NEOPLASIA (TUMOR) (ONCO-) PDF

NEOPLASIA (TUMOR)(ONCO-) PATH-333, KKU, 2017 Prof. B.K.Adiga  DEFINITION Sir Willis abnormal mass of Monoclonal tissue (NEW GROWTH), with uncoordinated growth, which Persist...

NEOPLASIA (TUMOR)(ONCO-) PATH-333, KKU, 2017 Prof. B.K.Adiga  DEFINITION Sir Willis abnormal mass of Monoclonal tissue (NEW GROWTH), with uncoordinated growth, which Persists even after removal of stimuli Transformed / Neoplastic cell 15/11/15 Prof.adiga,KKU. 2  Cell or tissue type Benign Malignant ……oma …carcinoma/…sarcoma Epithelial tissue: 1.Surface epithelium - ….Carcinoma-SCC,BCC,TCC Papilloma Adenocarcinoma 2.Glandular- Adenoma Mesenchymal or …..Sarcoma C.Tissue Adipose tissue Lipoma Liposarcoma Fibrous tissue Fibroma Fibrosarcoma Cartilage tissue Chondroma Chondrosarcoma Bone Osteoma Osteosarcoma Smooth muscle Leiomyoma Leiomyosarcoma Striated muscle Rhabdomyoma Rhabdomyosarcoma 15/11/15 Prof.adiga,KKU. 3  Misnomers: Tumor-not benign. Not tumors. Lymphoma, Granuloma, Hepatoma Tuberculoma, Melanoma Seminoma, Atheroma, Mesothelioma Mycetoma; Choristoma 15/11/15 Prof.adiga,KKU. 4  TERATOMA Germ cell tumor showing tissues of 3 embryonic layers(ectoderm,endoderm,mesoderm) 3 types- Mature cystic teratoma(benign-dermoid cyst); immature teratoma(malignant) & specialised teratoma (struma ovarii) 15/11/15 Prof.adiga,KKU. 5  Character Teratoma Embryonal tumours(blastoma) Origin Germ cell Embryonic cell Age Young& middle age Within first 5 years of life Behaviour Benign or malignant Highly malignant Sites Ovary(most Kidney, brain, adrenal. common).testes,midline Retina,liver, types Mature, Immature Nephroblatoma, Medullo... monodermal Neuro…,Retino…, Hepato…, Cystic Teratoma 15/11/15 Prof.adiga,KKU. 6 CHARACTERISTICS- BENIGN/MALIGNANCY BENIGN MALIGNANT SLOW RATE OF GROWTH RAPID Well circumscription/ + _ CAPSULE DIFFERENTIATION WELL DIFFERENTIATION WELL TO POOR (maturity) DIFFERENTIATION INVASION _ (grows by expansion) + METASTASIS _ (localised) (distant spread) + 15/11/15 Prof.adiga,KKU. 7 Differentiation: Well,Moderate,Poorly.Anaplasia: Undifferentiated(loss of differentiation). 15/11/15 Prof.adiga,KKU. 8  INVASION: Local spread a) Detachment of tumour cell from each other: reduced adhesiveness to one another, due to diminished formation of spot desmosome & loss of E-cadherin b) Adhesion of tumour cells to matrix components: Attachment of tumour cells to laminin & fibronectin c)Degradation of ECM : Discharge of lysosomal enzymes- release of collagenase, stromlysin and other proteinases- damaging the surrounding cells & stromal elements d) Locomotion (Migration of tumour cell): Cancer cells have increased motility due to Autocrine motility factor 15/11/15 Prof.adiga,KKU. 9  METASTASIS (DISTANT SPREAD) process whereby malignant cells spread from site of origin (primary tumour) to form other tumours (secondary) at distant sites. Most definitive feature of malignancy Metastatic pathways: 1)Lymphatic spread.(common in carcinoma) 2)Blood spread.(common in sarcoma) 3)Intracavitary spread (transcoelomic/epithelial surface- common in ovary(Krukenberg tumor)). 4)Implantation (surgical wound) Angiogenesis:angiogenic factors(VEGF,FGF) produced by tumour cells/ inflammatory cells 15/11/15 Prof.adiga,KKU. 10  NODAL METASTASIS -Distant lymphnode groups are affected latter ;finally the thoracic duct is involved and the malignant cells enter the general circulation -Sentinel node – first regional lymphnode affected by cancer -Retrograde lymphatic spread is a spread in a reverse direction to the usual flow ▪ Morphology of lymphnode- enlarged, hard, C/S-greywhite Virchows node Metastases in lymphnode 15/11/15 Prof.adiga,KKU. 11  Common sites for DISTANT METASTASIS Through systemic veins- to lung; through portal veins- to liver. Bone also common site; usually osteolytic lesion, rarely osteoblastic(prostate cancer) 15/11/15 Prof.adiga,KKU. 12  MORPHOLOGY OF COMMON TUMORS GROSS SURFACE – Smooth/irregular/shape/size/ulceration/invasion/capsulated/well circumscribed CUT SECTION – solid/cystic/hemorrhage/necrosis MICROSCOPY – capsule/invasion/differentiation/pleomorphism/mitosis/necrosis/lymphovascular invasion 15/11/15 Prof.adiga,KKU. 13  Benign Epithelial Tumours Papilloma: tumours of surface epithelium appear as warty or finger like projections(papillae), lined by epithelium & show fibro-Vascular core. Types- squamous/Columnar/Transitional ADENOMA: tumour derived from glandular or secretory cells. Types- solid/cystic/papillary cystic/sessile/ pedunculated ▪ POLYP: Tumor/ swelling protruding into hallow organ, commonly adenoma/papilloma. 15/11/15 Prof.adiga,KKU. 14  Benign mesenchymal tumors: LEIOMYOMA: tumour of smooth muscles, most common in uterus; single or multiple. It is spherical, Sharply demarcated(although without fibrous capsule). C/S: solid with a pale grey or pink whorly appearance Micro:Interlacing bundles of smooth muscle fibres in whorled pattern LIPOMA: tumour of the lipocyte. Sites:usually subcutaneous (shoulder, back, buttock) tissue G/P: mobile, painless, lobulated soft mass variable in size (3-5)cm. ‫رقيقه‬ C/S: bulging, pale yellow& greasy; delicate fibrous capsule. 15/11/15 Prof.adiga,KKU. 15  Malignant epithelial tumours (CARCINOMA) Account for 90% of death from Cancer. Middle and old age (40-60). Gross:infiltrating solid mass/ Malignant ulcer/ Polypoid (fungating or exophytic) mass. Consistency: usually hard(due to desmoplasia) 15/11/15 Prof.adiga,KKU. 16 Ulcerative Type: starts as dome shaped mass, centre of which undergo ischaemic necrosis, later leaving an ulcer with irregular, elevated everted /rolled margins. Depending on extent of desmoplasia: ▪ Medullary carcinoma- When the desmoplastic reaction is slight, groups of tumour cells are large and separated by thin fibrovascular tissue; ▪ Scirrhous carcinoma-When small groups of tumor cells embedded in abundant dense fibrous tissue, tumor feels hard. 15/11/15 Prof.adiga,KKU. 17 15/11/15 Prof.adiga,KKU. 18  Squamous cell carcinoma ▪ Site: Skin,mouth,pharynx,oesophagus,anus. Also in sites where stratified squamous epithelium develops by metaplasia(lung,cervix) ▪ MICRO: at the base of dysplastic epithelium, carcinoma cells seen infiltrating into the underlying connective tissue. ▪ As the groups of carcinoma cells enlarge, the older cells come to the center producing keratin, giving characteristic laminated appearance called epithelial pearls(cell nests). ▪ amount of keratin is the best guide to its degree of differentiation 15/11/15 Prof.adiga,KKU. 19  ADENOCARCINOMA malignant cells are arranged in acinar pattern, Degree of differentiation depends on amount of gland formation. Sites: common in large intestine, breast, stomach, prostate,ovary etc. Types:Cystadenocarcinoma - Tumour with actively secreting cells, cystic spaces are formed&lined by malignant cells;common in ovary Papillary adenocarcinoma - papillary processes, lined by carcinomatous epithelium, project into lumen;common in thyroid Mucoid adenocarcinoma - excessive extracellular mucin secretion;common in colon Signet ring cell carcinoma – excessive intracellular mucin secretion pushing nucleus to periphery; no gland formation; common in stomach 15/11/15 Prof.adiga,KKU. 20  locally malignant tumour (BORDERLINE MALIGNANT TUMOR) Usually locally recurrent, & no metastasis. E.g.- Basal cell carcinoma,skin; Borderline serous/mucinous ovarian tumors; Oral Verrucous carcinoma ; Osteoclastoma 15/11/15 Prof.adiga,KKU. 21  CARCINOMA IN SITU (Intraepithelial or preinvasive carcinoma) early malignant changes in epithelial cells affecting full thickness of epithelium;before invasion of the basement membrane. Gross: difficult to be detected by naked eye, but may appear as slight thickening(cervix uteri, skin,buccal mucosa/bronchial mucosa) Micro: epithelium show features of malignancy(pleomorphism, inreased N/C ratio,hyperchromatism,mitosis),loss of polarity. 15/11/15 Prof.adiga,KKU. 22  MALIGNANT MESENCHYMAL TISSUE TUMOURS( SARCOMA) cause only about 3% of death from all forms of cancer. Cut surface- fleshy, pink with necrosis/hemorrhage Arranged singly, spindly/polygonal, frequent giant cells Highly vascular& blood vessels poorly formed- hemorrhage & early blood spread 15/11/15 Prof.adiga,KKU. 23 character carcinoma Sarcoma Definition Malignant epithelial tumour Malignant mesenchymal tumour Incidence very common Much less common Age In middle & old age Occurs at all times of life; Gross picture Fungating,ulcerative / infiltrative Form bulky mass vascularity Less vascular More vascular Growth Some what slowly growing usually very rapid metastases a)early lymphatic metastases a)lymphatic spread rare b)Blood b)blood metastases a little later born metastases common& early Radiosensitivity radiosensitive radioresistant Structure arranged in groups and columns. a)Arranged in diffuse sheets. Stroma well formed. Haemorrhage b)Stroma poorly formed. necrosis less extensive except in c)Haemorrhage and necrosis anaplastic tumours extensive 15/11/15 Prof.adiga,KKU. 24  GRADING OF CANCER Based on the microscopic appearance of a neoplasm. Depend on degree of differentiation higher grade means-lesser degree of differentiation and the worse the biologic behavior of neoplasm. I Well differentiated II Moderately differentiated III Poorly differentiated IV Nearly anaplastic (Undifferentiated) 15/11/15 Prof.adiga,KKU. 25  Staging of cancer Based on extent of spread of the tumour clinically Higher stage means- more spread-bad prognosis E.g.-AJC staging of Carcinoma cervix; Stage Extent of spread 0 Carcinoma in situ (no invasion) I Confined to the cervix II Limited local spread III Great local spread e.g. to lower vagina/pelvis IV Lymph node or distant metastases. 15/11/15 Prof.adiga,KKU. 26  TNM System of staging depends on the size of the primary tumour, Its extent of spread to regional lymph nodes and the presence or absence of metastasis. T1.T2.T3.T4 indicate the size of tumour (No) absence of lymph node involvement (N1) involvement of few L.N. (N2) Many nodes (M0) No distant spread, (M1) few distant spread (M2)many distant spread e.g. T2.N1.M0 15/11/15 Prof.adiga,KKU. 27  TUMOUR MARKERS tumour associated molecules that can be detected in the serum. The substance is not tumour-specific ‫النها مواد طبيعيه في الجسم وليست خاصه‬ ‫ زيادتها تدل ع السرطان‬، ‫بالسرطان‬ May be used as a diagnostic marker because it is secreted in much greater quantities by tumour cells. :‫نستخدمها ملعرفة‬ Mainly useful to monitor the disease course after treatment(prognostic) and to detect recurrence of tumor. E.g.- HCG- Choriocarcinoma AFP-Hepatocellular carcinoma Calcitonin-Thyroid medullary ca. CA125- Ovarian serous ca. PSA- Prostate adenoca. 15/11/15 Prof.adiga,KKU. 28  CLINICAL FEATURES OF neoplasms Secretion- hormones, chemicals- systemic effects, Pressure effects – on organs, adjacent structures Ulceration-bleeding, infection Obstructions- in hollow organs/ducts Invasion- direct spread – organ damage Recurrence – organ damage Lymphnode metastasis – massive/radical surgery Distant Metastasis –organ damage- incurable Effects of chemotherapy/radiotherapy-immunosuppression 15/11/15 Prof.adiga,KKU. 29  Paraneoplastic syndrome: syndromes that are not the result of direct effects of tumour but due to substances secreted by certain tumours derived from nonendocrine cells(ectopic hormone secretion) Clinical syn. Forms of cancer Causal mechanism Cushing syndrome Bronchogenic (small cell) ACTH orACTH –like carcinoma substance hyponatremia. bronchogenic carcinoma. ADH or ADH-Like sub hypercalcemia Sq. cell carcinoma of the lung PTH-like substance Thrombophlebitis Adenocarcinoma pancreas Procoagulants 15/11/15 Prof.adiga,KKU. 30  Malignant cachexia patients with cancer, suffer from loss of appetite, loss of weight associated with loss of depot fat and catabolism of muscle protein, weakness and tiredness. due to secretion of cyto-proteins (such as tumour necrosis factor TNF). 15/11/15 Prof.adiga,KKU. 31 ‫مواد مسرطنه‬  CARCINOGENESIS Cancer - Genetic disease of somatic cells Caused mainly by environmental factors Not contagious; usually not hereditary Less than 10% - familial / hereditary(germ cell mutation) Carcinogen- cancer causing agent; Mutagen - agent causing mutation. MAJOR Carcinogens: Chemicals, Radiation, Biological(viral/bacterial), chronic inflammation 15/11/15 Prof.adiga,KKU. 32  ❖Carcinogenic process: multistep process require initiating and promoting agents. growth persists in the absence of the causative agents – ‘HIT & RUN” Initiation: event that actually induce the lesion in the cells genome, that bestows neoplastic potential(transformed cell). Promotion: event stimulating clonal proliferation of the initiated transformed cells(monoclonal) Progression:events of further many mutations & acquiring new characteristics 15/11/15 Prof.adiga,KKU. 33  Chemical Carcinogenesis Direct-acting Compounds(No metabolic conversion required) Indirect - acting Compounds( Procarcinogens ) Metabolic Activation Ultimate Carcinogens Form covalent bonds with DNA & RNA 15/11/15 Prof.adiga,KKU. 34  2 - Naphthylamine Liver Hydroxylation 2 -Amino-1-naphthol [ Powerful carcinogen ] Detoxification Glucuronide Bladder Beta Glucuronidase Papillary 2 -Amino -1- naphthol tumour ( Powerful carcinogen ) 15/11/15 Prof.adiga,KKU. 35  Major Chemical Carcinogens: A. Direct acting carcinogens 1. Alkylating agents a) Beta - propiolactone b) Dimethyl sulphate 2. Acylating agents a) 1 - acetyl - imidazole b) Dimethyl carbamyl chloride B. Procarcinogens 1. Polycyclic & heterocyclic aromatic hydrocarbons a) Benzanthracene b) Benzopyrene 2. Aromatic Amines, Amides, Azo dyes a) 2 - Naphthylamine ( B - Naphthylamine ) 4. Others b) Benzidine * Nitrosamines 3. Natural plant & microbial products * Vinyl chloride * Asbestos a) Aflatoxin B1 – Aspergillus flavus * Nickel & chromium 15/11/15 Prof.adiga,KKU. 36  Cigarette Smoking & Lung Cancer 3, 4 Benzopyrene Affects about 10% Smokers(Aryl hydrocarbon hydroxylase ) Other tumours associated with smoking: Carcinoma of Esophagus,Pancreas, kidney, Urinary bladder Hormones And Neoplasia: Breast Cancer Carcinoma of Endometrium Carcinoma of Prostate 15/11/15 Prof.adiga,KKU. 37  Some common chemical carcinogens 15/11/15 Prof.adiga,KKU. 38  Radiation carcinogenesis 15/11/15 Prof.adiga,KKU. 39  Effect of radiations on cells *The ionizing radiation- Acute leukaemia, Papillary thyroid carcinoma Ultraviolet radiation – skin cancer- SCC,BCC,Melanoma 15/11/15 Prof.adiga,KKU. 40  Viral carcinogenesis Oncogenic DNA viral genome is directly incorporataed into host cell DNA. Oncogenic RNA viral genome is transcribed into DNA by reverse transcriptase prior to incorporation(oncogenic retrovirus) 15/11/15 Prof.adiga,KKU. 41  Oncogenic viruses VIRUS TUMOR Human Papilloma Virus(HPV 6, 11) Squamous cell papilloma Human Papilloma Virus (HPV16, 18) Cervical carcinoma Epstein Barr Virus Burkitts lymphoma, Nasopharyngeal carinoma Hepatitis B Virus Hepatocellular carcinoma HTLV T cell leukaemia/Lymphoma HIV Cerebral Lymphoma 15/11/15 Prof.adiga,KKU. 42  Heredity and Cancer Hereditary predisposition Close relatives of cancer patients have three times greater risk of developing the same neoplasm(breast, colon, endometrium, ovary, endocrine cancer)…..Lynch syndrome Increased cancer risk with inherited mutations of tumor suppressor genes. Occur in younger age and may be multiple often called hereditary nonpolyposis colorectal cancer (HNPCC) 15/11/15 Prof.adiga,KKU. 43  Premalignant conditions Local/systemic disorders giving rise to increased risk of developing malignant neoplasms Hereditary preneoplastic disorders: – Proliferative states: Familial polyposis of the colon, basal cell nevus syndrome of the skin. – Unstable DNA syndromes (xeroderma pigmentosa). Acquired Preneoplastic Disorders – Regenerative, hyperplastic, and dysplastic proliferations - e.g.. chronic ulcerative colitis, Chronic non-healing ulcer, cervical dysplasia, Barretts esophagus, Urinary bladder bilharziasis, liver cirrhosis, endometrial hyperplasia, colonic villous adenoma. 15/11/15 Prof.adiga,KKU. 44  MOLECULAR BASIS OF CANCER GENES AFFECTED: 1. PROTO-ONCOGENES[ ONCOGENES ] 2. TUMOUR SUPPRESSOR GENES, 3. GENES THAT REGULATE APOPTOSIS, 4. DNA REPAIR GENES (Indirect) 5. Telomerase gene(cell immortality) Stages of cell growth stimulation: 1.Growth factor binding to its receptor, 2.Transient activation of growth factor receptor activates signal transducing proteins, 3.Transmission of signal across the cytosol to the nucleus [ second messengers ], 4.Induction and activation of nuclear transcription, 5. Entry of the cell into the cell cycle 15/11/15 Prof.adiga,KKU. 45  Selected oncogenes & associated tumours Growth factor receptors: EGF- receptor family = erb-B1 -SCC lung, erb-B2 - Breast, ovarian, lung, stomach ca Signal transducing proteins: GTP - Binding = ras - cancers of lung, colon, pancreas etc., Non-receptor tyrosine kinase = abl - CML, Nuclear Regulatory Proteins: Transcriptional activators = myc - Burkitt lymphoma, N-myc - Neuroblastoma, 15/11/15 Prof.adiga,KKU. 46  Tumour Suppressor Genes: Rb - retinoblastoma, Osteosarcoma, p53 - Most common human mutation among cancers, - Molecular policeman/ Guardian of the genome WT-1 - Wilm’s tumour, P16 (INK4a) - Pancreatic,breast, esophageal cancers, melanoma; BRCA-1 & 2 – Carcinomas of breast, ovary NF-1 - Neuroblastomas, Neurofibromatosis – I NF-2 - Schwannomas & meningiomas, Neurofibromatosis type II APC - Familial adenomatous polyposis coli/ carcinoma colon, stomach 15/11/15 Prof.adiga,KKU. 47 ROLE OF VARIOUS GENES 15/11/15 Prof.adiga,KKU. 48  HALLMARKS OF CANCER CELL :Autonomous & Instability 15/11/15 Prof.adiga,KKU. 49 CANCER - MULTISTEP PROCESS 15/11/15 Prof.adiga,KKU. 50  DIAGNOSTIC PROCEDURES FNAC (fine needle aspiration cytology) cytological smears(Pap smear for cervical cancer) Biopsy(most definitive investigation) frozen sections(per operative procedure) TECHNIQUES of BIOPSY: Needle biopsy:1-2 mm wide & 2cm long Endoscopic biopsy;2-3 mm size, multiple Incision biopsy: sample is variable in size depending onnature of lesion. Excision biopsy: whole abnormal lesion surgically removed. 15/11/15 Prof.adiga,KKU. 51  ancillary studies Immunohistochemistry(e.g. cytokeratin for carcinoma, LCA for lymphoma, Vimentin for sarcoma, AFP for yolk sac tumor,PSA-prostate ca,ER-breast ca) Cytogenetics (e.g. Ewing sarcoma) flow cytometry(e.g.leukaemia/lymphoma) electron microscopy(e.g. neurosecretory granules in neuroendocrine tumor) 15/11/15 Prof.adiga,KKU. 52  SCREENING TESTS Investigations for the early diagnosis of premalignant/early malignant conditions. Examples:- PAP smear – cervical dysplasia/carcinoma Serum PSA – prostate carcinoma Stool occult blood – colonic carcinoma Mammography – breast carcinoma 15/11/15 Prof.adiga,KKU. 53