General oncology: benign and malignant tumors. Classification. Cancerogenesis. 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 The Hallmarks of Cancer Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57–70. The Hallmarks of Cancer Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646–74. The Hallmarks of Cancer 1. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57–70. 2. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646–74. 3. Hanahan D. Hallmarks of Cancer: New Dimensions. Cancer Discov. 2022 Jan;12(1):31-46. The Hallmarks of Cancer 1. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57–70. 2. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646–74. 3. Hanahan D. Hallmarks of Cancer: New Dimensions. Cancer Discov. 2022 Jan;12(1):31-46. 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 theory 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 Classification of tumors (1): nBenign tumors 1.Suffix –oma (fibroma, chondroma, adenoma, papilloma, cystadenoma,…) 2.Well differentiated (usually organoid – structure of benign tumors with expressed morphological (and functional respectively) similarity of tissue of origin) 3.Usually encapsulated 4.Usually cohesive, expansivelly and slowly growing well-demarcated masses (surrounding tissue often with signs of pressure atrophy); usually easy surgical removal 5.Usually no invasion or infiltration of the surrounding tissue 6.No metastases Classification of tumors (2): nMalignant tumors (malignant epithelial tumors – carcinomas, malignant mesenchymal tumors – sarcomas,….) 1.Loss of differentiation (different levels-tumor well, moderately and poorly differentiated) 2.Locally invasive, poorly demarcated, infiltrating the surrounding tissue 3.Metastases (tumor implants discontinuous with the primary tumor) 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 nThe extent to which neoplastic cells resemble comparable normal cells, both morphologically and functionally nAnaplasia: lack of differentiation (tumor parenchyma resembles the tissues of embryonal organs) n nPleomorphism (variation of cells and nuclei in size and in shape) nIncreased size of nuclei nNuclear atypia (hyperchromasie due to the abundance of DNA, increased N/C ration (nucleus-to-cytoplasm ratio) nIncreased number and size of nucleoli nTumor giant cells nIncreased proliferation – mitoses (atypical, bizarre mitotic figures in malignant tumors) nLoss of polarity nBasophilic cytoplasm n Grading of pancreatic ductal adenocarcinoma Grade Glandular structure Mitoses (per 10 HPF) Nuclear structure Well differentiated (I) - well differentiated tubular or duct-like structures; mucin secreting columnar cells in single layers or papillary projections - desmoplastic stromal reaction <5 slight pleomorphism, small nucleolus Moderately differentiated (II) - moderately differentiated ductal, tubular, microglandular, cribriform structures - irregular mucin production 6-10 conspicious pleomorphism and nucleoli Poorly differentiated (III) - poorly differentiated glandular structures, mucoepidermoid and pleomorphic, undif. structures - abortive mucin production >10 pronounced pleomorphism, enlarged nuclei and prominent nucleoli + grade IV: undifferentiated tumor Well differentiated vs poorly differentiated pancreatic ductal adenocarcinoma WD PD 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 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/premalignant lesions n (dysplasia/intraepithelial neoplasia) n -Adenomatous polyps of colon -CIN, VIN, EIN, PanIN, PIN, -Atypical ductal or lobular hyperplasia 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 n - most low grade dysplasias do not progress into invasive carcinoma n - high risk of progression into invasive carcinoma in high grade dysplasia n nIntraepithelial neoplasia/dysplasia n nDysplastic changes can involve the entire thickness of the epithelium – preinvasive neoplasm – carcinoma in situ 10_01B Carcinoma in situ 19 Cervical intraepithelial neoplasia grade III/ CIN III = high grade The role of inflammation in carcinogenesis nproduction of reactive oxygen species (ROS), cytokine release, and upregulation of pro-inflammatory transcription factors n nMediators of the inflammatory pathways (e.g., NF-κB, COX-2, 5-LOX, IL-8,…): -induce genetic damage -promote cell proliferation -inhibit apoptosis -regulate the tumor associated angiogenesis Relationship between inflammation and cancer. nIBD – colorectal cancer nHelicobacter pylori chronic gastritis – gastric cancer nchronic viral hepatitis – hepacellular carcinoma nesophagitis (Barret´s esophagus) – esophageal carcinoma nliver fluke infection – cholangiocellular carcinoma nchronic pancreatitis – pancreatic cancer Pancreatic intraepithelial neoplasms (PanIN): microscopic precursor of pancreatic ductal adenocarcinoma. PanIN 1A, 1B, 2 = low grade, PanIN3 = high grade nPanIN-1A nPanIN-1B nPanIN-2 nPanIN-3 n panin PanIN: non-invasive intraductal epithelial proliferation Oncogenesis of pancreatic ductal adenocarcinoma: current accepted linear model of progression. nActivation of oncogenes n KRAS, MYB, AKT2, AIB1 nInactivation of tumor suppressor genes n p16, TP53, DPC4, BRCA2, LKB1/STK11 nDNA Mismatch Repair n MSH2, MLH1,…. nEpigenetic alterations, dysregulation of oncoproteins, activation of Hedgehog and Notch signalling pathways n n Hruban et al. Progression model of pancreatic cancer. Clin Cancer Res 2000; 6: 2969-2972. PanIN lesions: low grade vs high grade PANIN_86 PANIN_29 PANIN_19 PANIN_42 PanIN 1A PanIN 2 PanIN 3 PanIN 1B Histogenetic classification of tumors nEpithelial tumors n nMesenchymal tumors n nNeuroectodermal tumors n nEmbryonal tumours n (germ cell tumors + organ specific (hepatoblastoma, n pancreatoblastoma, nephroblastoma,…) n 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 tumours nFrom superficial epithelium n (papilloma/carcinoma) n nFrom glandular epithelium (adenoma/adenocarcinoma) n nFrom specialized organs (adenoma/adenocarcinoma)…liver, kindey, adrenal gland n n 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 Squamous cell carcinoma (skin, oral cavity, oesophagus,…lung (squamous metaplasia) spinaliom01 Squamous cell carcinoma Squamous cell carcinoma spinaliom03 spinaliom04 Keratinisation, mitoses in SCC Intercellular bridges- tonofilaments Papillocarcinoma – urinary bladder papilom01 Poorly differentiated carcinoma High mitotic count Pleomorfism, anizocytosis, anizonucleosis, hyperchromasia, prominent nucleoli, …. Immunohistochemistry in dagnostics of poorly differentiated tumours, tumours of unknown origin,.. Markers of epithelial tissue: cytokeratins, EMA, CEA,…. Adenoma – benign tumour – glandular epithelium nAdenomatous polyps of colon and rectum - adenomas: § tubullar § vilous § tubulovillous - - - § acinar (salivary glands) § follicular (thyroid gland) § solid (liver, adrenal gland) § cystadenoma (ovarium): uniloculare, multiloculare; papilliferum, evertens) § oncocytic - oncocytoma n - Adenomatous polyp – tubullar adenoma _colon-polyps-1-387n _s5-12-tub-adenom-2x-he Adenomatous polyps of large intestine Tubular adenoma, low grade dysplasia Multiple adenomatous polyps in familiar adenomatous polyposis (AD; APC gene) Follicular adenoma - thyroid 9 adenom stitnice2 Cystadenoma – ovary Mucinous versus serous WHO-OvarianTumours_017 06 Oncocytoma 07-02-28-1-12 07-02-28-1-11 Expression of mitochondrial antigen - immunohistochemistry Adenocarcinoma (malignant, from glandular epithelium) § Medullary (parenchyma > stroma) § Scirhotic (↑desmoplastic stroma) § nAdenocarcinoma - GIT (colorectal, stomach, …..): § Intestinal type § Diffuse (scirhotic) § Mucinous, gelatinous - nHepatocelullar carcinoma (trabecular) nAdenoid cystic carcinoma (salivary gland, respiratory tract) nCarcinomas of glands of mesodermal origin (renal cel carcinoma) - - - - - - _s4-5-carc-10x-he mucinca02 Adenocarcinoma, intestinal type Adenocarcinoma – gelatinous, mucinous _s4-6-zaludek-dif-ca-40x-he _s4-6-ca-diff-zaludek-40x-pas Diffuse adenocarcinoma; with signet ring cells (PAS+ mucin) HE PAS _s4-5-carc-10x-he mucinca02 Adenocarcinoma, intestinal type Adenocarcinoma – gelatinous, mucinous Neuroendocrine neoplasia (NEN) nDefinition n nNENs are epithelial or neuroectodermal neoplasias defined by the presence of small or large vesicular granules containing proteins with hormonal or neural effects, expressing markers of membrane proteines localized on small „synaptic“ vesicles (synaptophysin) or large „hormonal“ granules “ (chromogranin A) Neuroendocrine neoplasia (NEN) (carcinoid tumours) nSpectrum of tumours from well differentiated neuroendocrine tumours (previously called carcinoids) to poorly differentiated neoplasms with neuroendocrine features (small and large cell neuroendocrine carcinoma) n n Localisation: GIT, respiratory tract,… (derived from neuroendocrine cells in this organs) n nNeuroendocrine differentiation (neurosecretory granules: chromogranin+, synaptofysin+ …detected by immunohistochemistry) n n nAssociated paraneoplastic syndromas -carcinoid syndroma- serotonin n(skin flushing, abdominal pain, diarrhea, difficulty breathing, rapid heart rate, low blood pressure, skin lesions on the face (telangiectasias), and wheezing, fibrosis of tricuspidal and pulmonary valves) n -Cushing syndroma – ACTH - -syndrome of inappropriate antidiuretic hormone (SIADH) secretion - -Eaton-Lambert syndroma n(autoimmune myastenic disorder characterized by muscle weakness of the limbs, antibodies against presynaptic voltage-gated calcium channels) Neuroendocrine tumour (NET) Neuroendocrine carcinoma (NEC) nNeuroendocrine tumor - NET G1/G2/G3 n well differentiated neuroendocrine tumor n low grade (G1/G2) and high grade (G3) n (previously called carcinoids and atypical, malignant carcinoids) n nNeuroendocrine carcinoma - NEC (G3) n poorly differentiated neuroendocrine neoplasm n neuroendocrine carcinomas, high grade malignant tumors - Small cell neuroendocrine carcinoma - Large cell neuroendocrine carcinoma - nMixed neuroendocrine noneuroendocrine neoplasm (MiNEN) n(previously called MANEC) n Well differentiated neuroendocrine neoplasia Neuroendocrine tumour – NET (previously carcinoid) Poorly differentiated neuroendocrine neoplasm Neuroendocrine carcinoma (NEC) Small cell neuroendocrine carcinoma MALOB02 MALOB03 Mesenchymal tumors 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 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 nPrecursor lesion of testicular germ cell tumours: germ cell neoplasia in situ (GCNIS) 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 nGerm cell tumor of a single histological type (pure forms) -Seminoma/dysgerminoma nNon-seminomatous germ cell tumour: -Embryonal carcinoma -Yolk sack tumor -Polyembryoma -Chorioncarcinoma -Teratoma n - differentiated mature n - differentiated immature n - with malignant transformation – with somatic type malignancy 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 * Prepubertal and postpubertal type (often within mixed germ cell tumorus) Germ cell tumors characteristics Classification of testicular germ cell tumours nGerm cell tumours derived from GCNIS n(aggressive, oncological therapy) n nTumours of a single histological type (pure forms) n Seminoma n Non-seminomatous germ cell tumours n - Embryonal carcinoma n - Yolk sack tumours, postpubertal type n - Choriocarcinoma n - Teratoma, postpubertal type n nMixed germ cell tumorus (of more than one histological type) n n nGerm cell tumours unrelated to GCNIS n(biologically favourable) n - Spermatocytic seminoma (older men, locally aggressive, nonmetastic) n - Teratoma – prebubertal type n - Yolk sack tumour – prepubertal type n - Mixed teratoma and yolk sack tumour – prepubertal type 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 Extragonadal germ cell tumors (EGT) nGerm cell tumor in primary extragonadal localisation, M>F n nFrom primordial germ cells? Migration failure? Localisation failure of totipotent cells? Ectopic germ cell in healthy individuals? n nIn midline structures (descent tracts of germ cells into the gonadal blastema) -Diencephalopineal region, sacrococcygeal region, in anterior mediastinum, retroperitoneum,…, thymus, prostate, stomach,…… -Seminomatous and nonseminomatous, both poor and mixed -A worse prognosis; exception: EG seminoma n n Mesothelioma nPleura, peritoneum, pericardium, tunica vaginalis, genital tract (benign adenomatoid tumor) n nMalignant mesothelioma 1.Epitheloid type 2.Sarcomatoid type 3.Mixed type 4. -Asbestos exposure -50 % die within 12 months - nBenign mesotheliomas rare: n- Well differentiated papillary mesothelioma -Benign adenomatoid tumour (tunica vaginalis, genital tract) - -Solitary fibrous tumor – soft tissue tumour - previously called benign mesothelioma - n 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; central nervous system, cerebellum) Neuroblastoma (PNS; peripheral nervous system, adrenals) Retinoblastoma …..all mentioned are pediatric tumors Arachnoidal cells Meningioma Nerve sheath cells Schwannoma, neurofibroma Malignant schwannoma, neurofibrosarcoma ANS; autonomous nervous system Paragangliomas, chemodectomas, pheochromocytoma + secondary, metastatic tumors CNS tumors nClinicopathological features: nCNS tumors do not metastasise to othe organs - (only infiltration of adjacent tissues and spreading through - CSF pathways) nLocal effects -Signs related to the site of the tumor -e.g. epilepsy with a temporal lobe tumor, paraplegis in spinal cord tumor nMass effects -Signs and symptoms of space occupying lesions -Vasogenic oedema around CNS tumor -Herniation -Hydrocephalus in posterior fossa tumor 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 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…..