Lec 12. Neoplasia I, Dr. Daniel Bonfil- Full Slides PDF

COM 5081 – Fundamentals of Pathology Neoplasia I R. Daniel Bonfil, Ph.D. Professor of Pathology Department of Medical Education Dr. Kiran C. Patel College of Allopathic Medicine [email protected] February 06, 2024 Lecture Outline 1. Define neoplasia. 2. Describe differences between benign and maligna...

COM 5081 – Fundamentals of Pathology Neoplasia I R. Daniel Bonfil, Ph.D. Professor of Pathology Department of Medical Education Dr. Kiran C. Patel College of Allopathic Medicine [email protected] February 06, 2024 Lecture Outline 1. Define neoplasia. 2. Describe differences between benign and malignant neoplasms. 3. Describe main routes of metastatic dissemination. 4. Describe differences between hyperplastic, dysplastic and metaplastic changes. 5. Describe the classification of tumors based on tissue of origin (tumor Nomenclature). 6. Define tumor grade and tumor stage. 7. Describe carcinogenic agents implicated in cancer development. What is a Neoplasm? A neoplasm is a group of cells of common origin that escaped from normal restrains on cell proliferation and show a relatively autonomous growth. Although some neoplasms (e.g., leukemias, ascitic tumors) grow as cell suspensions, most neoplasms grow as solid masses of tissue called tumors. Neoplasia refers to the process of tumor formation. In the modern sense of the term, tumor (from Latin, “swelling”) is used as a synonym of solid neoplasm. However, not all tumors are cancerous. NEOPLASMS BENIGN MALIGNANT = CANCER Grow as a compact mass that remains at the site of origin Penetrate surrounding tissue (invade), and sometimes spread to distant tissues (metastasize) Solid Neoplasms Are Not Made up Only of Tumor Cells All tumors - benign and malignant have two basic components: STROMA PARENCHYMA Parenchyma: neoplastic cells. Stroma: non-neoplastic milieu in which tumor cells grow, including connective tissue, blood vessels, inflammatory cells, and extracellular matrix (ECM). Also know as “tumor microenvironment.” Fibroadenoma of the breast Kumar V, Abbas AK, Aster JC. Robbins & Cotran Pathologic Basis of Disease, 10th ed. Copyright © 2021 by Elsevier, Inc. Main Features Used to Distinguish between Benign and Malignant Tumors a. Differentiation: degree to which neoplastic parenchymal cells resemble the original normal cells of the tissue. b. Invasion: direct extension and penetration by tumor cells into neighboring tissues. c. Metastasis: spread of tumor cells from their primary location to noncontiguous tissues of the body. a. Differentiation in Benign and Malignant Tumors BENIGN MALIGNANT Well-differentiated parenchymal cells (resemble normal tissue of origin). Wide range of parenchymal cell differentiation (well-, poorly-, or un-differentiated). Lack of differentiation = Anaplasia (aka “cellular atypia”) From: Pathology Reference Center. © 2018 Elsevier, Inc. Anaplasia is an irreversible loss of cell differentiation Cytologic evidence of anaplasia includes: Pleomorphism (variation in size and shape of cells) Nuclear abnormalities (increased size, hyperchromatism, prominent nuclei) Atypical mitoses Loss of cellular polarity (loss of recognizable patterns of cell orientation to each other) Cross A. Underwood's Pathology: A Clinical Approach, 7th ed., © 2019 Elsevier Ltd. a. Differentiation in Benign and Malignant Tumors Anaplasia: a Hallmark of Malignancy a. Differentiation in Benign and Malignant Tumors Normal versus Anaplastic Cells: an Example Normal Colon Glands with nuclei of the cells at the periphery, displaced by mucin droplets. Cells and nuclei are uniform in size. Carcinoma of the Colon Disrupted tissue architecture. Cells do not contain mucin droplets. Nuclei have irregular shapes and sizes. Modified from: Loeffler AG, Hart MN,. Introduction to Human Disease: Pathophysiology for Health Professionals, 7th ed. Copyright © 2020 by Jones & Bartlett Learning, LLC b. Invasion BENIGN MALIGNANT - NOT invasive - Often circumscribed to site of origin - Often surrounded by fibroblasts and ECM - INVASIVE, breaching the underlying basement membrane (BM) (or ECM once in stroma) - In neoplasms that arise from cells that do not synthesize a BM, histological assessment of invasion is difficult to be done Degradation of BM; tumor the degrade ECM Modified from: Cross A. Underwood's Pathology: A Clinical Approach, 6th ed., 2013. © 2013 Elsevier Ltd. Carcinoma in situ These lesions display cytologic features of malignancy without invasion of the basement membrane (BM). Currently, the classification of carcinoma in situ as cancer is controversial, since transformed cells do not cross the BM and do not spread to adjacent tissues. Carcinomas in situ are now considered to be premalignant conditions that may not progress or may last for several years before progressing to invasive disease. Cervical “Squamous Intraepithelial Lesion” (SIL) BM intact From: Kumar V, Abbas AK, Aster JC. Robbins Basic Pathology, 10th ed., 2017. © 2018 by Elsevier Inc. c. Metastasis BENIGN MALIGNANT - NEVER metastatic - Can metastasize (disseminate to other sites) Metastatic cancer is named based on the site where the cancer began. The development of metastases (term also used to define secondary tumors resulting from this process) is responsible for 90% of cancer deaths. Three Main Routes of Metastatic Dissemination Routes of metastases exemplified by a cancer of the colon c. Metastasis Lymphatic dissemination: through the lymphatic system to neighboring or distant lymph nodes (typical of carcinomas) Hematogenous dissemination: through the bloodstream to distant organs (typical of sarcomas) Transcoelomic dissemination: direct seeding in body cavities such as peritoneal and pleural cavities (e.g., ovarian cancer, and some lung cancers) Annular Primary tumor Cross A. Underwood's Pathology: A Clinical Approach, 7th ed., © 2019 Elsevier Ltd. Axillary lymph node c. Metastasis Metastatic breast cancer cells Breast carcinoma with lymph node (LN) metastasis dilated lymphatic channel Tumor lies lateral to the nipple. White arrows indicate LNs involved by metastatic carcinoma. Largest arrow shows the first LN involved in the chain (“sentinel lymph node”). The yellow arrow indicate a 3rd LN free of tumor. Modified from: Herrington CS. Muir’s Textbook of Pathology, 15th ed., 2014. Kumar V, Abbas AK, Aster JC. Robbins & Cotran Pathologic Basis of Disease, 10th ed., Copyright © 2021 by Elsevier, Inc. Lymphatic dissemination c. Metastasis Hematogenous dissemination Malignant tumor that invaded the adipose tissue and penetrated into a small vein. Modified from: Strayer DS, Rubin E. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 7th ed., 2014. Copyright © 2018 by Wolters Kluwer. Liver metastases from colorectal cancer (usually with tumors that drain via the portal circulation). Selby K, Hernandez-Alejandro R. CMAJ 186: 1163-6, 2014. © 2014 Canadian Medical Association. Transcoelomic dissemination c. Metastasis Peritoneal carcinomatosis – metastatic ovarian carcinoma Malignant neoplasms that arise in organs adjacent to body cavities (e.g., ovaries, GI and lung) can penetrate into a natural “open field.” Most often involved is the peritoneal cavity. Pleural and pericardial cavities may be affected too. Kumar V, Abbas AK, Aster JC. Robbins & Cotran Pathologic Basis of Disease, 10th ed., Copyright © 2021 by Elsevier, Inc. Tissue Changes that are not Cancer (but may develop into cancer if non-physiological) Hyperplasia. Increased number of parenchymal cells. Tissue is organized and looks normal under a microscope (e.g., hyperplasia of female breast at puberty, pregnancy, or lactation). Dysplastic nevus (mole) Hyperplasia and mild dysplasia are often reversible with cessation of the stimulus or offending factor causing them. From Wikimedia Commons, the free media repository. Dysplasia. Disordered growth of cells that look abnormal under the microscope, mainly on how the tissue is organized (only used for epithelial cells). Tissue Changes that are not Cancer (but may develop into cancer if non-physiological) Increased number of parenchymal cells that look normal Disordered growth of cells that look abnormal https://www.cancer.gov/publications/dictionaries/cancer-terms Tissue Changes that are not Cancer (but may develop into cancer if non-physiological) Normal Breast Duct Benign Ductal Hyperplasia Epithelium that is only two cell layers thick Epithelial cells proliferate and grow into the duct lumen Modified from: Loeffler AG, Hart MN,. Introduction to Human Disease: Pathophysiology for Health Professionals, 7th ed. Copyright © 2020 by Jones & Bartlett Learning, LLC Tissue Changes that are not Cancer (but may develop into cancer if non-physiological) Spectrum from normal to mild-severe dysplasia and SIL in one field Normal Mild dysplasia Moderate dysplasia Severe dysplasia/SIL* *SIL, squamous intraepithelial lesions (carcinoma in situ) Author of this image: Dr. Ed Uthman, Creative Commons Tissue Changes that are not Cancer (but may develop into cancer if non-physiological) Metaplasia. One cell type is replaced by another. Normal glandular epithelium of the stomach Glandular epithelium of the stomach with Goblet cells (arrows) Goblet cells (large, intracytoplasmic vacuole of mucin) are normally found in the intestinal and respiratory tracts. From: companion site for Coleman WB, Tsongalis GJ. Molecular Pathology – The molecular basis of human disease, 2009. © Academic Press. CLASSIFICATION OF TUMORS On the basis of: Biologic behavior and tissue of origin (Nomenclature) Malignancy of tumor (Tumor grade) Tumor size and extension of spread (Tumor stage) TUMOR NOMENCLATURE Cancer is not just one disease, but hundreds of diseases Cancer (like benign neoplasms) can start in virtually any tissue of the body. Cancers are alike in some ways, but they are different in the ways they grow and spread (→ distinct characteristics and prognoses). TUMOR NOMENCLATURE How do We Name Neoplasms? Neoplasms are composed of proliferating neoplastic cells but also contain nonneoplastic supportive stroma (connective tissue and blood vessels). Tumors are named according to the neoplastic component: (Cell type) + (modifier to indicate benign/malignant) + (site of origin) TUMOR NOMENCLATURE Benign Neoplasms arising from Mesoderm Prefix indicating tissue of origin Tissue of origin Fibrous tissue Fat (adipose tissue) Cartilage Bone Blood vessel Smooth muscle Striated muscle Prefix FibroLipoChondroOsteoHemangio- or angioLeiomyoRhabdomyo- All these body tissues derive from the middle primary germ layer known as mesoderm + oma E.g., fibroma lipoma chondroma osteoma hemangioma leiomyoma rhabdomyoma Neoplasms that affect blood cells and lymph nodes (also derived from mesoderm) are always malignant. TUMOR NOMENCLATURE Benign Neoplasms arising from Epithelium Different names based on characteristics of epithelium Type of Epithelium Name Glandular Non-glandular Basal cells of skin Adenoma Papilloma - The name of a papilloma or adenoma is incomplete unless prefixed by the name of the specific epithelial cell type (if papilloma) or glandular origin (if adenoma) Examples: Colonic adenomatous polyps, and thyroid adenomas Most papillomas (e.g., skin and genital warts) are caused by Human papillomavirus (HPV), others (e.g., breast intraductal papillomas) are not. Kumar V, Abbas AK, Aster JC. Robbins Basic Pathology, 10th ed., 2017. © 2018 by Elsevier Inc. TUMOR NOMENCLATURE Malignant Neoplasms arising from Mesoderm Prefix indicating tissue of origin Tissue of origin Fibrous tissue Fat (adipose tissue) Cartilage Bone Blood vessel Smooth muscle Striated muscle Prefix FibroLipoChondroOsteoHemangio- or angioLeiomyoRhabdomyo- + sarcoma E.g., fibrosarcoma liposarcoma chondrosarcoma osteosarcoma hemangiosarcoma leiomyosarcoma rhabdomyosarcoma TUMOR NOMENCLATURE Malignant Neoplasms arising from Epithelium Organ (or referred to organ) + “carcinoma” or “carcinoma of” + organ Examples: Breast carcinoma or carcinoma of the breast Gastric carcinoma or carcinoma of the stomach TUMOR NOMENCLATURE Exceptions to the Tumor Nomenclature Rules Malignant tumors with suffix (instead of sarcoma or carcinoma) –oma Melanoma (in skin), seminoma (testis), mesothelioma (in the lining of the lungs, abdomen, or heart), and lymphoma (lymphoproliferative tumor). Leukemia refers to a malignant proliferation of leukocytes, which does not have an equivalent benign counterpart. Tumors for which an eponym is used Tumors that include the name of the person who first recognized or described the lesion. Examples: Burkitt lymphoma - a B-cell lymphoma associated with the Epstein–Barr virus (EBV) Ewing sarcoma - a malignant tumor of bone Hodgkin disease - a malignant lymphoma (AKA Hodgkin lymphoma) Their names do not provide any hint about their histogenesis. TUMOR NOMENCLATURE ❑ Pleomorphic Tumors Tumors with more than one line of differentiation →distinct subpopulations of cells. Mixed tumor of the parotid gland Classic example: “mixed” tumor of the parotid gland, which contains: ▪ Epithelial components ▪ Myxoid stroma forms cartilage and bone All these components derive from a single neoplastic clone capable of producing both epithelial and mesenchymal cells (this is why the preferred designation is pleomorphic adenoma, rather than mixed tumor) Kumar, V, Abbas AK, Aster JC, Deyrup AT, Das A. Robbins & Kumar Basic Pathology, 11th ed. Copyright © 2023 by Elsevier Inc. TUMOR NOMENCLATURE ❑ Teratomas (benign) and Teratocarcinomas (malignant) Mixed tumors with cells derived from more than one germ layer, and sometimes all three (endoderm, ectoderm, and mesoderm). Cystic teratoma of the ovary Note the presence of hair, sebaceous material, and a tooth ❑ Blastomas Kumar V, Abbas AK, Aster JC. Robbins & Cotran Pathologic Basis of Disease, 10th ed. Copyright © 2021 by Elsevier, Inc. Most are pediatric tumors (usually below 5 years of age). Histologically similar to the embryonic form of the organ in which they arise. Examples: retinoblastoma, which arises in the eye. neuroblastoma, which arises in the adrenal medulla or nerve ganglia. hepatoblastoma, which arises in the liver. CLASSIFICATION OF TUMORS On the basis of: Biologic behavior and tissue of origin Malignancy of tumor (Tumor grade) Tumor size and extension of spread (Tumor stage) Tumor Grade Histologic estimate of malignancy of a tumor Criteria: ◼ Degree of cellular differentiation from low grade (welldifferentiated) to high grade (poorly differentiated/anaplastic) ◼ Number of Mitosis Grading of cancer is important for determining prognosis! - Pathologists often assign a numerical “grade”. There are specific grading systems for different types of cancers - ◼ Degree of cellular differentiation from low grade (well differentiated) to high grade (poorly differentiated/anaplastic) Well-differentiated Adenocarcinoma of the Colon Poorly differentiated Adenocarcinoma of the Colon Glandular structures similar to those in normal mucosa A more solid growth pattern with little evidence of gland formation Cross A. Underwood's Pathology: A Clinical Approach, 7th ed., © 2019 Elsevier Ltd. CLASSIFICATION OF TUMORS On the basis of: Biologic behavior and tissue of origin Malignancy of tumor (Tumor grade) Tumor size and extension of spread (Tumor stage) Tumor Stage (TNM Staging) Clinical estimate of tumor size and extent of tumor spread TNM Staging System criteria: ◼ T refers to primary Tumor size and invasiveness ◼ N refers to spread to regional lymph Nodes ◼ M refers to presence (or not) of distant Metastasis The major staging system currently in use is the American Joint Committee on Cancer (AJCC) TNM system Tumor Stage (TNM Staging) (cont.) T = Primary Tumor TX Cannot be assessed. T0 Cannot be measured. T1, T2, T3, T4 Refers to size and/or invasion. The higher the number, the larger the tumor or the more invasive. N = Regional Lymph Nodes NX Cannot be assessed. N0 No metastases in nearby lymph nodes (LNs). N1, N2, N3 Involvement of increasing number and range of LNs. Higher number after the N , more LNs with cancer. M = Distant Metastasis MX Cannot be assessed. M0 No distant metastases. M1 Distant metastases. TUMOR GRADING AND STAGING (cont.)  Tumor Stage (TNM System) Cross A. Underwood's Pathology: A Clinical Approach, 7th ed., © 2019 Elsevier Ltd. ETIOLOGY OF CANCER: CARCINOGENIC AGENTS 1. Chemical Carcinogens 2. Physical Carcinogens 2. Oncogenic Viruses and Microbes 1. Chemical Carcinogens Chemical carcinogens directly damage DNA, leading to mutations that transform normal cells into cancerous cells. DIRECT-ACTING CARCINOGENS - No metabolic conversion needed to become carcinogenic (e.g., alkylating agents, such as cyclophosphamide). INDIRECT-ACTING CARCINOGENS – Only active when converted by endogenous metabolic systems (such as cytochrome P-450 [CYP] monooxygenases). 1. Chemical Carcinogens (cont.) EXAMPLE OF INDIRECT-ACTING CARCINOGENS Polycyclic aromatic hydrocarbons (PAHs) – can be formed when cooking meats over open flame or very high temperatures metabolized in the body by CYPs and epoxide hydrolase PAH adhere to meat Epoxide (e.g., benzo[a]pyrene) covalent adducts with DNA 1. Chemical Carcinogens (cont.) Multistep process that involves: a) INITIATION - irreversible genetic alteration = mutation) b) PROMOTION –clonal expansion of the mutated cell through induction of cell division ( “fixation” of mutation) – reversible effect From: Kumar V, Abbas AK, Aster JC. Robbins Basic Pathology, 10th ed., 2017. © 2018 by Elsevier Inc. 1. Chemical Carcinogens associated with human cancers Polycyclic Aromatic Hydrocarbons (PAH) – smoke of burned coal, oil, gas, wood, garbage, and tobacco → Lung cancer Chemotherapeutic drugs → Solid and hematological cancers at later time Nitrosamines – can be formed in the stomach from nitrites found in cured sandwich meats, bacon, salami or sausages → Gastric adenocarcinomas Aflatoxin B1 – produced by the fungus Aspergillus flavus in improperly stored grains and nuts → Hepatocellular carcinoma 2. Physical Carcinogens Almost all types of radiations in high doses act as carcinogens, causing double-strand DNA breaks and chromosomal aberrations. IONIZING RADIATIONS (e.g., miners exposed to radioactive elements and survivors of the atomic bombs in Hiroshima and Nagasaki, with significant increase in incidence for thyroid, lung, breast cancers) NON-IONIZING RADIATIONS (e.g., UV radiation from sun and tanning beds, which can cause non-melanoma skin cancers [basal cell carcinomas and squamous cell carcinomas] and melanomas) 2. Physical Carcinogens (cont.) Generation of Pyrimidine Dimers in DNA by UV light Patients with xeroderma pigmentosum have a defect in the “nucleotide excision repair system” that normally eliminates the pyrimidine dimer. These patients have increased predisposition to skin cancer. 3. Oncogenic Viruses and Microbes DNA and RNA viruses have proved to be oncogenic in animals. However, their causative effect in human cancer remains uncertain. HTLV-1 virus is a causative agent of human cancer. Other “oncogenic” viruses are considered to be highly “associated” with neoplasms in humans. 3. Oncogenic Viruses and Microbes (cont.) Retroviruses RNA DNA Promoter gene c-onc (protooncogene) v-onc 1) v-onc is reversed transcribed to DNA 2) c-onc (protooncogene) Modified from: Cross A. Underwood's Pathology: A Clinical Approach, 6th ed., © 2013 Elsevier Ltd. 3. Oncogenic Viruses and Microbes (cont.) Human T-cell lymphotropic virus (HTLV-I) Retrovirus (single-stranded RNA virus) that mainly infects T-cells. Firmly linked to the adult T-cell leukemia/lymphoma (ATLL), endemic in certain parts of Japan and the Caribbean basin. TAX gene of HTLV-1 activates the transcription of genes important for T cell proliferation and differentiation [e.g., c-fos and IL-2 (interleukin-2)]. Spread by breast feeding, sexual intercourse, or blood-blood contact. 3. Oncogenic Viruses and Microbes (cont.) Condyloma acuminatum on cervix of an HPV-infected Pt. Human Papilloma Virus (HPV) DNA viruses with tropism for epithelial cells. Their full cycle only in squamous cells. Over 100 HPV serotypes. About 1/3 associated with genital tract lesions. HPVs 16 and 18 strongly associated with cancer of uterine cervix (HPV 16 also in tumors of oropharynx, tonsils, and larynx). Biopsy of condyloma Sexual intercourse is the most common route of transmission, but also via skin-skin contact (through small tears in skin/mucosa). Some types preventable by vaccine. characteristic koilocytes Modified from: Strayer DS, Rubin E. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 7th ed., 2014. Copyright © 2018 by Wolters Kluwer. 3. Oncogenic Viruses and Microbes (cont.) Human Papilloma Virus (HPV) (cont.) Major oncoproteins of HPV are E6 and E7. They inhibit the effect of tumor suppressor genes (p53 and Rb) facilitating immortalization and proliferation of cells infected. From: Kumar V, Abbas AK, Aster JC. Robbins Basic Pathology, 10th ed., 2017. © 2018 by Elsevier Inc. 3. Oncogenic Viruses and Microbes (cont.) Epstein-Barr Virus (EBV) Member of Herpesviridae family of DNA viruses that transforms B cells in lymphoblasts. 95% of population have Abs against EBV. Others develop self-limited infectious mononucleosis (“kissing disease”). Spread through saliva. EBV is found in Burkitt lymphomas (aggressive Bcell lymphoma) endemic in some areas of Africa, and in 100% of nasopharyngeal carcinomas. from: Strayer DS, Rubin E. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 7th ed., 2014. Copyright © 2018 by Wolters Kluwer. 3. Oncogenic Viruses and Microbes (cont.) Epstein-Barr Virus (EBV) (cont.) In endemic forms of Burkitt lymphoma, EBV would infect B cells by binding to C’ receptor CD21 → B cell proliferation. Concomitant infections (e.g., malaria) could impair immune response (infected B cells are not killed by cytotoxic T lymphocytes) → Some EBV-infected B cell clones persist. EBV is not detected in most sporadic (non-endemic) Burkitt lymphomas, but virtually all endemic and sporadic tumors have t(8;14) or other translocations that dysregulate MYC. Activated MYC oncogene would contribute to B cell oncogenesis independently of EBV infection. From: Kumar V, Abbas AK, Aster JC. Robbins Basic Pathology, 10th ed., 2017. © 2018 by Elsevier Inc. 3. Oncogenic Viruses and Microbes (cont.) Hepatitis B and C Viruses (HBV and HCV) HBV (double-stranded DNA virus), HCV (singlestranded RNA virus). Both viruses associated with development of hepatocellular carcinoma. Chronic inflammation due to virus infection leads to hepatocyte death, followed by regenerative compensation (proliferation) → transformation Another H): virally-encoded HBx gene → protein that interferes with p53 TSG function. Hemorrhagic hepatocellular carcinoma Spread via contaminated blood, semen, body fluids. From: Strayer DS, Rubin E. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 7th ed., 2014. Copyright © 2018 by Wolters Kluwer. 3. Oncogenic Viruses and Microbes (cont.) Kaposi Sarcoma-associated Herpesvirus Double-strand DNA virus, also known as Human Herpes Virus 8 (HHV 8). AIDS-Associated Kaposi Sarcoma Sequences of the virus found in specimens of Kaposi Sarcoma, a vascular neoplasm that is the most frequent tumor in AIDS patients. It encodes proteins that interfere with the function of p53 and Rb TSGs → immortalize and activate proliferation of cells infected. Commonly spread via sexual contact and saliva. HIV(+) patient exhibiting multiple erythematous papules on the thigh. From: Pathology Reference Center. © 2018 Elsevier, Inc. 3. Oncogenic Viruses and Microbes (cont.) Helicobacter pylori Bacillus (bacterium) implicated in the development of gastric adenocarcinoma and gastric lymphoma. Mainly spread through saliva. Potential mechanism involves epithelial proliferation on a background of chronic inflammation (mainly due to ROS). Helicobacter pylori Chronic gastritis Atrophic gastritis Gastric Intestinal metaplasia adenocarcinoma of gastric cells Park SH, Kangwan N, Park JM, Kim EH, Hahm KB. World J Gastroenterol 19: 8986-95, 2013. Thank you!