Cancerogenesis and neoplasia. Oncology. Markéta Hermanová Neoplasia, tumor - definition  „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) Genetic and regulatory changes →functional dysregulation of proliferation that becomes autonomous + failure of the process of natural cell death Clonal proliferation/expansion of the transformed cell (tumors are monoclonal) Sporadic mutations in somatic cell or germline mutations    Carcinogenesis  Multistep process at both phenotypic and genetic levels Nonlethal genetic damage (or mutation) - exogenic factors (radiation, chemicals, viruses,…) - endogenic factors (toxic radicals, genome instability, failure of DNA damage repair, chromosomal rearrangements,…) - germline mutations   Clonal expansion of a single precursor cell that has incurred the genetic damage (tumors are monoclonal) Targets of genetic damage  The growth-promoting protooncogenes The growth-inhibiting tumor suppressor genes (dominant; support of cell proliferation)  (recessive; inhibition of growth) Gatekeepers (p53, RB) Caretakers (genes involved in maintenance of genome integrity and DNA repair)    Genes regulating he programmed cell death (apoptosis) Genes involved in DNA repair Oncogenic microRNA Molecular basis of cancer The role of tumor suppressor p53 Composition of tumors:    Parenchyma (proliferating neoplastic cells) Stroma (connective tissue and blood vessels, source of mediators promoting the tumor growth and angiogenesis) (Cancer stem cells – tumor initiating cells)    Cross-talk between stroma and parenchyma Tumors with abundant parenchyma: soft and flashy Tumors with abundant collagenous stroma – with desmoplastic stroma: stony hard - scirrhous Cancer stem cells – tumor initiating cells  subpopulation 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 resistent to conventional therapies a source of the tumor relapse after eradication of the bulk of the tumor oncological research focused in further understanding of CSCs and in the development of terapeutic strategies targeted at CSCs.    Cancer stem cell therapy Classification of tumors   - According to their biological behavior: Benign Semimalignant and potentionally malignant Malignant Histogenetic classification of tumors (morphologic classification according to tissue of origin) epithelial mesenchymal neuroectodermal germ cell mixed Feature Growth rate Mitoses Differentiation Nuclear morphology Benign tumors slow Infrequent Good Often normal Malignant tumors Relatively rapid Frequent and often atypical Variable, often poor Usually hyperchromatic, irregular outline, multiple nucleoli and pleomorphic Yes Frequent Often poorly defined, irregular Common Common on skin and serous surfaces Often endophytic Invasion Metastases Border Necrosis Ulceration Growth on skin or mucosal surfaces No Never Often circumscribed or encapsulated Rare Rare Often exophytic Semimalignant and potentially malignant tumors       Different levels of loss of differentiation Tissue and cellular atypia Usually increased proliferation, atypical mitoses Invasive, poorly demarcated; sometimes partially expansivelly growing No metastases Basalioma of the skin       Differentiated No tissue and cellular atypia No atypical mitoses Expansivelly growing, often encapsulated Sometimes metastases Pleomorphic adenoma of salivary glands Comparison between benign leiomyoma and malignant leiomyosarcoma Differentiation of tumor  Differentiation: the extent to which neoplastic cells resemble comparable normal cells, both morphologically and functionally Anaplasia: lack of differentiation (tumor parenchyma resembles the tissues of embryonal organs)  Grading and differentiation of tumors     Grade I: well differentiated tumor Grade II: moderately differentiated tumor Grade III: poorly differentiated tumor Grade IV: undifferentiated/anaplastic tumor * High grade tumors associated with poor prognosis. Metastases   Benign tumors do not metastasize Invasiveness of malignant tumor enables metastatic spreading Three pathways of metastatic spreading: Hematogenous spread Lymphatic spread (especially in carcinomas; sentinel lymph node) 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, ….)  1. 2. 3. Risk factors of cancer      Genetic predisposition to cancer Aging Lifestyle (tabacco, diet and nutrition, alcohol, sexual and reproductive behaviors, hormonal exposure) Occupational or environmental exposure to different carcinogens Stress, immune defficiency Genetic predisposition to cancer AD 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) (MEN 1, 2; NF1,2; p16; BRCA1, 2; VHL; Peutz-Jeghers sy,….)   Defective DNA repair syndromes (AD) (hereditary nonpolypoid colon cancer (Lynch sy); MSH2, MSH6, MLH1) Familial cancer (breast, pancreas, ovary) AR inherited cancer syndromes (defective DNA repair, genetic instability; Fanconi anemia, ataxia teleangiectasia, xeroderma pigmentosum,…) Interactions between genetic and epi-genetic factors    Nonhereditary predisposing conditions  Chronic inflammation and cancer Precancerous conditions Adenomatous polyps of colon Intraepithelial neoplasia (IN)/dysplasia (CIN (cervical), VIN (vulvar), PanIN (pancreatic), PIN (prostatic)  - - Atypical ductal or lobular hyperplasia in breast Dysplasia  In epithelia A loss of uniformity of the individual cells as well as loss in their architectural orientation Low grade vs high grade dysplasia; low grade dysplasia often reversible, high grade dysplasia with a high risk of progression into invasive cancer Intraepithelial neoplasia/dysplasia = almost synonyms High grade dysplastic changes involving the entire thickness of the epithelium = preinvasive neoplasm = carcinoma in situ     High grade dysplasias/in situ carcinomas HG dysplasia/carcinoma in situ in bronchi: dysplasia in metaplastic squamous epithelium in bronchi 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.       IBD (idiopathic bowel disease) – colorectal cancer Helicobacter pylori chronic gastritis – gastric cancer chronic viral hepatitis – hepacellular carcinoma reflux esophagitis (Barret´s esophagus) – esophageal carcinoma liver fluke infection – cholangiocellular carcinoma chronic pancreatitis (both sporadic and hereditary)– pancreatic cancer Histogenetic classification of tumors      Epithelial tumors Mesenchymal tumors Neuroectodermal tumors Germ cell tumors Mixed tumors Principal characteristics of carcinomas and sarcomas Feature Origin Behaviour Frequency Preferred route of metastasis In situ phase Age group Carcinoma Epithelium Malignant Common Lymph (into lymph nodes) Yes Usually over 50 years Sarcoma Connective/mesenchymal tissue Malignant Relatively rare Blood (into liver, bones, brain, …..) No Usually bellow 50 years Epithelial tumors Epithelium Squamous Transitional Basal cell Glandular Benign Squamous cell papilloma Transitional cell papilloma Basal cell papilloma Adenoma Malignant Squamous cell carcinoma Transitional cell carcinoma Basal cell carcinoma Adenocarcinoma Carcinomas Squamous cell carcinoma Papillocarcinoma Polyps of large intestine Adenomatous polyps of large intestine Tubular adenoma, low grade dysplasia Adenocarcinomas Adenocarcinoma, intestinal type Adenocarcinoma – gelatinous, mucinous Tissue of origin Smooth muscle Striated muscle Adipose tissue Blood vessels Bone Cartilage Soft tissues Mesothelium Benign Leiomyoma Rhabdomyoma Lipoma Angioma Osteoma Chondroma Malignant Leiomyosarcoma Rhabdomyosarco-ma Liposarcoma Angiosarcoma Osteosarcoma Chondrosarcoma Synovial sarcoma Benign mesothelioma Malignant mesothelioma + hematooncological malignancies: leukemias and lymphomas Neuroectodermal umors     Tumors of central nervous system (CNS) Tumors of peripheral nervous system (PNS) Tumors of autonomous nervous system (ANS) (parasympathetic and sympathetic) Melanocytic tumors Classification of neuroectodermal tumors Cell of origin Glial cells Tumor Astrocytoma (both low grade and high grade) Oligodendroglioma (both low grade and high grade) Glioblastoma (Ependymoma) Medulloblastoma (CNS) Neuroblastoma (PNS) Retinoblastoma Meningioma Schwannoma, neurofibroma Malignant schwannoma, neurofibrosarcoma Paragangliomas, chemodectomas, pheochromocytoma Nevus Malignant melanoma Primitive neuroectodermal cells Arachnoidal cells Nerve sheath cells ANS Pigmented cells/melanocytes Glioblastoma multiforme Oligodendrogliom Neurinom (Schwannom, neurilemmom) Malignant melanoma Germ cell tumors  Derived from germ cells Somatic differentiation (teratomas – mature, immature) Extrasomatic differentiation (chorioncarcinoma, yolk sack tumor) testis, ovary + extragonadal germ cell tumors in mediastinum, retroperitoneum, epiphyseal region , sacrococcygeal localisation,…    Histogenesis of germ cell tumors Differentiation of primitive cell along the gonadal line (gonocyte, spermatogonia), without developed differentiation potencies - Seminoma Primitive germ cell of origin Undifferentiated cell - Embryonal carcinoma Totipotent cell Extraembryonally differentiated - Yolk sack tumor - Chorioncarcinoma Intraembryonally differentiated Teratoma (mature, immature, with malignant transformation of somatic elements) - (Polyembryoma) - Seminoma (dysgerminoma) Spermatocytic seminoma Embryonal carcinoma Yolk sack tumor Polyembryoma Chorioncarcinoma Teratoma (differentiated mature, differentiated immature, with malignant transformation) Mixed germ cell tumor (40 %) Oncomarkers: aFP, hCG, hPL, PLAP, CEA, LDH (detection in serum and/or tissues; diagnostics and monitoring of patients during/after a treatment)   Germ cell tumors characteristics tumor Seminoma Embryonal carcinoma Yolk sack tumor age structure 40-50 Solid, polygonal clear cells, stromal lymfocytic infiltration. oncomarker 10 % hCG 90 % hCG and/or aFP 20-30 Undifferentiated, pleiomorphic cells in sheets, solid, tubullary and papillary; necroses 3 Poorly differentiated cells, broad 90 % aFP spectrum arrangement of cuboidal and columnar cells, glomeruloid formation Chorioncarcinom 20-30 Cytotrophoblast and syncytiotrophoblast withour villous a formation, haemorhage, necroses 100 % hCG 50 % hCG and/or aFP 90 % hCG and/or aFP Teratoma Mixed tumors * no age predilection * Tissues of 3 germ layers in various stage of differentiation components; e. g. teratoma+embryonal carcinoma 15-30 Variable presence of different Diagnosis of neoplasias   Early detection and staging important for successful treatment The role of screening programs in early diagnostics Laboratory values (incl. tumor markers), radiography, endoscopy, isotope scan, CT scan, mammography, MRI and tissue biopsy (histopathological examination (incl. molecular pathology and genetics) → tumor typing))  diagnostic algorithm clinical signs clinical examination cancer suspicion yes no diagnostic imaging techniques (x-ray, CT, MRI,…USG,…) no suspected cancer Cancer staging → therapy yes benign tumor, pseudotumor exploratory biopsy typing, grading, staging malignant tumor Tumor code  WHO International Classification of Diseases for Oncology (ICD-O): numerical classification and coding system by topography and morphology TNM Classification of Malignant Tumors (UICC), AJCC Cancer Staging Manual: coding system of tumor stage WHO Classification of Tumours, Pathology and Genetics: histologic classification by organ system   Tumor code   Topography (localization) C00.0 – C80.9 (lip – unknown primary localization) Subdivision: C34 lung C34.0 main bronchus C34.1 upper lobe … Tumor code Morphology (histology): digital  4 digits – basic histogenetic structure 8070 – tumor of squamous cell 8140 – tumor of glandular cell Tumor code Morphology (histology): digital  5. digit – biologic behaviour /0 benign (incl. low grade dysplasia) /1 uncertain, intermediate biologic behaviour, low malignant potential /2 high grade dysplasia, carcinoma/melanoma in situ /3 malignant, primary localization /6 malignant, metastasis /9 malignant, unknown if primary or metastatic Tumor code Morphology (histology): digital  6. digit : grading/differentiation of malignant tumors 1 – 4 well – moderate – low – undifferentiated 8140/0 adenoma 8140/31: well differentiated adenocarcinoma in primary localization System of tumor staging  TNM (tumor, nodes, metastases) system used for solid tumors Tumor (T): the size of primary tumor; 0-4 Regional lymph nodes (N): regional lymph node involvement; 04 Metastasis (M): 0 if no distant metastasis present; 1 if distant metastases are present    Tumor code       T0 no evidence of primary tumor Tis tumor in situ T1,T2,T3,T4 increasing size/local extension TX primary tumor cannot be assessed similarly N0, N1-4, NX M0,M1 Tumor code Example: C16.1 M-8140/33 pT3,pN3,pM1 Poorly differentiated adenocarcinoma of stomach fundus with extension into subserosal connective tissue, metastases in 7 or more LN, with distant metastases Seminoma Germ cell tumors – undifferentiated: embryonal carcinoma Germ cell tumors: extraembryonal differentiation Choriocarcinoma Yolk sack tumor Germ cell tumors: intraembryonal differentiation Mature teratoma Immature teratoma Antineoplastic treatment modalities   Curative (with intent to cure) Palliative (provides symptomatic relief but does not cure) Surgical treatment (in solid tumors with a goal of total resection) Adjuvant therapies: Irradiation therapy Chemotherapy (especially effective in hematooncological malignancies) Immunotherapy Hormonal therapy (breast, prostate) Targeted therapy (biologic therapy); individualized, personalized Hematopoietic cell transplantation *neoadjuvant therapy (aims to reduce the size or extent of the cancer before using radical treatment intervention)   - Paraneoplastic syndromes  Local effects of tumor growth +paraneoplastic effects of tumors  (=signs and symptoms undirect to either primary tumor or its metastases) Causes of paraneoplastic syndromes  Vasoactive tumor products, produced by tumor cells (e.g. serotonin, histamin, catecholamins, prostaglandins,…) Ectopic hormone production by tumor cells (ACTH in small cell lung carcinoma,..) Osteolytic skeletal metastases causing hypercalcaemia Unidentified tumor products or circulating immune complexes (vasculitis, nephritis,…) Production of autoantibodies by tumor cells (paraneoplastic polymyositis, myastenic syndrome, scleroderma,…)     * musculoskeletal, neurologic and cutaneous manifestations are often in paraneoplastic syndromes Thank you for your attention…..