7. Neoplasia Flashcards
A 40-year-old man has a history of intravenous drug use. Physical examination shows needle tracks in his left antecubital fossa. He has mild scleral icterus. Serologic studies for HBsAg and anti-HCV are positive. He develops hepatocellular carcinoma 15 years later. Which of the following viral characteristics best explains why this patient developed hepatocellular carcinoma?
□ (A) Viral integration in the vicinity of protooncogenes
□ (B) Viral capture of protooncogenes from host DNA
□ (C) Viral-induced injury followed by extensive hepatocyte regeneration
□ (D) Viral inactivation of RB and p53 gene expression
□ (E) Viral infection of inflammatory cells with host immunosuppression
(C) Although the hepatitis B virus (HBV) and hepatitis C virus (HCV) genomes do not encode for any transforming proteins, the regenerating hepatocytes are more likely to develop mutations, such as inactivation of p53. HBV does not have a consistent site of integration in the liver cell nuclei, and it does not contain viral oncogenes. Many DNA viruses, such as human papillomavirus, inactivate tumor suppressor genes, but there is no convincing evidence that HBV or HCV can bind to p53 or RB proteins. Also, the HBV-encoded regulatory element, called HBx, disrupts normal growth of infected hepatocytes. Neither HBV nor HCV infects immune cells.
A 48-year-old woman notices a lump in her left breast. On physical examination, the physician palpates a firm, nonmovable, 2-cm mass in the upper outer quadrant of the left breast. There are enlarged, firm, nontender lymph nodes in the left axilla. A fine-needle aspiration biopsy is performed, and the cells present are consistent with carcinoma. A mastectomy with axillary lymph node dissection is performed, and carcinoma is present in two of eight axillary nodes. Which of the following factors is most likely responsible for the lymph node metastases?
□ (A) Increased laminin receptors on tumor cells
□ (B) Presence of keratin in tumor cells
□ (C) Diminished apoptosis of tumor cells
□ (D) Tumor cell monoclonality
□ (E) Lymphadenitis
(A) Several pathologic mechanisms play a role in the development of tumor metastases. The tumor cells first must become discohesive and detach from the primary site and then attach elsewhere to become metastases. Tumor cells tend to have many more laminin receptors than do normal cells, allowing them to attach more readily to basement membranes at distant sites. Keratin is a marker of epithelial differentiation, not metastatic ability. A reduction in apoptosis allows greater proliferation, but not metastases. Monoclonality is a feature of neoplasia, but further tumor heterogeneity helps to increase the chance for metastases to occur. Inflammation probably does not play a major role in metastasis.
A 30-year-old woman who has had multiple sexual partners sees her physician because she has had vaginal bleeding and discharge for the past 5 days. On physical examination, she is afebrile. Pelvic examination shows an ulcerated lesion arising from the squamocolumnar junction of the uterine cervix. A cervical biopsy is performed. Microscopic examination reveals an invasive tumor containing areas of squamous epithelium, with pearls of keratin. In situ hybridization shows the presence of human papillomavirus type 16 (HPV-16) DNA within the tumor cells. Which of the following molecular abnormalities in this tumor is most likely related to infection with HPV-16?
□ (A) Trapping of the RAS protein in a GTP-bound state
□ (B) Increased expression of laminin receptor genes
□ (C) Inability to repair DNA damage
□ (D) Functional inactivation of the RB1 protein
□ (E) Increased expression of epidermal growth factor receptor
(D) The oncogenic potential of human papillomavirus (HPV), a sexually transmissible agent, is related to products of two early viral genes—E6 and E7. E7 binds to RB protein to cause displacement of normally sequestered transcription factors, which nullifies tumor suppressor activity of the RB protein. E6 binds to and inactivates the p53 gene product. Trapping of GTP-bound RAS protein can occur in many tumors but is not related to HPV infection. Laminin receptor expression correlates with metastatic potential of a malignant neoplasm. Inability to repair DNA damage plays a role in some colon and skin cancers. Increased epidermal growth factor receptor expression is a feature seen in many pulmonary squamous cell carcinomas, and the related ERBB2 (HER2) receptor is seen in some breast carcinomas.
An experiment involving carcinoma cells grown in culture studies the antitumor surveillance effects of the innate immune system. These carcinoma cells fail to express MHC class I antigens. It is observed, however, that carcinoma cells are lysed in the presence of one type of immune cell that has been activated by IL-2. Which of the following immune cells is most likely to function in this manner?
□ (A) CD4+ lymphocyte □ (B) CD8+ lymphocyte □ (C) Macrophage □ (D) Neutrophil □ (E) NK cell □ (F) Plasma cell
(E) Several types of immune cells can recognize and help destroy tumor cells. Tumor antigens that are displayed via MHC class I molecules can be recognized by cytotoxic CD8+ cells. Many cancers do not display their antigens well, however, and when MHC class I molecules are not displayed, NK cells are triggered to target these cells for lysis. Macrophages may work in concert with CD8+ cells and NK cells to phagocytize and kill tumor cells when up-regulated by interferon-γ. CD4+ “helper” cells do not play a direct anticancer role. Neutrophils are ineffective against cancer cells, but may be attracted to areas of tumor necrosis. Plasma cells may produce antibodies directed against tumor antigens, but such antibodies are ineffective in controlling tumors.
A 44-year-old woman sees her physician because she feels lumps in the right axilla. The physician notes right axillary lymphadenopathy on physical examination. The nodes are painless but firm. Which of the following is the most likely diagnosis?
□ (A) Ductal carcinoma of the breast □ (B) Acute mastitis with breast abscess □ (C) Leiomyosarcoma of the uterus □ (D) Cerebral glioblastoma multiforme □ (E) Squamous dysplasia of the larynx
(A) Lymphatic spread, especially to regional lymph nodes draining from the primary site, is typical of a carcinoma. Infection from a breast abscess can spread to the lymph nodes, but the resulting nodal enlargement is typically associated with pain—a cardinal sign of acute inflammation. Sarcomas uncommonly metastasize to lymph nodes. Central nervous system (CNS) malignancies rarely metastasize outside of the CNS. Dysplasias do not metastasize because they are not malignancies.
A 20-year-old man has a raised, irregular, pigmented lesion on his forearm that has increased in size and become more irregular in color over the past 4 months. Physical examination shows a 0.5 × 1.2 cm black-to-brown lesion with irregular borders. An excisional biopsy specimen shows a malignant melanoma that extends into the reticular dermis. Family history indicates that the patient’s paternal uncle died of metastatic melanoma that spread to the liver after excision of a primary lesion on the foot. His grandfather required enucleation of the left eye because of a “dark brown” mass in the eyeball. Which of the following genes is most likely to have undergone mutation to produce these findings?
□ (A) BCL2 (anti-apoptosis gene) □ (B) C-MYC (transcription factor gene) □ (C) IL2 (growth factor gene) □ (D) Lyn (tyrosine kinase gene) □ (E) p16 (cell cycle inhibition) □ (F) p53 (DNA damage response gene) □ (G) PDGF (growth factor overexpression)
(E) This patient has a family history of malignant melanoma. Familial tumors often are associated with inheritance of a defective copy of one of several tumor suppressor genes. In the case of melanomas, the implicated gene is called p16, or INK4a. The product of the p16 gene is an inhibitor of cyclin-dependent kinases. With loss of control over cyclin-dependent kinases, the cell cycle cannot be regulated, favoring neoplastic transformation. BCL2 is present in some lymphoid neoplasms. The C-MYC gene is mutated in various carcinomas, but is not known to be specifically associated with melanomas. TheIL2 mutation is associated with some T cell neoplasms. TheLyn mutation is seen in some immunodeficiency states. p53 mutations occur in many cancers, but not specifically in familial melanomas. PDGF can be overexpressed in some central nervous system gliomas and some osteosarcomas.
A 32-year-old woman has experienced dull pelvic pain for the past 2 months. Physical examination shows a right adnexal mass. An abdominal ultrasound scan shows a 7.5-cm cystic ovarian mass. The mass is surgically excised. The surface of the mass is smooth, and it is nonadherent to surrounding pelvic structures. On gross examination, the mass is cystic and filled with hair. Microscopically, squamous epithelium, tall columnar glandular epithelium, cartilage, and fibrous connective tissue are present. Which of the following is the most likely diagnosis?
□ (A) Adenocarcinoma □ (B) Fibroadenoma □ (C) Glioma □ (D) Hamartoma □ (E) Mesothelioma □ (F) Rhabdomyosarcoma □ (G) Teratoma
(G) A teratoma is a neoplasm derived from totipotential germ cells that differentiate into tissues that represent all three germ layers: ectoderm, endoderm, and mesoderm. When the elements all are well differentiated, the neoplasm is “mature” (benign). Adenocarcinomas have malignant-appearing glandular elements. Fibroadenomas have a benign glandular and stromal component; they are common in the breast. Gliomas are found in the central nervous system. Hamartomas contain a mixture of cell types common to a tissue site; the lung is one site for this uncommon lesion. A mesothelioma arises from the lining of thoracic and abdominal body cavities. A rhabdomyosarcoma comprises cells that poorly resemble striated muscle; most arise in soft tissues.
A 30-year-old man has a 15-year history of increasing numbers of multiple benign skin nodules. On physical examination, the firm nodules average 0.5 to 1 cm and appear to be subcutaneous. Further examination shows numerous oval 1- to 5-cm pigmented skin lesions. Ophthalmoscopic examination shows hamartomatous nodules on the iris. A biopsy specimen of one skin nodule shows a neoplasm that is attached to a peripheral nerve. Which of the following mechanisms of transformation is most likely related to the mutation that this patient has inherited?
□ (A) Persistent activation of the RAS gene
□ (B) Increased production of epidermal growth factor
□ (C) Decreased susceptibility to apoptosis
□ (D) Impaired functioning of mismatch repair genes
□ (E) Inactivation of the RB gene
(A) This patient has clinical features of neurofibromatosis type 1. The NF1 gene encodes a GTPase-activating protein that facilitates the conversion of active (GTP-bound) RAS to inactive (GDP-bound) RAS. Loss of NF1 prevents such conversion and traps RAS in the active signal-transmitting stage. All other listed mechanisms also are involved in carcinogenesis, but in different tumors.
A study of patients treated with chemotherapy protocols for cancer shows that 10% of them subsequently develop a second cancer, a much higher incidence compared with a control group not receiving chemotherapy. These chemotherapy protocols included the alkylating agent cyclophosphamide. What is the most likely mechanism of action by this alkylating agent for development of the subsequent carcinomas in these treated cancer patients?
□ (A) Activation of protein kinase C □ (B) Activation of endogenous viruses □ (C) Blockage of TGF-β pathways □ (D) Direct DNA damage □ (E) Inhibition of DNA repair □ (F) Inhibition of telomerase
(D) Chemical carcinogens have highly reactive electrophile groups that can directly damage DNA, leading to mutations. Direct-acting agents, such as alkylating chemotherapy drugs, do not require conversion to a carcinogen. Some agents, such as polycyclic hydrocarbons, require metabolic conversion to a carcinogen and are called indirect-acting agents. Phorbol esters are examples of promoters of chemical carcinogenesis that cause tumor promotion by activating protein kinase C. This enzyme phosphorylates several substrates in signal transduction pathways, including those activated by growth factors, and the cells divide. Forced cell division predisposes the accumulation of mutations in cells previously damaged by exposure to a mutagenic agent (initiator). The TGF-β pathways work via growth inhibition. Proteins such as p53 that function in DNA repair pathways can become nonfunctional through mutation. Viral infections such as hepatitis B and C tend to promote growth by binding to p53 and inactivating its protective function. Telomerase activity is not affected by carcinogens.
A 50-year-old woman undergoes screening colonoscopy as part of a routine health maintenance workup. An isolated 1- cm pedunculated polyp is found in the sigmoid colon. The excised polyp histologically shows well-differentiated glands with no invasion of the stalk. Which of the following investigational research procedures can distinguish most clearly whether the polyp represents hyperplasia of the colonic mucosa or a tubular adenoma?
□ (A) Histochemical staining for mucin
□ (B) Flow cytometry to determine the frequency of cells in the S phase
□ (C) Determination of clonality by pattern of X chromosome inactivation
□ (D) Immunoperoxidase staining for keratin
□ (E) Immunoperoxidase staining for factor VIII
(C) A true neoplasm is a monoclonal proliferation of cells, whereas a reactive proliferation of cells is not monoclonal. Reactive and neoplastic cellular proliferations may have similar histochemical and immunohistochemical staining patterns based on the type of cells that are present. Flow cytometry is effective at indicating the DNA content, aneuploidy, and growth fraction, but does not indicate clonality.
A 66-year-old woman has worked all of her life on a small family farm on the Kanto plain near Tokyo. She has had no previous major illnesses, but has been feeling increasingly tired and weak for the past year. On physical examination, she is afebrile, but appears pale. Laboratory studies show hemoglobin, 11.3 g/dL; hematocrit, 33.8%; platelet count, 205,200/mm3; and WBC count, 64,000/mm3. Immunophenotyping yields the findings shown in the figure. Assuming that the dominant cell population is clonal, which of the following viral agents is most likely involved in this patient’s disease process?
□ (A) Human papillomavirus □ (B) HIV-1 □ (C) Epstein-Barr virus □ (D) Human T cell lymphotropic virus type 1 □ (E) Hepatitis B virus
(D) The largest cell population, determined to be clonal, is marking for CD4. This patient has a T cell leukemia, which develops in approximately 1% of individuals infected with human T cell lymphotropic virus type 1. Human papillomavirus is best known for causing squamous epithelial dysplasias and carcinomas. HIV-1 infection causes AIDS. Infection with Epstein-Barr virus is associated with various cancers, including Burkitt lymphoma and nasopharyngeal carcinoma. Infection with hepatitis B virus may result in hepatic cirrhosis, in which hepatocellular carcinoma may arise.
A 50-year-old woman saw her physician after noticing a mass in the right breast. Physical examination showed a 2-cm mass fixed to the underlying tissues beneath the areola and three firm, nontender, lymph nodes palpable in the right axilla. There was no family history of cancer. An excisional breast biopsy was performed, and microscopic examination showed a well-differentiated ductal carcinoma. Over the next 6 months, additional lymph nodes became enlarged, and CT scans showed nodules in the lung, liver, and brain. The patient died 9 months after diagnosis. Which of the following molecular abnormalities is most likely to be found in this setting?
□ (A) Inactivation of one BRCA1 gene copy
□ (B) Deletion of one p53 gene copy
□ (C) Amplification of the ERBB2 (HER2) gene
□ (D) Deletion of an RB gene locus
□ (E) Fusion of BCR and C-ABL genes
(C) Increased expression of ERBB2 (HER2) can be detected immunohistochemically in the biopsy specimen. One third of breast cancers may show this change. Such amplification is associated with a poorer prognosis. Detection of a specific gene product in the tissue has value for determination of prognosis. BRCA1 and p53 mutations, if inherited in the germ line, can predispose the patient to breast cancer and other tumors. With BRCA1, there is family history of breast cancer, and p53 mutation predisposes to many types of cancers. An inherited deletion of RB gene predisposes to retinoblastoma. The BCR-ABL fusion product, seen in chronic myeloid leukemia, results from t(9;22).
In a family of five children, a 12-year-old girl and a 14-year-old boy have been affected by skin nodules that have developed over the past 5 years. On physical examination, both children are of appropriate height and weight. The skin lesions are 1- to 3-cm maculopapular nodules that are erythematous to brown-colored and have areas of ulceration. Biopsy specimens of the skin lesions show squamous cell carcinoma. The children have no history of recurrent infections, and their parents and other relatives are unaffected. Which of the following mechanisms is most likely to produce neoplasia in these children?
□ (A) Infection with human papillomavirus
□ (B) Failure of nucleotide excision repair of DNA
□ (C) Ingestion of food contaminated with Aspergillus flavus
□ (D) Inactivation of p53
□ (E) Chromosomal translocation
(B) The children described in the question have an autosomal recessive condition known as xeroderma pigmentosum. Affected individuals have extreme photosensitivity, with a 2000-fold increase in the risk of skin cancers. The DNA damage is initiated by exposure to ultraviolet light; however, nucleotide excision repair cannot occur normally in xeroderma pigmentosum. Human papillomavirus is a sexually transmitted disease that is associated with the development of genital squamous cell carcinomas. Aspergillus flavus, found on moldy peanuts and other foods, produces the potent hepatic carcinogen aflatoxin B1. Inactivation of the p53 tumor suppressor gene is found in many sporadic human cancers and in some familial cancers, but these cancers are not limited to the skin. Chromosomal translocations are often involved in the development of hematologic malignancies, although they are not often seen in skin cancers.
A 55-year-old man visits the physician because of hemoptysis and worsening cough. On physical examination, wheezes are auscultated over the right lung posteriorly. A chest radiograph shows a 6-cm perihilar mass on the right. A fine-needle aspiration biopsy yields cells consistent with non–small cell bronchogenic carcinoma. Molecular analysis of the neoplastic cells shows a p53 gene mutation. Which of the following mechanisms has most likely produced the neoplastic transformation?
□ (A) Inability to hydrolyze GTP □ (B) Microsatellite instability □ (C) Lack of necrosis □ (D) Loss of cell cycle arrest □ (E) Transcriptional activation
(D) The p53 mutation involving both alleles is one of the most common genetic mutations in human cancers, including the most common—lung, colon, and breast cancers. The loss of this tumor suppressor indicates that the cell cycle is not properly arrested in the late G1 phase; when DNA damage occurs, DNA repair cannot be completed before the cell proliferates. Inability to hydrolyze GTP is a result of RAS oncogene activation. Microsatellite instability occurs with mutation in genes, such as hMSH2, that repair DNA damage. BCL2 mutation is one of the best-known mechanisms for apoptotic arrest in neoplasms. Transcriptional activation is a feature of the MYC proto-oncogene.
A 5-year-old child has difficulty with vision in the right eye. On physical examination, there is leukokoria of the right eye, consistent with a mass in the posterior chamber. MR imaging shows a mass that nearly fills the globe. The child undergoes enucleation of the right eye. Molecular analysis of the neoplastic cells indicates absence of both copies of a tumor suppressor gene that controls the transition from the G1 to the S phase of the cell cycle. Which of the following genes is most likely to have the mechanism of action that produced this neoplasm?
□ (A) BCR-ABL □ (B) BCL2 □ (C) hMSH2 □ (D) K-RAS □ (E) NF1 □ (F) p53 □ (G) RB
(G) The RB gene is a classic example of the two-hit mechanism for loss of tumor suppression. About 60% of these tumors are sporadic. Others are familial, and there is inheritance of a mutated copy of the RB gene. Loss of the second copy in retinoblasts leads to the occurrence of retinoblastoma in childhood. Researchers do not know why patients who inherit a mutant RB gene through the germline develop retinoblastoma rather than other types of tumors. The RB gene controls the G1 to S transition of the cell cycle; with loss of both copies, this important checkpoint in the cell cycle is lost. The BCR-ABL fusion gene in chronic myelogenous leukemia is an example of overexpression of a gene product producing neoplasia. The BCL2 gene is an inhibitor of apoptosis. The hMSH2 gene is present in most cases of hereditary nonpolyposis colon cancer and functions in DNA repair. Many cancers have the K-RAS gene, which acts as an oncogene. The NF1 gene product acts as a tumor suppressor; this is a component of neurofibromatosis (which usually does not involve the eye), and the neoplasms typically appear at a later age. Many cancers have the p53 tumor suppressor gene mutation, but this is not typical of childhood ocular neoplasms.
