View
266
Download
2
Category
Preview:
Citation preview
7/28/2019 Ch7 Neoplasm
1/97
Neoplasia
7/28/2019 Ch7 Neoplasm
2/97
NEOPLASIA (TUMORS)
Definitions
Nomenclature
Biology of Tumor Growth
Epidemiology
Molecular Basis of Cancer
Molecular Basis of Carcinogenesis
Agents (The Usual Suspects)
Host Defense (Tumor Immunity)
Clinical Features of Tumors
7/28/2019 Ch7 Neoplasm
3/97
Defnition of Neoplasia
A neoplasm is an abnormal mass of tissue, the
growth of which exceeds and is
uncoordinated with that of the normal tissues
and persists in the same excessive manner
after cessation of the stimuli which evoked
the change-Willis
Genetic changes
Autonomous
Clonal
7/28/2019 Ch7 Neoplasm
4/97
Nomenclature Benign Tumors
-oma = benign neoplasm (NOT carcin-, sarc-, lymph-,
or melan-)
Mesenchymal tumors (mesodermal derived)
chrondroma: cartilaginous tumor
fibroma: fibrous tumor osteoma: bone tumor
Epithelial tumor (ecto- or endo- derived)
adenoma: tumor forming glands
papilloma: tumor with finger like projections
papillary cystadenoma: papillary and cystic tumor forming
glands
polyp: a tumor that projects above a mucosal surface
7/28/2019 Ch7 Neoplasm
5/97
7/28/2019 Ch7 Neoplasm
6/97
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 28 July 2005 03:41 PM)
2005 Elsevier
7/28/2019 Ch7 Neoplasm
7/97
Colonic Polyp: Tubular Adenoma
Stalk
Tumor
7/28/2019 Ch7 Neoplasm
8/97
7/28/2019 Ch7 Neoplasm
9/97
7/28/2019 Ch7 Neoplasm
10/97
7/28/2019 Ch7 Neoplasm
11/97
7/28/2019 Ch7 Neoplasm
12/97
7/28/2019 Ch7 Neoplasm
13/97
7/28/2019 Ch7 Neoplasm
14/97
Tumors with mixed differentiation mixed tumors: e.g. pleomorphic adenoma of salivary gland
carcinosarcoma
Teratoma tumor comprised of cells from more than one germ layer
arise from totipotent cells (usually gonads)
benign cystic teratoma of ovary is the most common teratoma
Aberrant differentiation (not true neoplasms) Hamartoma: disorganized mass of tissue whose cell types are
indiginous to the site of the lesion, e.g., lung
Choriostoma: ectopic focus of normal tissue (heterotopia),e.g., pancreas, perhaps endometriosis too
Misnomers hepatoma: malignant liver tumor
melanoma: malignant skin tumor
seminoma: malignant testicular tumor
lymphoma: malignant tumor of lymphocytes
7/28/2019 Ch7 Neoplasm
15/97
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 28 July 2005 03:41 PM)
2005 Elsevier
7/28/2019 Ch7 Neoplasm
16/97
7/28/2019 Ch7 Neoplasm
17/97
7/28/2019 Ch7 Neoplasm
18/97
Natural History Of Mal ignan t Tumors
1. Malignant change in the target
cell, referred to as
transformation
2. Growth of the transformed cells
3.Local invasion
4. Distant metastases.
7/28/2019 Ch7 Neoplasm
19/97
Differentiation
Well differentiated neoplasm Resembles mature cells of tissue of origin
Poorly differentiated neoplasm
Composed of primitive cells with littledifferentiation
Undifferentiated or anaplastic tumor
Correlation with biologic behavior Benign tumors are well differentiated
Poorly differentiated malignant tumors usually
have worse prognosis than well differentiated
malignant tumors.
7/28/2019 Ch7 Neoplasm
20/97
If cells LOOK BAD, they are probably going to BEHAVE BADLooking bad means NOT looking like the cells they supposedly
arose from!
7/28/2019 Ch7 Neoplasm
21/97
If cells LOOK GOOD, they are probably going to BEHAVE GOODLooking good means looking like the cells they supposedly arose from!
7/28/2019 Ch7 Neoplasm
22/97
ANAP ASIA CANCER
7/28/2019 Ch7 Neoplasm
23/97
***Pleomorphism
Size shape
Abnormal nuclear morphology
***Hyperchromasia High nuclear cytoplasmic ratio Chromatin clumping
Prominent nucleoli
Mitoses Mitotic rate
Location of mitoses
Loss of polarity
ANAPLASIA = CANCER
7/28/2019 Ch7 Neoplasm
24/97
7/28/2019 Ch7 Neoplasm
25/97
Dysplasia
Literally means abnormal growth Malignant transformation is a multistep process
In dysplasia some but not all of the features of
malignancy are present, microscopically
Dysplasia may develop into malignancy Uterine cervix
Colon polyps
Graded as low-grade or high-grade, often prompting
different clinical decisions
Dysplasia may NOT develop into malignancy
HIGH grade dysplasia often classified with CIS
7/28/2019 Ch7 Neoplasm
26/97
7/28/2019 Ch7 Neoplasm
27/97
7/28/2019 Ch7 Neoplasm
28/97
Tumor Growth Rate Doubling time of tumor cells
Lengthens as tumor grows
30 doublings (109 cells) = 1 g (months to years)
10 more doublings (1 kg) = lethal burden ()
Fraction of tumor cells in replicative pool May be only 20% even in rapidly growing tumors
Tumor stem cells
Rate at which tumor cells are shed or lost Apoptosis
Maturation
Implications for therapy
7/28/2019 Ch7 Neoplasm
29/97
clonal
7/28/2019 Ch7 Neoplasm
30/97
7/28/2019 Ch7 Neoplasm
31/97
Features of Malignant Tumors
Cellular features
Local invasion Capsule Basement membrane
Metastasis
Unequivocal sign of malignancy Seeding of body cavities
Lymphatic
Hematogenous
7/28/2019 Ch7 Neoplasm
32/97
7/28/2019 Ch7 Neoplasm
33/97
7/28/2019 Ch7 Neoplasm
34/97
7/28/2019 Ch7 Neoplasm
35/97
7/28/2019 Ch7 Neoplasm
36/97
7/28/2019 Ch7 Neoplasm
37/97
7/28/2019 Ch7 Neoplasm
38/97
7/28/2019 Ch7 Neoplasm
39/97
Significance of Nodal Mets
Example of breast cancer
Halsted radical mastectomy Sentinel node biopsy
Prognostic
Number of involved nodes is an importantcomponent of TNM staging system
Therapeutic
Overall risk of recurrence Extent of nodal involvement
Histologic grade and other considerations
Adjuvant chemotherapy
7/28/2019 Ch7 Neoplasm
40/97
7/28/2019 Ch7 Neoplasm
41/97
7/28/2019 Ch7 Neoplasm
42/97
7/28/2019 Ch7 Neoplasm
43/97
7/28/2019 Ch7 Neoplasm
44/97
7/28/2019 Ch7 Neoplasm
45/97
7/28/2019 Ch7 Neoplasm
46/97
7/28/2019 Ch7 Neoplasm
47/97
Change In Incidence Of Various Cancers With
Migration From Japan To The United States
Predisposing Factors for Cancer
7/28/2019 Ch7 Neoplasm
48/97
Predisposing Factors for Cancer Age
Most cancers occur in persons 55 years
Childhood cancers Leukemias & CNS neoplasms
Bone tumors
Genetic predispostion Familial cancer syndromes
Early age at onset Two or more primary relatives with the cancer (soil theory)
Multiple or bilateral tumors
Polymorphisms that metabolize procarcinogens, e.g., nitrites
Nonhereditary predisposing conditions Chronic inflammation?
Precancerous conditions Chronic ulcerative colitis
Atrophic gastritis of pernicious anemia
Leukoplakia of mucous membranes
Immune collapse?
7/28/2019 Ch7 Neoplasm
49/97
Defnition of Neoplasia
A neoplasm is an abnormal mass of tissue, the growthof which exceeds and is uncoordinated with that of
the normal tissues and persists in the same excessive
manner after cessation of the stimuli which evoked
the change - Willis
Genetic changes
Autonomous Clonal
7/28/2019 Ch7 Neoplasm
50/97
TRANSFORMATION &
7/28/2019 Ch7 Neoplasm
51/97
TRANSFORMATION &
PROGRESSION Self-sufficiency in growth signals
Insensitivity to growth-inhibiting signals
Evasion of apoptosis Defects in DNA repair: Spell checker
Limitless replicative potential: Telomerase
Angiogenesis
Invasive ability
Metastatic ability
7/28/2019 Ch7 Neoplasm
52/97
7/28/2019 Ch7 Neoplasm
53/97
7/28/2019 Ch7 Neoplasm
54/97
7/28/2019 Ch7 Neoplasm
55/97
7/28/2019 Ch7 Neoplasm
56/97
PROTO- Mode of Associated Human
7/28/2019 Ch7 Neoplasm
57/97
Category
PROTO
Oncogene
Mode of
Activation
Associated Human
Tumor
Signal
TransductionProteins
GTP-binding K-RAS Point mutation Colon, lung, and pancreatic
tumors
H-RAS Point mutation Bladder and kidney tumors
N-RAS Point mutation Melanomas, hematologic
malignancies
Nonreceptor
tyrosine kinase
ABL Translocation Chronic myeloid leukemia
Acute lymphoblastic leukemia
RAS signal
transduction
BRAF Point mutation Melanomas
WNT signal
transduction
-catenin Point mutation Hepatoblastomas,
hepatocellular carcinoma
Mode of
7/28/2019 Ch7 Neoplasm
58/97
Category
PROTO-
Oncogene
Mode of
Activation Associated Human
Tumor
NuclearRegulatory
Proteins
Transcrip.
activators
C-MYC Translocation Burkitt lymphoma
N-MYC Amplification Neuroblastoma,
small cell
carcinoma of lungL-MYC Amplification Small cell
carcinoma of lung
C
7/28/2019 Ch7 Neoplasm
59/97
MYCEncodes for transcription factors
Also involved with apoptosis
7/28/2019 Ch7 Neoplasm
60/97
P53 and RASp53
Activates DNA repair
proteins
Sentinel of G1/Stransition
Initiates apoptosis
Mutated in more than50% of all human
cancers
RAS H, N, K, etc., varieties
Single most common
abnormality ofdominant oncogenes in
human tumors
Present in about 1/3 ofall human cancers
7/28/2019 Ch7 Neoplasm
61/97
Tumor (really GROWTH)
7/28/2019 Ch7 Neoplasm
62/97
Tumor (really GROWTH )suppressor genes
TGF- COLON E-cadherin STOMACH NF-1,2 NEURAL TUMORS APC/-cadherin GI, MELANOMA SMADs GI RB RETINOBLASTOMA P53 EVERYTHING!! WT-1WILMS TUMOR p16 (INK4a) GI, BREAST (MM if inherited) BRCA-1,2 BREAST KLF6 PROSTATE
7/28/2019 Ch7 Neoplasm
63/97
Evasion of APOPTOSIS
BCL-2
p53
MYC
7/28/2019 Ch7 Neoplasm
64/97
DNA REPAIR GENE DEFECTS
DNA repair is like a spell checker
HNPCC (Hereditary Non-Polyposis Colon
Cancer [Lynch]): TGF-, -catenin, BAX Xeroderma Pigmentosum: UV fixing gene
Ataxia Telangiectasia: ATM gene
Bloom Syndrome: defective helicase
Fanconi anemia
7/28/2019 Ch7 Neoplasm
65/97
7/28/2019 Ch7 Neoplasm
66/97
7/28/2019 Ch7 Neoplasm
67/97
7/28/2019 Ch7 Neoplasm
68/97
7/28/2019 Ch7 Neoplasm
69/97
7/28/2019 Ch7 Neoplasm
70/97
METASTATIC GENES?
NM23
KAI-1KiSS
CHROMOSOME CHANGES
7/28/2019 Ch7 Neoplasm
71/97
CHROMOSOME CHANGES
in CANCER
TRANSLOCATIONS and INVERSIONS
Occur in MOST Lymphomas/Leukemias
Occur in MANY (and growing numbers) ofNON-hematologic malignancies also
Malignancy Translocation Affected Genes
Chronic myeloid leukemia (9;22)(q34;q11) Ab1 9q34
7/28/2019 Ch7 Neoplasm
72/97
Chronic myeloid leukemia (9;22)(q34;q11) Ab1 9q34
bcr22q11
Acute leukemias (AML and ALL) (4;11)(q21;q23) AF4 4q21
MLL 11q23(6;11)(q27;q23) AF6 6q27
MLL 11q23
Burkitt lymphoma (8;14)(q24;q32) c-myc8q24
IgH 14q32
Mantle cell lymphoma (11;14)(q13;q32) Cyclin D 11q13
IgH 14q32
Follicular lymphoma (14;18)(q32;q21) IgH 14q32
bc l-2 18q21
T-cell acute lymphoblastic leukemia (8;14)(q24;q11) c-myc8q24
TCR- 14q11
(10;14)(q24;q11) Hox11 10q24
TCR- 14q11
Ewing sarcoma
(11;22)(q24;q12)
Fl-1 11q24
Carcinogenesis is MULTISTEP
7/28/2019 Ch7 Neoplasm
73/97
Carcinogenesis is MULTISTEP NO single oncogene causes cancer
BOTH several oncogenes AND severaltumor suppressor genes must be involved
Gatekeeper/Caretaker concept
Gatekeepers: ONCOGENES and TUMORSUPPRESSOR GENES
Caretakers: DNA REPAIR GENES Tumor PROGRESSION
ANGIOGENESIS
HETEROGENEITY from original single cell
Carcinogenesis:
7/28/2019 Ch7 Neoplasm
74/97
Carcinogenesis:
The USUAL (3) Suspects
Initiation/Promotion concept: BOTH initiators AND promotors are needed
NEITHER can cause cancer by itself
INITIATORS (carcinogens) causeMUTATIONS
PROMOTORS are NOT carcinogenic by
themselves, and MUST take effect AFTER
initiation, NOT before
PROMOTORS enhance the proliferation ofinitiated cells
7/28/2019 Ch7 Neoplasm
75/97
7/28/2019 Ch7 Neoplasm
76/97
Q: WHO are the usual suspects?
Inflammation? Teratogenesis?
Immune
Suppression?
Neoplasia?
Mutations?
A: The SAME 3 that are
7/28/2019 Ch7 Neoplasm
77/97
A: The SAME 3 that are
ALWAYS blamed!
1) Chemicals
2) Radiation
3) InfectiousPathogens
CHEMICAL CARCINOGENS:
7/28/2019 Ch7 Neoplasm
78/97
INITIATORS
DIRECT
-Propiolactone
Dimeth. sulfate
Diepoxybutane
Anticancer drugs
(cyclophosphamide,
chlorambucil,
nitrosoureas, and others) Acylating Agents
1-Acetyl-imidazole
Dimethylcarbamyl chloride
PROCARCINOGENS
Polycyclic and Heterocyclic
Aromatic Hydrocarbons
Aromatic Amines, Amides,
Azo Dyes Natural Plant and Microbial
Products
Aflatoxin B1 Hepatomas
Griseofulvin Antifungal
Cycasin from cycads
Safrole from sassafras
Betel nuts Oral SCC
CHEMICAL CARCINOGENS:
7/28/2019 Ch7 Neoplasm
79/97
INITIATORS
OTHERS Nitrosamine and amides (tar, nitrites)
Vinyl chloride angiosarcoma in Kentucky Nickel
Chromium
Insecticides
Fungicides
PolyChlorinated Biphenyls (PCBs)
CHEMICAL CARCINOGENS:
7/28/2019 Ch7 Neoplasm
80/97
PROMOTORS
HORMONES
PHORBOL ESTERS (TPA), activate kinase C
PHENOLS
DRUGS, many
Initiated cells respond and proliferateFASTER to promotors than normal cells
RADIATION CARCINOGENS
7/28/2019 Ch7 Neoplasm
81/97
RADIATION CARCINOGENS
UV: BCC, SCC, MM (i.e., all 3)
IONIZING: photons and particulate
Hematopoetic and Thyroid (90%/15yrs) tumorsin fallout victims
Solid tumors either less susceptible or require a
longer latency period than LEUK/LYMPH
BCCs in Therapeutic Radiation
VIRAL
7/28/2019 Ch7 Neoplasm
82/97
VIRAL CARCINOGENESIS
HPV SCC EBV Burkitt Lymphoma HBV HepatoCellular Carcinoma (Hepatoma) HTLV1 T-Cell Malignancies KSHV Kaposi Sarcoma
H l i C C OG S S
7/28/2019 Ch7 Neoplasm
83/97
H. pylori CARCINOGENESIS
100% of gastric lymphomas (i.e., M.A.L.T.-omas)
Gastric CARCINOMAS also!
HOST DEFENSES
7/28/2019 Ch7 Neoplasm
84/97
HOST DEFENSES
IMMUNE SURVEILLENCECONCEPT
CD8+ T-Cells NK cells
MACROPHAGES
ANTIBODIES
7/28/2019 Ch7 Neoplasm
85/97
CYTOTOXIC CD8+ T-CELLS are the main eliminators of tumor cells
How do tumor cellsi ill ?
7/28/2019 Ch7 Neoplasm
86/97
escape immune surveillance?
Mutation, like microbes
MHC molecules on tumor cell surface
Lack of CO-stimulation molecules, e.g.,(CD28, ICOS), not just Ag-Ab recognition
Immunosuppressive agents
Antigen masking
Apoptosis of cytotoxic T-Cells (CD8), i.e.,
the damn tumor cell KILLS the T-cell!
Eff t f TUMOR th HOST
7/28/2019 Ch7 Neoplasm
87/97
Effects of TUMOR on the HOST
Location anatomic ENCROACHMENT HORMONE production
Bleeding, Infection
ACUTE symptoms, e.g., rupture, infarction
METASTASES
CACHEXIA
7/28/2019 Ch7 Neoplasm
88/97
CACHEXIA Reduced diet: Fat loss>Muscle loss
Cachexia: Fat loss AND Muscle loss
TNF ( by default) IL-(6)
PIF (Proteolysis Inducing Factor)
7/28/2019 Ch7 Neoplasm
89/97
ENDOCRINE
7/28/2019 Ch7 Neoplasm
90/97
Cushing syndrome Small cell carcinoma of lung ACTH or ACTH-like substance
Pancreatic carcinoma
Neural tumors
Syndrome of inappropriateantidiuretic hormonesecretion
Small cell carcinoma of lung;intracranial neoplasms
Antidiuretic hormone or atrialnatriuretic hormones
Hypercalcemia Squamous cell carcinoma of lungParathyroid hormone-related protein
(PTHRP), TGF-, TNF, IL-1
Breast carcinoma
Renal carcinoma
Adult T-cell leukemia/lymphoma
Ovarian carcinoma
Hypoglycemia Fibrosarcoma Insulin or insulin-like substance
Other mesenchymal sarcomas
Hepatocellular carcinomaCarcinoid syndrome Bronchial adenoma (carcinoid) Serotonin, bradykinin
Pancreatic carcinoma
Gastric carcinoma
Polycythemia Renal carcinoma Erythropoietin
Cerebellar hemangioma
Hepatocellular carcinoma
GRADING/STAGING
7/28/2019 Ch7 Neoplasm
91/97
GRADING/STAGING
GRADING: HOWDIFFERENTIATED ARE THE
CELLS?STAGING: HOW MUCH
ANATOMIC EXTENSION? TNM
Which one of the above do youthink is more important?
7/28/2019 Ch7 Neoplasm
92/97
ADENOCARCINOMA GRADINGLets have some FUN!
7/28/2019 Ch7 Neoplasm
93/97
Lets have some FUN!
7/28/2019 Ch7 Neoplasm
94/97
7/28/2019 Ch7 Neoplasm
95/97
TUMOR MARKERS
7/28/2019 Ch7 Neoplasm
96/97
TUMOR MARKERS
HORMONES: (Paraneoplastic Syndromes) ONCOFETAL: AFP, CEA
ISOENZYMES: PAP, NSE
PROTEINS: PSA, PSMA (M = membrane) GLYCOPROTEINS: CA-125, CA-195, CA-153
MOLECULAR: p53, RAS
NOTE: These SAME substances which can
be measured in the blood, also can be stained
by immunochemical methods in tissue
MICRO-ARRAYS
7/28/2019 Ch7 Neoplasm
97/97
MICRO ARRAYS
THOUSANDS of genes identified fromtumors give the cells their own identity
and FINGERPRINT and may give
important prognostic information as well
as guidelines for therapy. Some say this
may replace standard histopathologicidentifications of tumors.
What do you think?
Recommended