neoplasia path notes

8/11/2019 Neoplasia Path notes

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Neoplasia

Shivayogi Bhusnurmath, MD

Department of Pathology

St Georges University school of

Medicine

Shivayogi Bhusnurmath- Neoplasia

Neoplasia

Objectives:The students should be able to:-

Define and use in proper context the following termsadenoma, anaplasia, angiogenesis, aplasia, atrophy, blastoma, cachexia, cancer, carcinogen, carcinoma,carcinoma in situ, choristoma, dermoid cyst, desmopdifferentiation, doubling time, protooncogene, DNA reenzyme, dysplasia, grade, growth fraction, hamartomhyperplasia, hypertrophy, hypoplasia, immunosurveiinvasion, Krukenberg tumor, lymphoma, malignant,metaplasia, metastasis, mixed tumor, neoplasia, occumalignancy, oncogene,Pap smear, papilloma,

paraneoplastic syndrome, preneoplastic condition,Philadelphia chromosome, pleomorphism, point mutpolyp, premalignant, prognosis, progression, sarcomstage, teratoma, translocation, tumor, tumor associatantigen, tumor marker, tumor specific antigen, tumorsuppressor gene


Objectives:

The students should be able to:-

1. Recapitulate regulators of cell cycle, protonocogenes,

oncogenes, tumor suppressor genes, point mutations,

chromosomal translocations, gene amplifications from

immunology course

2. Distinguish disorders of growth like hyperplasia,

hypoplasia, aplasia, hypertrophy, atrophy, metaplasia,

hamartoma and dysplasia and give suitable examples.

3. Define neoplasia, and explain each component of the

definition.

4. Explain why understanding the pathology of neoplasia is

important.


5. Theoretically distinguish benign from malignanttumors.(behavior,gross appearance,microscopic fea

6. Explain the classification based on tissue of origin wsuitable examples (epithelial, connective tissue, lymteratomas, blastomas).

7. Explain how a cancer cell differs in morphology fromnormal cell

8. Describe the modes of spread of tumors and themechanisms involved therein (direct, lymphatic, vasserosal).

9. Illustrate the geographic variation in the incidence otumors with suitable examples.

10.Explain the different theories of development of tum

(carcinogenesis - agents, oncogenes, steps). Link thviruse, RNA virus and bacterium to human tumors- a

in the handout


11. Explain the genetic basis of carcinogenesis including

examples listed in the handout. Explain the concept of

recessive cancer genes and the two hit hypothesis.

12. Correlate the oncogenes with tumorogenesis inRetinoblastoma, Colonic Carcinoma, Breast Ca,

neuroblastoma, Burkitts Lymphoma, Chronic myeloid

leukemia and chronic lymphatic leukemia.

13. Derive the local and systemic effects of tumor on the host.

14. Define paraneoplastic syndromes and give examples.Name

the tumors they are most closely associated with

15. Identify situations, which predispose to the development of

cancer (preneoplastic lesions).-listed in handout

16. Explain the concept of carcinoma in situ and its

significance.


16. Explain the role played by the immune system towa

recognition and control of tumor. Also recognize co

in this field that could be useful in diagnosis and trea

of cancer (tumor antigens, Antibodies, Immunosurve

Immunotherapy).

17. Explain the difference between grading and staging

tumors. Recognize the significance of

these(classification,prognosis,choice of therapy).

18. Explain the effects produced by the tumor on the ho

19. Using the example of carcinoma of uterine cervix di

incidence, etiology, epidemiology, clinical features,

prevention, early diagnosis,(pap smears), treatment.



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Importance of neoplasia

Common cause of death (others-

infection, cardiovascular)

Increasing incidence (longevity,

smoking)

Mostly fatal

New varieties coming up

Early diagnosis, prevention, control,

cure.


Why study


Figure out how do they

start

Figure out how they can

stopped

Some Lymphomas and

leukemias can now be

cured!

Terminology Tumor- swelling (also in

inflammation) But usually usedfor neoplasia)

Cancer- (Latin-crab)- adheresobstinately

Oncology (Oncos- tumor)

NeoplasiaShivayogi Bhusnurmath- Neoplasia Shivayogi Bhusnurmath- Neoplasia

Hyperplasia

Increase in the size of an organ dto an increase in the number of ce

in the organ

Differs from Hypertrophy

Increase in size of an organ due t

increase in the Size of individual

within the organ

Hyperplasia involves cellular

proliferation

both may be found together in cesituations.

Hyperplasia


Metaplasia


Abnormality of differentiatio

Mature of one type is replac

mature cell of another type

Reversible


3/13

Dysplasia

Loss of uniformity of cells

Loss in architectural orientation

Pleomorphism

Hyperchromasia + large nucleus

Increased mitosis(but normal appearance)

Maturation in basal region and mitosis inupper layers(haphazard)

Polyclonal; cervix, bronchus, penis etc


Dysplasia


Neoplasia- definition

Neo plasia = New growth

An abnormal mass of tissue

The growth of which exceeds and is

uncoordinated with that of normal

tissues.

And which persists in the absence of

the stimulus that caused it to occur.


Purposeless growth

competes with host cells fo

nutrition

autonomous but-depends o

host for blood (nutrients,

oxygen)Shivayogi Bhusnurmath- Neoplasia

Classification- Why

Communication- talk the same

language Want to know how it behaves

Mild or dangerous

Which tissue it is arising from

Treatment choices


Benign vs Malignant


Benign

- Slowly growing (compress surrounding

- Encapsulated

- Resemble tissue of origin

- Absence of infiltration of surrounding ti

- Do not spread to distant sites (localized

- Cured by removal

Rarely cause problems but!

- Compression of adjacent structure (CNS

- Production of Hormone

- Bleeding


4/13

Malignant- cancer


Less resemblance to original tissue

Rapid growth

Locally invasive, spreading tentacles,

into surrounding tissues (Crab) - no

capsule

Tend to recur after removal

Also spread to distant parts of the body

(metastases)

Tend to progress to cause death (if not

completely destroyed by therapy)

Tissue of origin

Benign Malignant *

Epithelial Adenoma Adeno Carcino

(polyp, Squamous Ce

papilloma) Carcinoma

Conn Tissue Lipoma Liposarcoma

Fibroma Fibrosarcoma

Osteoma Osteosarcoma Lymph Node Nil Lymphoma

Mixed Salivary gland,

breast, skin


Tissue of origin

Benign Malignant *

Epithelial Adenoma Adeno Carcinoma

(polyp, Squamous Cell




Osteoma Osteosarcoma

Lymph Node Nil Lymphoma


breast, skin


Tissue of origin

Benign Malignant *

Epithelial Adenoma Adeno Carcino

(polyp, Squamous Cel







breast, skin


Tissue of origin

Benign Malignant *

Epithelial Adenoma Adeno Carcinoma(polyp, Squamous Cell







breast, skin


Tissue of origin

Benign Malignant *

Epithelial Adenoma Adeno Carcino(polyp, Squamous Cel







breast, skin



5/13

Mixed tumors

Epithelium and connective

tissue

eg. Mixed tumor of salivary

glands-benign

Synovial sarcoma-malignant


Classification- contd

Teratoma Ectoderm, Endoderm

(germ cells) Mesoderm (Testis, O

Blastomas Embryonal cell rests

(embryonal Neuroblastoma,

rests) Retinoblastoma

Nephroblastoma

(Wilms tumor)

Tumor like Hamartoma

Conditions Choristoma


Teratoma

Tumors arise from totipotent cells -

potential to differentiate into

ectoderm,endoderm and mesoderm

Gonads, mediastinum, retroperitoneum

(cells that have dropped off during

migration in embryogenesis)

eg- Dermoid cyst of ovary-benign,

teratoma of testis-malignant








Nephroblastoma

(Wilms tumor)




Blastoma

Tumor arising from embryonal cells

committed to form a particular organ eg- kidney (nephroblastoma), Liver

(hepatoblastoma)

try to mimic primitive tissue of that

organ- eg. primitive tubules, glomeruli,

connective tissue








Nephroblastoma

(Wilms tumor)





6/13

Tumor like lesions


Hamartoma - collection of normal tissues

indigenous to the area but

in abnormal proportion e.g. -

blood vessels, fat, nerve fibers,

collagen ; bronchial

hamartoma,

Nevus, Hemangioma (neoplasms)

Choristoma-Presence of normal tissuein abnormal location

e.g. pancreatic cells in

stomach, gastric cells in

Meckels diverticulum...

General concept

Benign tumors start as benign

tumors and remain benign

Malignant tumors arise as

malignant tumors (sometimes

preceded by dysplasia)

Benign tumors do not become

malignant


Exceptions to the rule

Colonic adenomas Carcinoma

Nevus

Melanoma

Basal cell carcinoma (infiltrates, no

metastasis)

Giant cell tumor of bone (recurs after

removal but no metastasis)

Malignant gliomas do not metastasize


Distinction benign vs maligna

Benign Malign

Differentiation High Poor

Uniformity High Poor

Mitoses Few Many

Blood Vessels Well formed P

Necrosis No Yes

Nucleus Normal Abnor

Recurrence No Yes


Growth


Multiplication plus differentiation

Anaplasia- lack of differentiation Tumors arise from stem cells

(reserve cells)in specialized tissues-

not the full differentiated cells

X +Maturation-->Well differentiated .

X +No maturation->Poorly

differentiated tumor (not

dedifferentiation)

Features of poor differentia

Cellularpleomorphism (many sha

Nuclear changes

- Hyperchromatic: coarse clumped chroma

- Nucleus large relative to cell size

Increased Nuclear - cytoplasmic ratio

- Variability in size and shape

- Maybe multiple

- Mitotic figures numerous- atypical



7/13


8/13

Infiltration and metastasis

Detachment from adjacent cells- reduced

expression of cathedrin E

Break through basement membrane

Collagen IV, glycoproteins, proteoglycans

Only some cells can - why?

Receptors for basement membrane

Collagenase, plasminogen activator, cathepsinB

Liver, lung - commonest sites of metastasis

Bone,adrenals,kidney,brain etc

flow, receptors on endothelial cells, chemotaxis

Why should we know this?


Lymph node enlargement in tum


Tumor cells can spread to draining

lymph nodes--LN enlargement due

spread of cancer- usually Carcino

LN put up tumor specific immune

response and kill the tumor cells-

reactive LN hyperplasia andenlargement

LN enlargement does not necessa

mean dissemination of cancer.

Metastasis

Site of metastasis depends upon

Type of tumor

Geographic location

(systemic,portal)

Lymphatic drainage

Permissiveness of target organ

Blood supply to target organ

Receptors on endothelial cells of

vessels in target organ


Is there a gene for metastas

Oncogenes for collagenase,

cathepsin etc

reduced expression of nm23 ?

KAI 1,KISS gene ?


Krukenberg tumor Bilateral ovarian masses

uniform,retain shape of the ovaries

signet ring cells (mucous) on histology

not a primary ovarian malignancy

usually primary is in GI.tract

how did it spread to the ovaries?

primarily presents clinically as ovarian

mass

the GI lesion may be silent clinically


Oncogenes-Self revision from Immunology cour


Protooncogenes, normal cell cyc

Rb gene, cyclins and cdk system

GF, receptors for GF, second

messengers, nuclear transcriptio

factors

Genes regulating Apoptosis, p53

DNA repair genes

Anti oncogenes

Cancer suppressor genes


9/13

Oncogenes-


Growth factors - eg fibroblast GF,

Growth factor receptors - eg-egf, csf

Second messengers eg GTP,Tyrosine

Kinase

Nuclear transcription - eg myc,fos,jun

Cyclin, CDK

Autocrine loop - increased

multiplication

Rb gene - normal, role in

Retinoblastoma,

- two hit hypothes

Li Fraumeni syndrome


Carcinogenesis

Embryonal rests (blastomas)-retain potential formultiplication

Repeated cell divisions in response to any

continual injury e.g. viral or alcoholic hepatitis-

some of the dividing cells develop chromosomal

damage leading to cancer(in cirrhosis)

Genetic mutation

= Point mutations - Pancreas, colon

= Translocations - chronic myeloid

leukemia, Burkitts

= Deletions - Retinoblastoma, colon

= Gene amplifications - Neuroblastoma, breast


Features of transformed c

Self sufficiency of growth signals

Insensitivity to growth inhibitory facto

Resistance to apoptosis

Defective DNA repair

Unrestricted proliferation

Angiogenesis

Invasion

metastasisShivayogi Bhusnurmath- Neoplasia

Types of insults (Carcinogens)

Physical--radiation -read up

Chemical--(initiator,promoter)--read up

Biological

hormones,virus,toxins,parasites

helicobacter pylori

Immunodeficiency


Test for chemical carcinoge

Chemical carcinogens- Mutagens

Test the ability to induce mutationSalmonella Typhimurium

Correlated 70-90%

Used for screening chemicals

Ames Test



10/13

Biological agents Viral

= HPV, HS Cervical (DNA)

= EB - Burkitts, Nasopharyngeal (DNA)

= Hep B - Hepatoma (DNA)

= HTLV - Lymphoma (RNA)

Hormones

= Oncogenetic - endometrial,estrogen

Breast - Prolactin

Vaginal (children - Diethyl stilbesterol)

= Dependant - prostate, breast, thyroid (TSH)


Bacterial

Helicobacter pylori

Gastric malignancies

Earlier detected with peptic ulc

Now related to lymphoma (MA

Carcinoma Treat with long term antibiotic


Biology of tumor growth

Transformation

Growth

Invasion

Metastasis


How long does it take to produce a

clinically detectable mass?

1 gm-10~9 cells in 30 doublings

Normal cells 30 doublings-90 days BU

tumor cells cell cycle is prolonged

months to years

Another 30 doublings--1Kg tumor

So by the time clinically detected-alre

completed a major part of its life cycl


Tumor cell kinetics Doubling time

Growth fraction (clinically evident - tumors - most

cells in Go: Surgery S and M phase--drugs

become effective)

Cell loss ( apoptosis, ischemia, host defense)

Latent period- years

Angiogenesis - (growth factors, endothelial

chemotaxis

and mitosis, stromal proteolysis)- FGF, VEGF,

PDGF

Angiostatin, Thrombospondin (inhibit)

Why should we know these?


Inherited carcinoma syndrom


Retinoblastoma- two hit hypothe

Familial Adenomatous Polyposis(FAP)

Multiple endocrine Adenomas - I,

Neurofibromatosis (von

Recklinghausens)

Wilms Tumor

Li Fraumeni Syndrome (p53) brea

colon, sarcoma


11/13

Hereditary preneoplastic syndromes


Defective DNA repair

= Xeroderma pigmentosa

= Blooms Syndrome

= Fanconis Anemia

= Ataxia telengectasia

Immune Deficiency= X linked agammaglobulinemia

= Wiskott Aldrich syndrome

= X linked Lymphoproliferative

syndrome

Familial carcinomas

Breast

Ovary

Colon

Higher risk in families-

mechanism not worked out


Preneoplastic conditions Statistically high risk of development of

carcinomas

Scars, Cirrhosis, Endometrial Hyperplasia

Bronchial dysplasia, Cervical dysplasia

Chronic atrophic gastritis, Leukoplakia

Adenoma colon, Ulcerative colitis

Xeroderma Pigmentosa


Effect of cancer on the pati


Use up nutrition

Discharge waste (Parasite)

Local -

= Lump, pressure, bleed, pain, ulc

= Inflammation, edema

= block, rupture vessels, tubes

Systemic -

= Wasting

= Fever

= Hormones

Metastasis= Cachexia (catabolism, bleed,

infection, ??)

Paraneoplastic syndromes


Unexplained systemic manifestation

10-15% cancers Ectopic hormone production

= Lung - ACTH, ADH, PT,

Serotonin

= Liver - Insulin

= Kidney - Polycythemia

= Myopathy, neuropathy ??

= Deep vein thrombosis ??

Grading of tumors

Microscopic Grade I - Well differentiated (resembl

original)

Grade IV - Poorly differentiated(anaplasia)

Grade II and III in between

Relate to Prognosis



12/13

Staging of tumors (TNM)

Clinical, not microscopic

Tumor size - T1, T2, T3, T4

LN - No, N1, N2, N3

METASTASIS - Mo M1

eg. Breast cancer - T2, N2, M1

Extent of spread, Prognosis, Choice of

Treatment


Occult and dormant cance

Occult cancer: Primary very small

clinically not detectable but there

be evidence of metastasis or

paraneoplastic syndromes. The pr

site may be difficult to detect

Dormant cancer: metastasis notdetected at the time of surgery but

surface later


Immunopathology

Tumor in Animals

= Ag detection, Transplant, Ab protect

= Tumor specific Ag (TSA)

Tumor in Humans

= Tumor Associated Ag (TAA)

= AFP (Liver), CEA (gut), Oncofetal Ag.

= PSA (Prostate)

= Tumor Antibodies - research


Immunosurveillance

Traffic Police Macrophages, NK cells, T cells, B cells

Failure

= loss of Ag, Loss of MHC

expression

= little Ag, Immune Suppression

by tumor products

Immunotherapy

= L + 1L2 inject (LAK cells)

= Cytokines, tumor L, Abs + toxin

incidence in Immunodeficient


Geographic tumors

Agents, Lifestyles, Genetic

Japan - stomach(less in US immigrants)

Africa - hepatoma (hep.B, aflatoxin) NZ - skin (uv exposure)

India - oral(tobacco,betel nut)

USA - lung, breast

Central Africa- Burkitts lymphoma (less in

US immigrants)

(Moslems- low incidence of carcinoma of

cervix)


Steps in the diagnosis of canc

Clinical history, exam, radiology

LAB - Fluid cytology, FNAC, Needle bio

Lumpectomy, Resection

STUDY = arrangement (architecture)

= resemblance to normal

(differentiation)- grading

= nuclear, cytoplasmic features

(anaplasia)

= mitosis



13/13

Steps in the diagnosis of cancer

= Immunocytochemistry (cytokeratin,vimentin, CALLA)

= Oncofetal Ag, Hormones, Enzymes(acid P04ase)

= Electron microscopy(melanin, neuroendocrine granules)

= gene rearrangement

Staging-TNM- clinical, path, imaging

Surgery/radiotherapy/chemotherapy

Follow up screening for residual tumor/recurrence/ metastasis


Tumor markers


CELLS (fordiagnosis)

carcinoma-

CEA,EMA

Hepatoma-AFP

ChorioCa-HCG

Neuroendo-S-100

Conn.tissue-vimentin

vascular-factor viii

related Ag

Lymphoid-

factorVlll relate

Ag

proliferating ce

Ki67 or PCNA

SERUM (for diag& screening)

PSA,HCG,AFPd phosphatase

Alk.phosphata

(bone mets)

Carcinoma cervix


Used to be common (cauliflower like

growths)

Post coital bleeding

Routine Pap smear screening

Detect changes 10-15 years earlier

CIN - I, II, III, Micro Invasive, Invasive

HPV strains -sexually transmitted

disease

Cone biopsy / hysterectomy

neoplasia path notes

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