2 - Neoplasia Flashcards
What prevents a benign tumor from becoming malignant?
They don’t develop subsequent mutations, or don’t develop the right ones to metastasize.
They retain well-controlled growth, benign histologic features.
What allows malignant tumors to metastasize?
They develop subsequent multiple mutations, overexpressions, acquired enzyme pathways (eg telomerases), loss of cell adhesion markers
They develop capacity for invasion & metastasis
They acquire gross & microscopic features of malignancy
Steps in normal physiologic cell proliferation
GF binds TM GF-Receptor Signal Transduction 2nd messengers & kinase pathway DNA transcription Cell Cycling (G1-S-G2-M)
Inactive RAS
Bound to GDP
Activated RAS
Switched out by GTP
Active RAS inactivates itself by
Hydrolyzing GTP to GDP.
Mutation preventing this inactivation leads to cancer.
The most commonly mutated proto-oncogene in human tumors
RAS
Steps downstream of RAS
PI3K
AKT
mTOR
or
RAF
MAPK
KRAS
Human homologue of the Kirsten Rat Sarcoma Oncogene
NRAS
Human homologue of the Neuroblastoma RAS Oncogene
Melanoma steps
Benign Nevus Dysplastic Nevus Radial Growth Phase Vertical Growth Phase Metastatic Melanoma
Melanoma - Benign Nevus
BRAF mutation
Benign, limited growth
Melanoma - Dysplastic Nevus
Previous: BRAF
CDKN2A loss
PTEN loss
Premalignant, lesions may regress.
Random atypia
Melanoma - Radial Growth Phase
Previous:
BRAF mutation
CDKN2A loss
PTEN loss
Increased CD1
Decreased differentiation
Unlimited hyperplasia
Cannot grow in soft agar
Clonal proliferation
Melanoma - Vertical Growth Phase
Previous: BRAF mutation CDKN2A loss PTEN loss Increased CD1
E-Cadherin Loss N-Cadherin Expression αVβ3 Integrin Expression MMP-2 Expression Survivin Reduced TRPM1
Crosses basement membrane
Grows in soft agar
Forms tumor
Melanoma - Metastatic
Previous: BRAF mutation CDKN2A loss PTEN loss Increased CD1 E-Cadherin Loss N-Cadherin Expression αVβ3 Integrin Expression MMP-2 Expression Survivin
Absent TRPM1
Dissociates from primary tumor
Grows at distant sites
ERBB1 (EGF receptor)
Overexpressed in 80% of squamous cell lung cancer
HER2/NEU (ERBB2)
Amplified in 25 - 30% of breast cancers
Bad prognosis
Treat with HER2/NEU antibodies to block the signals of cell division
Benign Tumor - Gross Path
Usually Small (grows to a limited size, then stops) Well-Circumscribed Closely resembles tissue of origin Does not invade or metastasize. May be encapsulated in fibrous tissue
Malignant Tumor - Gross Path
May be small or may reach large size Poorly circumscribed Differentiation may range from well to poorly differentiated. Cytologic features of malignancy Capable of invasion and metastasis.
Malignant Tumor - Histo
Increased Nucleus:Cytoplasm ratio Nuclear hyperchromatism Prominent Nucleoli Nuclear Pleomorphism Increased mitotic rate
Squamous Cell Carcinoma - Where could it come from?
Skin Esophagus Lung Cervix Anus
Identify squamous cell carcinoma of the skin
Look for keratin pearls
Squamous Cell Carcinoma - Identifier
Tonofilaments (Intercellular bridges)
Perpendicular between tumor cells
Adenocarcinoma
Malignant gland formation
Back-to-back gland growth
Nuclear features of malignancy
Often necrotic (due to outgrowth of blood supply)
Sarcoma
Malignant tumor of the mesenchymal tissue (adipose, fibroblasts, muscle)
Ex: Leiomyosarcoma of the uterus
Gross: Hemorrhage, necrosis
Microscopic: Pleomorphic nuclei, mitotic figures
Lymphoma
“Fish-Flesh appearance”
Malignant lymphoma in LNs
Sarcomas
Malignant Lymphoma
Tumors derived from T cells and B cells
Dysplasia
Nuclear atypia
Mild architectural changes
Pre-malignant (at risk for cancer)
High Grade Dysplasia
In situ carcinoma
Carcinoma in situ
Epithelial cells have cytologic features of malignancy
Still ABOVE basement membrane
Ex: DCIS in breast (Ductal carcinoma in situ)
Adenoma of the colon
Pencil nuclei neatly arranged, polarized basally, not very atypical, picket fence arrangement.
Adenoma with high grade dysplasia
Very atypical nuclei
Crowded
In situ carcinoma
Most breast carcinomas
Arise from duct epithelium
Invasive Breast Carcinoma - White
Fibrous
Invasive Breast Carcinoma - Yellow
Necrosis from having outgrown blood supply
Invasive Breast Carcinoma - Desmoplasia
Reactive fibrous tissue response
Neoplastic cells incite a local fibroblastic response in the primary sites as well as distant ones.
That’s why lymph nodes become hard and fixed!!
Paget’s Disease of Bone
Hyperproliferative bony disease
Paget’s Disease of the Nipple
Intraductal breast cancer spreading to skin of nipple
3 theories of which malignant cells metastasize
Subclone Theory
Cancer Stem Cell Theory
Genetic Signature Theory
Subclone Theory
A sequence of mutation events lead to one of the cells eventually being able to metastasize
Cancer Stem Cell Theory
All mutations happen in the stem cells at the beginning of the lineage
Genetic Signature Theory
Many malignant cells at different stages have the signature genes allowing metastasis
Steps to metastasis
Invasion of BM & ECM
Intravasation & Vascular Dissemination
Extravasation, Colonization, Growth
Invasion of Basement Membrane & Extracellular Matrix
Loss of E-Cadherin (loosening of tumor cells)
Inappropriate expression of SNAIL & TWIST, which regulate E-Cadherin expression
Secondarily - Beta-Catenin (proliferator) is no longer sequestered by E-Cadherin, so more tumor cells can proliferate too.
Degradation of Basement Membrane & Extracellular Matrix
Increase: Matrix MetalloProteinase Cathepsin D Urokinase plasminogen activator Type IV Collagenase
MMP9
Gelatinase
Acts on BM Type IV Collagen
Change in attachment of tumor cells to ECM proteins
Upregulate laminin integrins, make em sticky for extracellular matrix
Locomotion of Tumor Cells
Epithelial cells change their appearance to look more like stroma. Express vimentin and smooth muscle actin
Epithelial Mesenchymal Transition
Intravasation & Vascular Dissemination
Mass squeezes into capillary, shear stress frees some cells.
NK cells induce apoptosis
Macrophages phagocytose
Platelets adhere to tumor cells
TNF-α & IFN-γ change the endothelium to be more permissive.
This means the large majority are killed in transit, but some cells migrate successfully.
Extravasation, colonization & growth - Sites
Lungs Bone Brain Lymph Nodes Liver
Extravasation, colonization & growth - Mechanisms
Angiogenesis EMT Chemokine expression Adhesion molecules Down-regulate "metastasis suppressor proteins"
Example: Renal Cell Carcinoma metastasizes to the lungs
Tumor cell reaches the alveolar space via blood vessels.
Tumor cell induces vascular sprouting via:
TGF-α, β PDGF FGF EGF Angiogenin HIF-1α VEGF Angiopoietin 1 & 2
Types of VEGF
A B C D E
VEGF-C
Lymphangiogenesis
VEGF-A
VEGF-B
VEGF-D
VEGF-E
Angiogenesis
Endothelial mitosis
Why does Breast Cancer with CXCR7 metastasize to the lung and liver?
Because there are target chemokine receptors in those organs!
Carcinoma Metastasis
Typically travels via lmyphatics to regional lymph nodes.
Sarcoma Metastasis
Typically travels via veins to lungs & bone
What metastasizes to the lung?
Colorectal Cancer
Breast Cancer
Renal Cell Carcinoma (invades renal veins, moves to IVC, RA, RV & PA)
Hepatocellular Carcinoma
What metastasizes to the liver?
Colorectal Cancer Pancreas Cancer Other GI (Carcinoid, bile ducts) Lung Cancer Breast Cancer
What metastasizes to the bone?
Breast Cancer (Osteolytic - often presents with pathologic fracture or osteoblastic) Prostate Cancer (Osteoblastic - typically causes excess production of bone, when it metastasizes there) Renal Cell Cancer
What metastasizes to the brain neuroaxis?
Typically via vertebral veins
Lung Cancer
Breast Cancer
Melanoma
Renal Cell Carcinoma
Gastric Carcinoma
Signet Ring Carcinoma
Metastasizes to: Virchow's Node (supraclavicular) St. Mary Joseph's Nodule (lymph node near the umbilicus) Krukenberg tumor (Bilateral ovarian mets)
Another place lung cancer metastasizes
Adrenal Glands
If you’re doing flow cytometry to sort out lymphocytes on a heme specimen
Don’t put it in formalin!
Call pathology and find out the best method!
Peripheral tumors in the lung
More likely to be adenocarcinomas than the central ones.
EMT
Epithelial - Mesenchymal Transition
Epithelial cells change their surface molecules to change their shape and blend in with nearby spindle cells.
Important in metastasis.
Muscle Cell Marker expressed in EMT
Vimentin
What cell marker makes you slide through tissue better?
Smooth Muscle Actin
Krukenberg Tumor
Bilateral Ovarian metastasis of gastric carcinoma
