Neoplasia II Epidemiology and Clinical Aspects PDF

NEOPLASIA II Epidemiology and Clinical Aspects David N. Lewin, M.D. [email protected] 843-876-5608 OUTLINE: 1. Epidemiology a. Cancer Incidence 2. Factors Predisposing to Malignancy a. Environmental Factors b. Age and Cancer c. Heredity d. Acquired Predisposing Conditions e. Interactions Between Envir...

NEOPLASIA II Epidemiology and Clinical Aspects David N. Lewin, M.D. [email protected] 843-876-5608 OUTLINE: 1. Epidemiology a. Cancer Incidence 2. Factors Predisposing to Malignancy a. Environmental Factors b. Age and Cancer c. Heredity d. Acquired Predisposing Conditions e. Interactions Between Environmental and Genetic Factors 3. Clinical Aspects of Neoplasms a. Local Effects b. Cancer Cachexia c. Hormonal Effects 4. Grading and Staging 5. Pathology Diagnosis of Neoplasms a. Evaluation of Tumors OBJECTIVES: After studying this unit you should be able to: 1. Understand the importance of epidemiology to the origin of cancer. 2. Know the most prevalent cancers and the cancers that cause the most deaths in males and females. 3. Be aware of the important trends over time of cancer death rates for males and females. 4. Understand the impact of age, heredity, and acquired preneoplastic disease in carcinogenesis. 5. Understand how the three basic classes of carcinogens inflict damage. 6. Know the major chemical carcinogens 7. Understand UV radiation damage and the individuals at high risk. 8. Understand the effects of tumors on the host with respect to location, functional activity, cachexia, and paraneoplastic syndromes. page 179 David N. Lewin, M.D. Neoplasia II 9. Know the basics of tumor staging 10. Compare the different morphologic methods of laboratory diagnosis of cancer. 11. Understand the cytogenetic and molecular laboratory methods of cancer diagnosis and prognosis READING REFERENCE: pp. 196-200, 223-241; Robbins Basic Pathology, Tenth Edition page 180 David N. Lewin, M.D. Neoplasia II REVIEW QUESTIONS Select the best answer: ____ 1. Pre-malignant conditions include all of the following conditions EXCEPT: A. B. C. D. E. Cervical squamous dysplasia Chronic alcoholism leading to micronodular cirrhosis of the liver Chronic ulcerative colitis Endometrial hyperplasia following prolonged estrogen therapy Multiple leiomyomas of the uterine myometrium ____ 2. A 29 year old woman with a history of multiple sexual partners over the last 15 years has a routine physical examination with no abnormal findings. On pelvic examination, the cervix shows no abnormalities, but a Pap smear is taken and dysplastic cells are reported to be present. A cervical biopsy is performed and shows microscopic features of a high grade dysplasia involving the cervical squamous epithelium. What is the most appropriate statement to make to the patient: A. B. C. D. E. Antibiotic therapy will be necessary Excision of this lesion insures a good prognosis No further treatment is indicated You have inherited a BRCA-1 mutation You probably have widespread metastases ____ 3. A surgical pathology report indicates that a certain neoplasm is graded as grade I on a scale of I to IV. Clinically, this neoplasm is found to be stage I. These findings imply that this neoplasm: A. B. C. D. E. Has an in situ component Has probably arisen from epithelium May spread via lymphatics Is unlikely to be malignant Is well-differentiated and localized ____ 4. A lump in the right breast is discovered on physical examination of a 48-yearold woman. The mass is 4 cm in diameter and appears fixed to the chest wall. Another 2 cm mass is palpable in the left axilla. A chest radiograph reveals multiple 0.5 to 2 cm nodules in both lungs. Which of the following classifications best indicates the stage of her disease: A. B. C. D. E. T1 N1 M0 T1 N0 M1 T2 N1 M0 T3 N0 M0 T4 N1 M1 page 181 David N. Lewin, M.D. Neoplasia II ____ 5. A 60-year-old man with a 90 pack year history of smoking experiences an episode of hemoptysis. A chest radiograph reveals a 5 cm right upper lobe lung mass. A fine needle aspirate of this mass yields cells consistent with small cell anaplastic ("oat cell") carcinoma. On physical examination he has puffiness of the face, some pedal edema, bruises of the skin, and a blood pressure of 165/100 mm Hg. A bone scan shows no metastases. Immunohistochemical staining of the tumor cells is likely to be positive for: A. B. C. D. E. ACTH Erythropoietin Gastrin Insulin Parathormone related peptide ____ 6. A mass lesion in the right upper lobe of lung found by chest radiograph is removed by wedge resection and sent to Surgical Pathology, where a neoplasm is diagnosed. Which of the following findings is the best predictor of prognosis? A. B. C. D. E. Differentiation Grade Necrosis Location in the lung Stage ____ 7. A 51-year-old man has worked in a factory producing plastic pipe. He has weight loss, nausea, and vomiting. His serum alkaline phosphatase is 405 U/L with AST 67 U/L, ALT 55 U/L, and total bilirubin 1.2 mg/dL. An abdominal CT scan reveals a 12 cm right liver lobe mass. Liver biopsy reveals a neoplasm composed of spindle cells forming irregular vascular channels. The cells demonstrate vimentin positivity and cytokeratin negativity with immunohistochemical staining. Exposure to which of the following substances most likely led to development of this neoplasm: A. Asbestos B. Benzene C. Cyclophosphamide D. Radon E. Vinyl chloride ____ 8. A 22-year-old woman has a palpable nodule in the right lobe of her thyroid gland. A fine needle aspirate of the nodule reveals cells present consistent with a papillary carcinoma of the thyroid. No lymphadenopathy is noted. A chest x-ray shows no masses. There are no other family members affected by this disorder. She works as a secretary for an accounting firm part time and is earning a college degree. Which of the following findings would you consider most relevant in her past history: A. Ataxia telangiectasia B. Blunt trauma from a fall page 182 David N. Lewin, M.D. Neoplasia II C. Chronic alcoholism D. Exposure to arsenic compounds E. Radiation therapy in childhood ____ 9. A 1.2 cm darkly pigmented skin lesion is excised from the dorsum of the right hand of a previously healthy 42 year old man. He noted that this lesion had become larger and darker with more irregular outlines over the past three months. No other skin lesions are noted. Several nontender enlarged lymph nodes are palpable in the right axilla. Which of the following risk factors is most important for development of this neoplasm: A. Allergy to latex gloves B. Cigarette smoking C. Chronic exposure to ultraviolet radiation D. Inheritance of a faulty Rb gene E. Prior job-related asbestos exposure Answers and explanations: 1. E; Objective #4 a. The following are pre-neoplastic conditions that predispose to a variety of cancers: endometrial hyperplasia and endometrial adenocarcinoma, cirrhosis and hepatocellular carcinoma, cervical dysplasia and squamous cell carcinoma, and ulcerative colitis and colon adenocarcinoma. Leiomyomas of the uterus are a benign lesion and not thought to be the precursor lesion of leiomyosarcoma. 2. B; Objective 4 and 10 a. The clinical scenario describes both cytology and biopsy diagnosis of cervical dysplasia (the precursor lesion for squamous cell carcinoma of page 183 David N. Lewin, M.D. Neoplasia II the cervix). High grade dysplastic lesions are unlikely to regress (unlike low grade lesions) and likely to progress to invasive carcinoma over time. These lesions should be excised or ablated to prevent this progress. It is not appropriate to do nothing. Antibiotic treatment would be appropriate for a bacterial infection. The lesion is not yet invasive so there is no risk of widespread metastases. BRCA-1 mutations are typically associated with breast cancer and not cervical cancer (which is associated with HPV infection). 3. E; Objective #9 a. An early stage and low grade neoplasm (grade 1 and stage 1) is by definition well-differentiated and localized to the organ from which it arose. Only malignant neoplasms are staged. Epithelial malignancies are most common, however non-epithelial lesions such as lymphoma and sarcomas are graded and staged. An early stage lesion does not have lymph node involvement. The lesion may or may not have an in-situ component, this is not a component of the grade or stage. 4. E; Objective #9 a. The description is of a breast carcinoma with lymph node and metastatic disease (tumor in the lung). The T stage is based on the size of the tumor and involvement of the chest wall (T4a with chest wall involvement). Thus this would be T4 N1 (lymph node positive) M1 (metastatic disease). Knowing the T stage is not necessary in the way this question is written. 5. A; Objective #5 a. Many tumors produce hormones or other substances to give systemic effects (paraneoplastic syndrome). Small cell carcinoma of the lung can produce ACTH to give a cushing syndrome (as described in the question). Tumor cells produce and will stain for ACTH. 6. E: Objective #9 a. For most tumors, stage is the most powerful predictor of prognosis. 7. E: Objective #6 a. The question describes an angiosarcoma of the liver. These tumors are associated with vinyl chloride which is used as an adhesive for plastics. Benzene is associated with leukemias, radon with lung cancers, asbestos with mesotheliomas. Cyclophosphamide is a anticancer drug that is a direct-acting carcinogen implicated in second malignancies. 8. E: Objective #5 a. Radiation is a risk factor for many cancers, including thyroid cancer. Alcoholism is a risk factor for cirrhosis and liver cancer, ataxia telangiectasia is a disease with defects in DNA repair which has a risk of lymphoma and leukemia. Blunt trauma is not typically a risk factor for cancer. Arsenic is a risk factor for lung, skin and hemangiosarcoma. 9. C: Objective #7 a. The question describes a melanoma of the skin which has metastasized to lymph nodes. The major risk factor of melanoma is chronic ultraviolet radiation (sunlight). Cigarette smoking is related to lung cancer. Latex allergy is not related to any cancer. RB gene inheritance is associated with retinoblastoma. Asbestos is associated with mesothelioma. page 184 David N. Lewin, M.D. Neoplasia II NOTES: page 185 9/7/2022 Neoplasia II: Epidemiology and Clinical Aspects David Lewin, M.D. Medical University of South Carolina 1 9/7/2022 Siegel RL et al. CA Cancer J Clin 2019;0:1-28 Siegel RL et al. CA Cancer J Clin 2019;0:1-28 Trends in Incident Rates 2 9/7/2022 Cancer Incidence https://nccd.cdc.gov/uscs/statevsnational.aspx Rahib L, et al. Cancer Res 1-9, 2014 DOI 10.1158/0008-5472 3 9/7/2022 http://www.scdhec.net/co/phsis/biostatistics /SCCCR/pdfdocs/6yrSCFacts-Fig.pdf 4 9/7/2022 Siegel RL et al. CA Cancer J Clin 2019;0:1-28 Cancer Deaths https://nccd.cdc.gov/uscs/statevsnational.aspx 5 9/7/2022 Siegel RL et al. CA Cancer J Clin 2019;0:128 6 9/7/2022 Trends in Cancer Mortality Rates Siegel RL et al. CA Cancer J Clin 2019;0:128 Trends in Cancer Mortality Siegel RL et al. CA Cancer J Clin 2019;0:1-28 7 9/7/2022 Rahib L, et al. Cancer Res 1-9, 2014 DOI 10.1158/0008-5472 Incidence and Mortality # 14 #36 https://nccd.cdc.gov/uscs/cancersrankedbystate.aspx 8 9/7/2022 Factors predisposing to malignancy    Environmental Age Heredity     Inherited cancer syndromes Familial cancers Syndromes of defective DNA repair Acquired pre-neoplastic conditions http://www.scdhec.n et/co/phsis/biostatist ics/SCCCR/pdfdocs/6 yrSCFacts-Fig.pdf 9 9/7/2022 http://www.scdhec.net/co/phsis/biostatistics/SCCCR/pdfdocs/6yrSCFacts-Fig.pdf OVERVIEW  Three Classes of Carcinogens    Chemical Radiation Viral 10 9/7/2022 CHEMICAL CARCINOGENS   Natural and Synthetic Agents Highly reactive electrophiles (electron deficient)    React with RNA, DNA or cellular proteins Direct –Acting Indirect-Acting CHEMICAL CARCINOGENS 11 9/7/2022 Direct Acting Agents Weak carcinogens Require no chemical transformation    Chemotherapeutic drugs  Alkylating agents    Cyclophosphamide, chlorambucil, nitrosoureas Second malignancy decades later Acylating agents  1-Acetyl-imidazole, Dimethylcarbamyl chloride Indirect Agents  Require metabolic conversion before they become active.    Procarcinogen- initial chemical Ultimate carcinogen: active end product Examples  Polycyclic hydrocarbons: fossil fuels, active epoxides bind DNA   Benz[a]anthracene: skin cancer Benzo[a]pyrene: cigarette smoke- lung cancer 12 9/7/2022 Indirect Agents Continued  Examples  Aromatic amines and azo dyes  Converted in liver by P-450    Nitrosamines and amides   Beta-naphthylamine: Bladder ca in rubber factories Azo dyes: developed for food color Formed endogenously in acid environment of stomach  GI cancers? Aflatoxin B  Aspergillus in grains  Hepatocellular cancer Mechanism of Action of Chemical Carcinogens    Mutagenic  Ras, TP53 mutations Promoter  Augmenting agents by themselves not carcinogenic  Produce cell proliferation  Must follow mutagenic chemical “initiator”  Tetradecanoylphorbolacetate (TPA)  Activate protein kinase C Patients at High risk  Genetic disorders i.e. Genomic instability (HNPCC) 13 9/7/2022 14 9/7/2022 Lung with Carbon Pigment (Black Dots) Malignant Mesothelioma of the Pericardial Sac 15 9/7/2022 Radiation Carcinogenesis  Types of radiation  Ultraviolet rays of sunlight    X-rays    Early developers: skin cancer ENT ca with irradiation: thyroid cancer Nuclear fission   Melanoma, Squamous cell carcinoma, basal cell carcinoma DNA damage by forming pyrimidine dimers Survivors of nuclear bomb: leukemia Radionuclides  Miners: lung cancer  Ionizing radiation: chromosome breakage, translocations and point mutations 16 9/7/2022 Cervical Squamous Cell Carcinoma Low grade dysplasia of cervix 17 9/7/2022 18 9/7/2022 Retinoblastoma (Eye) 19 9/7/2022 Clinical aspects of neoplasms  Local effects    Location, Location, Location Cancer cachexia Hormonal effects  Paraneoplastic syndromes 20 9/7/2022 Lung Carcinoma with obstruction of bronchus Endocrine Tumor 21 9/7/2022 Endocrine Tumor 22 9/7/2022 Grading Tumors  The extent to which the architectural and cellular features of a tumor recapitulate the histology of the parent tissue is termed “grade” 23 9/7/2022 Normal Breast Gland Moderately differentiated Adenocarcinoma 24 9/7/2022 Poorly Differentiated Adenocarcinoma of Breast Staging Tumors  The size and anatomic extent of tumor are components of tumor “stage,” which is of greater clinical value than “grade” when determining prognosis 25 9/7/2022 Most Tumors are now staged with the “TNM” system: T = Tumor size/ extent N = Lymph node status M= Metastasis 26 9/7/2022 An example of gastric cancer http://www.scdhec.net/co/phsis/biostatistics/SCCCR/pdfdocs/6yrSCFacts-Fig.pdf 27 9/7/2022 Pathology Diagnosis of Neoplasms  Requirements:     Proper sampling: Histology or Cytology Appropriate tissue handling and fixation Excellent tissue processing, sectioning and staining Adequate clinical information Evaluation of Tumors  Diagnostic Features   What is the lesion Prognostic  How will the lesion behave 28 9/7/2022 Tools    Clinical Findings Gross Findings Histologic Findings     Immunohistochemical findings Flow cytometry Cytogenetic findings Molecular biologic findings Immunohistochemistry: Application of Antibodies to Tissue  Identification  Intermediate filaments      Cytokeratin = epithelial Vimentin = mesenchymal Desmin = muscle Neurofilament = nerve Glial fibrillary acidic protein (GFAP) = central nervous system  Prognostication/ Treatment  Breast Cancer    Estrogen receptor Progesterone receptor Her2/neu 29 9/7/2022 S-100: Neural tissue 30 9/7/2022 Molecular/ Cytogenetic  Diagnosis of malignancy  Molecular findings help define disease    Prognosis and behavior    BCR-ABL in CML Diagnosis of hereditary predisposition   HER-2/NEU in breast cancer N-MYC in neuroblastoma Detection of minimal residual disease   Philadelphia chromosome in Chronic Myelogenous Leukemia T-cell or B-cell gene rearrangement in lymphoma Germ-line mutation of tumor suppressor genes Therapeutic decision-making  Targeted therapies: V600E BRAF mutations in melanoma respond well to BRAF inhibition drugs 31 9/7/2022 32