Neoplastic progression
-plasia definitions Reversible Hyperplasia––↑in number of cells. Metaplasia––1 adult cell type is replaced by another. Often 2°to irritation and/or environmental exposure (e.g., squamous metaplasia in trachea and bronchi of smokers). Dysplasia––abnormal growth with loss of cellular orientation, shape, and size in comparison to normal tissue maturation; commonly preneoplastic. Irreversible Anaplasia––abnormal cells lacking differentiation; like primitive cells of same tissue, often equated with undifferentiated malignant neoplasms. Neoplasia––a clonal proliferation of cells that is uncontrolled and excessive. Desmoplasia––fibrous tissue formation in response to neoplasm.
(Adapted, with permission, from McPhee S et al. Pathophysiology of Disease: An Introduction to Clinical Medicine, 3rd ed. New York: McGraw-Hill, 2000: 84.)
Epithelial cell layer
Basement membrane Normal
HyperplasiaCarcinoma in situ/ preinvasive
Invasive carcinoma
Blood or lymphatic vessel
Metastatic focus
• Normal cells with basal → apical differentiation
• Cells have increased in number––hyperplasia • Abnormal proliferation of cells with loss of size, shape, and orientation––dysplasia
• In situ carcinoma • Neoplastic cells have not invaded basement membrane • High nuclear/cytoplasmic ratio and clumped chromatin • Neoplastic cells encompass entire thickness • Tumor cells are monoclonal
• Cells have invaded basement membrane using collagenases and hydrolases • Can metastasize if they reach a blood or lymphatic vessel
Metastasis––spread to distant organ • Must survive immune attack • “Seed and soil” theory of metastasis • Seed = tumor embolus • Soil = target organ––liver, lungs, bone, brain. . . • Angiogenesis allows for tumor survival
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Tumor grade vs. stage Grade Degree of cellular differentiation based on Stage usually has more prognostic histologic appearance of tumor. Usually graded value than grade. I–IV based on degree of differentiation and Stage = Spread. number of mitoses per high-power field; character TNM staging system: of tumor itself. T=size of Tumor Stage Degree of localization/spread based on site and N=Node involvement size of 1° lesion, spread to regional lymph M = Metastases nodes, presence of metastases; spread of tumor in a specific patient.
Tumor nomenclature Cell type Benign Malignanta Epithelium Adenoma, papilloma Adenocarcinoma, papillary carcinoma Mesenchyme Blood cells Leukemia, lymphoma Blood vessels Hemangioma Angiosarcoma Smooth muscle Leiomyoma Leiomyosarcoma Skeletal muscle Rhabdomyoma Rhabdomyosarcoma Bone Osteoma Osteosarcoma Fat Lipoma Liposarcoma > 1 cell type Mature teratoma (women) Immature teratoma and mature teratoma (men)
aThe term carcinomaimplies epithelial origin, whereas sarcomadenotes mesenchymal origin. Both terms imply malignancy.
Tumor differences Benign Usually well differentiated, slow growing, well demarcated, no metastasis. Malignant May be poorly differentiated, erratic growth, locally invasive/diffuse, may metastasize.
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PATHOLOGY—NEOPLASIA (continued)
Disease Condition Neoplasm associations with 1. Down syndrome 1. ALL (we ALL fall Down), neoplasms AML 2. Xeroderma pigmentosum, albinism 2. Melanoma, basal cell carcinoma, and especially squamous cell carcinomas of skin 3. Chronic atrophic gastritis, pernicious anemia, 3. Gastric adenocarcinoma postsurgical gastric remnants 4. Tuberous sclerosis (facial angiofibroma, seizures, 4. Astrocytoma, angiomyo- mental retardation) lipoma, and cardiac rhabdomyoma 5. Actinic keratosis 5. Squamous cell carcinoma of skin 6. Barrett’s esophagus (chronic GI reflux) 6. Esophageal adenocarcinoma 7. Plummer-Vinson syndrome (atrophic glossitis, 7. Squamous cell carcinoma esophageal webs, anemia; all due to iron of esophagus deficiency) 8. Cirrhosis (alcoholic, hepatitis B or C) 8. Hepatocellular carcinoma 9. Ulcerative colitis 9. Colonic adenocarcinoma 10. Paget’s disease of bone 10. 2° osteosarcoma and fibrosarcoma 11. Immunodeficiency states 11. Malignant lymphomas 12. AIDS 12. Aggressive malignant lymphomas (non-Hodgkin’s) and Kaposi’s sarcoma 13. Autoimmune diseases (e.g., Hashimoto’s 13. Benign and malignant thyroiditis, myasthenia gravis) lymphomas 14. Acanthosis nigricans (hyperpigmentation and 14. Visceral malignancy epidermal thickening) (stomach, lung, breast, uterus) 15. Dysplastic nevus 15. Malignant melanoma 16. Radiation exposure 16. Sarcoma
Oncogenes Gain of function →cancer. Need damage to only 1 allele. Gene Associated tumor abl CML c-myc Burkitt’s lymphoma bcl-2 Follicular and undifferentiated lymphomas (inhibits apoptosis) erb-B2 Breast, ovarian, and gastric carcinomas ras Colon carcinoma L-myc Lung tumor N-myc Neuroblastoma ret Multiple endocrine neoplasia (MEN) types II and III c-kit Gastrointestinal stromal tumor (GIST)
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Tumor suppressor Loss of function →cancer; both alleles must be lost for expression of disease. genes Gene Chromosome Associated tumor Rb 13q Retinoblastoma, osteosarcoma BRCA1 17q Breast and ovarian cancer BRCA2 13q Breast cancer p53 17p Most human cancers, Li-Fraumeni syndrome p16 9p Melanoma APC 5q Colorectal cancer WT1 11p Wilms’ tumor NF1 17q Neurofibromatosis type 1 NF2 22q Neurofibromatosis type 2 DPC 18q Pancreatic cancer DPC––Deleted in Pancreatic Cancer. DCC 18q Colon cancer DCC––Deleted in Colon Cancer.
Tumor markers PSA Prostate-specific antigen. Used to screen for Tumor markers should not be prostate carcinoma. used as the 1°tool for cancer Prostatic acid Prostate carcinoma. diagnosis. They may be used phosphatase to confirm diagnosis, to CEA Carcinoembryonic antigen. Very nonspecific but monitor for tumor recurrence, produced by 70% of colorectal and pancreatic and to monitor response to cancers; also produced by gastric and breast therapy. carcinomas. α-fetoprotein Normally made by fetus. Hepatocellular carcinomas. Nonseminomatous germ cell tumors of the testis (e.g., yolk sac tumor). β-hCG Hydatidiform moles, Choriocarcinomas, and Gestational trophoblastic tumors. CA-125 Ovarian, malignant epithelial tumors. S-100 Melanoma, neural tumors, astrocytomas. Alkaline phosphatase Metastases to bone, obstructive biliary disease, Paget’s disease of bone. Bombesin Neuroblastoma, lung and gastric cancer. TRAP Tartrate-resistant acid phosphatase. Hairy cell leukemia––a B-cell neoplasm. CA-19-9 Pancreatic adenocarcinoma.
Oncogenic viruses Virus Associated cancer HTLV-1 Adult T-cell leukemia HBV, HCV Hepatocellular carcinoma EBV Burkitt’s lymphoma, nasopharyngeal carcinoma HPV Cervical carcinoma (16, 18), penile/anal carcinoma HHV-8 (Kaposi’s Kaposi’s sarcoma, body cavity fluid B-cell sarcoma–associated lymphoma herpesvirus)
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PATHOLOGY—NEOPLASIA (continued)
Chemical Toxin Affectedorgan carcinogens Aflatoxins Liver (hepatocellular carcinoma) Vinyl chloride Liver (angiosarcoma) CCl4 Liver (centrilobular necrosis, fatty change) Nitrosamines (e.g., in smoked foods) Esophagus, stomach Cigarette smoke Larynx, lung, renal cell carcinoma, transitional cell carcinoma Asbestos Lung (mesothelioma and bronchogenic carcinoma) Arsenic Skin (squamous cell carcinoma) Naphthalene (aniline) dyes Bladder (transitional cell carcinoma) Alkylating agents Blood (leukemia)
Paraneoplastic effects of tumors Neoplasm Causes Effect Small cell lung carcinoma ACTH or ACTH-like peptide Cushing’s syndrome Small cell lung carcinoma and ADH SIADH intracranial neoplasms Squamous cell lung carcinoma, PTH-related peptide, TGF-β, TNF, IL-1 Hypercalcemia renal cell carcinoma, and breast carcinoma Renal cell carcinoma, Erythropoietin Polycythemia hemangioblastoma Thymoma, small cell lung Antibodies against presynaptic Ca2+ Lambert-Eaton syndrome carcinoma channels at neuromuscular junction (muscle weakness) Leukemias and lymphomas Hyperuricemia due to excess nucleic acid Gout, urate nephropathy turnover (i.e., cytotoxic therapy)
Psammoma bodies Laminated, concentric, calcific spherules seen in: PSaMMoma: 1. Papillary adenocarcinoma of thyroid Papillary (thyroid) 2. Serous papillary cystadenocarcinoma of ovary Serous (ovary) 3. Meningioma Meningioma 4. Malignant mesothelioma Mesothelioma
Metastasis to brain 1° tumors that metastasize to brain––Lung, Lots of Bad Stuff Kills Glia. Breast, Skin (melanoma), Kidney (renal cell Typically multiple well- carcinoma), GI. Overall, approximately 50% circumscribed tumors at of brain tumors are from metastases. gray-white border.
Metastasis to liver The liver and lung are the most common sites of Metastases>> 1° liver tumors. metastasis after the regional lymph nodes. 1° Cancer Sometimes Penetrates tumors that metastasize to the liver––Colon > Benign Liver. Stomach > Pancreas > Breast > Lung.
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Metastasis to bone These 1° tumors metastasize to bone––Prostate, P. T. Barnum Loves Kids. Thyroid, Testes, Breast, Lung, Kidney. Lung=Lytic. Metastases from breast and prostate are most Prostate =blastic. common. Breast=Both lytic and blastic. Metastatic bone tumors are far more common than 1° bone tumors.
Cancer epidemiology
Male Female Deaths from lung cancer have Incidence Prostate (32%) Breast (32%) plateaued in males but Lung (16%) Lung (13%) continue to ↑in females. Colon and rectum (12%) Colon and rectum (13%) Cancer is the 2nd leading Mortality Lung (33%) Lung (23%) cause of death in the United Prostate (13%) Breast (18%) States (heart disease is 1s
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