Cancerogenesis and neoplasia. Oncology. Markéta Hermanová Neoplasia, tumor - definition n„abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissues and persists after cessation of the stimuli which evoked the change“ (Willis) n nGenetic and regulatory changes →functional dysregulation of proliferation that becomes autonomous + failure of the process of natural cell death n n Clonal proliferation/expansion of the transformed cell n (tumors are monoclonal) n nSporadic mutations in somatic cell or germline mutations n n n Carcinogenesis nMultistep process at both phenotypic and genetic levels n nNonlethal genetic damage (or mutation) n - exogenic factors (radiation, chemicals, viruses,…) n - endogenic factors (toxic radicals, genome instability, failure of n DNA damage repair, chromosomal rearrangements,…) n - germline mutations n nClonal expansion of a single precursor cell that has incurred the genetic damage (tumors are monoclonal) n Targets of genetic damage nThe growth-promoting protooncogenes n(dominant; support of cell proliferation) nThe growth-inhibiting tumor suppressor genes n(recessive; inhibition of growth) -Gatekeepers (p53, RB) -Caretakers (genes involved in maintenance of genome integrity and DNA repair) nGenes regulating he programmed cell death (apoptosis) nGenes involved in DNA repair nOncogenic microRNA Molecular basis of cancer onkol The role of tumor suppressor p53 Composition of tumors: nParenchyma (proliferating neoplastic cells) nStroma (connective tissue and blood vessels, source of mediators promoting the tumor growth and angiogenesis) n(Cancer stem cells – tumor initiating cells) n n nCross-talk between stroma and parenchyma nTumors with abundant parenchyma: soft and flashy nTumors with abundant collagenous stroma – with desmoplastic stroma: stony hard - scirrhous Cancer stem cells – tumor initiating cells nsubpopulation of tumor cells that possess self-renewal properties and are able to differentiate into multiple cell types providing various cell lines, which enable the progression of an incipient tumor n nresistent to conventional therapies n na source of the tumor relapse after eradication of the bulk of the tumor n noncological research focused in further understanding of CSCs and in the development of terapeutic strategies targeted at CSCs. origin scs therapy 2 Cancer stem cell therapy n Classification of tumors nAccording to their biological behavior: -Benign -Semimalignant and potentionally malignant -Malignant n nHistogenetic classification of tumors (morphologic classification according to tissue of origin) -epithelial -mesenchymal -neuroectodermal -germ cell -mixed n Feature Benign tumors Malignant tumors Growth rate slow Relatively rapid Mitoses Infrequent Frequent and often atypical Differentiation Good Variable, often poor Nuclear morphology Often normal Usually hyperchromatic, irregular outline, multiple nucleoli and pleomorphic Invasion No Yes Metastases Never Frequent Border Often circumscribed or encapsulated Often poorly defined, irregular Necrosis Rare Common Ulceration Rare Common on skin and serous surfaces Growth on skin or mucosal surfaces Often exophytic Often endophytic Semimalignant and potentially malignant tumors nDifferent levels of loss of differentiation nTissue and cellular atypia nUsually increased proliferation, atypical mitoses nInvasive, poorly demarcated; sometimes partially expansivelly growing nNo metastases nBasalioma of the skin nDifferentiated nNo tissue and cellular atypia nNo atypical mitoses nExpansivelly growing, often encapsulated nSometimes metastases nPleomorphic adenoma of salivary glands Comparison between benign leiomyoma and malignant leiomyosarcoma Differentiation of tumor nDifferentiation: the extent to which neoplastic cells resemble comparable normal cells, both morphologically and functionally n n nAnaplasia: lack of differentiation (tumor parenchyma resembles the tissues of embryonal organs) n Grading and differentiation of tumors nGrade I: well differentiated tumor nGrade II: moderately differentiated tumor nGrade III: poorly differentiated tumor nGrade IV: undifferentiated/anaplastic tumor n n n* High grade tumors associated with poor prognosis. Metastases nBenign tumors do not metastasize nInvasiveness of malignant tumor enables metastatic spreading n nThree pathways of metastatic spreading: 1.Hematogenous spread 2.Lymphatic spread (especially in carcinomas; sentinel lymph node) 3.Direct seeding of body cavities or surfaces (implantation on serous surfaces (peritoneum, pleura, pericardium), on mucosal layers of tubular organs , withinjoint space, in subarachnoid space, ….) 4. n Risk factors of cancer nGenetic predisposition to cancer nAging nLifestyle (tabacco, diet and nutrition, alcohol, sexual and reproductive behaviors, hormonal exposure) nOccupational or environmental exposure to different carcinogens nStress, immune defficiency n n Genetic predisposition to cancer nAD inherited cancer syndromes (inherited mutation in a single allele of a tumor suppressor gene; the second hit in somatic cells): 1.RB tumor suppressor gene (childhood retinoblastoma) 2.APC tumor suppressor gene (familial adenomatous polyposis) 3.p53 tumor suppressor gene (Li-Fraumeni syndrome) n(MEN 1, 2; NF1,2; p16; BRCA1, 2; VHL; Peutz-Jeghers sy,….) n nDefective DNA repair syndromes (AD) n (hereditary nonpolypoid colon cancer (Lynch sy); MSH2, MSH6, MLH1) n nFamilial cancer (breast, pancreas, ovary) n nAR inherited cancer syndromes (defective DNA repair, genetic instability; Fanconi anemia, ataxia teleangiectasia, xeroderma pigmentosum,…) n nInteractions between genetic and epi-genetic factors 1. 1. Nonhereditary predisposing conditions nChronic inflammation and cancer n nPrecancerous conditions -Adenomatous polyps of colon -Intraepithelial neoplasia (IN)/dysplasia n (CIN (cervical), VIN (vulvar), PanIN (pancreatic), PIN (prostatic) -Atypical ductal or lobular hyperplasia in breast n Dysplasia nIn epithelia n nA loss of uniformity of the individual cells as well as loss in their architectural orientation n nLow grade vs high grade dysplasia; low grade dysplasia often reversible, high grade dysplasia with a high risk of progression into invasive cancer n nIntraepithelial neoplasia/dysplasia = almost synonyms n nHigh grade dysplastic changes involving the entire thickness of the epithelium = preinvasive neoplasm = carcinoma in situ High grade dysplasias/in situ carcinomas 10_01B HG dysplasia/carcinoma in situ in bronchi: dysplasia in metaplastic squamous epithelium in bronchi 19 CIN III : cervical intraepithelial neoplasia, high grade, in metaplastic squamous epithelium in endocervical gland Relationship between inflammation and cancer: increased risk of cancer in chronic inflammation. nIBD (idiopathic bowel disease) – colorectal cancer nHelicobacter pylori chronic gastritis – gastric cancer nchronic viral hepatitis – hepacellular carcinoma nreflux esophagitis (Barret´s esophagus) – esophageal carcinoma nliver fluke infection – cholangiocellular carcinoma nchronic pancreatitis (both sporadic and hereditary)– pancreatic cancer Histogenetic classification of tumors nEpithelial tumors nMesenchymal tumors nNeuroectodermal tumors nGerm cell tumors nMixed tumors Principal characteristics of carcinomas and sarcomas Feature Carcinoma Sarcoma Origin Epithelium Connective/mesenchymal tissue Behaviour Malignant Malignant Frequency Common Relatively rare Preferred route of metastasis Lymph (into lymph nodes) Blood (into liver, bones, brain,…..) In situ phase Yes No Age group Usually over 50 years Usually bellow 50 years Epithelial tumors Epithelium Benign Malignant Squamous Squamous cell papilloma Squamous cell carcinoma Transitional Transitional cell papilloma Transitional cell carcinoma Basal cell Basal cell papilloma Basal cell carcinoma Glandular Adenoma Adenocarcinoma Carcinomas spinaliom01 papilom01 Squamous cell carcinoma Papillocarcinoma Polyps of large intestine _colon-polyps-1-387n _s5-12-tub-adenom-2x-he Adenomatous polyps of large intestine Tubular adenoma, low grade dysplasia Adenocarcinomas _s4-5-carc-10x-he mucinca02 Adenocarcinoma, intestinal type Adenocarcinoma – gelatinous, mucinous Tissue of origin Benign Malignant Smooth muscle Leiomyoma Leiomyosarcoma Striated muscle Rhabdomyoma Rhabdomyosarco-ma Adipose tissue Lipoma Liposarcoma Blood vessels Angioma Angiosarcoma Bone Osteoma Osteosarcoma Cartilage Chondroma Chondrosarcoma Soft tissues Synovial sarcoma Mesothelium Benign mesothelioma Malignant mesothelioma + hematooncological malignancies: leukemias and lymphomas Neuroectodermal umors nTumors of central nervous system (CNS) nTumors of peripheral nervous system (PNS) nTumors of autonomous nervous system (ANS) n (parasympathetic and sympathetic) nMelanocytic tumors Classification of neuroectodermal tumors Cell of origin Tumor Glial cells Astrocytoma (both low grade and high grade) Oligodendroglioma (both low grade and high grade) Glioblastoma (Ependymoma) Primitive neuroectodermal cells Medulloblastoma (CNS) Neuroblastoma (PNS) Retinoblastoma Arachnoidal cells Meningioma Nerve sheath cells Schwannoma, neurofibroma Malignant schwannoma, neurofibrosarcoma ANS Paragangliomas, chemodectomas, pheochromocytoma Pigmented cells/melanocytes Nevus Malignant melanoma Glioblastoma multiforme 20 glioblastom 40x 02 glioblastom 100x 01 Oligodendrogliom Oligodendroglioma Neurinom (Schwannom, neurilemmom) neurinom neurinom 100x 01 neurinom 100x 02 Malignant melanoma 7 7 Germ cell tumors nDerived from germ cells n nSomatic differentiation (teratomas – mature, immature) n nExtrasomatic differentiation (chorioncarcinoma, yolk sack tumor) n ntestis, ovary + extragonadal germ cell tumors in mediastinum, retroperitoneum, epiphyseal region , sacrococcygeal localisation,… n Primitive germ cell of origin Differentiation of primitive cell along the gonadal line (gonocyte, spermatogonia), without developed differentiation potencies - Seminoma Totipotent cell Undifferentiated cell - Embryonal carcinoma Extraembryonally differentiated - Yolk sack tumor - Chorioncarcinoma Intraembryonally differentiated Teratoma (mature, immature, with malignant transformation of somatic elements) - (Polyembryoma) Histogenesis of germ cell tumors -Seminoma (dysgerminoma) -Spermatocytic seminoma -Embryonal carcinoma -Yolk sack tumor -Polyembryoma -Chorioncarcinoma -Teratoma (differentiated mature, differentiated immature, with malignant transformation) n nMixed germ cell tumor (40 %) n nOncomarkers: aFP, hCG, hPL, PLAP, CEA, LDH (detection in serum and/or tissues; diagnostics and monitoring of patients during/after a treatment) n tumor age structure oncomarker Seminoma 40-50 Solid, polygonal clear cells, stromal lymfocytic infiltration. 10 % hCG Embryonal carcinoma 20-30 Undifferentiated, pleiomorphic cells in sheets, solid, tubullary and papillary; necroses 90 % hCG and/or aFP Yolk sack tumor 3 Poorly differentiated cells, broad spectrum arrangement of cuboidal and columnar cells, glomeruloid formation 90 % aFP Chorioncarcinoma 20-30 Cytotrophoblast and syncytiotrophoblast withour villous formation, haemorhage, necroses 100 % hCG Teratoma * Tissues of 3 germ layers in various stage of differentiation 50 % hCG and/or aFP Mixed tumors 15-30 Variable presence of different components; e. g. teratoma+embryonal carcinoma 90 % hCG and/or aFP * no age predilection Germ cell tumors characteristics Diagnosis of neoplasias nEarly detection and staging important for successful treatment nThe role of screening programs in early diagnostics n nLaboratory values (incl. tumor markers), radiography, endoscopy, isotope scan, CT scan, mammography, MRI and tissue biopsy (histopathological examination (incl. molecular pathology and genetics) → tumor typing)) n diagnostic algorithm clinical signs clinical examination yes no diagnostic imaging techniques (x-ray, CT, MRI,…USG,…) suspected cancer yes no exploratory biopsy malignant tumor benign tumor, pseudotumor typing, grading, staging Cancer staging → therapy cancer suspicion Tumor code nWHO International Classification of Diseases for Oncology (ICD-O): numerical classification and coding system by topography and morphology n nTNM Classification of Malignant Tumors (UICC), AJCC Cancer Staging Manual: coding system of tumor stage n nWHO Classification of Tumours, Pathology and Genetics: histologic classification by organ system Tumor code nTopography (localization) C00.0 – C80.9 (lip – unknown primary localization) n Subdivision: C34 lung n C34.0 main bronchus n C34.1 upper lobe n … Tumor code n Morphology (histology): digital n 4 digits – basic histogenetic structure n 8070 – tumor of squamous cell n 8140 – tumor of glandular cell n Tumor code nMorphology (histology): digital n5. digit – biologic behaviour n /0 benign (incl. low grade dysplasia) n /1 uncertain, intermediate biologic behaviour, low malignant potential n /2 high grade dysplasia, carcinoma/melanoma in situ n /3 malignant, primary localization n /6 malignant, metastasis n /9 malignant, unknown if primary or metastatic n n Tumor code nMorphology (histology): digital n 6. digit : grading/differentiation of malignant tumors n1 – 4 well – moderate – low – undifferentiated n8140/0 adenoma n8140/31: well differentiated adenocarcinoma in primary localization System of tumor staging nTNM (tumor, nodes, metastases) system used for solid tumors n nTumor (T): the size of primary tumor; 0-4 n nRegional lymph nodes (N): regional lymph node involvement; 0-4 n nMetastasis (M): 0 if no distant metastasis present; 1 if distant metastases are present Tumor code nT0 no evidence of primary tumor nTis tumor in situ nT1,T2,T3,T4 increasing size/local extension nTX primary tumor cannot be assessed n similarly N0, N1-4, NX nM0,M1 Tumor code nExample: n C16.1 n M-8140/33 npT3,pN3,pM1 nPoorly differentiated adenocarcinoma of stomach fundus with extension into subserosal connective tissue, metastases in 7 or more LN, with distant metastases Seminoma n testis_seminoma_2 Germ cell tumors – undifferentiated: embryonal carcinoma Embryonal_carcinoma_intermed_mag 1603817-1607642-1612177-1704012 Testes_GCT_EC1 Germ cell tumors: extraembryonal differentiation Testes_GCT_ChorioCA1 Testes_GCT_YST5_SchillerDuvall m13370-95 Testes_GCT_ChorioCA5 Choriocarcinoma Yolk sack tumor Germ cell tumors: intraembryonal differentiation n n n Testes_GCT_ImmatureTeratoma2 F%20fel%20ovary%20teratoma%20YB59468%2005wl Mature teratoma Immature teratoma Antineoplastic treatment modalities nCurative (with intent to cure) nPalliative (provides symptomatic relief but does not cure) n nSurgical treatment (in solid tumors with a goal of total resection) nAdjuvant therapies: -Irradiation therapy -Chemotherapy (especially effective in hematooncological malignancies) -Immunotherapy -Hormonal therapy (breast, prostate) -Targeted therapy (biologic therapy); individualized, personalized -Hematopoietic cell transplantation - n*neoadjuvant therapy n (aims to reduce the size or extent of the cancer before using radical treatment intervention) - n n n Paraneoplastic syndromes nLocal effects of tumor growth n n+paraneoplastic effects of tumors n(=signs and symptoms undirect to either primary tumor or its metastases) n n Causes of paraneoplastic syndromes nVasoactive tumor products, produced by tumor cells (e.g. serotonin, histamin, catecholamins, prostaglandins,…) n nEctopic hormone production by tumor cells (ACTH in small cell lung carcinoma,..) n nOsteolytic skeletal metastases causing hypercalcaemia n nUnidentified tumor products or circulating immune complexes (vasculitis, nephritis,…) n nProduction of autoantibodies by tumor cells (paraneoplastic polymyositis, myastenic syndrome, scleroderma,…) n n* musculoskeletal, neurologic and cutaneous manifestations are often in paraneoplastic syndromes n Thank you for your attention…..