Neoplasia Path Notes

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 terms-
adenoma, anaplasia, angiogenesis, aplasia, atrophy, benign,
blastoma, cachexia, cancer, carcinogen, carcinoma,
carcinoma in situ, choristoma, dermoid cyst, desmoplasia,
differentiation, doubling time, protooncogene, DNA repair
enzyme, dysplasia, grade, growth fraction, hamartoma,
hyperplasia, hypertrophy, hypoplasia, immunosurveillance,
invasion, Krukenberg tumor, lymphoma, malignant,
metaplasia, metastasis, mixed tumor, neoplasia, occult
malignancy, oncogene,Pap smear, papilloma,
paraneoplastic syndrome, preneoplastic condition,
Philadelphia chromosome, pleomorphism, point mutation,
polyp, premalignant, prognosis, progression, sarcoma,
stage, teratoma, translocation, tumor, tumor associated
antigen, tumor marker, tumor specific antigen, tumor
suppressor 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 malignant
tumors.(behavior,gross appearance,microscopic features)
6. Explain the classification based on tissue of origin with
suitable examples (epithelial, connective tissue, lymphoid,
teratomas, blastomas).
7. Explain how a cancer cell differs in morphology from a
normal cell
8. Describe the modes of spread of tumors and the
mechanisms involved therein (direct, lymphatic, vascular,
serosal).
9. Illustrate the geographic variation in the incidence of
tumors with suitable examples.
10. Explain the different theories of development of tumors
(carcinogenesis - agents, oncogenes, steps). Link the DNA
viruse, RNA virus and bacterium to human tumors- as listed
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 in
Retinoblastoma, 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 towards
recognition and control of tumor. Also recognize concepts
in this field that could be useful in diagnosis and treatment
of cancer (tumor antigens, Antibodies, Immunosurveillance,
Immunotherapy).
17. Explain the difference between grading and staging of
tumors. Recognize the significance of
these(classification,prognosis,choice of therapy).
18. Explain the effects produced by the tumor on the host
19. Using the example of carcinoma of uterine cervix discuss
incidence, etiology, epidemiology, clinical features,
prevention, early diagnosis,(pap smears), treatment.
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 be
stopped
Some Lymphomas and
leukemias can now be
cured!
Terminology
Tumor- swelling (also in
inflammation) But usually used
for neoplasia)
Cancer- (Latin-crab)- adheres
obstinately
Oncology (Oncos- tumor)
Neoplasia
Shivayogi Bhusnurmath- Neoplasia Shivayogi Bhusnurmath- Neoplasia
Hyperplasia
Increase in the size of an organ due
to an increase in the number of cells
in the organ
Differs from Hypertrophy
Increase in size of an organ due to an
increase in the Size of individual cells
within the organ
Hyperplasia involves cellular
proliferation
both may be found together in certain
situations.
Hyperplasia
Metaplasia
Abnormality of differentiation
Mature of one type is replaced by
mature cell of another type
Reversible
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 in
upper 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 for
nutrition
autonomous but-depends on
host for blood (nutrients,
oxygen)
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 tissue)
- Encapsulated
- Resemble tissue of origin
- Absence of infiltration of surrounding tissues
- Do not spread to distant sites (localized)
- Cured by removal
Rarely cause problems but!
- Compression of adjacent structure (CNS)
- Production of Hormone
- Bleeding
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 Carcinoma
(polyp, Squamous Cell
papilloma) Carcinoma
Conn Tissue Lipoma Liposarcoma
Fibroma Fibrosarcoma
Osteoma Osteosarcoma
Lymph Node Nil Lymphoma
Mixed Salivary gland,
breast, skin
Tissue of origin
Benign Malignant *
breast, skin
Tissue of origin
Benign Malignant *
breast, skin
Tissue of origin
Benign Malignant *
breast, skin
Tissue of origin
Benign Malignant *
breast, skin
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, Ovary)
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)
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 tissue
in 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 oCarcinoma
Nevus oMelanoma
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 malignant
Benign Malignant
Differentiation High Poor
Uniformity High Poor
Mitoses Few Many
Blood Vessels Well formed Poor
Necrosis No Yes
Nucleus Normal Abnormal
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 differentiation
Cellular pleomorphism (many shapes)
Nuclear changes
- Hyperchromatic: coarse clumped chromatin
- Nucleus large relative to cell size
Increased Nuclear - cytoplasmic ratio
- Variability in size and shape
- Maybe multiple
- Mitotic figures numerous- atypical
Components of a tumor
Actual tumor cells: Monoclonal
Derived from original single mutated
cell
Stromal cells: from host tissue
around
Blood vessels
Fibrous tissue / desmoplasia (more
in adenocarcinomas)
Support system for tissues
Dysplasia vs neoplasia
Dysplasia
Several of the features of neoplasia
Nuclear abnormalities
Loss of cellular relationships
BUT
Reversible to some extent
Polyclonal (one clone eventually may
become malignant)
Chance of becoming carcinoma
Sequence
Dysplasia -mild, moderate, severe
Intraepithelial neoplasia (Cervix -CIN-I, II, III)
Carcinoma in situ
Severe dysplasia and Ca in situ similar
Invasive Carcinoma
Is it sequential?
Which of them is reversible?
Time lag in years
Sequence
Dysplasia -mild, moderate, severe
Intraepithelial neoplasia (Cervix -CIN-I, II, III)
Carcinoma in situ
Severe dysplasia and Ca in situ similar
Invasive Carcinoma
Is it sequential?
Which of them is reversible?
Time lag in years
Sequence
Transformation from normal to
cancer cell
Growth of transformed cell
Local infiltration
Distant metastasis
Spread of tumor
Detachment
Break through basement membrane
Entry into vessel
Travel in bloodstream
Emerge from vessel at another site
Colonize
OTHERS: Lymphatics to draining
Lymph nodes, Serosal surfaces
(ovary), natural passages (ureter)
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 tumors
Tumor cells can spread to draining
lymph nodes--LN enlargement due to
spread of cancer - usually Carcinomas
LN put up tumor specific immune
response and kill the tumor cells-
reactive LN hyperplasia and
enlargement
LN enlargement does not necessarily
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 metastasis?
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 course
Protooncogenes, normal cell cycle
Rb gene, cyclins and cdk system
GF, receptors for GF, second
messengers, nuclear transcription
factors
Genes regulating Apoptosis, p53,
DNA repair genes
Anti oncogenes
Cancer suppressor genes
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 hypothesis
Li Fraumeni syndrome
Carcinogenesis
Embryonal rests (blastomas)-retain potential for
multiplication
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 cell
Self sufficiency of growth signals
Insensitivity to growth inhibitory factors
Resistance to apoptosis
Defective DNA repair
Unrestricted proliferation
Angiogenesis
Invasion
metastasis
Types of insults (Carcinogens)
Physical--radiation -read up
Chemical--(initiator,promoter)--read up
Biological
hormones,virus,toxins,parasites
helicobacter pylori
Immunodeficiency
Test for chemical carcinogens
Chemical carcinogens- Mutagens
Test the ability to induce mutations in
Salmonella Typhimurium
Correlated 70-90%
Used for screening chemicals
Ames Test
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 ulcers
Now related to lymphoma (MALT),
Carcinoma
Treat with long term antibiotics
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 BUT
tumor cells cell cycle is prolonged
months to years
Another 30 doublings--1Kg tumor
So by the time clinically detected-already
completed a major part of its life cycle
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 syndromes
Retinoblastoma- two hit hypothesis
Familial Adenomatous Polyposis Coli
(FAP)
Multiple endocrine Adenomas - I, II
Neurofibromatosis (von
Recklinghausens)
Wilms Tumor
Li Fraumeni Syndrome (p53) breast,
colon, sarcoma
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 patient
Use up nutrition
Discharge waste (Parasite)
Local -
= Lump, pressure, bleed, pain, ulcer
= 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 (resembles
original)
Grade IV - Poorly differentiated
(anaplasia)
Grade II and III in between
Relate to Prognosis
Staging of tumors (TNM)
Clinical, not microscopic
Tumor size - T
1
, T
2
, T
3
, T
4
LN - No, N
1
, N
2
, N
3
METASTASIS - Mo M
1
eg. Breast cancer - T
2
, N
2
, M
1
Extent of spread, Prognosis, Choice of
Treatment
Occult and dormant cancer
Occult cancer: Primary very small and
clinically not detectable but there may
be evidence of metastasis or
paraneoplastic syndromes. The primary
site may be difficult to detect
Dormant cancer: metastasis not
detected at the time of surgery but may
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 oinject (LAK cells)
= Cytokines, tumor L, Abs + toxin
n 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 cancer
Clinical history, exam, radiology
LAB - Fluid cytology, FNAC, Needle biopsy,
Lumpectomy, Resection
STUDY = arrangement (architecture)
= resemblance to normal
(differentiation)- grading
= nuclear, cytoplasmic features
(anaplasia)
= mitosis
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 (for
diagnosis)
carcinoma-
CEA,EMA
Hepatoma-AFP
ChorioCa-HCG
Neuroendo-S-100
Conn.tissue-
vimentin
vascular-factor viii
related Ag
Lymphoid-
factorVlll related
Ag
proliferating cells-
Ki67 or PCNA
SERUM (for diagnosis
& screening)
PSA,HCG,AFP,Aci
d phosphatase,
Alk.phosphatase
(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

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Neoplasia Path Notes

Uploaded by

Copyright:

Available Formats

Neoplasia

You might also like