Sei sulla pagina 1di 43

NEOPLASIA

DEFINITIONS
Neoplasia = the process of new growth Neoplasia Neoplasm = new growth (Tumor (Tumor) ) Tumor = Oncos (Greek) Oncology = The study of tumors or neoplasms Cancer = common term for the malignant tumors

Definitions

Neoplasm
An abnormal tissue mass whose growth exceeds and is uncoordinated with that of adjacent normal tissue and whose growth persists after cessation of the stimuli that provoked it

Tumor Benign and Malignant


3

Tumors - consist of
Neoplastic cell (parenchyma parenchyma) ) 2) supportive supportive stroma (connective tissue and blood vessel),
stroma parenchyma

1)

desmoplasia
4

NOMENCLATURE
Tumors consist of parenchyma and supportive stroma, nomenclature is based on parenchyma
Fibroadenoma of the breast

NOMENCLATURE
Cancer Prefixes Point to Location
Prefix adenoadeno chondrochondro erythroerythro hepatohepato lipolipo lympholympho melanomelano myelomyelo myomyo osteoosteo Meaning gland cartilage red blood cell liver fat lymphocyte pigment cell bone marrow muscle bone

hemangiohemangio - blood vessels

NOMENCLATURE
Tumors consist of parenchyma and supportive stroma, nomenclature is based on parenchyma

Benign tumors

Fibroadenoma of the breast

oma : most benign tumors Adenoma = adeno + oma gland (= benign glandular tumor)
7

Nomenclature Benign tumors

Papillomas benign tumor with visible finger-like or warty projections

Nomenclature

Benign tumors

Cystadenomas benign tumors that form cystic masses

Cystadenomas

10

Nomenclature

Benign tumors

Polyp macroscopic lesion on mucosal surface

11

Nomenclature

Malignant tumors
Sarcomas malignant tumors arising from mesenchymal tissue Carcinomas malignant neoplasms of epithelial origin Adenocarcinoma Adeno carcinoma carcinomas with a glandular growth pattern Squamous cell carcinoma carcinomas producing recognizable squamous cells
12

Different Kinds of Cancer

Some common carcinomas:


Lung Breast (women)

Leukemias: Leukemias :
Bloodstream

Lymphomas:
Lymph nodes

Colon Bladder Prostate (men)

Some common sarcomas:


Fat Bone Muscle

Nomenclature

Malignant tumors

Adenocarcinoma Adenocarcinoma carcinomas with a glandular growth pattern

14

Nomenclature

Malignant tumors

Squamous cell carcinoma carcinomas producing recognizable squamous cells

15

Nomenclature

Malignant tumors
Melanoma carcinoma of melanocytes Seminomas carcinomas of testicular origin

16

Nomenclature

Malignant tumors Melanoma carcinoma of melanocytes

17

Nomenclature

Malignant tumors
Seminomas carcinomas of testicular origin

18

Nomenclature

Tumor with More Than One Neoplastic Cell Type


Pleomorphic adenoma mixed tumor Teratoma tumor with a variety of parenchymal cell types representative of more than one germ layer, usually all three

19

Nomenclature

Pleomorphic adenoma mixed tumor


mixed tumor of the parotid gland contains epithelial cells forming ducts and myxoid stroma that resembles cartilage

20

10

Nomenclature

Pleomorphic adenoma showing cartilagenous stroma

21

Nomenclature

Cystic teratoma (Dermoid cyst)

22

11

Nomenclature

Cystic teratoma (Dermoid cyst)

23

Nomenclature

NonNon -neoplastic growth disturbances


Choristoma an ectopic focus of mature tissue found at an abnormal location Hamartoma focal overgrowth of cells or tissue elements that occurs in an organ where such elements are normally present

24

12

an increased number of cells Hyperplasia an while generally preserving the normal tissue structure increase in the size of individual Hypertrophy increase cells, cells , which may result in enlargement of the organ, but preserves normal architecture Metaplasia process in which fullyfully-differentiated cells of one type are replaced by fullyfully -differentiated cells of another type
25

CHARACTERISITICS OF BENIGN AND MALIGNANT NEOPLASMS Differentiation and Anaplasia


Differentiation Benign tumors are well well-differentiated (low low-grade) grade) Malignant tumors can be well differentiated (lowlow-grade grade) ) or poorly differentiated (high high-grade) grade)
26

13

Anaplasia
lack of differentiation Pleomorphic nuclei Hypertrophied cells Hyperchromatic and convoluted nuclei Increased nuclear nuclear/ /cytoplasmic ratio Mitotic figures Tumor giant cells with multiple nuclei
27

Anaplasia

Anaplastic tumor of the skeletal muscle (rhabdomyosarcoma). Note the marked cellular and nuclear pleomorphism, hyperchromatic nuclei, and tumor giant cells.
28

14

Differentiation and Anaplasia


Normal Benign Well Well-diff. malignant

Poorly diff. malig.

Anaplastic

Benign neoplasm of Smooth muscle


29

Dysplasia
loss of uniformity of the individual epithelial cells loss in their architectural orientation pleomorphism and hyperchromatic may not progress to cancer if dysplastic changes are marked and involve the entire thickness of the epithelium (preinvasive neoplasm neoplasm) ) = carcinoma in situ
30

15

Dysplasia Alterations in cell size and morphology, with or without disorganized growth pattern

31

Carcinoma in situ. A, This lowlow-power view shows that the entire thickness of the epithelium is replaced by atypical dysplastic cells. There is no orderly differentiation of squamous cells. The basement membrane is intact and there is no tumor in the subepithelial stroma. B, A highhigh-power view of another region shows failure of normal differentiation, marked nuclear and cellular pleomorphism, and numerous mitotic figures extending toward the surface
32

16

Rate of growth
Growth rate of tumors correlates with their level of differentiation differentiation, , and thus most malignant tumors grow more rapidly than do benign tumors

33

Local invasion
benign tumors grow as cohesive expansile masses that remain localized to their site of origin and do not have the capacity to infiltrate, invade, or metastasize

growth of cancers is accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue

34

17

Metastasis
Malignant Tumor Pathways of spread body cavities and surfaces (tumor seeding) peritoneal, pleural, pericardial lymphatic spread Carcinomas > Sarcomas hematogenous spread Sarcomas > Carcinomas
35

36

18

37

38

19

39

BIOLOGY OF TUMOR GROWTH


malignant change in the target cell transformation growth of the transformed cells local invasion distant metastases
40

20

BIOLOGY OF TUMOR GROWTH

kinetics of tumor cell growth tumor angiogenesis tumor progression and heterogeneity mechanisms of invasion and metastasis
41

BIOLOGY OF TUMOR GROWTH

kinetics of tumor cell growth


by the time a solid tumor is clinically detected, it has already completed a major portion of its life cycle Rate of growth depends on three variables The doubling time of tumor cells Growth fraction - proliferative pool Cell production and loss
42

21

Cell cycle

43

44

22

Rates of tumor cell growth (malignant) From 1 transformed cell to smallest clinically detectable mass (1 gm) of 109 cells = 30 doublings To reach 1012cells (1 kg) requires only 10 additional doublings

45

BIOLOGY OF TUMOR GROWTH

kinetics of tumor cell growth tumor angiogenesis tumor progression and heterogeneity mechanisms of invasion and metastasis
46

23

tumor angiogenesis
neo neovascularization vascularization angiogenesis is a necessary biologic correlate of malignancy critical for growth and spread of tumors TumorTumor -associated angiogenic factor Vascular endothelial growth factor
(VEGF)

Basic fibroblast growth factor (bFGF)

47

48

24

kinetics of tumor cell growth tumor angiogenesis tumor progression and heterogeneity mechanisms of invasion and metastasis
49

tumor progression and heterogeneity

50

25

51

kinetics of tumor cell growth tumor angiogenesis tumor progression and heterogeneity mechanisms of invasion and metastasis
52

26

mechanisms of invasion and metastasis


clonal expansion, growth, diversification, angiogenesis metastatic subclone adhesion to and invasion of basement membrane passage through ECM growth intravasation interaction with host lymphoid cells tumor cell embolus adhesion to basement membrane angiogenesis metastatic deposit extravasation
53

54

27

MOLECULAR BASIS OF CANCER


Nonlethal genetic damage or genetic alterations lies at the heart of carcinogenesis A tumor is formed by the clonal expansion of a single precursor cell (genetic damage or mutation)
55

Molecular Basis of cancer

Four classes classes of normal regulatory genes are the pricipal targets of genetic damage
the growthgrowth-promoting proto proto-oncogenes the growthgrowth-inhibiting tumor suppressor genes genes that regulate programmed cell death (apoptosis apoptosis) ) genes involved in DNA repair
56

28

MOLECULAR BASIS OF CANCER

Oncogenes and Cancer


derived from proto proto-oncogenes, cellular genes that promote normal growth and differentiation
growth factors growth factor receptors signal transduction nuclear regulatory proteins cell cycle regulators
57

GF

GFR

Oncogene activation involves a gain of function Activation by point mutation of the oncogene eg. eg. RAS family genes (HRAS, KRAS, and NRAS
Growth factor eg. eg. TGF RTK

Cytoplasm
Grb2 Grb2 SOS

Nucleus
Changes in Gene FOS expression

Ras

Raf MEK

MAPK

Point mutation of RAS family genes is common in human cancers

Cell cycle (cell proliferation)


58

29

Figure 7-32 Model for action of RAS genes. genes. When a normal cell is stimulated through a growth factor receptor, inactive (GDP(GDP-bound) RAS is activated to a GTP GTP-bound state. Activated RAS recruits RAF and stimulates the MAPMAP-kinase pathway to transmit growth growth-promoting signals to the nucleus. The mutant RAS protein is permanently activated because of inability to hydrolyze GTP, leading to continuous stimulation of cells without any external trigger. The anchoring of RAS to the cell membrane by the 59 Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 18 November 2005 01: 01:31 PM) farnesyl moiety is essential for its action.
2005 Elsevier

Oncogene activation involves a gain of function Activation by chromosomal rearrangement eg. eg. BCR BCR-ABL fusion gene in Philadelphia (Ph1) chromosome in chronic myeloid leukemia leukemia

reciprocal translocation between chromosomes 9 and 22 = t(9 t(9;22 22) )


60

30

BCRBCR -ABL fusion gene in Ph1 Ph1 chromosome


ABL gene BCR gene

BCR-ABL BCRfusion gene 8.5 kb BCRBCR-ABL mRNA p210 BCR BCR-ABL hybrid protein

Oncogenic BCR/ABL tyrosine kinase (nonreceptor


tyrosine kinase kinase) )

hematopoietic progenitor cell

malignant transformatio n

excessive production of immature granulocytes

clonal myeloproliferation
61

MOLECULAR BASIS OF CANCER CANCER: : Insensitivity to growth inhibitory signals _ Tumor suppressor genes

Tumor Suppressor genes


Tumor-suppressor proteins - regulate cell growth growt h by: by:Apply pplying ing brakes (growth inhibitory signal) to cell proliferation Forming a regulatory network of checkpoints that prevent uncontrolled cell growth eg. by mutation) Loss of function (eg. lead to tumor formation
62

31

MOLECULAR BASIS OF CANCER CANCER: : Insensitivity to growth inhibitory signals _ Tumor suppressor genes

Tumor suppressor protein localization


Cell surface TGF TGF- receptor receptor, , E-cadherin Under plasma membrane NF NF1 1 Cytoskeleton NF NF2 2 Cytosol APC Nucleus Rb Rb, , p53 53, , BRCA BRCA1 1, BRCA BRCA2 2

63

Retinoblastoma
Two hit Hypothesis Retinoblastoma Tumor suppressor (Rb)

64

32

Role of RB as a cellcell-cycle regulator

65

Genes that Regulate Apoptosis


p53 upregulates heterodimers of bax that promote mitochondrial cytochrome c release and apoptosis heterodimers of bcl bcl-2 block bax and promote growth

66

33

Role of the p53 gene in maintaining the integrity of the genome

67

Figure 7-31 Subcellular localization and functions of major classes of cancer cancer-associated genes. The protooncogenes are colored red, cancer suppressor genes blue, DNA repair genes green, and genes that regulate apoptosis purple.
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 18 November 2005 01: 01:31 PM) 2005 Elsevier

68

34

Molecular Basis of cancer

Carcinogenesis is a multistep process at both the phenotypic and the genetic levels

69

Molecular Basis of Cancer_Multistep Carcinogenesis


Flow chart depicting a simplified scheme of the molecular basis of cancer.

70

35

Molecular Basis of Cancer_Multistep Carcinogenesis

71

72

36

Molecular model for the evolution of colorectal cancers through adenoma adenoma-carcinoma sequence
Wild-type Wildp53 NORMAL COLON MUCOSA AT RISK ADENOMAS

Oncogene-induced Oncogenesenescence

CARCINOMA Germ-line or Somatic Germmutations of tumor suppressor genes (first hit) Inactivation of normal allels (second hit)

Proto-oncogene Protomutations

APC at 5q21

APC -catenin

K-RAS at 12p 12p12

Homozygous loss of additional tumor suppressor genes Over Over-expression of COXCOX-2

Additional mutations Gross chromosomal alterations Telomerase, Other genes


73

p53 at 17p 17p13 LOH at 18p 18p12 (SMAD 2 and 4)

CARCINOGENIC AGENTS AND THEIR CELLULAR INTERACTIONS Chemical carcinogenesis


Steps

initiation to appropriate carcinogen


metabolic activation of carcinogens molecular targets of chemical carcinogens (e.g., DNA)

initiation causes mutations promoters induce tumors in initiated initiated cells effects of promoters are reversible
74

37

Stages of Chemical carcinogenesis


initiator Initiation promotor Promotion Transformed cell genetic instability Normal cell

Progression
75

Chemical Carcinogens
direct acting alkylating agents, polycyclic aromatic hydrocarbons, aromatic amines and azo dyes, naturally occurring carcinogens, nitrosamines and amides, promoters of chemical carcinogenesis

76

38

Radiation carcinogenesis
Ultraviolet rays skin cancer: melanoma, melanoma, squamous cell carcinoma Ionizing radiation (x (x-rays, rays, gamma-rays, rays, alphaparticles, particles , beta- particles, particles, protons, protons, neutrons) neutrons) atomic bomb high incidence of leukemia (after an average of 7-10 y) x-ray (during infancy and childhood) childhood) thyroid cancers (9%) Electrolectro-magnetic wave, microwave
77

Viral and microbial carcinogenesis Oncogenic DNA viruses


Human papillomavirus (HPV type 16 and 18) 18) squamous cell carcinoma of cervix (cervical carcinoma carcinoma) EpsteinEpstein -Barr virus (EBV EBV) Burkitts lymphoma (endemic in Africa Africa) ) B-cell lymphoma (AIDS patients) patients) Hodgkins disease Nasopharyngeal carcinoma
78

39

Oncogenic DNA viruses


Hepatitis B virus chronic HBV infection (+ aflatoxins aflatoxins) ) hepatocellular carcinoma Human immunodefficiency virus (HIV HIV) ) and Human herpes simplex virus type 8 (human HSV HSV8 or HHV HHV-8) Kaposi sarcoma (vascular tumor tumor) )

79

Oncogenic RNA viruses


Human T-cell leukemia virus type 1(HTLV HTLV-I) T-cell leukemia T-cell lymphoma

IL: interleukin GM GM-CSF:granulocyte CSF:granulocytemaccrophage colonycolonystimulating factor

80

40

CLINICAL FEATURES OF TUMORS


Effects of Tumor on Host
Local and hormonal effects Small pituitary adenoma - compress and destroy surrounding normal gland Brain tumor - compression effect Benign tumors may produce over expression of hormones - adenoma of adrenal gland
81

Effects of Tumor on Host


Primary or metastatic tumor in vital organ Cancer cachexia - wasting, weakness, anorexia, and anemia Paraneoplastic syndromes -small cell carcinoma of lung, pancreatic carcinoma, neural tumor produces ACTH or ACTH ACTH-like substance and causes Cushings syndrome syndrome -renal carcinoma, cerebellar hemangioma produce erythropoietin and causes polycythemia

82

41

Grading and Staging of tumors


Grading of a cancer - is based on the degree of differentiation of the tumor cells and the number of mitoses within the tumor as presumed correlates of the neoplasms aggressiveness Staging of cancers - is based on the size of the primary lesions, its extent of spread to regional lymph nodes, nodes , and the presence or absence of bloodblood -borne metastases 83

Laboratory diagnosis of cancer


histologic and cytologic methods
-Tissue biopsy, fine fine-needle aspiration - cytologic (Pap) smears

Immunocytochemistry
-categorization of undifferentiated malignant tumors -categorization of leukemias and lymphomas -determination of site of origin of metastatic tumors -detection of molecules that have prognostic or therapeutic significance
84

42

molecular diagnosis 1. diagnosis of malignant neoplasms 2. prognosis of malignant neoplasms 3. detection of minimal residual disease 4. diagnosis of hereditary predisposition to cancer Other techniques flow cytometry tumor markers
85

86

43