what is a neoplasm
disease caused by uncontrolled proliferation of cells that have undergone genetic alterations (mutations)
characterize benign lesions
expansive
slow growth
well differentiated
no metastasis
characterize malignant lesions
infiltrative
fast growth
atypical / poor differentiation
metastasis typical
what is invasion
extension beyond immediate local environment
-ie in epithelial cells, extension through VM
cells separate from neighboring cells and locomote / migrate
routes of metastasis
direct seeding of body cavities (peritoneum, pleura, pericardium) lymphatic hematogenous -venous (through capillary bed) -arterial (from or through lung)
common sites of metastasis
lymph node
liver (receives large volume of venous drainage)
lung (moves cells into arterial circulation)
bone
brain
most common skeletal malignancy
bone metastases (far more common than primary bone tumors) **hematopoietic tumors are the second most common malignancy of bone
presentation of bone metastasis
multifocal involvement axial skeleton > long bones > small bones (corresponds to blood flow / red marrow) pathologic fracture (due to weakened bones)
pathways of spread of bone metastasis
direct extension
lymphatic or hematogenous
intraspinal seeding
most common type of metastatic lesions in bone
lytic lesions = increased bone resorption
bone matrix changes that support lytic lesion formation
tumor cells secrete PGEs, cytokines, PTHrP
- upregulate RANKL on osteoblasts and stromal cells
- stimulate osteoclast activity
- bone resorption
bone matrix changes that support tumor cell growth
stromal cells secrete growth factors
treatment / prognosis of bone metastases
poor prognosis (stage 4)
local treatment: surgery / fixation, radiation, bisphosphonates
systemic treatment: chemo, target therapy, immunotherapy, hormonal therapy
most common primary site of bone metastases in adults
prostate
breast
kidney
lung
most common primary site of bone metastases in children
neuroblastoma
wilms tumor
ewing sarcoma
rhabdomyosarcoma
primary sites that cause lytic bone lesions
RCC lung cancer GI carcinoma thyroid cancer melanoma adrenal carcinoma pheochromocytoma uterine carcinoma wilms ewings HCC squamous cell of the skin
primary sites that cause sclerotic bone lesions
prostate (most common) breast transitional cell carcinoma carcinoid medulloblastoma neuroblastoma mucinous adenocarcinoma of the GI tract small cell lung cancer
system of cancer staging
TNM
T: characteristics of primary tumor (size, extent of invasion)
N: involvement of regional lymph nodes
M: distant metastasis
cancer grading
histo determination of degree of differentiation
enabling characteristics of cancer
- failure of DNA repair
- tumor promoting inflammation
hallmarks of cancer
- activation of growth promoting oncogenes
- inactivation of tumor suppressor genes
- alteration in genes that regulate apoptosis
- angiogenesis
- escape from immunity
- additional mutations (enabling replicative immortality, deregulating cellular energetics)
translocations associated with cancer
dysregulation of gene expression -c-MYC (8;14) (Burkitt) -BCL2 (14;18) (follicular) -cyclin D1 (11;14) (mantle) structural alteration of gene -BCR/ABL (9;22) (CML)
deletions associated with cancer
RB (retinoblastoma)
gene amplifications associated with cancer
N-MYC (neuroblastoma)
HER-2/neu (breast cancer)
chromothrypsis
extensive chromosomal breaks and rearrangements
osteosarcoma, glioma
point mutations associated with cancer
RAS (many cancers)
epigenetic changes associated with cancer
local hypermethylation (silencing) global changes in methylation changes in histones
noncoding RNAs associated with cancer
altered expression of microRNAs (miRs)
-interaction with oncogenes and tumor suppressor genes
driver mutations
contribute to development of the malignant phenotype
passenger mutations
no effect on proliferation; but may lead to neo-antigens and affect immune surveillance
reflect loss of ability to maintain genomic integrity
more common than driver mutations
tumor mutational burden
as # of mutations increases, there is a decrease in successful DNA repair
as # of mutations increases, there is an increased expression of abnormal antigens (cant be targeted by immune response if immune response is turned on)
immune response to tumors
lymphoid response to tumors and in draining lymph nodes
increased incidence of tumors in immunodeficiency
tumor specific T cells and Abs
tumor suppression by stimulating host T cell surveillance
anti tumor mechanisms (immune surveillance)
cytotoxic CD8+ T lymphocytes
NK cells
macrophages
how do cancers escape immune surveillance
immune response guides cancer evolution (cancer immunoediting)
tumor derived immune suppression and immune tolerance
what are examples of tumor antigens
products of mutated genes
aberrantly expressed proteins
antigens from oncogenic viruses
oncofetal antigens
altered cell surface glycoproteins and glycolipids
cell type specific differentiation antigens
what is the result of tumor antigens
affect immune response to tumor
-T and B cell response
-inhibition / silencing of immune response
serve as markers for tumors
-diagnosis
-screening
cell specific differentiation antigens can be targets for immunotherapy
ways that tumors can escape from immune surveillance
- immunodeficiency / immunosuppression
- outgrowth of antigen-negative variants (cancer immunoediting)
- loss of MHC molecules
- activation of immunoregulatory pathways (checkpoints)
- secretion of immunosuppressive factors
- induction of Treg cells
checkpoints that can be modified by tumor cells
downregulation of costimulatory factors on APCs
-APC fails to sensitize T cell
-inhibits T cell by activating CTLA-4
upregulation of PD-L1/PD-L2 on tumor cells
-activate PD-1 on T cell with consequent T cell inhibition
hormonal tumor markers
HCG (trophoblastic)
calcitonin (medullary carcinoma of the thyroid)
catecholamines (pheochromocytoma)
oncofetal antigen tumor markers
a-fetoprotein (HCC, yolk sac) carcinoembryonic antigen (GI carcinoma, lung, pancreas)
isoenzyme tumor markers
prostatic acid phosphatase (prostate cancer)
specific protein tumor markers
PSA (prostate)
immunoglobulins (MM)
mucin and glycoprotein tumor markers
CA 19-9 (colon and pancreatic cancer) CA 125 (ovarian)
hallmarks of cancer
avoid immune destruction evading growth suppressors enabling replicative immortality tumor promoting inflammation activating invasion and metastasis genomic instability inducing resisting cell death deregulating cellular energetics sustaining proliferative signaling
what are oncogenes
products of an oncogene has growth promoting effects
-excessive production
-abnormal product unresponsive to normal inhibitory influences
mutations (gain of function) yield an oncogene
examples of oncogenes
growth factors growth factor receptors -RET (MEN) -her-2-neu (breast cancer) signal transducing protein -RAS non-receptor tyrosine kinase -ABL (CML) transcription factors -MYC (Burkitt, neuroblastoma) cyclins/CDKs -cyclin D1 (mantle)
what are tumor suppressor genes
products of a tumor suppressor gene has growth inhibiting effect (gatekeeper genes)
- insufficient production
- abnormal product
how do you inactivate a tumor suppressor gene
requires inactivation of both alleles or inactivation of a protein product
- inactivation of one allele only with one normal allele is sufficient to prevent neoplasia
- loss of heterozygosity predisposes to neoplasia
- many oncogenic DNA viruses (HPV) act by inactivating tumor suppressor genes