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General Pathology (DENF 2701) Topic: Neoplasia Fall, 2004; Wednesdays, 10:00-12:00 am; Room 132 Course Director: Dr. Jerry Bouquot Room 3.094B; 713-500-4406; 713-520-1250 (home) Neoplasia “New Growth”; From Latin Word for Crab Cancer: Neoplasms are not controlled by the body – Continue to replicate indefinitely – Tumors may flourish, even while the host is wasting away – Cancers induce increased blood supply Cancer: 2nd leading cause of US deaths -- After cardiovascular disease Oncology = study of tumors (“oncos” = tumor, “logos” = study of) -- Oncologist = physician who treats cancer exclusively – Hemoncologist = specializes in leukemias, lymphomas, etc. -- Hematologist = blood doctor, treats leukemias, lymphomas, etc. – Surgical oncologist; Radiation oncologist Typically monoclonal Malignant (cancers): invade, destroy, metastasize (distant spread) Benign: nonmalignant neoplasm; add suffix “-oma” Features of Neoplasms Benign v. Malignant Benignant Malignant Rate of growth Slow Rapid Type of growth Expansile only Expansile and/or invasive Similarity to original tissue/cells Very similar Not similar Uniformity of cells Uniform Cells vary in shape (pleomorphic) and size Mitotic rate Low (few mitoses) Medium to high (many mitoses), may be abnormal or in abnormal location Nuclear/cytoplasmic ratio Normal High Nuclei Normal, uniform Enlarged, pleomorphic, dark (hyperchromatic) Neoplasia Benign v. Malignant Leiomyoma Benign Smooth Muscle Neoplasm Photos: Kumar, Cotran, Robbins. Robbins Basic pathology, 7th ed., Saunders, Philadelphia, 2003; Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995. Neoplasms Benign v. Malignant Thyroid Adenoma Breast Adenocarcinoma Breast Adenocarcinoma Photo: Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995. Tumor Names Tissue of Origin Benign Malignant Fibrous Fibroma Fibrosarcoma Bone Osteoma Osteosarcoma Cartilage Chondroma Chondrosarcoma Adipose Lipoma Liposarcoma Nerve Neurofibroma Neurofibrosarcoma Smooth muscle Leiomyoma Leiomyosarcoma Skeletal muscle Rhabdomyoma Rhabdomyosarcoma Gland Adenoma Adenocarcinoma Squamous epithelium Papilloma Squamous cell carcinoma Melanocyte Nevocellular nevus Malignant melanoma Lymphoid Lymphoid hyperplasia Lymphoma Neoplasia Differentiation of Cells/Tissue Well differentiated: cells look mature and similar to original cells -- Grade I = cells are well differentiated -- Grades II and III: moderately differentiated --Grade IV = poorly differentiated Not very good at prognosis Poorly differentiated: cells look immature and irregular -- Grade IV; high grade -- Often means worse prognosis More mature or differentiated cells retain function – e.g. squamous cell carcinoma makes keratin (keratin pearls, epithelial pearls) -- e.g. mucoepidermoid carcinoma makes mucus (mucin) Neoplasia Differentiation of Cells/Tissue Anaplasia (“to form backwards”): very undifferentiated -- Primitive cells Stem cells of some tumors undergo divergent differentiation – e.g. pleomorphic adenoma (mixed tumor) of salivary glands – e.g. fibroadenoma of breast Certain tumors induce stromal change (not differentiation) -- Fibrosis (desmoplasia) -- New vessels (angiogenesis) Squamous Cell Carcinoma Microscopic Grading Grade I Grade II Grade III Grade IV Loss of Differentiation & Maturity Well differentiated adenocarcinoma of colon Benign neoplasm of colon Photos: Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995. Loss of Differentiation Anaplastic carcinoma of colon Poorly differentiated adenocarcinoma of colon Photos: Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995. Signs of Dysplasia Not Necessarily Associated with Cancer Pleomorphic (abnormal shape) -- Cells and/or nuclei Enlargement...cells or nuclei Reduced cytoplasmic/nuclear ratio -- Large nucleus compared to cell size -- 1:1 vs. 1:4 - 1:6 for normal Hyperchromatic nuclei -- Chromatin is course, clumped Increased mitotic rate -- Numerous mitotic figures Bizarre mitoses: abnormal shape -- e.g. tripolar/quadripolar mitoses -- e.g. abnormal location Signs of Dysplasia Not Necessarily Associated with Cancer Lack of cohesion (detached cells) Prominent, perhaps multiple nucleoli Loss of polarity (no orientation) Bizarre cells Problem: some dysplasias are not related to cancer e.g. Developmental anomalies Bone dysplasias Problem: not all dysplasias progress to malignancy (precancer) Photos: Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995; Kumar, Cotran, Robbins. Robbins Basic pathology, 7 th ed., Saunders, Philadelphia, 2003. The Dysplastic Cell Photo: J. Bouquot. Pract Perio Aesth Dent, 1995. Extra Credit Question Melanoma is a malignancy of which of the following cells? A. B. C. D. E. Fibroblast Osteoblast Melanocyte Nevus cell Smooth muscle cell Teratoma A Type of Neoplasm as Well as Developmental Anomaly Usually congenital More than one germ-cell type From multipotential cells -- Therefore usually found in ovary or testis Usually helter-skelter mix of tissue types -- May be so mature that small “babies” develop May be benign or malignant Not a hamartoma (mass of disorganized tissue indigenous to the site) Not a choristoma (congenital anomaly, a heterotopic rest of cells) Cervical teratoma is usually fatal -- Because it presses on vessels, airways, esophagus Ovarian Teratoma Cervical Teratoma Pituitary Teratoma With Teeth Photo: Dr. J. Bouquot, West Virginia University, Morgantown, West Virginia Pituitary Teratoma Neoplasia Invasion Cuniculatum (Verrucous?) Carcinoma One of two things that most clearly separate benign from cancer – Exceptions: Basal cell carcinoma (skin) Verrucous carcinoma (mouth) Prostate carcinoma -- Exceptions: Hemangioma Lymphangioma Lipoma Not all benign neoplasms are encapsulated Hemangioma -- Usually a well-defined cleavage plane After the ability to metastasize, the ability to invade is the most reliable feature of malignancy Photos: P. Morgan, Guys Hospital, London, England; J. Bouquot, West Virginia University, Morgantown, West Virginia. Carcinoma in situ Top-to-Bottom Dysplasia Severe Dysplasia Photos: Kumar, Cotran, Robbins. Robbins Basic pathology, 7th ed., Saunders, Philadelphia, 2003. Local Invasion Colonic adenocarcinoma (left) invades into muscle (right) Photo: Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995. Neoplasia Metastasis Secondary implants of cancer cells separate from 10 tumor The most unique thing about malignancy (v. benignancy) Carcinomas spread via lymphatics to local lymph nodes – Oral cancer: cervical enlarged, firm, fixed (perhaps matted) lymph nodes – Breast cancer (usually is in upper outer quadrant): axillary lymph node involvement (perhaps with lymphedema) – Lung cancer: bronchial lymph node involvement Usually ipsilateral (on same side of body) node -- May be contralateral (opposite side of body) Sarcomas spread via blood stream -- Therefore: pulmonary mets usually Usually metastasis is from long-standing, large cancers -- There are exceptions!! Cellular Events Needed for Metastasis Photos: Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995. Local Lymphatic Invasion Para-Aortic Lymph Nodes Photo: Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995. Main Routes of Tumor Spread Carcinoma of the Lung Hilar Lymph Nodes (cancer = white deposits Photo: Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995. Most Common Sites of Distant Metastasis Liver Metastases Photos: Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995; Kumar, Cotran, Robbins. Robbins Basic pathology, 7th ed., Saunders, Philadelphia, 2003. Epidemiologic Terms Incidence rate: number of newly diagnosed cancers/year Mortality rate: number of patients dying from cancer/year Prevalence rate: number of cancers diagnosed in a certain population at a given point in time (point prevalence) Relative frequency rate: proportion of all cancers represented by an individual cancer Epidemiologic studies (case-control studies, differences in incidence between groups, etc.) are the best “proof” of etiology (cause), but they are very expensive and time-consuming Incidence of Cancer More than 100 Different Types of Cancer Photo: Kumar, Cotran, Robbins. Robbins Basic pathology, 7th ed., Saunders, Philadelphia, 2003. Cancer Age as an Etiologic Factor Frequency of cancer generally increases with age Cancers are constantly arising in our bodies, but our immune system kills them off With increasing age: -- Less effective immune system -- Less controlled cell division (more mutations) -- More exposure to carcinogens Young age = sarcomas; old age = carcinomas The major cancer deaths in children under 15 years of age: -- Leukemia -- CNS tumors -- Lymphomas -- Soft tissue sarcomas -- Bone sarcomas Cancer Risk Increases with Age Long-term exposure & less effective immune system Photo: Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995. Trends in Cancer Incidence 1930 - 2000 Photo: Kumar, Cotran, Robbins. Robbins Basic pathology, 7th ed., Saunders, Philadelphia, 2003. Oral Cancer Age- & Gender-Specific Incidence Rates Photo: Neville, et al. Oral and maxillofacial pathology, 2002. Cancer Hereditary Factors Hereditary predisposition toward cancer development is common Inherited cancer syndromes -- 5-10% of cancers -- Often have specific molecular markers Familial retinoblastoma: autosomal dominant (AD) -- 40% are familial -- 10,000x more risk Familial adenomatous polyposis (FAP) of colon (AD) -- Gardner’s syndrome also has jaw osteomas Colon cancer (other than FAP): familial Cancer Hereditary Factors Multiple endocrine neoplasia (MEN) syndrome (AD) Neurofibromatosis types 1 and 2 (AD) Breast cancer: familial; BRCA gene Ovarian cancer: familial Xeroderma pigmentosum: autosomal recessive (AR) Ataxia telangiectasia: AR Bloom syndrome: AR Fanconi anemia: AR Inherited Syndromes Associated with Cancer Associated Genetic Defect Syndrome Tumor Genetic Defect Multiple endocrine neoplasia syndrome (MEN) Tumors of endocrine organs Mutation, chromosomes 10 & 11 Polyposis coli Adenomas and adenocarcinomas of colon Absent tumor suppressor gene Li-Fraumeni Breast carcinoma and sarcomas Mutated tumor suppressor gene Xeroderma pigmentosum Skin carcinoma Abnormal DNA repair Familial retinoblastoma Retinoblastoma Absent tumor suppressor gene Neurofibromatosis, type I Neuroma, neurofibroma, neurofibrosarcoma Abnormal tumor suppressor gene Genetically Associated Cancers The cancer may not be in the mouth MEN (Multiple Endocrine Neoplasia) IIB or III. Painless yellow-white nodules of the tongue. Photo: ESTOP. . Acanthosis nigricans Ataxia-Telangiectasia Cowden syndrome Dyskeratosis congenita Gardner’s syndrome Gorlin syndrome (nevoid basal cell carcinoma syndrome) Mucosal neuroma syndrome (MEN IIB, MEN III) Neurofibromatosis Peutz-Jeghers syndrome Trisomy 21 (Downs syndrome) Tuberous sclerosis Xeroderma pigmentosum Progression of Cancer Pathogenesis Photo: Kumar, Cotran, Robbins. Robbins Basic pathology, 7th ed., Saunders, Philadelphia, 2003. Cancer Phenotypes Genetic Requirements Self-sufficiency (promotes cell growth without signals) -- Mutated protooncogenes >> oncogenes >> oncoproteins (not regulated) Cancer cells produce the same growth factors which influence them Cancer cells create excess receptors to these growth factors -- e.g. excess epidermal growth factor receptors are in 80% of squamous cell carcinomas of lungs Example: Overexpression of MYC protooncogene -- MYC is in nucleus of all cells -- When overexpressed: increased cyclin-dependent kinases (CDKs) to move cell cycle into an active phase (especially G1 to S) Example: Mutation of RAS gene --Most common oncogene abnormality in tumors (30%) -- Cell is told to continue to proliferate Photo: Kumar, Cotran, Robbins. Robbins Basic pathology, 7th ed., Saunders, Philadelphia, 2003. Cancer Phenotypes Genetic Requirements Insensitivity to growth-inhibitory signals – TP53 (p53) tumor suppressor gene: exerts antiproliferation effects, regulates DNA-damage repair, regulates apoptosis; affected by stress -- TP53 is one of the most common mutations in cancers Evasion of apoptosis Limitless replicative potential – Telomere length maintenance is seen in virtually all cancers Cancer Phenotypes Genetic Requirements Increased Expression of Growth Factor Receptors Oncogenes in Neoplastic Transformation Photos: Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995. Cancer Phenotypes Genetic Requirements Mutant Transcription Factor Production Mutation in Transducer Protein Gene Photos: Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995. Cancer Phenotypes Genetic Requirements Over-Production of Factors that Prevent Cell Death Photo: Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995. Cancer Phenotypes Genetic Requirements Development of sustained angiogenesis – Cannot metastasize without angiogenesis – When the angiogenic switch is turned on: cancer proliferations and then metastasis Ability to invade and metastasize -- Tumor cells must detach from themselves, attach to stroma >> degrade/destroy the stroma (via metalloproteinases) >> migrate Some tumors show organ tropism (metastases favor certain organs) -- Related to adhesion molecules and receptors Karyotype Changes in Cancer Balanced translocations -- Philadelphia chromosome (chronic myelogenous leukemia) -- Usually 22 & 9 -- Burkitt lymphoma (usually 8 & 14) -- Follicular B-cell lymphoma (usually 14 & 18) Deletions (more common in solid tumors) -- Retinoblastoma (13q) -- Colorectal carcinoma (17p, 5q, 18q) 3. Gene amplification -- neuroblastoma -- Breast cancer (N-MYC and HER-2 genes) Carcinogenesis Major problem: nonlethal genetic damage or mutations Probably “cause” 65% of all cancers -- Heredity is “cause” of 26-40% Carcinogens: -- Chemical -- Radiant energy -- Microbial agents Carcinogenesis is a multistep phenomenon (tumor progression) – Involves genes regulating DNA repair, angiogenesis, invasion, metastasis Carcinogenesis Three classes of regulatory genes are the main targets: 1) Protooncogenes (promote growth) -- Mutant alleles = oncogenes (dominant genes) 2) Antioncogenes (growth-inhibiting cancer suppressor genes) -- Tumor suppressor genes -- Both alleles must be damaged (recessive oncogenes) 3) Genes controlling apoptosis (programmed cell death) DNA repair genes affect cell proliferation and survival -- If disabled: widespread mutations Photo: Kumar, Cotran, Robbins. Robbins Basic pathology, 7th ed., Saunders, Philadelphia, 2003. Carcinogenesis Ionizing Radiation Photo: Kumar, Cotran, Robbins. Robbins Basic pathology, 7th ed., Saunders, Philadelphia, 2003. Human Papillomaviruses in Oral Lesions 24 genotypes have been isolated from oral lesions & mucosa Lesion Genotype(s) * Herpes simplex virus Normal mucosa 6, 7, 11, 16, 18, 31, 33, etc. was a red herring? Verruca vulgaris (common wart) 2 a – e, 4, 6, 40 Papilloma (squamous papilloma) 6 a – f, 11 a, b Condyloma acuminatum 2, 6, 11 a, b, 16, 18, 53, 54 Focal epithelial hyperplasia (Heck’s disease) 13, 32 Smokeless tobacco keratosis 2, 6 Leukoplakia, no dysplasia 2, 6,11,16,18 Leukoplakia with epithelial (koilocytic) dysplasia 2, 6, 11, 16, 18, 31, 33, 35 Carcinoma in situ 2, 6, 11, 16, 18, 31, 33, 35 Keratoacanthoma 26, 37 Verrucous carcinoma 2 a – e, 6, 11, 16, 18 Squamous cell carcinoma 16, 18, 31, 33, 35 * genotypes in bold yellow are isolated in at least 1/3 of all cases with HPV Carcinogenesis Viruses Implicated in Human Neoplasia Virus Neoplasm Burkitt’s lymphoma Epstein-Barr virus (EBV) Nasopharyngeal carcinoma Some B-cell lymphomas Some Hodgkin’s disease Hepatitis B virus (HBV) Hepatocellular carcinoma Human papillomavirus (HPV) Cervical carcinoma Some skin carcinomas Human papillomavirus (HPV) Some oral and laryngeal carcinomas HTLV-1 T-cell leukemia/lymphoma Neoplasia Environmental Etiologic Factors Carcinogens (chemicals associated with cancer production): – Arsenic (lungs, skin, hemanigiosarcoma) -- e.g. smelting metals, fungicides – Asbestos (lungs, mesothelioma, GI tract) -- e.g. fire retardant, sound insulator – Benzene (leukemia, Hodgkin’s lymphoma) -- e.g. light oils, dry cleaning, solvents – Berylium (lungs) -- e.g.. rocket fuel, nuclear reactors – Cadmium (prostate) -- e.g. yellow dyes including food dyes, batteries Carcinogenesis Associated Chemicals Chromium (lungs) e.g. preservative, metal alloys, pigments Ethylene oxide (leukemia) e.g. ripening of fruits & nuts; rocket fuels, fumigation, sterilizing Nickel (nose, lungs) e.g. metal plating and alloying, ceramics, batteries, stainless steel welding Radon (lungs) e.g. from decay of uranium, in quarries, mines, seeps into home basements Vinyl chloride (liver, angiosarcoma) e.g. refrigerant, monomer for vinyl polymers, plastic adhesive Causes of Oral Carcinoma The happy, toothless smoker Tobacco smoking Tobacco chewing Betel/pan/areca chewing Alcohol abuse Precancer Plummer-Vinson disease (severe Fe deficiency) Human papillomavirus 16/18 Chronic infection? Syphilitic glossitis History of irradiation History of sun damage (lip) History of H&N carcinoma Increasing age Cancer Host Defenses Tumor elicits CD8+ cytotoxic T-cell response – e.g carcinoembryonic antigen (CEA) – e.g Oncogenic viruses (EBV, HPV) – e.g Prostate-specific antigen (PSA) Antitumor effector mechanisms – Cytotoxic T lymphocytes (especially against virus-induced cancers) – Natural Killer (NK) cells (don’t need prior sensitization; may be first line of defense) – Macrophages (once activated, exhibit selective cytotoxicity against tumor cells) – Humoral mechanisms from complement activation and induction of antibody-dependent cellular cytotoxicity by NK cells Immunosurveillance – Without it: increased cancer risk (5% in congenitally immunosuppressed patients (usually lymphoma) Neoplasia Clinical Features Typically a mass, with or without surface ulceration Compression on surrounding tissues Ulceration with bleeding May produce hormones (even if tumor is from tissue which normally produces no hormones) Cachexia (wasting syndrome): progressive weight loss and “wasting” – Usually terminates with fatal infection – Usually correlated with extent of tumor and metastasis – Anorexia is common – May be from TNF and IL-1 from activated macrophages – No good explanation for how this happens Tumor Markers Some tumors create unique molecules -- may be used in diagnosis Marker Tumor Alpha fetoprotein (AFP) Hepatocellular carcinoma Germ cell tumors Human chorionic gonadotrophin (HCG) Trophoblastic tumors Acid phosphatase Prostatic carcinoma Carcinoembryonic antigen (CEA) Gastrointestinal carcinoma Hormones Endocrine tumors Precancers and Preneoplastic Conditions Cancer development is NOT inevitable! Persistent regeneration -- Squamous cell carcinoma at edge of fistula or draining wound e.g. osteomyelitis -- Hepatocarcinoma in cirrhosis of the liver e.g. alcoholism Hyperplastic proliferations -- Endometrial carcinoma in atypical endometrial hyperplasia Dysplastic proliferations -- Bronchogenic carcinoma in dysplastic bronchial mucosa e.g. cigarette smoking -- Colorectal carcinoma Photo: Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995. Precancers and Preneoplastic Conditions Chronic atrophic gastritis -- Gastric carcinoma in pernicious anemia i.e. vitamin B12 deficiency Chronic ulcerative colitis -- Colorectal carcinoma Villous adenoma of colon -- Colorectal carcinoma Leukoplakia of mouth, vulva, penis -- Squamous cell carcinoma Photo: E. Lalonde, West Virginia University, Morgantown, West Virginia. Clinical Appearance Matters Verruciform Leukoplakia, Granular leukoplakia, Verrucous Leukoplakia Carcinoma in situ Hyperkeratosis Photo: J. Pindborg, Univ. Copenhagen, Copenhagen, Denmark. Photo (left): J. Pindborg, Royal College of Dentistry, Copenhagen, Denmark. Erythroleukoplakia Speckled Leukoplakia Corrugated thick and thin leukoplakia of the oral floor and ventral tongue, with pink areas surrounded by white. Oral Precancers Increased Risk (Not 100%!) Leukoplakia in syphilitic glossitis From: Schwimmer, 1876, Budapest Leukoplakia Erythroplakia Smokeless tobacco keratosis Lichen planus (erosive) Reverse smoker’s palate Oral submucous fibrosis Smooth, red tongue in PlummerVinson disease Actinic cheilosis Paraneoplastic Syndromes No good explanation for how this happens Hypercalcemia -- Ttumor cells make parathyroid hormone-related protein (PTHrP) Cushing syndrome -- Tumor cells make ACTH or ACTH-like peptides Nonbacterial thrombotic endocarditis -- Hypercoagulability state induced by tumor cells Venous thrombosis -- Hypercoagulability Polycythemia -- Tumor cells make erythropoietin Staging of Cancers Clinical Classification Stage shows severity of clinical features of the tumor Usually staged without sophisticated imaging technologies -- This may change soon Stage I = small, localized tumor Stage IV = huge or metastatic tumor Not bad at forming prognosis -- Stage I is good -- Stage IV is very bad TNM staging system: – T = tumor size, in cm. – N = presence of tumor in local/regional lymph nodes – M = presence of tumor at a distant site (beyond local lymph nodes; e.g. “below the clavicles”) Tables used to establish the stage, combining the TNM evaluations The TNM Staging System Tumor size: T0 = no tumor T1 = <2 cm. in size T2 = 2-4 cm. in size T3 = >4 cm. in size Lymph node involvement: N0 = no positive nodes N1 = few ipsilateral nodes N2 = many ipsilateral nodes or contralateral nodes Distant metastasis: M0 = no metastasis M1 = metastasis below the clavicle Mx = suspected metastasis Photo: Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995. Prognosis Varies with Cancer Site 5-Year Survival Rates Photo: Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995. Cancer Once Uniformly Lethal 1900: <5% survival 1945: 20% survival 1986: 50% survival 2003: 63% survival ACS 2015 goal: 50% reduction in mortality rates ACS 2015 goal: 25% reduction in incidence rates How: prevention, early detection, Adenocarcinoma at autopsy, circa 1856 quality management, research