Neoplasia Pathology flash Points by Prof Ejaz Waris
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1. Neoplasia refers to new growth or tumor formation, which can be benign or malignant. Benign tumors remain localized and non-invasive, while malignant tumors can invade other structures and metastasize to distant sites. 2. All tumors contain neoplastic cells and supportive stroma. Benign tumors are well-differentiated and grow slowly, while malignant tumors show a range of differentiation from well to undifferentiated and grow more rapidly with ability to invade and metastasize. 3. Carcinogenesis is a multistep process involving accumulation of genetic mutations that alter cellular pathways controlling growth, survival, angiogenesis and metastasis, resulting in malignant transformation.
Neoplasia Pathology flash Points by Prof Ejaz Waris
- 1. NEOPLASIA FLASH POINTS DR EJAZ WARIS , FCPS PROFESSOR OF PATHOLOGY , SMDC 1. Neoplasia means “new growth,” and a new growth is called a neoplasm 2. A tumor is said to be benign when its microscopic and gross characteristics are considered relatively innocent, implying that it will remain localized, it cannot spread to other sites, and it is generally amenable to local surgical removal 3. Malignant, as applied to a neoplasm, implies that the lesion can invade and destroy adjacent structures and spread to distant sites (metastasize) to cause death 4. All tumors, benign and malignant, have two basic components: (1) clonal neoplastic cells that constitute their parenchyma and (2) reactive stroma made up of connective tissue, blood vessels, and variable numbers of macrophages and lymphocytes. 5. In some tumors, the stromal support is scant and so the neoplasm is soft and fleshy. In other cases the parenchymal cells stimulate the formation of an abundant collagenous stroma, referred to as desmoplasia. 6. Benign epithelial tumors include papilloma , adenoma , cyst adenoma and papillary cystadenoma 7. Benign mesenchymal tumors include chondroma , osteoma , fibroma and lipoma 8. Malignant tumors arising in mesenchymal tissue are usually called sarcomas (Greek sar = fleshy), because they have little connective tissue stroma and so are fleshy (e.g., fibrosarcoma, chondrosarcoma, leiomyosarcoma, and rhabdomyosarcoma). 9. Carcinomas are malignant tumors arising from epithelium. E.g include Squamous cell carcinoma , adenocarcinoma , Renal cell carcinoma , basal cell carcinoma and transitional cell carcinoma 10. Squamous cell carcinoma would denote a cancer in which the tumor cells resemble stratified squamous epithelium, and adenocarcinoma denotes a lesion in which the neoplastic epithelial cells grow in glandular patterns. 11. Infrequently, divergent differentiation of a single neoplastic clone along two lineages creates what are called mixed tumors. The best example of this is the mixed tumor of salivary gland origin – pleomorphic adenoma. 12. Teratomas arise from more than one germ cell layer.They are mostly benign ( common site is ovary (dermoid cyst ) ,however they may be immature or malignant. 13. When all the component parts are well differentiated, it is a benign (mature) teratoma; when less well differentiated, it is an immature, potentially or overtly, malignant teratoma 14. Hamartomas present as disorganized but benign-appearing masses composed of cells indigenous to the particular site. 15. choristoma. This congenital anomaly is better described as a heterotopic rest of cells. For example, a small nodule of well-developed and normally
- 2. organized pancreatic substance may be found in the submucosa of the stomach, duodenum, or small intestine. 16. Differentiation refers to the extent to which neoplastic parenchymal cells resemble the corresponding normal parenchymal cells, both morphologically and functionally; lack of differentiation is called anaplasia. In general, benign tumors are well differentiated 17. Malignant neoplasms are characterized by a wide range of parenchymal cell differentiation, from surprisingly well differentiated to completely undifferentiated 18. well , moderately,poorly and undifferentiated tumors are 4 ranges of differentiation. 19. Lack of differentiation, or anaplasia, is considered a hallmark of malignancy. 20. Classical features of a malignant cell include : Hyperchromatic nuclei , high N/C ratio , pleomorphism , abnormal mitoses , scanty cytoplasm and prominent nucleoli 21. Dysplasia is encountered principally in epithelia, and it is characterized by a constellation of changes that include a loss in the uniformity of the individual cells as well as a loss in their architectural orientation 22. When dysplastic changes are marked and involve the entire thickness of the epithelium but the lesion remains confined by the basement membrane, it is considered a preinvasive neoplasm and is referred to as carcinoma in situ 23. dysplasia is precancerous howver does not necessarily progress to cancer. 24. the growth rate of tumors correlates with their level of differentiation, and thus most malignant tumors grow more rapidly than do benign lesions 25. Nearly all benign tumors grow as cohesive expansile masses that remain localized to their site of origin and do not have the capacity to infiltrate, invade, or metastasize to distant sites, as do malignant tumors which always infiltrate and invade. 26. Metastases are tumor implants discontinuous with the primary tumor. Metastasis unequivocally marks a tumor as malignant because benign neoplasms do not metastasize. 27. With few exceptions, all malignant tumors can metastasize. The major exceptions are most malignant neoplasms of the glial cells in the central nervous system, called gliomas, and basal cell carcinomas of the skin 28. Dissemination of cancers may occur through one of three pathways: (1) direct seeding of body cavities or surfaces, (2) lymphatic spread, and (3) hematogenous spread. 29. Sometimes mucus-secreting appendiceal carcinomas fill the peritoneal cavity with a gelatinous neoplastic mass referred to as pseudomyxoma peritonei 30. Transport through lymphatics is the most common pathway for the initial dissemination of carcinomas 31. In breast cancer, determining the involvement of axillary lymph nodes is very important for assessing the future course of the disease and for selecting suitable therapeutic strategies 32. Hematogenous spread is typical of sarcomas but is also seen with carcinomas
- 3. 33. Certain cancers have a propensity for invasion of veins. Renal cell carcinoma often invades the branches of the renal vein and then the renal vein itself to grow in a snakelike fashion up the inferior vena cava, sometimes reaching the right side of the heart. Hepatocellular carcinomas often penetrate portal and hepatic radicles to grow within them into the main venous channels 34. Seeding of body cavities and surfaces may occur whenever a malignant neoplasm penetrates into a natural “open field.” Most often involved is the peritoneal cavity.carcinoma of the ovaries is classical example. 35. ). Cancer is the main cause of death among women aged 40 to 79 and among men aged 60 to 79 36. The common neoplasms of infancy and childhood include the so-called small round blue cell tumors such as neuroblastoma, Wilms tumor, retinoblastoma, acute leukemias, and rhabdomyosarcomas 37. Carriers of a mutant of the RB tumor suppressor gene have a 10,000-fold increased risk of developing retinoblastoma, usually bilateral. They also have a greatly increased risk of developing a second cancer, particularly osteosarcoma. 38. In MEN-2, thyroid, parathyroid, and adrenals are involved, while in MEN-1, the pituitary, parathyroid, and pancreas are involved 39. In 1863 Virchow proposed that cancer develops at sites of chronic inflammation. These include ulcerative colitis, Helicobacter pylori gastritis, viral hepatitis, and chronic pancreatitis 40. Certain non-neoplastic disorders—the chronic atrophic gastritis of pernicious anemia, solar keratosis of the skin, chronic ulcerative colitis, and leukoplakia of the oral cavity, vulva, and penis—have such a well-defined association with cancer that they have been termed precancerous conditions 41. Nonlethal genetic damage lies at the heart of carcinogenesis. 42. A tumor is formed by the clonal expansion of a single precursor cell that has incurred genetic damage (i.e., tumors are monoclonal) 43. Four classes of normal regulatory genes—the growth-promoting proto- oncogenes, the growth-inhibiting tumor suppressor genes, genes that regulate programmed cell death (apoptosis), and genes involved in DNA repair—are the principal targets of genetic damage. 44. Loss of gene function caused by damage to a single allele is called haploinsufficiency 45. Carcinogenesis is a multistep process at both the phenotypic and the genetic levels, resulting from the accumulation of multiple mutations 46. ESSENTIAL ALTERATIONS FOR MALIGNANT TRANSFORMATION : Self sufficiency in growth signals , Insensitivity to growth-inhibitory signals , Evasion of apoptosis, Limitless replicative potential, Sustained angiogenesis, Ability to invade and metastasize, Defects in DNA repair. 47. Genes that promote autonomous cell growth in cancer cells are called oncogenes, and their unmutated cellular counterparts are called proto- oncogenes 48. Point mutation of RAS family genes is the single most common abnormality of proto-oncogenes in human tumors.
- 4. 49. other protooncogenes include RET , abl , Kit , N-Myc , C-myc 50. The most well-studied example of a signal-transducing oncoprotein is the RAS family of guanine triphosphate (GTP)-binding proteins (G proteins). 51.ABL –BCR fusion is seen in CML (Chronic myeloid leukemia) 52.C-Kit oncogene is linked with GIST (Gastrointestinal tumor) 53. Whereas oncogenes drive the proliferation of cells, the products of tumor suppressor genes apply brakes to cell proliferation 54.Major antioncogenes include RB,P53,APC,BRCA and wt-1. 55.Two hit hypothesis is seen in the pathology of tumors showing antioncogenes loss or mutation. Classical example :Two mutations (hits), involving both alleles of RB at chromosome locus 13q14, are required to produce retinoblastoma 56.A little over 50% of human tumors contain mutations in p53 gene.major antioncogene : mode of action of this gene is DNA repair of damaged DNA and proapoptotic functions. 57. p53 links cell damage with DNA repair, cell cycle arrest, and apoptosis 58. Invasion and metastasis are biologic hallmarks of malignant tumors 59. In several epithelial tumors, including adenocarcinomas of the colon and breast, there is a down-regulation of E-cadherin expression 60. ERBB2 amplification occurs in about 20% of breast cancers, 61. Initiation causes permanent DNA damage (mutations). It is therefore rapid and irreversible and has “memory.” Initiation alone, however, is not sufficient for tumor formation 62. Promoters can induce tumors in initiated cells, but they are nontumorigenic by themselves 63. Most of the known carcinogens are metabolized by cytochrome P-450– dependent mono-oxygenases 64. There is a strong correlation between the dietary level of the food contaminant Aspergillus and the incidence of hepatocellular carcinoma in parts of Africa and the Far East 65. For the change to be heritable, the damaged DNA template must be replicated 66. In humans there is a hierarchy of vulnerability of different tissues to radiation-induced cancers. Most frequent are the acute and chronic myeloid leukemia. Cancer of the thyroid follows closely but only in the young. In the intermediate category are cancers of the breast, lungs, and salivary glands. 67.History of more exposure to radiations in childhood is associated with carcinoma thyroid. 68.Human Tcell leukemia virus is the only oncogenic RNA virus. 69. Of the various human DNA viruses, four—HPV, Epstein-Barr virus (EBV), hepatitis B virus (HBV), and Kaposi sarcoma herpesvirus, also called human herpesvirus 8—have been implicated in the causation of human cancer 70. high-risk HPVs (e.g., types 16 and 18) have been implicated in the genesis of several cancers, particularly squamous cell carcinoma of the cervix and anogenital region.
- 5. 71.EBV is linked with Hodgkin lymphoma;Burkitt’s lymphoma, nasopharyngeal and some gastric carcinomas and rare forms of T cell lymphomas and natural killer (NK) cell lymphomas 72. Though not a DNA virus, HCV is also strongly linked to the pathogenesis of liver cancer 73. H. pylori infection is implicated in the genesis of both gastric adenocarcinomas and gastric lymphomas 74.Paraneoplastic syndromes majorly include : Cushing’s syndrome caused by small cell carcinoma of lung and pancreatic carcinoma. Syndrome of inappropriate ADH secretion caused by small cell ca lung Hypercalcemia caused by squamous cell carcinoma lung. 75. The endocrinopathies are frequently encountered paraneoplastic syndromes 76. Grading of a cancer is based on the degree of differentiation of the tumor cells and, in some cancers, the number of mitoses or architectural features 77. The staging of cancers is based on the size of the primary lesion, its extent of spread to regional lymph nodes, and the presence or absence of blood-borne metastases. The major staging system currently in use is the American Joint Committee on Cancer Staging. This system uses a classification called the TNM system—T for primary tumor, N for regional lymph node involvement, and M for metastases 78. Fine-needle aspiration of tumors :this procedure involves aspirating cells and attendant fluid with a small-bore needle, followed by cytologic examination of the stained smear. This method is used most commonly for the assessment of readily palpable lesions in sites such as the breast, thyroid, and lymph nodes 79. Flow cytometry has also proved useful in the identification and classification of tumors arising from T and B lymphocytes and from mononuclear-phagocytic cells 80.Major Tumor markers to be remembered are : CA 125 – Ca ovary CEA – Many tumors including ca colon ,pancreas,lung PSA –Ca prostate AFP –Hepatoma 81.Major immunostains include : Cytokeratin – Carcinomas Vimentin – Sarcomas LCA – Lymphomas S-100 – Neural tumors 82.A sentinel lymph node Is defined as the first node in a regional lymphatic basin that’s receives lymph flow from the primary tumor. 83.RB Gene is the Governer of cell cycle. 84.CA 125 , CA stands for cancer of carbohydrate antigen.
- 6. 83.Mutations that contribute to the development of malignant phenotype are referred to as the driver mutations.Many driver mutations needed to induce cancer. 84.RB Gene is the governer of the cell cycle. 85.In CA 125 , CA stands for Carbohydrate or cancer antigen.
- 7. 83.Mutations that contribute to the development of malignant phenotype are referred to as the driver mutations.Many driver mutations needed to induce cancer. 84.RB Gene is the governer of the cell cycle. 85.In CA 125 , CA stands for Carbohydrate or cancer antigen.