NEOPLASIADepartment of PathologyChang Gung Memorial Hospital

DEFINITIONNeoplasia: the process of new growthNeoplasm (tumor): new growthOncology: the study of tumorsCancer: malignant tumorsGenetic alterations excessive and unregulated proliferation that becomes autonomousArising from a single cell --- tumors are clonal

NOMENCLATURETumors are composed of: 1. Parenchyma: neoplastic cellsDetermines the behavior and pathologic consequences2. Stroma: connective tissue and blood vesselsThe growth and evolution of tumors depend on the stromaAbundant collagenous stroma desmoplasia

NOMENCLATUREBenign tumors: Mesenchymal tumors: attaching -oma to the cell of originFibroblastic cells FibromaCartilage ChondromaOsteoblasts Osteoma

NOMENCLATUREBenign tumors: Epithelial tumors: based on the cells of origin, microscopic architecture, or macroscopic patternAdenoma: forming glandular patterns or deriving from glandsPapilloma: forming papillary projectionsCystadenoma: forming large cystic cavitiesPolyp: projecting into the lumen

NOMENCLATUREMalignant tumors: Mesenchymal tumors: sarcomaFibroblasts FibrosarcomaFat cells LiposarcomaSmooth muscle cells LeiomyosarcomaStriated muscle cells Rhabdomyosarcoma

NOMENCLATUREMalignant tumors: Epithelial tumors: carcinomaAdenocarcinoma: with a glandular pattern microscopicallySquamous cell carcinoma: producing recognizable squamous cells

NOMENCLATUREMixed tumor: with divergent differentiationMixed tumor of salivary gland: epithelial components + myxoid stroma resembling cartilage pleomorphic adenomaTeratoma: composed of cell types of more than one germ layerArising from totipotent cellsPrincipally encountered in the gonads

NOMENCLATUREMelanoma: malignant melanocytic tumorHepatoma: malignant hepatocellular tumor (hepatocellular carcinoma)Seminoma: one of the malignant germ cell tumorsChoristoma: ectopic tissueHamartoma: disorganized tissue indigenous to the particular site

NOMENCLATUREThe nomenclature is important because specific designation have specific clinical implications.For example, cancer of the testis tells little of its clinical significanceSeminoma: tends to spread to lymph nodes; extremely radiosensitiveEmbryonal carcinoma: Not radiosensitive; tends to invade locally and spread throughout the body

BIOLOGY OF TUMOR GROWTHNatural history of malignant tumors: 1. Malignant change of the target cell (transformation)2. Growth of the transformed cell3. Local invasion4. Distant metastases

DIFFERENTIATION AND ANAPLASIADifferentiation: how much the tumor cells resemble comparable normal cells (both morphologically and functionally)Benign tumors: well differentiatedMalignant tumors: ranging from well differentiated to undifferentiatedAnaplasia: lack of differentiation --- a hallmark of malignant transformation

MORPHOLOGICAL CHANGES OF ANAPLASIAPleomorphism (of the cells and the nuclei): variation in size and shapeAbnormal nuclear morphologyHyperchromatic nucleiIncreased nucleus-to-cytoplasm (N/C) ratioVariable nuclear shapeCoarsely clumped chromatinLarge nucleoli

MORPHOLOGICAL CHANGES OF ANAPLASIAMitoses: atypical, bizarre mitotic figures (tripolar, quadripolar, or multipolar)Loss of polarity: growing in a disorganized fashionOther changes: Forming tumor giant cellsCentral areas of ischemic necrosis

DYSPLASIADysplasia:1. Loss in the uniformity of individual cells2. Loss in architectural orientationCarcinoma in situ: severe dysplasia involving the entire thickness of the epithelium without stromal invasion (a preinvasive neoplasm)Dysplasia does not necessarily progress to cancer.

RATES OF GROWTHThe growth rate of a tumor: 1. Doubling time of tumor cells2. Fraction of tumor cells that are in the replicative pool3. Rate at which cells are shed and lostThe growth fraction of tumor cells has a profound effect on their susceptibility to chemotherapy.

CANCER STEM CELLSA rare population of tumor stem cells exists among the heterogeneous group of cells that constitute a tumour. Have been found in breast cancer and acute myeloid leukemiaHave a low rate of replication

LOCAL INVASIONBenign tumors: grow as cohesive expansile massesFibrous capsuleMalignant tumors: progressive infiltration, invasion, and destruction of the surrounding tissueCarcinoma in situ: malignant cytologic features without invasion of the basement membrane

METASTASISMetastasis: tumor implants discontinuous with the primary tumorBenign tumors do not metastasize, whereas malignant tumors can metastasizePathways of spreadingSeeding of body cavities and surfacesLymphatic spread: common in carcinomasHematogenous spread: common in sarcomas

EPIDEMIOLOGYCancer is the #1 cause of death in Taiwan (27.3%, 2008)Cancer deaths In Taiwan (2008)Male: Liver (39.3%) > Lung (36.5%) > Colorectum (17.1%) > Oral cavity (14.8%) > Stomach (10.2%)Female: Lung (16.5%) > Liver (14.7%) > Colorectum 11.8%) > Breast (10.7%) > Stomach (5.1%)

AGEMost carcinomas occur in the later years of life ( 55 years)Common neoplasms of infancy and childhood:NeuroblastomaWilms tumorRetinoblastomaAcute leukemiaRhabdomyosarcoma

GENETIC PREDISPOSITION TO CANCERAutosomal dominant inherited cancer syndromes: Childhood retinoblastoma: RB gene10,000-fold increased risk of developing retinoblastoma, usually bilateralFamilial adenomatous polyposis: APC geneFated to develop colorectal carcinoma by age 50

GENETIC PREDISPOSITION TO CANCERDefective DNA repair syndromesHereditary non-polyposis colorectal cancer (HNPCC): DNA mismatch repair geneFamilial cancers

NON-HEREDITARY PREDISPOSING CONDITIONSChronic inflammation and cancerUlcerative colitis, Crohn disease, Helicobacter pylori gastritis, viral hepatitisPrecancerous conditionsChronic atrophic gastritis, actinic keratosis of the skin, leukoplakia of the oral cavity

MOLECULAR BASIS OF CANCERNon-lethal genetic damage carcinogenesisClonal expansion of a transformed cellPrincipal targets of genetic damage: Growth-promoting protooncogeneGrowth-inhibiting tumor suppressor genesGenes regulating apoptosisGenes involved in DNA repair

MOLECULAR BASIS OF CANCERCarcinogenesis is a multi-step process (tumor progression): accumulation of genetic alterations stepwise acquirement of phenotypic attributes, such as excessive growth, local invasiveness, and the ability to form distant metastases

CHEMICAL CARCINOGENESISInitiation: induction of certain irreversible changes (mutations) in the genome of cellsPromotion: tumor induction in previously initiated cellsThe effect of promoters is relatively short-lived and reversible

RADIATION CARCINOGENESISUltraviolet rays (especially UVB): Damage to DNAInduce an increased incidence of skin cancersIonizing radiation: To induce mutationsMost frequent induced cancers:Leukemias (except for chronic lymphocytic leukemia)Thyroid cancer in children

MICROBIAL CARCINOGENESISOncogenic DNA viruses: Human papillomavirus (HPV): uterine cervical cancerEpstein-Barr virus (EBV): endemic Burkitt lymphoma; nasopharyngeal carcinomaHepatitis B virus (HBV): hepatocellular carcinomaOncogenic RNA virus:Human T-cell leukemia virus type 1 (HTLV-1): adult T-cell leukemia/lymphoma

MICROBIAL CARCINOGENESISHelicobacter pylori:Gastric adenocarcinoma, intestinal typeGastric extranodal marginal zone B-cell lymphoma, mucosa-associated lymphoid tisse (MALT) type (so called MALToma)

EFFECT OF TUMORS ON THE HOSTLocation and impingement on adjacent structuresFunctional activity such as hormone synthesisBleeding and secondary infections when they ulcerate Initiation of acute symptoms caused by rupture or infarction

LOCAL AND HORMONE EFFECTSPituitary adenoma: destroy the remaining pituitary and lead to endocrinopathyIntestinal tumors: intestinal obstruction-cell adenoma of the pancreatic islets: insulin production fatal hypoglycemiaIntestinal tumors: melenaUrinary tract tumors: hematuria

CANCER CACHEXIACachexia: progressive loss of body fat, wasting, and profound weakness in cancer patientsPossible causes: Loss of appetiteReduced synthesis and storage of fat and increased mobilization of fatty acids from adipocytesCytokines

PARANEOPLASTIC SYNDROMESSymptoms not directly related to the spread of tumor or elaboration of hormones indigenous to the tissue from which the tumor aroseCommon paraneoplastic syndromes: EndocrinopathiesHypercalcemiaAcanthosis nigricansClubbing of fingers; hypertrophic osteoarthropathyThrombotic diathesis

GRADING AND STAGING OF TUMORSGrading:The degree of differentiation (higher grade = less differentiation)Presumably reflects the aggressiveness of the tumorStaging:Based on the size of the primary tumor, the extent of spread to regional lymph node, and the presence or absence of blood-borne metastases (TNM system)Staging is of greater clinical value than grading.

LABORATORY DIAGNOSIS OF CANCERHistologic and cytologic methodsSampling approaches: 1. Excision or biopsy2. Fine needle aspiration3. Cytologic smearsFrozen sectionHistologic evaluation within minutes

LABORATORY DIAGNOSIS OF CANCERImmunohistochemistryTo classify poorly differentiated malignant tumorsTo classify leukemias and lymphomasTo determine the primary site of metastatic tumorsTo detect molecules that have prognostic or therapeutic significance

LABORATORY DIAGNOSIS OF CANCERMolecular diagnosisDiagnosis of malignant tumorsPrognosis of malignant tumorsDetection of minimal residual diseaseDiagnosis of hereditary predisposition to cancerDNA microarray analysis and proteomics

LABORATORY DIAGNOSIS OF CANCERFlow cytometryTo identify cell-surface antigens of tumor cells classification of leukemias and lymphomasTo measure the DNA content (ploidy) of tumor cells a prognostic factor in certain malignancies

LABORATORY DIAGNOSIS OF CANCERTumor markersTumor-derived or tumor-associated molecules that can be detected in blood or other body fluidsThey are not primary methods of diagnosis.Main utilitiesTo support the diagnosisTo determine the response of therapyTo indicate relapse during follow-up