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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
Shivayogi Bhusnurmath- Neoplasia
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.
Shivayogi Bhusnurmath- Neoplasia
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
Shivayogi Bhusnurmath- Neoplasia
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.
Shivayogi Bhusnurmath- Neoplasia
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.
Shivayogi Bhusnurmath- Neoplasia
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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.
Shivayogi Bhusnurmath- Neoplasia
Why study
Shivayogi Bhusnurmath- Neoplasia
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
Shivayogi Bhusnurmath- Neoplasia
Metaplasia
Shivayogi Bhusnurmath- Neoplasia
Abnormality of differentiatio
Mature of one type is replac
mature cell of another type
Reversible
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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
Shivayogi Bhusnurmath- Neoplasia
Dysplasia
Shivayogi Bhusnurmath- Neoplasia
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.
Shivayogi Bhusnurmath- Neoplasia
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
Shivayogi Bhusnurmath- Neoplasia
Benign vs Malignant
Shivayogi Bhusnurmath- Neoplasia
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
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Malignant- cancer
Shivayogi Bhusnurmath- Neoplasia
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
Shivayogi Bhusnurmath- Neoplasia
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
Shivayogi Bhusnurmath- Neoplasia
Tissue of origin
Benign Malignant *
Epithelial Adenoma Adeno Carcino
(polyp, Squamous Cel
papilloma) Carcinoma
Conn Tissue Lipoma Liposarcoma
Fibroma Fibrosarcoma
Osteoma Osteosarcoma
Lymph Node Nil Lymphoma
Mixed Salivary gland,
breast, skin
Shivayogi Bhusnurmath- Neoplasia
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
Shivayogi Bhusnurmath- Neoplasia
Tissue of origin
Benign Malignant *
Epithelial Adenoma Adeno Carcino(polyp, Squamous Cel
papilloma) Carcinoma
Conn Tissue Lipoma Liposarcoma
Fibroma Fibrosarcoma
Osteoma Osteosarcoma
Lymph Node Nil Lymphoma
Mixed Salivary gland,
breast, skin
Shivayogi Bhusnurmath- Neoplasia
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Mixed tumors
Epithelium and connective
tissue
eg. Mixed tumor of salivary
glands-benign
Synovial sarcoma-malignant
Shivayogi Bhusnurmath- Neoplasia
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
Shivayogi Bhusnurmath- Neoplasia
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
Shivayogi Bhusnurmath- Neoplasia
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
Shivayogi Bhusnurmath- Neoplasia
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
Shivayogi Bhusnurmath- Neoplasia
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
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Tumor like lesions
Shivayogi Bhusnurmath- Neoplasia
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
Shivayogi Bhusnurmath- Neoplasia
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
Shivayogi Bhusnurmath- Neoplasia
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
Shivayogi Bhusnurmath- Neoplasia
Growth
Shivayogi Bhusnurmath- Neoplasia
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
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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?
Shivayogi Bhusnurmath- Neoplasia
Lymph node enlargement in tum
Shivayogi Bhusnurmath- Neoplasia
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
Shivayogi Bhusnurmath- Neoplasia
Is there a gene for metastas
Oncogenes for collagenase,
cathepsin etc
reduced expression of nm23 ?
KAI 1,KISS gene ?
Shivayogi Bhusnurmath- Neoplasia
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
Shivayogi Bhusnurmath- Neoplasia
Oncogenes-Self revision from Immunology cour
Shivayogi Bhusnurmath- Neoplasia
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
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Oncogenes-
Shivayogi Bhusnurmath- Neoplasia
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
Shivayogi Bhusnurmath- Neoplasia
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
Shivayogi Bhusnurmath- Neoplasia
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
Shivayogi Bhusnurmath- Neoplasia
Test for chemical carcinoge
Chemical carcinogens- Mutagens
Test the ability to induce mutationSalmonella Typhimurium
Correlated 70-90%
Used for screening chemicals
Ames Test
Shivayogi Bhusnurmath- Neoplasia
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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)
Shivayogi Bhusnurmath- Neoplasia
Bacterial
Helicobacter pylori
Gastric malignancies
Earlier detected with peptic ulc
Now related to lymphoma (MA
Carcinoma Treat with long term antibiotic
Shivayogi Bhusnurmath- Neoplasia
Biology of tumor growth
Transformation
Growth
Invasion
Metastasis
Shivayogi Bhusnurmath- Neoplasia
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
Shivayogi Bhusnurmath- Neoplasia
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?
Shivayogi Bhusnurmath- Neoplasia
Inherited carcinoma syndrom
Shivayogi Bhusnurmath- Neoplasia
Retinoblastoma- two hit hypothe
Familial Adenomatous Polyposis(FAP)
Multiple endocrine Adenomas - I,
Neurofibromatosis (von
Recklinghausens)
Wilms Tumor
Li Fraumeni Syndrome (p53) brea
colon, sarcoma
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Hereditary preneoplastic syndromes
Shivayogi Bhusnurmath- Neoplasia
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
Shivayogi Bhusnurmath- Neoplasia
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
Shivayogi Bhusnurmath- Neoplasia
Effect of cancer on the pati
Shivayogi Bhusnurmath- Neoplasia
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
Shivayogi Bhusnurmath- Neoplasia
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
Shivayogi Bhusnurmath- Neoplasia
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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
Shivayogi Bhusnurmath- Neoplasia
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
Shivayogi Bhusnurmath- Neoplasia
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
Shivayogi Bhusnurmath- Neoplasia
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
Shivayogi Bhusnurmath- Neoplasia
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)
Shivayogi Bhusnurmath- Neoplasia
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
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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
Shivayogi Bhusnurmath- Neoplasia
Tumor markers
Shivayogi Bhusnurmath- Neoplasia
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
Shivayogi Bhusnurmath- Neoplasia
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