Neoplasia.pdf

Neoplasia John Baker, M.D.  Objectives Define the following terms: neoplasia, neoplasm, cancer, tumor, benign, malignant. Discuss nomenclature and classification of neoplasms. Discuss clinical and morphologic differences between benign and malignant tumors Discuss clin...

Neoplasia John Baker, M.D.  Objectives Define the following terms: neoplasia, neoplasm, cancer, tumor, benign, malignant. Discuss nomenclature and classification of neoplasms. Discuss clinical and morphologic differences between benign and malignant tumors Discuss clinical risk factors for cancer, and the most common cancer sites in men, women, and children.  Objectives Recognize and discuss the “multi-step” nature of carcinogenesis at the molecular level Define and discuss various types of cancer genes and the mutation mechanisms that give rise to them List and explain the eight physiologic hallmarks of cancer cells. Discuss how malignant neoplasms are graded and staged. Discuss diagnostic techniques for cancer  Cancer Second leading cause of death in the U.S. 2020 projections (ACS): 1.8 million new cases 600K deaths Not a single disease, but a class of diseases  Neoplasia—Overview One of the basic pathologic processes that leads to disease Neo=new plasia/plasm=growth Growth of tissue which is autonomous and clonal (arising from a single cell) Neoplasia is the process Neoplasm is the result “Neoplasm” vs. “tumor” Technically, “tumor” means swelling (not necessarily neoplastic), but in common usage tumor and neoplasm are interchangeable  Types of neoplasms Classification based on clinical behavior and pathologic examination Benign Clinically innocuous tumors Closely resemble tissue of origin Do not invade or metastasize Malignant (“Cancer”) Demonstrates invasion and/or metastasis Wide range of clinical severity Other (less than 5 percent)  Benign Neoplasms Nomenclature: usually designated by suffix –oma. Adenoma (glandular tissue) Lipoma (adipose tissue) Leiomyoma (smooth muscle) Teratoma (germ cells) Fibroadenoma, mixed tumor (glandular and mesenchymal tissue) Colon Tubular Adenoma Lipoma Leiomyoma Mature Cystic Teratoma (Dermoid Cyst)  Benign Neoplasms Clinical Significance Cosmesis (skin and soft tissue tumors) Functionality (endocrine tumors) Differentiation from malignant neoplasms Impingement on vital structures (atrial myxoma, meningioma)  Benign “Neoplasms” Hamartoma, Choristoma Hamartoma—Proliferation of tissue types native to organ of origin Pulmonary hamartoma—bronchial cells, smooth muscle, cartilage Choristoma—Proliferation of one or more tissue types not usually seen in site of origin Osseous choristoma in soft tissue Pancreatic choristoma in stomach Uncertain whether neoplastic or hyperplastic  Malignant Neoplasms Differentiation: extent to which tumor microscopically resembles tissue of origin Benign and low grade malignant tumors are usually well differentiated High grade malignant tumors are poorly differentiated or undifferentiated Anaplasia: Extreme degree of undifferentiation Invasion and metastasis All malignant tumors display at least local invasion of adjacent tissue, and have the potential for metastasis.  Malignant Neoplasms Nomenclature Carcinoma: arising from epithelial tissue Adenocarcinoma Squamous cell carcinoma Urothelial Carcinoma Sarcoma: arising from mesenchymal (connective) tissue Liposarcoma Leiomyosarcoma Carcinosarcoma: both epithelial and mesenchymal elements  Malignant Neoplasms Nomenclature exceptions Lymphoma (malignant lymphoma), leukemia, and myeloma Melanoma (malignant melanoma) Mesothelioma (malignant mesothelioma) Hepatoma (hepatocellular carcinoma) Seminoma/dysgerminoma (germ cells)  Malignant tumors Invasion Invasion of adjacent tissue (primary tumor) Microscopic invasion of adjacent stroma Grossly apparent invasion of other parts of organ or area Invasion of adjacent organs Colon Adenocarcinoma Colon Adenocarcinoma Invasion Lung Carcinoma Femur Osteosarcoma  Malignant Tumors Metastasis Defined as spread of tumor to physically discontinuous site Lymphatic metastasis Often to regional lymph nodes Preferred route for most carcinomas Hematogenous metastasis Via blood vessels, usually to distant sites Preferred route for sarcomas, although also seen in distant carcinoma metastasis Body cavity metastasis: diffuse seeding of peritoneal or pleural cavities by adjacent tumors  Colon Carcinoma with Lymph Node Metastasis Metastatic Carcinoma to Liver Metastatic Carcinoma Body Cavity Seeding  “Other” Neoplasms Tumors that fall in between benign and malignant Usually show invasion or body cavity seeding, but lack potential for lymphatic or hematogenous metastasis Examples: “Borderline” (low malignant potential) ovarian tumors Some soft tissue tumors  Noninvasive (in situ) Carcinoma and Dysplasia Composed of cells with neoplastic morphologic and molecular features that have not invaded or metastasized High risk for development of invasive carcinoma Examples: Ductal carcinoma in situ (DCIS) of breast Anogenital squamous intraepithelial lesions Papillary urothelial carcinoma Cancer Epidemiology and Risk Factors  Cancer Incidence by Site (U.S. 2020 Projections) MEN (n=894,000) WOMEN (n=913,000) Prostate (21%) Breast (30%) Lung (13%) Lung (12%) Colon/Rectum Colon/Rectum (9%) (8%) Bladder (7%) Uterus (7%) Melanoma (7%)  Cancer Deaths by Site (U.S. 2020 Projections) MEN (n=321,000) WOMEN (n=285,000) Lung (23%) Lung (22%) Prostate (10%) Breast (15%) Colon/Rectum Colon/Rectum (9%) (9%) Pancreas (8%) Pancreas (8%)  Cancer in Children Most Common Sites Leukemia Brain/CNS Bone/Soft Tissue Lymphoma  Cancer Risk Factors Environmental Hereditary/Genetic Hormonal Predisposing conditions Age  Environmental Risk Factors Probably most important Chemical, radiation, and infectious agents Increase risk of cancer by causing DNA damage Geographic variation in some cancers Gastric carcinoma Hepatocellular carcinoma Insular thyroid carcinoma  Chemical Carcinogens Tobacco and Alcohol Lung, Liver, Head/Neck, Pancreas, Bladder carcinomas Synergistic effect Occupational/environmental carcinogens Asbestos, Radon, Benzene, Arsenic, Formaldehyde, etc.  Other Carcinogenic Factors Infectious agents (predominantly oncogenic viruses) Human Papillomavirus (HPV) (anogenital and oropharyngeal cancer) Epstein-Barr virus (EBV) (Burkitt lymphoma, nasopharyngeal carcinoma) Radiation (melanoma, thyroid cancer, postradiation sarcoma) Diet  Hormonal Risk Factors Tumors of reproductive or endocrine organs Endometrial carcinoma Breast carcinoma Prostate carcinoma Thyroid carcinoma  Predisposing Conditions Liver Cirrhosis Atrophic Gastritis Pagets Disease of Bone Familial Adenomatous polyposis (FAP) Ulcerative Colitis Barrett’s Esophagus Familial Adenomatous Polyposis  Multistep carcinogenesis -- Normal cell-cancer precursor cell (initial mutation(s) -- Cancer precursor cell-cancer cell (additional mutations) -- Cancer cell-clinically apparent tumor (additional mutations, subclones)  Cancer Genes  When mutated, give rise to (or predispose to) tumor development  Mutations may be acquired or inherited  Inherited genes:  BRCA (breast, ovarian)  MEN (multiple endocrine neoplasia)  RB (retinoblastoma)  Cancer Genes--Types  Oncogenes  Promote cell growth  Proto-oncogene—normal gene from which oncogene arises  Tumor suppressor genes  Slow or prevent tumor growth  Mutation causes decrease or loss of activity  Apoptosis regulating genes  Types of mutations  Driver mutations: directly affect function of a gene  Passenger mutations: Do not directly contribute to carcinogenesis, but:  More numerous than driver genes  May be present in specific pattern that identifies a carcinogen  May affect response to therapy  Mechanisms of mutation  Point mutations  Alteration of one or a few DNA nucleotides, leading to alteration in protein structure  Chromosomal abnormalities  Alteration in chromosome structure  Sometimes specific to a particular tumor  May be detected with cytogenetic testing  Types of chromosomal abnormalities  Gene Rearrangement  Chromosomal translocations or inversions  Often highly specific to a tumor  8:14 translocation in Burkitt lymphoma  Philadelphia chromosome (Ph) in chronic myeloid leukemia (9:22)  Numerous soft tissue tumors  Types of Chromosome Abnormalities  Gene Amplification  Production of multiple (more than 2) copies of a gene, resulting in:  Overexpression of gene product  Visibility of amplified genes on testing  Examples:  HER2 in breast cancer  N-MYC in neuroblastoma Gene Amplification  Types of Chromosome Abnormalities  Deletion: Loss of part of a chromosome  Aneuploidy: alteration in number of chromosomes  Physiologic Hallmarks of Cancer Cells  Growth self-sufficiency  Insensitivity to growth inhibitory factors  Altered metabolism  Evasion of apoptosis  Unlimited replication potential (immortality)  Sustained angiogenesis  Ability to invade and metastasize  Ability to evade host immune systems  Growth Self-Sufficiency  Growth factors  Malignant tumors make their own growth factors  Growth factor receptors often amplified or overexpressed  Epidermal growth factor receptor (EGFR) in lung and head/neck cancers  HER2 in breast cancer  Other (“downstream”) factors (e.g., RAS)  Transcription factors and cyclins  Drive DNA synthesis  Insensitivity to Growth Inhibitory Factors  Loss of cell cycle control  Mutation of RB, p16, CDK4, cyclin D)  Mutation in TP53 gene  p53 protein promotes repair of, and prevents replication of, damaged DNA  Altered Cell Metabolism  “Aerobic glycolysis” (Warburg effect)  Generation of ATP from glucose by glycolysis (fermentation) in the presence of oxygen  Seen in both cancer cells and in normal, rapidly growing cells  Provides metabolic intermediates for growth in addition to ATP  Causes markedly increased glucose uptake  Evasion of Apoptosis  Inhibition of activation of intrinsic (mitochondrial) apoptosis mechanism  Loss of p53 activity and/or increase in MDM2 activity  Decreased mitochondrial release of cytochrome c due to increased activity of anti-apoptotic factors  Decreased activity of caspases  Unlimited Replication Potential  Cancer cells, unlike normal cells, can replicate/divide indefinitely  Insensitivity to normal aging mechanisms  Increased telomerase activity  Aided by loss of RB and p53 activity  Sustained Angiogenesis  Malignant tumors generate their own blood supply (“neovascularization”)  Supply of nutrients and oxygen  Secretion of growth factors by neovascular endothelium  Stimulation of angiogenesis factors and suppression of angiogenesis inhibitors  Tissue Invasion  Loosening of connections between tumor cells  Degradation of basement membrane  Locomotion/spread through invaded tissues  Invasion of Vasculature and Metastasis  Malignant tumors frequently gain access to vessels, but clinically significant metastatic disease is not as frequent  Patterns of metastasis  Lymph node  Hematogenous (distant)  Body cavities Evasion of Immune Systems  Tumor cells are (or should be) recognized and destroyed by cytotoxic T lymphocytes (CTLs) by CTL recognition of surface tumor antigens.  Evasion mechanisms:  Alteration of antigenic expression  “Immune checkpoint” proteins that inactivate CTLs (e.g., PD-L1) Clinical Features of Cancer  Cachexia  Loss of body fat and body mass in cancer patients  Not related to calorie demands of the tumor  Paraneoplastic syndromes  Clinical findings coexisting with a malignant tumor that are not directly derived from the tumor or tissue of origin  10-15 percent of cancer patients (usually advanced or clinically aggressive tumors)  May be presenting symptom  May alone cause significant morbidity/mortality Most common paraneoplastic syndromes  Cancer hypercalcemia  Ectopic hormone secretion by tumor  Most commonly ACTH production by small cell lung carcinoma  Hypercoagulability  Venous thrombosis  Thrombotic endocarditis  Grading and Staging of Cancer  Grading: Microscopic assessment of degree of differentiation of a cancer  Staging: Clinical, gross, and microscopic assessment of extent of invasion and/or metastasis of a cancer  Treatment and prognosis usually based more on staging than on grading  Tumor Grading  In general, high grade vs low grade  Low grade: very differentiated, microscopically looks very much like tissue of origin  High grade: poorly differentiated or undifferentiated, looks nothing like tissue of origin  Variable number of “intermediate” grades  Anaplasia: very undifferentiated, “ugly” tumor  Follicular Carcinoma (low grade) Normal Thyroid Anaplastic Carcinoma (high grade) Anaplasia  Tumor Grading  Often reported as “Grade x/y”  X is the grade, y is number of possible grades  Grade 4/4 is high grade. Grade 2/4 is moderately low grade  A few tumors have defined, criteria based grading systems  Gleason system—prostate (most clinically relevant)  FIGO system—endometrium  Nottingham system—Breast  Fuhrman system—kidney  Tumor Staging  “TNM” staging system  Used by American Joint Committee on Cancer (AJCC)  Three main parameters:  Extent of primary tumor invasion (T stage)  Extent of lymph node metastasis (N stage)  Extent of distant metastasis (M stage)  Overall tumor stage (usually, 1 thru 4) based on TNM data  Can be based on either clinical (c prefix) or pathologic (p prefix) criteria  Tumor Staging  T stage  Based on tumor size and/or extent of invasion of primary organ or adjacent tissue/organs  Usually T1, T2, T3, or T4  N stage  Based mostly on number and/or location of metastatic nodes  NX, N0, N1, N2, N3  M stage: Usually M0 or M1 Lung Cancer Staging Criteria  Tumor Staging Example-Lung  A 62 year old man has a lung tumor which, on core needle biopsy, is squamous cell carcinoma. A lobectomy and mediastinal lymph node sampling is performed. The tumor grossly measures 1.5 cm in size and is confined to the lung lobe with negative margins. Several examined mediastinal lymph nodes are microscopically free of tumor.  AJCC stage pT1b pN0.  Tumor Staging Example-Colon  A 59 year old man has a colon tumor discovered on screening colonoscopy. Biopsy shows adenocarcinoma, and a right hemicolectomy and mesenteric node dissection are performed. Microscopic sections of the tumor show that it invades the colonic muscularis propria. Metastatic disease is observed microscopically in five of fifteen examined mesenteric nodes.  AJCC stage pT2 pN2a.  Tumor Staging Example-Thyroid  A 39 year old woman undergoes a total thyroidectomy for a large multinodular goiter. Gross examination shows multiple nodules. Microscopically, most of the nodules are benign, but one nodule in each lobe shows papillary thyroid carcinoma, measuring 2.1 cm in the right lobe and 1.3 cm in the left lobe, both nodules confined to the thyroid. No lymph nodes were removed.  AJCC stage mpT2 pNX.  Tumor Staging Example-Breast  A 95 year old female long term care resident has a breast lump detected on a routine physical examination. Mammography shows a 4 cm irregular mass and two distinct, enlarged axillary nodes. Core needle biopsy of the breast mass shows invasive ductal carcinoma.  Because of the patient’s age and medical comorbidities, the family decides not to pursue further therapy.  AJCC stage cT2 cN1.  Diagnosis of Cancer Imaging Studies  Computerized Axial Tomography (CAT) scan  Magnetic Resonance Imaging (MRI) scan  Positron Emission Tomography (PET) scan  Diagnosis of Cancer Serum Markers  Some used for screening, some used for post-therapy surveillance  Variable sensitivity and specificity  Examples:  Carcinoembryonic Antigen (CEA) (colon)  Prostate Specific Antigen (PSA)  CA125 (ovary)  HCG, AFP (germ cell tumors)  Diagnosis of Cancer Biopsy  The “gold standard” of cancer diagnosis  A pathologic diagnosis of cancer must be made before therapy is undertaken  Diagnosis of Cancer Biopsy Techniques  Cytology techniques  Fine needle aspiration (FNA)  Scrape/smear (Pap testing)  Tissue biopsy  Core needle biopsy  Endoscopic biopsy  Incisional biopsy  Excisional biopsy  Biopsy Stains  Routine stains  H & E (tissue)  Papanicolaou, Romanowsky (cytology)  Histochemical stains (Mucin, Elastic, PAS, etc.)  Immunostains  Very important to determine differentiation  Occasionally important in diagnosis of malignancy  Also used to measure prognostic markers  Estrogen receptor and HER2 in breast tumors  PD-L1 in lung and other tumors  Ancillary techniques  Flow Cytometry  Immunoprofile of lymphoid lesions  Cytogenetic techniques  Karyotyping  Fluorescence in situ hybridization (FISH)  HER2 testing  Specific chromosomal abnormalities  Molecular testing