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NON-NEOPLASTIC PROLIFERATION
H M Nadjib Dahlan Lubis
Bag.Patologi Anatomi
Fak Kedokteran USU/UISU Medan
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Control of GrowthNet balance: - Proliferation Proto-oncogen
- Differentiation Death
Abnormal Growth
Atrophy: size: tissue, organ size, number- normally formed
- distinct from: agenesis, aplasia, hypoplasia (abn
organ development)
Hypertrophy: size size of individula cells
Hyperplasia: size number of component cells
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Causes of Atrophy-
cytoplasm,
number of organelles
Types
Disuse - Immobilized skletal muscle & bone: - cast
- bed restBone: Reabs > formation size trabecuae
osteoporosis
Denervation damage to lower motor neuron
Loss of trohic hormon: Endometrium, breast, endocrine
Lack of nutrients Protein-calorie malnutrition (marasmus)Ischemia: Cereb Vasc dis Cereb atrophy
Senile: brain, heart ischemia
Pressure: spinal cord, vertebrae neop spinal canal
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Causes of Hypertrophy & Hyperplasia
- Phy: cardiac demand
- Path: - stimulus of demand (-)
- - Myocardian hypertrophy: Hypertension, valv, cong HD (-)
- - Endometrial hyperplasia estrogen (near menopause)
- - Bilat adr hyperplasia ACTH
- - Thyroid: Graves dis TSH auto Ab + TSH rec
- - Prostate Androgen
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Hypertrophy
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Metaplasia = abn cell diff: mature cells is replaced by diff type of mature
cell (not normal for the tiss involved)
Reversible, most common: epithelium: potential for diff in stem
cell chronic physical, chemical irritation
Squamous Metaplasia= Nonsqu pse str coll / cuboid squ epithelium
Loc: - Endocervix
- Bronchial mucosa
- Endometrium, urinary bladder
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Mucous secreting Squamous Fibrous Bone
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Glandular Metaplasia Esophagus: squamous glandular, mucus secreting acid
reflux
Stomach, intestine: gastric mucosa intestinal mucosa
(intestinal metaplasia vice versa (gastric metaplasia)
Ovary: serous & mucinous cyst
Mesenchym: scar, fibroblastic prolif osseous metaplasia
Clinical Significance
Little
Loss of cilia & mucus (bronchi) predispose: infection
No increased risk cancer
However: dysplastic changes (often present) cancer :
SCC in bronchus
Adenoca in esophagus
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Dysplasia= Abn of differentiation & maturation
A. Nuclear
- size nucleus: - absolute
- relative: to cyto (N/C ratio- Hyperchromatism ( chromatine content)- Abn chr distribution (coarse clumping)
- Nuc memb irregularities: thickening, wrinkling
B. Cytoplasmic
Failure of normal diff: - lack of keratinization in squ cells
- lack of mucin in gl epit
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C. Rate of cell multiplication- mitotic in many layer (N: mitotic in basal layer)- Individual mitoses: N
D. Disordered Maturation
- Retain resemblance to basal stem cells as move upward
- Keratin production: fail
Grading - Mild
- Moderate- Severe
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SignificancePremalignant one step short of cancer
= Cervical Intraepithelial Neoplasia (CIN)
Carcinoma in situ (CIS) is included in CIN, however:
- True neoplasm with all of features of malignant exc invasiveness
SevereDysplasia = CIS : - Clinical significance
- Treatment
Riskof dysplasia to develope invasive cancer
- Grade
- Duration
- Site
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Differences: Dysplasia & CancerInvasiveness
Dysplasia & CIS: - do not invade BM
- do not spread cb lymphatics (-), bl ves (-)
Cancer: invade BM
spread lymphatic, bl ves excision
Reversibility
Dysplasia: - may return to normal
- severe dysp may be irreversible
Cancer: irreversible,
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Microscopic exam
Cytology must be confirmed by biopsy
Nuclear & cytoplasmic features diag & grading
Well established: - cervix
- urinary bladder
- lung
Other sites: GIT, Breast: difficult infl & regeneration
atypia
Papanicolaou: - early detection & therapy of cervical dysplasia
- cancer of cervix past 20 years
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NEOPLASTIC
PROLIFERATION
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Neoplasia (New growth)Abn of cell diff, maturation, & control of growth
Formation of masses of abnor tissue (tumors)
Tumor applied to any swelling, now: suspected neoplasm
Benign/Malignant ? Depend on spread.
Benign remain localized
Cancer = Mal neo, grips surrounding (claw like crab)
Rupert Willis (1950s): Abn mass of tiss, growth exceeds,
uncoordinated, persist after cessation o/t stimuli
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Biologic Behavior 2 extremes
Benign: - grow slowly, do not invade surr or spread
- rarely live threatening
so: - hormon secr
- critical location: cranial nerve & compress med
Malignant: - grow rapidly
- infiltrate & destroy surr, metastasize lethal
Intermediate: - locally invasive, low metastatic potential
- called locally aggressive neo ( low-grade neo): BCC
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Basis for Classification
Site
Biologic behavior
Cell (tissue) of origin (histogenetic Classification) Embryologic derivation
Differentiation potential of cell of origin
Etilogy
Gross or microscopic feature
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Prediction of Biol Behavior by Path. ExamTreatment: based on biol behavior
Benign: excision
Locally aggressive: excising + wide margin
Malignant: - local wide removal
- freg + reg LN
- + systemic treatment for met neo cells
Pathologist Ben/Mal ? : - Hist & Cyto feature
- Cumulative clinicopath of neo. Type
- No absolute criteria
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Benign MalignantGross Smooth surface
Fibrotic cap
Compressed surr
Irregular surface
Encaps (-)
Destruct surr
Size Small to largeVery large
Small to large
Growth Slow Rapid
Fatal Rarely Fatal: untreated
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Benign MalignantGrowth Compression Invasion
Differentiation
Resembling to normal
tiss of orig
High
+
Well/poor
- (anaplasia)
Similarity To N, one another
uniform
Cyto abn, enlarged,
hyperchr, irr nuc, large
nucl, pleomorphism
Mitosis Few, N , abn, bizarre mitotic
Blood vessels Well formed Numerous, poorly formed
Lack endot lining
Necrosis Unusual, degenerative -+ + hemorrhage: common
Distant spread
(Metastasis)
- +
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Abnormal Mitosis
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Benign Malignant
DNA content N Degree of
DifferentiationAdditional Chr
Karyotype N Aneuploidy
Polyploidy
Clonal genetic
abn
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Rate of GrowthAssessment of growth rate: clinical information: serialMic: - number of mitotic
- met activ of nuclei: - enlarged
- dispersed chromatin
- large nucleoli
Size
No bearing
Carcinoid of appendix: ben, unless > 2 cm
- < 2 cm: do not met- Ben & malignant: his identical
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Degree of DifferentiationDegree to which a neoplastic cell resembles the normal
mature cells
Benign: fully (well) diff closely resembleN tissue
Malignant: variable degree of diff, littleresemblance to N
poorly diff.
Anaplasia:noresemblance to N
More cellular
Higher mitotic rate:- smooth muscle uterus relevance
- pheochromocytoma (adr med) little relevance
Cytologic feature of malignancy
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D. Changes in DNAAbn DNA content Neoplasm. Abn Degree of Mal Deg
Hyperchromatism: crude assessment of DNA content
Malignant cells: Hyperchromatic
Flow cytometry: DNA content mal cell degree of mal:
- Malignant Lymphoma
- Bladder tumor
- Astocytic neo
Cytogenetic: aneuplidy & polyploidy indicative ofmalignancy
Molecular techniques: clonal deletion, translocations, abnoncogen exp
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E. Infiltration & InvasionBen: - noninfiltrative, capsule: compressd & fibr N tiss
Mal: - infiltrating margin
Exception: Ben: - granular cell T
- dermatofibroma lack caps, + inf margin- carcinoid T
F. Metastasis
Non contiguous / distant growthIdentification: difficult the only evidence is metastasis
90% pheochromocytoma: ben, no criteria for identifying the10% that will metastasize.
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HistogenesisTotipotent Cells
= capable of differentiating (maturing) any cell type = zygote
Zygote embryo fetus
Postnatal: the only totipotent cells = germ cells:
- gonad (most commonly)
- retroperit, mediast, pineal
Germ cell neo
- minimal diff
- mal primitive germ cells: seminoma & embryonal ca
- develop variety of tiss: - trophoblast (chorioca.)
- yolk sac (yolk sac ca)
- somatic (teratoma)
Teratoma
- somatic diff: 3 germ layer: endo, ecto, mesoderm brain, resp, intes muc,cartilage, bone, skin, teeth, hair
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Embryonic Pluripotent Cells
Pluripotent cells mature different cell types
Neo renal anlage cells (nephroblastoma) diff renal tubulusor muscle, cartilage, & bone Embryoma/Blastoma
Emb pluripot cells: fetal & first few years occur early childhood,
rarely in adult
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Differentiated CellsPost natal: differentiated, adult type cells
Most neo from differentiated cell
Nomenclature
Epithelial N
- Ben: Adenoma, Papilloma
- Mal: Carcinoma: - Adenoca (gland)
- SCC & Transit ca (epithel)
Mesenchymal N
Ben: cell of origin + oma
Mal: cell of origin + sarcoma
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Adenoma
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Skin Papilloma: Common Wart
Papilloma within duct
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Papilloma + Adenoma = Adenomatous Polyp
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Lipoma
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Chondroma in tubular bones o/t hand
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Leiomyoma
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Carcinoma o/t Glandular Organ
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Sarcomas
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Benign Cystic Teratoma
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Spread of Tumor
Spread of Tumor
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Spread of Tumor
E ti
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ExceptionsSound benign but really malignant
Lymphoma, plasmacytoma, melanoma, glioma, astrocytoma
Sound malignant but really benign
Osteoblastoma, chondroblastoma, because of + blastoma
Leukemia
Mixed T: > 1 neoplastic cell type
Mal Mixed T: - Adenosquamous ca
- Mal fibrous histiocytoma
- Carcinosarcoma (lung), Mal Mixed Mullerian T (uterus)- 2 separate cell line ?
- 1 multipotent cell type
Cell of origin is unknown: - Wilms T nephroblastoma
- Grawitzs renal adenoca.
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Hamartoma & ChoristomaTumor like developmental anomaly
Not true N
Abn, disorganized, prol masses of several different adult cell type
Hamartoma
Tissue normally present in the organ
Lung: bronchial ep & cartilage
Choristoma
Tissue not normally present
Smooth muscle & pancreatic acini & duct in the wall of
stomach
Incidence & Distribution
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Incidence & DistributionIncidence & Mortality Rates (1996)
Indonesia Medan
1. Cervix 1. Breast
2. Breast 2. Cervix
3. Lymph nodes 3. Skin
4. Skin 4. Lymphnodes
5. Nasopharynx 5. Nasopharynx
6. Ovary 6. Liver
7. Rectum 7. Soft tissue
8. Soft tissues 8. Thyroid
9. Thyroid 9. Other sites
10. Colon 10. Lung
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Age : Male: 55-64
Female : 45-54Male+ Female: 45-54
Cause of death
US: 1. IHD 2. Cancer: 500.000 annually
Ind: 1. Infection 2. IHD/Cancer
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Occupational, Social, & GeographicCigarette smokingTobacco sewing
Borne several children, breast feeding lower inc breast
cancer, Nun >< EBV Burkit L, HPV Tumor
Natural Killer Cells
IL-2 active NK
Cl I def escape T-cell recog
ADCC
Macrophages
T- cell IFN active mac oxyg metabolit
NK cell TNF
Humoral: - activation compl
- induction of ADCC by NK cells
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Tumor Immunity
Gen Alteration Surface Ag (nonself by imm sys)
Tumor Antigen
Tumor-specific Ag (TSA) only tumor cells, normal(- )
Tumor-associated Ag (TAA) tum cells & normal cell
TSA (peptides within tumor cells) presented surface byClass I MHC cytotoxic T-cell response
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Tumor Antigen Tumor-Specific Shared Ag: - MAGE, GAGE,
- BAGE, RAGE
Tissue-Specific Ag: tumor cell & normal untransf
Ag Resulting from Mutations: peptides derived from
mutated p53, K-ras, CDK4, bcr-c-abl
Overexpressed Ag: c-erbB2 (or neu) protein
Viral: E7 protein of HPV-16
Other Tumor Ag
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Other Tumor Antigen
TAA, normal self prot not imm resp
Detection Diagnosis
Ab against useful for imm the
Oncofetal Ag: - AFP, CEA
Differentiation Ag:
- CD10 (CALLA): early B Lcy & B-cell Leu , Loma
- Prostate-Specific Ag: normal & cancer
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Immunotherapy of Human Tumor Adoptive Cellular Therapy atients bloodLcy cultured w IL2 in vitroLymphokine-activated Killer LAK), antitumorreinfused Tum spe CTC enriched among Tumor Infiltrating Lcy Lcy harvested f resected tumor cultured in IL-2
reinfused
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H
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HD
A
A
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