid, and carbohydrate), S phase (DNA replication), and the G2 phase (ATP synthesis). Mitosis (M) is the stage in which the cell divides into two daughter cells. Checkpoints occur at the G1/S and G2/M transitions, allowing the cell cycle to be stopped if damaged DNA is detected by cyclins and cyclin-dependent kinases. DNA repair mechanisms are activated, but if the DNA damage is too substantial, the cell undergoes apoptosis. The RB1 gene encodes the Rb protein that regulates the G1/S checkpoint. In its active form, Rb protein binds and inhibits E2F transcription factors, thereby halting the cell cycle. In contrast, when a cell is ready to divide, Rb protein is phosphorylated by cyclin-dependent kinases, allowing the cell to proceed through the G1/S checkpoint. Loss-of-function mutations affecting the Rb protein result in unrestricted progression through the G1/S checkpoint, leading to uncontrolled cell division. Inciting RB1 mutations have been linked to retinoblastoma and osteosarcoma. (Choice A) Many receptor tyrosine kinases have stimulatory effects on cell growth, and increased receptor activity occurs with a variety of cancers. For example, overexpression of EGFR and MET are associated with non-small cell lung cancer, and HER2 is associated with breast cancer. (Choice B) Abnormal K-Ras GTPase function due to a KRAS mutation prevents the conversion of GTP to GDP, which results in constant activation of the MAPK pathway and uncontrolled cellular proliferation. KRAS mutations are associated with lung and colorectal cancers, not retinoblastoma. (Choice C) Tumor suppressor protein p53 arrests the cell cycle at the G1/S checkpoint if DNA damage is detected and initiates cell apoptosis if DNA repair fails. Mutations of p53 are associated with most cancers, particularly Li-Fraumeni syndrome (sarcoma, breast, leukemia, and adrenal cancers). Rb and p53 proteins are both critical components of tumor suppression pathways, and their normal function complements one another to prevent cancer progression. (Choice E) BRCA1 and BRCA2 are two of many DNA repair genes that have been identified. When mutated, these genes are associated with an increased risk of breast and ovarian cancer. Educational objective: Retinoblastoma is associated with inactivating mutations of the RB1 tumor suppressor gene, which normally restricts cells from passing the G1/S checkpoint until the cell is ready to divide. Impaired function of the Rb protein allows unrestricted progression through the G1/S checkpoint, leading to uncontrolled cell division.

A 34-year-old woman comes to the office due to vague abdominal pain over the past several months. She has no significant past medical history. The patient does not use tobacco or alcohol. Temperature is 36.7 C (98.1 F). On physical examination, right upper quadrant fullness is present. Abdominal imaging reveals a dense liver mass. Angiography shows a well-demarcated, highly vascularized tumor surrounded by normal liver parenchyma. Which of the following substances most likely contributed the most to blood vessel development in this patient's tumor? Epidermal growth factor Fibroblast growth factor Insulin-like growth factor Interferon-gamma Interleukin-1

his patient has a highly vascularized liver tumor, possibly a benign hepatic hemangioma. Many cases are discovered incidentally. Angiogenesis (blood vessel formation) is predominantly driven by the following 2 substances: Vascular endothelial growth factor (VEGF): VEGF stimulates angiogenesis in a variety of tissues (normal, chronically inflamed, healing, or neoplastic). As VEGF increases endothelial cell motility and proliferation, new capillaries begin to sprout. Fibroblast growth factor (FGF): FGF-2 is produced by a wide range of cells and is involved in endothelial cell proliferation, migration, and differentiation. FGF-2 also appears to play an important role in embryogenesis by stimulating angioblast production. As a group, FGFs not only contribute to angiogenesis, but also to embryonic development, hematopoiesis, and wound repair (by recruiting macrophages, fibroblasts, and endothelial cells to damaged tissues). However, the laminin in basement membranes may pose a physical barrier to the sprouting of new blood vessels. (Choice A) Epidermal growth factor (EGF), not to be confused with VEGF, has a mitogenic influence on epithelial cells, hepatocytes, and fibroblasts. EGF does not appear to play as important a role in angiogenesis as VEGF or FGF-2. (Choice C) Insulin-like growth factor 1 (IGF-1), or somatomedin C, is synthesized predominantly by growth hormone-influenced hepatocytes and serves to stimulate cell growth and multiplication. IGF-1 does not appear to directly stimulate angiogenesis, but it can indirectly promote it by encouraging cell growth. (Choices D and E) Although the proinflammatory nature of interleukin-1 (IL-1) can induce the release of other proinflammatory cytokines that trigger cellular VEGF expression, IL-1 does not appear to directly stimulate angiogenesis. Similarly, although interferon-γ can indirectly promote neovascularization through activation of macrophages (can release VEGF), it does not appear to directly stimulate angiogenesis. Educational objective: The key growth factors that promote angiogenesis in neoplastic and granulation tissue are vascular endothelial growth factor (VEGF) and fibroblast growth factor. Proinflammatory cytokines (eg, interleukin-1, interferon-γ) can indirectly promote angiogenesis through increased VEGF expression. The laminin in basement membranes may pose a physical barrier to the sprouting of new blood vessels.