NEOPLASIA

NEOPLASIA

:new growth

Cancer 2nd leading cause of death in US When will there be a cure for cancer? - Not one disease but many disorders that share a profound growth dysregulation Ex.) Hodgkin lymphoma curable Pancreatic adenocarcinoma high mortality

Only hope for controlling cancer learning more about cause and pathogenesis understanding molecular pathogenesis (i)Basic morphologic & biologic properties of tumors (ii)Molecular basis of carcinogenesis

Nomenclature

Tumor

swelling produced by edema or hemorrhage into a tissue currently applied to neoplastic masses oncology : (Greek oncos = tumor) : study of tumors or neoplasms.

Cancer (): Common term for all malignant tumors ( )

Latin for crab = cancer "adheres to any part that it seizes upon in an obstinate manner like the crab."

British Oncologist Willis

A Neoplasm is an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of normal tissues and persists in the same excessive manner after cessation of the stimuli which evoked the change.

Neoplasm
*Tumor persistence
1) Genetic alterations that are passed down to the progeny of tumor cells 2) Genetic changes allow excessive & unregulated proliferation that becomes autonomous (independent of physiologic growth stimuli) 3) Clonal entire population of neoplastic cells within a individual tumor arises from a single cell that has genetic change

**2 Basic components of tumors

1. Parenchyma() : proliferating neoplastic cells (cutting edge) 2. Reactive stroma () (CT, BV) blood supply support for growth of parenchymal cells (framework)

Desmoplasia abundant collagenous stroma (scirrhous: stony hard)

Neoplasm

Biological behavior
Benign vs. Malignant

Histogenesis
Tissue or Cell of origin

Nomenclature: Benign tumor

Suffix -oma (-) Epithelial tumors -adenoma : glandular pattern, derived from gland -papilloma : finger-like projections from epithelial surface -cystadenoma : large cystic mass -polyp : grossly visible projection above a mucosal surface - benign (malignant polyp : polypoid cancer) Mesenchymal tumor -fibroblast : fibroma -cartilage : chondroma

Nomenclature: Benign tumor

*Exceptions: melanoma, hepatoma, seminoma (malignant) hematoma, granuloma, hamartoma (non-neoplastic)

-blastoma: neoplasm of embryonic cells ex) neuroblastoma(adrenal), retinoblastoma (eye)

Benign mesenchymal tumors

Benign mesenchymal tumors

Benign mesenchymal tumors

Colon; tubular adenoma

Papilloma

Cystadenomas

Epithelial

vs

Mesenchymal
spindle
diffuse

oval, round or polygonal

cell nests

desmoplastic stroma
vessels in stroma

no desmoplastic stroma
vessels between tumor cells

Malignant tumors

Mesenchymal tumor (sarcoma : )

fibrosarcoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma

Epithelial tumor (carcinoma : )

adenocarcinoma:

glandular microscopic pattern squamous cell carcinoma: producing squamous cells

Sarcoma

Carcinoma

Carcinoma

Sarcoma

Stomach; adenocarcinoma

Thigh; malignant fibrous histiocytoma

Mixed tumor :

Divergent differentiation of a single line of parenchymal cells Ex) Parotid gland: pleomorphic adenoma - epithelial & myxoid stroma(cartilage, bone)

Teratoma :

variety of parenchymal cell types from more than one germ layer, usually all three Arise from totipotential cells (normally in testis/ovary, abnormally sequestered in midline embryonic rests) Ex) Ovary: cystic teratoma(dermoid cyst)

Mixed tumor
Divergent

differentiation of a single line of parenchymal cells

Salivary gland; pleomorphic adenoma epithelial & myoepithelial origin

Teratoma
Made

up of cell types from more than one germ layer, usually all three

Ovary; Mature cystic teratoma

*
Choristoma

congenital anomaly, hectopic rest of normal tissue

ectopic pancreas in the small intestine

Ex) ectopic adrenal cells under the kidney capsule,

Hamartoma

disorganized, benig appearing mass, mature specialized cells or tissue indigenous to the particular site Ex) pulmonary chondroid hamartoma cartilage, vessels, bronchial-type structures, lymphoid tissue

Ileum;Ectopic pancreas

*Biology of Tumor Growth: Benign & Malignant Neoplasms

Natural History of Most Malignant Tumors

(1) Malignant change in the target cell [ transformation ] (2) Growth of the transformed cells (3) Local invasion (4) Distant metastases

*Characteristics of benign & malignant neoplasms

Criteria of differentiation benign vs. malignant tumors : 1. Differentiation & anaplasia 2. Rate of growth 3. Local invasion 4. Metastasis

1. Differentiation
Extent to neoplastic cells resemble comparable normal cells (morphologically & functionally) Well, moderately, poorly differentiated undifferentiated Benign tumor : well differentiated Malignant tumor : well to undifferentiated

Well differentiated

Poorly differentiated

*Anaplasia :

Lack of differentiation(to form backward) Hallmark of malignant transformation Results from failure of differentiation rather than dedifferentiation
Well-diff.

tumor : maturation of undifferentiated cells Undiff. tumor : proliferation without maturation

Morphologic changes of Anaplasia

Pleomorphism() variation in size and shape of cells & nuclei Abnormal nuclear morphology Hyperchromatic nuclei (abundant DNA) Increased N/C ratio ( 1:4 ~ 6 1:1 ) Variable nuclear shape Coarsely clumped chromatin, distributed along the nuclear membrane Large nucleoli

Morphologic changes of Anaplasia

Mitoses
Large

number of mitoses bizarre mitoses

atypical

(tripolar, quadripolar, multipolar spindles) Loss of polarity Other changes

Formation Scant

of tumor giant cells

vascular stroma necrosis of central area

ischemic

Dysplasia

Disordered growth Loss in the uniformity of the individual cells as well as a loss in their architectural orientation Considerable pleomorphism, hyperchromatic nuclei, abnormally large size of cells Frequent mitosis (abnormal locations in epithelium) Carcinoma in situ: entire thickness of the epithelium involved by dysplasia (preinvasive neoplasm) Does not necessarily progress to cancer Mild to moderate changes may be reversible

CIN I

CIN II

CIN III

SCC

Functional differentiation

Better differentiation = more completely retain functional capabilities Ex) Well-differentiated SCC : keratin Well-differentiated HCC : bile Ectopic hormone production Bronchogenic carcinoma : ACTH, PTH, insulin, glucagon More rapidly growing, more anaplastic tumor less likely specialized functional activity Cell in beingn tumors almost always WD resemble normal cells of origin Cells in cancer more or less differemtiated

2. Rates of Growth
How long does it take to produce a clinically overt tumor mass? **Pathologic Dynamo original transformed cell (10 m) 30 population doubling 10 9 cells(1gm) : the smallest clinically detectable mass only 10 additional doubling cycles : 10 12 cells(1kg)

By the time a solid tumor is clinically detected, it has already completed a major portion of its life span

Rate of growth : 3 main factor

(1) Doubling time of tumor cells (2) Fraction of tumor cells (growth fraction population in the proliferative pool) : susceptible to chemoTx. (3) Rate at which cells are shed or die in the growing lesion

Rate of growth
In general, the growth rate of tumors correlates with

their level of differentiation, and thus most malignant tumors grow more rapidly than do benign lesions
- Some benign tumors grow faster than malignant tumors

The rate of growth of benign as well as malignant

neoplasms may not be constant over time (eg.leiomyoma-hormonal effect ) Cancers show a wide range of growth
- Some malignant tumors grow slowly for years->suddenly increase in size->widely disseminate->death within a few mths - Some malignant tumors grow more slowly than benign tumors

CANCER STEM CELLS

& CANCER CELL LINEAGES
A clinically detectable tumor contains a heterogeneous population of cells, which originated from the clonal growth of the progeny of a single cell. Cancer stem cells(T-IC : tumor initiating cell) : the cells within a tumor that have the capacity to initiate and sustain the tumor More recent study - Breast ca, GM, colon ca, AML : 0.1-2% total cellularity - Some cancer : very common T-IC(25% total cellularity)

3. Local invasion
*Benign tumor

Cohesive, expansile masses Not have capacity to infiltrate, invade, metz Remains localized at site of origin Fibrous capsule : rim of compressed CT discrete, readily palpable and easily movable mass

*Malignant tumor

Progressive infiltration, invasion, and

destruction of the surrounding tissue

Poorly demarcated, lacking a well-defined cleavage plane

*Next to metastases, invasiveness is the most reliable feature of malignancy

4. Metastasis
Tumor implants discontinuous with the primary tumor

Unequivocally marks a tumor as malignant With a few exceptions, all cancers can metastasize (cf: Glioma, BCC : rarely metastasize) In general, the more aggressive, more rapidly growing, and the larger the primary, the greater the likelihood of metastasis 30% of newly diagnosed pts. with solid tumors present with metastasis Strongly reduce the possibility of cure

Pathways of Spread
1. Direct seeding of body cavities or surfaces 2. Lymphatic spread 3. Hematogenous spread

Seeding of body cavities and surfaces

Seeding of body cavities/surfaces

May occur when a malignant neoplasm penetrates

into a natural open field Peritoneal cavity(MC), pleural, pericardial, subarachnoid, joint space eg. Ovarian carcinoma(serous, mucinous) Pseudomyxoma peritonei mucus-secreting appendiceal carcinomas fill the peritoneal cavity with gelatinous neoplastic mass

Lymphatic spread

Most common pathway of initial dissemination of carcinoma Pattern of LN involvement follow the natural routes of lymphatic drainage

- Breast ca: UOQ axillary LN, innerQ-internal mammary LN - Lung ca: perihilar tracheobronchial, mediastinal LN

Sentinel LN Nodal enlargement in proximity to a cancer does not necessarily mean dissemination of the primary lesion
induce reactive change within nodes

- Drainage of tumor cell debris or tumor antigens may also

Hematogenous spread

Typical of sarcomas (also in carcinoma) Arteries less readily penetrated than veins Most common sites : lung, liver Vertebral metastasis of cancers arising near vertebral column embolize through the paravertebral plexus eg. Thyroid ca, prostate ca Certain cancers have a propensity for vein invasion eg. RCC : renal vein, HCC : portal vein

**Comparison of benign & malignant tumors

Comparison of benign & malignant tumors

EPIDEMIOLOGY

Cancer Incidence
US in 2008 (5 1 cancer death) 1,437,180 : new cancer case 565,650 : cancer death(23% of all mortality) MC tumors in men ; Prostate, lung, colorectum women ; Breast, lung, colon, rectum Earlier diagnosis by Pap smear : decline cervical ca. death breast ca. lung 2.5 lung ca. leading cause of death.

Geographic and Environmental Factors

1.

Geographic factor Remarkable differences in the incidence and death rates of specific forms

Death rate for Stomach ca: Japan (7~8 times) > US

Death rate for Lung ca: US(2 times) > Japan

Skin ca: New Zealand(6 times) > Iceland

Environmental & cultural factor

Environmental & cultural factor rather than genetic predisposition

2. Environmental factor UV rays, smog Drugs(methotrxate) Occupational hazards: asbestos, vinyl chloride At home : alcohol, high fat diet Alcohol abuse: Ca. of oropharynx, larynx, esophagus, HCC Cigarette smoking: Ca. of mouth, pharynx, larynx, esophagus, pancreas, bladder, lung Cervical cancer ; age at first intercouse, No. of sex partner HPV infection

Age
Most Ca. 55 years Main COD among women ; 40-79 yrs Men; 60-79 yrs -accumulation of somatic mutation -decline in immune competence Children

Cancer accounts for more than 10% of all deaths in children under 15 **Common neoplasm of infancy/childhood small round blue cell tumors (acute leukemia, neuroblastoma, Wilms tumor, retinoblastoma, rhabdomyosarcoma)

Genetic predisposition

Hereditary predispositions, as well as environmental influences are important in the development of a many types of cancer Less than 10% cancer Pt. : inherited mutations

3 categories 1. AD Inherited cancer syndromes 2. Familial cancers 3. Defective DNA repair Syndromes

Inherited Predisposition to Cancer

Inherited Cancer Syndromes (Autosomal Dominant) Gene Inherited Predisposition RB Retinoblastoma p53 Li-Fraumeni syndrome (various tumors) p16INK4A Melanoma APC Familial adenomatous polyposis/colon cancer NF1, NF2 Neurofibromatosis 1 and 2 BRCA1, BRCA2 Breast and ovarian tumors MEN1, RET Multiple endocrine neoplasia 1 and 2 MSH2, MLH1, MSH6 Hereditary nonpolyposis colon cancer PATCH Nevoid basal cell carcinoma syndrome Familial Cancers Familial clustering of cases, but role of inherited predisposition not clear for each individual Breast cancer Ovarian cancer Pancreatic cancer Inherited Autosomal Recessive Syndromes of Defective DNA Repair Xeroderma pigmentosum Ataxia-telangiectasia Bloom syndrome Fanconi anemia

1. AD Inherited Cancer Syndromes

Inheritance of a single mutant gene greatly increases risk of developing a tumor Autosomal dominant Point mutation in a single allele of tumor suppressor gene Retinoblastoma - RB tumor suppressor gene : 10,000 fold increased risk - Osteosarcoma Familial adenomatous polyposis - adenomatous polyposis coli(APC) tumor suppressor gene mutation - innumerable polypoid adenomas, 100% colonic adenocarcinoma by age 50

1. AD Inherited Cancer Syndromes

Li-Fraumeni syndrome - germline mutation of p53 gene MEN(multiple endocrine neoplasia)-1 - menin transcription factor gene mutation MEN(multiple endocrine neoplasia)-2 - RET tyrosinase gene mutation HNPCC(hereditary nonpolyposis colon cancer) - DNA mismatch repair gene inactivation

*Retinoblastoma
-40% inherited -RB tumor suppressor gene : 10,000 fold

Familial adenomatous polyposis(FAP) of colon - adenomatous polyposis coli (APC) tumor suppressor gene

Characteristics of inherited cancer SD

Tumors

involve specific sites and tissues

-MEN-2 (RET protooncogene): thyroid, adrenal,

parathyroid
Associated

with specific marker phenotype

-FAP, MEN: multiple benign tumors

-NF-1: caf-au-lait spots, Lisch nodules

2. Defective DNA repair Syndromes

Defects in DNA repair and resultant DNA instability Autosomal recessive Xeroderma pigmentosum, ataxia-telangectasia, Bloom syndrome, Fanconi anemia

Hereditary nonpolypoid colon cancer (HNPCC) autosomal dominant condition caused by inactivation of a DNA mismatch repair gene Cancer in colon, small intestine, endometrium, ovary)

3. Familial Cancers

higher frequency in certain families Virtually all the common types of sporadic cancers reported occur in familial forms. (carcinomas of colon, breast, ovary, brain, & melanomas) Features that characterize familial cancers Early age at onset Tumors arise in two or more close relatives of index case multiple or bilateral tumors Not associated with specific marker phenotypes Transmission pattern : not clear Inheritance of mutant genes BRCA-1, 2 (breast ca. : no more than 3%) p16 tumor suppressor gene (20% familial melanoma)

Interactions Between Genetic and NonGenetic Factors

Hereditary and acquired basis of a tumor - these factors often interact closely Tumor development depends on the action of multiple contributory genes Risk of developing the tumor can be greatly influenced by non-genetic factors. (breast cancer risk in female carriers of BRCA-1 or BRCA-2 mutations: almost x3 higher for women born after 1940) Genotype Inherited variations (polymorphisms) of enzymes that metabolize procarcinogens to active carcinogenic forms Ex) cytochrome P-450 - inherited susceptibility to lung cancers in cigarette smokers

NONHEREDITARY PREDISPOSING CONDITIONS Regenerative, hyperplastic and dysplastic proliferations may develop into cancer

Endometrial hyperplasia -- Endometrial ca. CIN -- Cervical ca. Bronchial mucosal metaplasia, dysplasia (smoker) -- Lung ca. Cirrhosis (regeneration) HCC(80%)

Chronic inflammation and cancer(TB 7-5) Genomic stress & mutation

Ulcerative colitis, Crohn disease, Helicobacter pylori gastritis, viral hepatitis, and chronic pancreatitis Production of cytokines (stimulate the growth of transformed cells) May increase the pool of tissue stem cells (subject to the effect of mutagens) Directly promote genomic instability in cells through the production of reactive oxygen species (ROS) : genotoxic ex) COX-2 : increased in colon cancer

NONHEREDITARY PREDISPOSING CONDITIONS

Precancerous conditions (non-neoplastic)

Chronic atrophic gastritis of pernicious anemia solar keratosis (actinic keratosis) chronic ulcerative colitis leukoplakia of mouth, vulva and penis

Benign neopalsia of precancerous : villous adenoma of colon(50%) Although some risk may be inherent, a large cumulative experience indicates that most benign neoplasms do not become cancerous. Generalization is impossible

Clinical Aspects of Neoplasia

Benign/malignant tumors may cause problems due to

1.
2.

3. 4. 5.

Location/impingement on adjacent structures Functional activity(hormone synthesis/paraneoplastic SD) Bleeding, secondary infection Symptoms due to rupture or infarction Cachexia or wasting

Local and hormonal effects

1) Location is crucial Endocrine gland insufficiency (eg: pit. adenoma serious hypopituitarism ) Neoplasm in gut as enlarge obstruction
2) Hormonal effect(functional activity) Endocrine gland (eg: -cell adenoma of pancreatic islet produce insulin to cause fatal hypoglycemia) Non-endocrine tumors produce hormine/hormone like material paraneoplastic syndrome

Cancer cachexia

Wasting syndrome showing -progressive loss of body fat and lean body mass -profound weakness, anorexia and anemia Correlate btw tumor burden & cachexia severity Anorexia caused by Abnormal taste/central control of appetite Increased basal metabolic rate High caloric expenditure TNF, cytokine(IL-1, interferon-, leukemia inhibitory factor): suppress appetite Loss of fat & muscle

Paraneoplastic syndromes

Symptom complexes in cancer patients that cannot readily be explained, either by local or distant spread or the elaboration of hormones 10% of malignant Pt. Importance 1. Earliest manifestation of occult neoplasm 2. Significant clinical problem(may be lethal) 3. Mimic metastatic disease

Grading and staging

Quantify the probable clinical aggressiveness Grade - level of differentiation Stage - extent of spread, parameters of clinical gravity Grade Degree of differentiation Number of mitoses, architectural features Nuclear grade, histologic grade Low & high / grade I ~IV Less clinical value than stage (correlation between histologic appearance and biologic behavior is less than perfect)

Stage () Based on size of primary lesion, lymph node extension and blood-borne metastasis Major staging systems : AJCC(American Joint Committee on Cancer Staging TNM stage T : primary tumor N : regional lymph node M : metastases TNM staging varies for each specific form of ca.

TNM Classification
T (tumor), N (node) & M (metastasis)
Primary tumor (T)
TX T0 Tis T1-T4 Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ Increasing size and/or local extent (depth of

invasion) of the primary tumor

TNM Classification
Regional lymph nodes (N) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1-N3 Increasing involvement of regional lymph node Note: Direct extension of tumor into a lymph node classified as a lymph node metastasis Note: Metastasis in other than regional lymph nodes classified as a distant metastasis Distant metastasis (M) MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis

Stage Grouping (Lung Ca)

Occult Carcinoma TX Stage 0 Tis Stage IA T1 Stage IB T2 Stage IIA T1 Stage IIB T2 (T3) Stage IIIA T1-T3 Stage IIIB Any T T4 Stage IV Any T N0 N0 N0 N0 N1 N1 (N0) N1, N2 N3 Any N Any N M0 M0 M0 M0 M0 M0 M0 M0 M0 M1

Laboratory Diagnosis of Cancer

1. Histologic & Cytologic Methods

Clinical data Excision / biopsy Needle aspiration Cytologic smears Quick-frozen section

Molecular diagnosis
1. Diagnosis of malignant neoplasms

Differentiation between benign from malignant proliferations of T or B cells(Ag receptor rearrangement) Detection of translocations or rearrangements in hematopoietic neoplasms(eg. CML: bcr-c-abl) Detection of translocations in small round cell tumor (eg. Ewings sarcoma: t(11;22)(q24;q12)) Cytogenetics, PCR, FISH

Molecular diagnosis
2. Prognosis of malignant neoplasms

Detection of certain genetic alterations which are associated with poor prognosis(eg. neuroblastoma: N-myc amplification, 1p deletion) Cytogenetics, FISH, PCR

3. Detection of minimal residual disease

Leukemia or lymphoma(eg. CML: bcr-c-abl) Colon ca(K-ras)

Molecular Profiles of Tumors

; microarrays (tissue and DNA) and proteomics

Tissue Microarray

Clinical effect to numerous molecular targets Population study and translational study

DNA Microarray

Expression Proteomics

Stanley Fields, Science 2001 291 1221

2D Gel Differential Expression and Identification

Samples
normal samples diseased samples serum, CSF drug time-course
MW IEF

Separation

Digestion

Identification
Protein A

Protein Y
Protein Z

1000s of samples =1000s of gels

100s of proteins/gel

10,000s proteins

THE END