2 Starts with vocabulary tumor (L.) = oncos (G.) = swelling = neoplasmneoplasm = new growth-oma = tumor; appended to tissue root = benign tumor of the tissue typefibroma, adenoma, papilloma, lipomafibrous tissue, glandular tissue, wartty, fattycancer = crab = malignant neoplasmcarcinoma = malignant tumor of epitheliumsarcoma = fleshy swelling = malignant tumor of mesenchymal tissue
3 Odd misuses of vocabulary Benign-sounding malignancieslymphoma, melanoma, mesothelioma, seminomaMalignant-sounding trivial lesionsHamartoma (hamarto = to sin, miss the mark, error)disorganized mass of cells indigenous to the sitedevelops and grows at same rate as surrounding normally organized tissue without compressionpulmonary chondroid hamartoma—island of disorganized, but histologically normal, cartilage, bronchi, and vesselsclonal translocation involving chromatin protein genesChoristoma (chore = to disperse)mass of histologically normal tissue in an abnormal locationcongenital anomaly—heterotopic rest of cellsduodenal pancreatoid choristoma—small nodule of well-developed and normally organized pancreatic substance in the submucosa of the duodenumFor images see
4 Pulmonary chondroid hamartoma PMCID: PMC(A) Gross photograph of the lower lobe of left lung shows a large cystic and solid mass containing variable size of multilocular cysts and solid component with numerous interstitial cartilaginous small nodules. (B) Multilocular cystic spaces with intervening lobulated fragments of cartilaginous tissue and hyalinized stroma (H&E stain, original magnification ×1). (C) There are islands of mature cartilage, adipose tissues and immature mesenchymal tissue containing spindle cells within the intervening stroma (H&E stain, original magnification ×100).
5 Behavior of tumors Benign tumors: Malignant tumors: are expansive, compressing adjacent tissuedo not recur when completely exciseddo not metastasizeusually grow slowlydo not cause cachexiaMalignant tumors:are invasive, replacing adjacent tissueoften recur even if completely excisedmay metastasizeoften grow quicklymay cause cachexia
6 Gross features of tumors Benign:a solitary masswell-demarcated from adjacent normal tissuesmay be encapsulatedcutaneous masses are usually easily moveablehas a uniform consistencyMalignant:may be solitary or multipleindistinct demarcation from adjacent tissuesusually not encapsulatedcutaneous mass attached to underlying tissuemay have a variable consistency due to soft or liquid centermay have finger-like projections, indicative of growth into lymphatic vesselsmay have metastasized to lungs, liver, or any other organ, with masses observed at surgery necropsy, or by imaging analyses
7 Histologic and cytologic features Benign:Well-differentiated cellsUniform cell size and shapeWell-demarcatedEncapsulatedFew mitotic figuresMitotic figures normal morphologyUniform nuclei, euploidOne nucleus per cellNucleolus single or not visibleTumor not within vesselsUniform appearanceEpithelium arranged on basement membranesOrderly supporting stromaMalignant:Poorly-differentiated (anaplasia)Variable size, shape (pleomorphism)Poorly demarcatedUnencapsulatedMany mitotic figuresMitotic figures have bizarre shapesVariably sized nuclei, aneuploidOccasional multiple nucleiNumerous or large nucleoliInvasion of lymphatics and veinsAreas of necrosis and hemorrhageEpithelium invades past basement membranesDense, abundant, fibrous supporting stroma (desmoplasia)
9 Benign SchwannomaThis schwannoma was resected from a nerve. This neoplasm arises from the Schwann cells that myelinate peripheral nerve fibers. Note the circumscribed nature of this benign neoplasm. Though benign, this neoplasm could cause dysfunction of the nerve by mass effect.The schwannoma is seen microscopically to be composed of spindle cells (like most neoplasms of mesenchymal origin), but the cells are fairly uniform and there is plenty of pink cytoplasm. These are characteristics for a benign neoplasm.
10 Benign v. Malignant liver tumors Here is a small hepatic adenoma, an uncommon benign neoplasm, but one that shows how well-demarcated a benign neoplasm is. It also illustrates how function of the normal tissue can be maintained, because this adenoma is making bile pigment, giving it a green color with formalin fixation.In contrast, this hepatocellular carcinoma is not as well circumscribed (note the infiltration of tumor off to the lowerleft) nor as uniform in consistency. It is also arising in a cirrhotic (nodular) liver.
11 Metaplasia, Dysplasia, Neoplasia Metaplasia is replacement of one type of cell for another normally present in tissueStimulated by irritation or hormoneReversible upon removal of stimulusDysplasia is loss of cellular uniformity and tissue architectureStimulated and reversible to a pointNeoplasia is new growth uncoordinated with normal tissueBy definition is NOT reversible
12 Metaplasia and dysplasia of esophagus This biopsy of the lower esophagus in a patient with chronic gastroesophageal reflux disease (GERD) shows columnar metaplasia (Barrett's esophagus) with goblet cells (arrow) that are typical of an intestinal type of epithelium. Squamous epithelium typical of the normal esophagus appears at the top.ESOPHAGUS-STOMACH: BASAL SQUAMOUS DYSPLASIA medium magnification view of the basal epithelium. The basal two thirds (right) of this epithelium is composed of primitive cells, while the upper third (left) has differentiated stratified squamous cells.
13 Neoplasm of skeletal muscle FIGURE 7–8 Anaplastic tumor of the skeletal muscle (rhabdomyosarcoma). Note the marked cellular and nuclear pleomorphism, hyperchromatic nuclei, and tumor giant cells.
14 Progression of dysplasia to neoplasia Dysplasia is usually applied to epitheliumabnormal variation in cell morphology (shape, size, nuclear and cytoplasmic staining)minor changes in architectural orientationloss of cell polarity adjacent to a basement membraneloss of orderly maturation from basal to superficial layersCervical dysplasia in womenusually associated HPV infectionmay progress to cervical carcinomadetected by routine cytological exams (Pap test)early detection has led to a dramatic decrease in the incidence of cervical cancer in USDysplastic changes are often found adjacent to foci of invasive carcinoma
15 Rate of neoplastic growth How long does it take to produce a clinically overt tumor mass?original transformed cell ~1ng mass30 doublings (2^30) yields 10^9 cells, 1 g10 more doublings yields 10^12 cells, 1kgFor more than ¾ total life span, tumor is not palpableHow long does 30 to 40 doublings take?doubling time of tumor cellsgrowth fraction of tumor cellsrate at which tumor cells are shed or die
16 FIGURE 7-11 Schematic representation of tumor growth FIGURE 7-11 Schematic representation of tumor growth. As the cell population expands, a progressively higher percentage of tumor cells leaves the replicative pool by reversion to G0, differentiation, and death.As tumors continue to grow, cells leave the proliferative pool in ever-increasing numbers as a result of shedding, lack of nutrients, necrosis, apoptosis, differentiation, and reversion to the nonproliferative phase of the cell cycle (G0). Thus, by the time a tumor is clinically detectable, most cells are not in the replicative pool. Even in some rapidly growing tumors, the growth fraction is only about 20% or less.
17 Tumor proliferationProportion of cells in growth fraction declines as tumor growsHigh growth fraction tumors progress rapidlyLeukemias, lymphomas, small-cell carcinomaLow growth fraction tumors progress slowlycell production 10% greater than lossColon, breast adenocarcinomaDoubling time of clinically detectable colon or lung tumors averages about 2 to 3 monthsCauses infiltration, invasion, and destruction of the surrounding tissue
18 Cancer cell lineages Tumor-initiating cells allow human tumor growth when transplanted into an immunodeficient mouse0.1% to 2% of the total cellularity, but could be as high as 25%Cancer stem cells arise fromnormal tissue stem cellstransformed, differentiated cellsCancer stem cells have a high intrinsic resistance to conventional therapies
19 Metastasis Benign neoplasms do not metastasize All malignant tumors can metastasizeExcept gliomas and basal cell carcinomas of the skinMetastatic spread strongly reduces the possibility of cureOvert metastases upon diagnosis in 30% cases, with occult metastases in 20% more
20 Pathways for metastases Direct seeding of body cavities or surfacesMost frequently peritoneal cavity by ovarian cancerLymphatic spreadcommon for dissemination of carcinomassarcomas may also use this routepattern of lymph node involvement follows the natural routes of lymphatic drainagebiopsy of sentinel nodes is often used to assess metastatisHematogenous spreadtypical of sarcomas but is also seen with carcinomasblood-borne cells follow the venous flow draining the site of the neoplasmliver and lungs are most frequently involved
21 Location preferenceDespite pathway of venous or lymphatic flow, some metastatic sites are frequently associated with some primary tumors:breast carcinoma spreads to bonebronchogenic carcinomas tend to involve the adrenals and the brainneuroblastomas spread to the liver and bonesDespite the large percentage of blood flow, skeletal muscles and spleen are rarely the site of secondary deposits
22 Cancer incidence, risk US risk of cancer death 1 in 5 1,437,180 new cancer cases and 565,650 deaths from cancer in 2008Plus 1 million non-melanoma skin cancers and 122,000 cases of carcinoma in situCancers of the lung, female breast, prostate, and colon/rectum constitute more than 50% of cancer diagnoses and deaths
24 Epidemiology of cancer Incidence varies with age, race, geographic factors, and genetic backgroundsCancers are most common at the two extremes of ageGeographic variation results mostly from different environmental exposuresMost cancers are sporadic, but some are familialHereditary predisposition may be autosomal dominant or autosomal recessiveDominant are usually linked to inheritance of a germ-line mutation of cancer suppressor genesRecessive are typically associated with inherited defects in DNA repairFamilial cancers tend to be bilateral and arise earlier in life than sporadic cancers
25 Chronic inflammation and cancer Virchow proposed that cancer develops at sites of chronic inflammationUnresolved chronic inflammation promotes tumorigenesisviral hepatitis or chronic gastritisimmune response may become maladaptivecompensatory proliferationgrowth factors, cytokines, chemokines, and other bioactive substances promote cell survival, tissue remodeling, and angiogenesis
26 Molecular basis of cancer Nonlethal genetic damageTumors are monoclonalFour classes of normal regulatory genes are principal targets of genetic damagegrowth-promoting proto-oncogenesgrowth-inhibiting tumor suppressor genesgenes that regulate programmed cell death (apoptosis)genes involved in DNA repairCarcinogenesis is a multistep processaccumulation of multiple mutations requiredmonoclonally initiated tumors evolve
27 Tumor progressionFIGURE 7–24 Tumor progression and generation of heterogeneity. New subclones arise from the descendants of the original transformed cell by multiple mutations. With progression the tumor mass becomes enriched for variants that are more adept at evading host defenses and are likely to be more aggressive.
28 Figure 6-16 Flow chart depicting a simplified scheme of the molecular basis of cancer
29 Steps of normal proliferation Growth factor binds to its specific receptorTransient, limited activation of the growth factor receptor with signal transductionTransmission of signal across the cytosol to nucleus via second messengers or signal transduction cascadeInitiation of DNA transcriptionEntry and progression into the cell cycle
30 Proto-oncogenes, oncogenes Proto-oncogenes: normal cellular genes whose products promote cell proliferationOncogenes: mutant versions of proto-oncogenes that function autonomously without a requirement for normal growth-promoting signalsOncoproteins: proteins encoded by oncogenes
31 Cancer growth self sufficiency Growth factorsAutocrine loopsGrowth factor receptorsOver-expression or always “on”Signal transduction proteinsIntermediates in cascade, especially Gproteins, phosphorylases, kinasesTranscription factorsCyclins and CDKsUncontrolled cell cycle progression
33 Cyclin D–CDK4, cyclin D–CDK6, and cyclin E–CDK2 regulate the G1-to-S transition by phosphorylation of the RB protein (pRB).Cyclin A–CDK2 and cyclin A–CDK1 are active in the S phase.Cyclin B–CDK1 is essential for the G2-to-M transition.Two families of CDKIs can block activity of CDKs and progression through the cell cycle. The INK4 inhibitors (p16, p15, p18, and p19) act on cyclin D–CDK4 and cyclin D–CDK6. The others (p21, p27, and p57) can inhibit all CDKs.
34 Insensitivity to supressor signals Classic example retinoblastoma geneBoth copies of gene must be inactivated to block holdFamilial predisposition due to one bad copySporadic cases arise from somatic mutations of both copies
35 RB Gene and Cell CycleRB controlls G1-to-S transition of the cell cycleactive RB (hypophosphorylated) binds to E2F preventing transcription of genes like cyclin E that are needed for DNA replication, resulting in G1 arrestGrowth factor signaling leads to cyclin D expression, activation of the cyclin D-CDK4/6 complexes, inactivation of RB by phosphorylation, and thus release of E2FLoss of cell cycle control is fundamental to malignant transformationAlmost all cancers will have disabled the G1 checkpoint, by mutation of either RB or genes that affect RB function, like cyclin D, CDK4, and CDKIsMany oncogenic DNA viruses, like HPV, encode proteins (e.g., E7) that bind to RB and render it nonfunctional.
36 The role of RB in regulating the G1-S checkpoint of the cell cycle The role of RB in regulating the G1-S checkpoint of the cell cycle. Hypophosphorylated RB in complex with the E2F transcription factors binds to DNA, recruits chromatin remodeling factors (histone deacetylases and histone methyltransferases), and inhibits transcription of genes whose products are required for the S phase of the cell cycle. When RB is phosphorylated by the cyclin D-CDK4, cyclin D-CDK6, and cyclin E-CDK2 complexes, it releases E2F. The latter then activates transcription of S-phase genes. The phosphorylation of RB is inhibited by CDKIs, because they inactivate cyclin-CDK complexes. Virtually all cancer cells show dysregulation of the G1-S checkpoint as a result of mutation in one of four genes that regulate the phosphorylation of RB; these genes are RB, CDK4, cyclin D, and CDKN2A [p16]. EGF, epidermal growth factor; PDGF, platelet-derived growth factor
37 Activation of normal p53 by DNA-damaging agents or by hypoxia leads to cell cycle arrest in G1 and induction of DNA repair, by transcriptional up-regulation of the cyclin-dependent kinase inhibitor CDKN1A (p21) and the GADD45 genes. Successful repair of DNA allows cells to proceed with the cell cycle; if DNA repair fails, p53 triggers either apoptosis or senescence. In cells with loss or mutations of p53, DNA damage does not induce cell cycle arrest or DNA repair, and genetically damaged cells proliferate, giving rise eventually to malignant neoplasms.