Nomenclature
desmoplasia = abundant collagenous stroma
scirrhous = rock hard tumors
Benign tumors
benign mesenchymal tumors: lipoma, fibroma, angioma, osteoma, leiomyoma
adenoma = epithelial tumor with gland pattern
cystadenoma = adenomas with cystic masses
(common in ovary)
papilloma = epithelial tumor with fingerlike projections
polyp = tumor projecting above mucosa (colon polyp)
Malignant tumors
carcinomas = epithelial origin
sarcomas = mesenchymal origin
mixed tumors = from a single germ layer but more than 1 cell type
teratomas = more than one germ cell layer (typical in testis or ovary)
Non-neoplasic lesions that are like tumors
choristomas = ectopic rests of non-transformed tissues
hamartomas = masses of disorganized tissue indigenous to a particular tissue
Characteristics of benign and malignant neoplasms
carcinoma in situ = lesion w/ marked dysplastic changes that involve entire thickness of epithelium
Local invasion
benign tumors o capsule o plane of cleavage
malignant tumors o lack well-defined capsule o no cleavage plane
Metastasis
single most important feature distinguishing benign from malignant
pathways of spread: o seeding of body cavities and surfaces
 ex. ovarian CA spreads transperitoneally to surface of abdominal viscera
 ex. appendiceal CA fill peritoneum with gelatinous neoplastic mass, pseudomyxoma peritonei o lymphatic spread
 lymph nodes draining tumors are frequently enlarged
 can result from metastatic tumor cell proliferation or reactive hyperplasia to tumor antigens o hematogenous spread
 typical of sarcomas
 favored route for certain carcinomas (ex. renal)
 veins frequently invaded
Autosomal dominant inherited CA syndromes
usually a point mutation in 1 allele of a tumor suppressor gene o RB in retinoblastoma o APC in familial adenomatous polyposis
Li-Framumeni syndrome (p53 mutations) are the only syndrome with increased general
predilection for CA
tumors develop only in selected tissues: o MEN-2 (RET tyrosine kinase mutation)
 thyroid, parathyroid, adrenal glands o MEN-1 (menin txn factor mutation)
 pituitary, parathyroids, pancreas
Defective DNA-repair syndromes
typically AR
predispose to DNA instability from environmental carcinogens
HNPCC is AD; inactivation of DNA mismatch repair gene
Familial CA
familial clustering of specific CAs but with no clear transmission pattern
early onset with multiple or B/L tumors
marker phenotype
usually AD
Precancerous conditions
certain disorders have a well-defined association with CA o leukoplakia of oral mucosa, penis, or vulva
some benign tumors are a focus of subsequent malignancy o colonic villous adenomas can develop into cancer as they enlarge
most malignant tumors arise de novo o uncommonly, arise in previously benign tumors
Molecular basis of CA
oncogenes = genes that promote autonomous cell growth in CA cells o mutations convert proto-oncogenes  constitutively active oncogenes (allow the cell to grow with self-sufficiency)
Categories of oncogenes
growth factors o tumors produce GF to which themselves can respond (autocrine stimulation loop)
growth factor receptors
signal-transducing proteins o RAS oncogene
 mutated RAS proteins are in
15-20% of all human tumors
 mutant RAS proteins lack
GTPase activity, therefore locked in signal-transmitting
GTP-bound form
 activated RAS activates MAP kinase  cell proliferation
alterations in nonreceptor tyrosine kinases o in chronic myeloid leukemia (CML), translocation of c-ABL with fusion to BCR gene makes hybrid protein that causes potent unregulated tyrosine kinase activity o activating point mutations in JAK2 tyrosine kinase constitutively activate
STAT txn factors
 associated with polycythemia vera & primary myelofibrosis
transcription factors o MYC oncogene = most commonly involved in human tumors; overexpression  malignancy
cyclins and CDKs o loss of cell cycle control is central to malignant transformation o critical cell cycle checkpoints = G1/S and
G2/M
Tumor suppressor genes
insensitivity to growth inhibition and escape from senescence
RB o prototypic tumor-suppressor gene o regulates G1/S checkpoint o lead to increased E2F txn factor activity o cells can cycle without growth stimulus
p53: guardian of the genome o prevents propagation of genetically defective cells o when cells stressed, p53 released from
MDM2 and acts as txn factor for genes that arrest cell cycle & promote DNA repair o G1 cell cycle arrest largely mediated through p53-dependent txn of CDK inhibitor p21 o if DNA repaired during cell cycle arrest,
MDM2 txn increases and p53 degraded, allowing cell to enter S phase o if DNA damage not repaired, p53 induces cellular senescence by altering E2F signaling pathways, or it can induce apoptosis o p53 mutated in >50% of all human CAs

o Li-Fraumeni syndrome = germline p53 mutations
Adenomatous polyposis Coli/β-catenin pathway o APC genes down-regulate growthpromoting signals in the WNT signaling pathway o APC protein is negative regulatory of βcatenin activity; binds and regulates the degradation of cytoplasmic β-catenin o in absence of normal APC = increased txn of c-MYC, cyclin D1, and others o if born with 1 mutant APC develop thousands of adenomatous polyps in colon o 70-80% of sporadic CA have APC LOH o also seen in hepatoblastomas and hepatocellular carcinomas
INK4a/ARF o p16/INK4a blocks RB phosphorylation
(maintains RB checkpoint) o p14/ARF prevents p53 destruction o mutations in bladder, head, and neck tumors, certain leukemias
TGF-β pathway o intracellular signaling via SMAD2 &
SMAD4 o seen in pancreatic and colon carcinomas
PTEN o PI3 kinase/AKT pathway
NF1 o codes for neurofibromin o LOH impairs conversion of active  inactive RAS
 cells continuously stimulated to divide o germline mutations predispose to benign neurofibromas
 some progress to malignancy
VHL o hereditary renal cell cancer, pheochromocytomas, hemangioblastomas of the CNS, retinal angiomas o part of ubiquitin ligase complex in degradation of HIF1α (hypoxia-inducible txn factor 1α) o mutations leads to cell growth and angiogenic factor production
WT1 o Wilms tumors o renal and gonadal differentiation o GU differentiation
Evasion of apoptosis
BCL2 = prototype anti-apoptosis protein o prevent apoptosis by limiting exit of cytochrome c from mitochondria
overexpression of BCL2 = extend cell survival
follicular B-cell lymphoma o most have t(14;18) translocation
Telomerase
CA cells reactivate telomerase to allow limitless replicative potential
more than 90% of human tumors show increased telomerase activity
Angiogenesis
new tumor vessels differ from normal vasculature by being dilated & leaky with slow and abnormal flow
angiogenic switch = production of angiogenesis factors or loss of inhibitors such as thrombospondin-1 (induced by p53), angiostatin, or endostatin
hypoxia = major driving factor for angiogenesis
(through HIF1α txn factor)
endothelial growth proteins = VEGF and bFGF
Invasion of ECM
detachment o loss of attachment in normal cells normally induces apoptosis (tumor cells have become resistant to this) o several carcinomas have down-regulation of epithelial E-cadherins
ECM degradation o tumors directly release proteases or induce stromal cells to produce them o MMP9 degrades epithelial and vascular
BM type IV collagen
ECM attachment o invading cells express adhesion molecules that allow interaction w/ ECM
migration o tumor cells have increased locomotion from increased autocrine cytokines and motility factors
Vascular dissemination and homing of tumor cells
tumor cells embolize in blood stream
some tumor cells express CD44; strongly bind high endothelial venules in lymph nodes
some tumor cells express receptors that interact with ligands in certain vascular beds (CXCR4 and
CCR7 in breast CA)
Genomic instability
3 types of DNA repair systems can be defected:
mismatch repair
nucleotide excision repair
recombination repair
Hereditary nonpolyposis colon cancer syndrome
pt inherits 1 defective copy of DNA repair genes involved in mismatch repair (MSH2 and MLH1)
variation in microsatellite length = hallmark of mismatch repair defects
Xeroderma pigmentosum
nucleotide excision repair genes required for fixing
UV light induced pyrimidine dimer formation
pts with defects in these genes develop skin cancers due to UV mutagenic defects
Diseases w/ defects in DNA repair by homologous
recombination
AR
Bloom syndrome o helicase is mutated o can’t do DNA repair by homologous recombination
Ataxia-telangiectasia o ATM gene mutation o protein kinase unable to sense DNA double-stranded breaks o allows DNA-damaged cells to proliferate and accumulate additional mutations
Faconi anemia
all have hypersensitivities to DNA damaging agents
(ionizing radiation or chemical cross linking agents)
Warburg effect
cancer cells preferentially use glycolysis for energy
PET scans visualize uptake of non-metabolizable glucose analogues
Dysregulation of CA-associated genes
Chromosomal changes
translocations are common in hematopoietic malignancies
shifting of proto-oncogenes away from normal regulatory elements  overexpression o t(8;14) in Burkitt lymphoma causes tightly regulated c-myc gene to move to immunoglobulin heavy chain gene locus
 overexpression
formation of new hybrid genes o t(9;22) Philadelphia chromosome creates fusion protein BCR-abl to form a fusion protein with constitutive kinase activity
deletions o more common in non-hematopoietic solid tumors o loss of critical tumors suppressor gene o 13q14 deletions contain RB gene
Gene amplification
reduplication and amplification of DNA sequences may underlie overexpression
N-myc overexpression in 25-30% of neuroblastomas and ERB-B2 overexpression in 20% of breast CA
Epigenetic changes
can silence tumor suppressor genes

p14ARF in GI cancers
p16INK4a in various malignancies
Radiation carcinogenesis
UV rays
sun’s UV rays (esp. UVB) can cause skin CA
non-melanoma skin CA assoc w/ cumulative exposures
damage to DNA from formation of pyrimidine dimers
xeroderma pigmentosum have nucleotide excision repair defect
Ionizing radiation
radiation from electromagnetic and particulate sources can all cause CA
they can cause CA directly or indirectly by generating free radicals
most common radiation induced CA = myeloid leukemia then, thyroid CA in children
Microbial carcinogenesis
H. pylori
can cause gastric carcinoma
some strains have cytotoxin-associated A (CagA) gene that induces unregulated proliferation
also associated with gastric lymphomas (MALToma)
HTLV-1
retrovirus
causes T cell leukemia/lymphoma
endemic in Japan & Caribbean
CD4+ T cell tropism
infection through transmission of infected cells
(sexual intercourse, blood products, breastfeeding)
transformation from viral-encoded Tax protein that inactivates p16/INK4a & enhances cyclin D activation  increased cell replication
Oncogenic DNA viruses
integrate into host cell genome and form stable association
virus may remain latent for years
HPV
types 1, 2, 4, and 7 = benign squamous papillomas
(warts)
types 6, 11 = genital warts w/ low malignant potential
types 16, 18 = cervical squamous cell CA
key feature = integration interrupts viral DNA within E1/E2 open reading frame  loss of E2 viral repressor & subsequent overexpression of E6 & E7 viral proteins
these proteins bind & inhibit functions of Rb and p53 and CDK inhibitirs
HPV infection alone not sufficient for carcinogenesis
smoking, other infections, dietary deficiencies, and hormones also required
EBV
herpesvirus
infects B cells & oropharyngeal epithelium
latently infected
LMP-1 constitutively activates NF-kB and JAK/STAT pathways to promote B cell proliferation/survival
EBNA-2 constitutively activates cyclin D and src proto-oncogenes
Burkitt lymphoma caused by t(8:14) or other translocations inactivating c-MYC
in central Africa and New Guinea, 90% of tumors contain EBV genome
B-cell lymphomas in immunosuppressed pts
Hodgkin lymphoma
nasopharyngeal carcinoma endemic in southern
China
HBV & HCV
70-85% of hepatocellular carcinomas due to HBV or
HCV infections
dominant effect from immunologically mediated chronic inflammation
HBV encodes regulatory element called HBx that can inactivate p53
Tumor immunity
Tumor antigens
tumor-specific antigens o products of mutated oncogenes o products of other mutated genes o marked overexpression o oncofetal antigens o altered cell surface glycolipids and glycoproteins
tumor-associated antigens include o oncofetal antigens (carcinoembryonic angien [CEA]) o lineage-specific antigens (CD10 on B cells)
useful for diagnosis and may be targets for immunotherapy
Antitumor effector mechanisms
CD8+ cytotoxic T lymphocyte (CTL)-mediated killing is principal mechanism of antitumor immunity
NK cells and activated macrophages may also contribute
Clinical aspects of neoplasia
Cancer cachexia
loss of body fat, lean body mass, profound weakness
driven by TNF and other cytokines elaborated by inflammatory cells in response to tumors
Paraneoplastic syndromes
small-cell lung CA causes Cushing syndrome by secreting ACTH
hypercalcemia is most common paraneoplastic syndrome; caused by bone resorption resulting from elaboration of PTH-like peptides
thrombotic diathesis result from production of thromboplastic substances by tumor cells, causing: o DIC o migratory thrombophlebitis (Trousseau syndrome) o valvular vegetations (nonbacterial thrombotic endocarditis)
Grading and staging of tumor
grading = based on degree of differentiation
staging = based on size of primary tumor and extent of local and distant spread
Lab Dx of CA
histologic examination is most important method of diagnosis
Tumor markers
PSA = elaborated by prostate epithelium o elevated levels can reflect malignancy o can also be seen with BPH or prostatic inflammation
Carcinoembryonic antigen (CEA) o normally produced by fetal gut, liver, and pancreas o can be elaborated by CA of the colon, pancreas, stomach, and breast o can be seen in non-neoplastic conditions
(cirrhosis, hepatitis, ulcerative colitis)
alpha-fetoprotein (AFP) o normally produced by fetal yolk sac and liver o elevated lvls occur in liver and testicular germ cell tumors o also can occur in non-neoplastic conditions (cirrhosis and hepatitis)