12/13 - Intro to Neoplasia & Diagnostic Methods Flashcards
Define Neoplasia?
Abnormal new growth - the growth of which exceeds and is uncoordinated with that of normal tissue and persists in the same excessive manner after cessastion of stimuli that evoked it.
What does tumor mean? What is it used interchangeably? What is a common misconception?
Originally meant “swelling” - now often used interchangably with neoplasia.
Tumor does NOT = cancer
Neoplasia does NOT = cancer
Define anaplasia? What is metastasis?
Anaplasia: lack of differentiation
Metastasis: growth at a distant site
Below are the six different major cells that can give rise to tumors. What is the name of a tumor whos origin is:
- Epithelial
- Mesenchymal
- Hematolymphoid
- Melanocytic
- CNS
- epithelial - carcinoma
- mesenchymal - sarcoma
- hematolymphoic - lymphoma, leukemia
- melanocytic - melanoma
- CNS - clioma, schwanoma
What three characteristics are used to classify tumors?
- Cell of origin (where it’s derived from): epithelial, mesenchymal, etc.
- Differntiation: appearance under the microscope: well, moderately, poor
- Behavior: benign or malignant
What are the three types of epithelia? What is the function of each?What is an important landmark?
- Simple squamous: protective/barrier function
- Simple cuboidal: covers many organs
- Simple columnar ciliated: lines intestines, lines places where you want to bring stuff into the bloodstream
Important landmark is the basal lamina
What is the name for glands that give rise to cancer?
Adeno - meaning “derived from glands”
Tumors of epithelial origin have what common features? What are they called when they are benign vs. maligneant? How can they be further classified?
Typically arise from ectoderm or endoderm germ layers
Benign: “oma” (exp. colonic adenoma)
Malignant: “carcinoma” (exp: adenocarcinoma)
Further classified by architecture: papillary, villous, sessile (flat and deep), cystic
What is the difference btween carcinoma and sarcoma?
Carcinoma - cancer of the epithelium
Sarcoma - cancer of mesenchymal origin (lamina propria)
What types of cells arise from the mesodermal germ layer?
Fibroblasts
Adipocytes
Smooth muscle
Skeletal muscle
Bone
Cartilage
Blood
What is the nomenclature (benign, malignant) for the following cells dervied from the mesodermal germ layer?
- Fibroblasts
- Adipocytes
- Smooth muscle
Fibroblasts: fibroma, fibrosarcoma
Adipocytes: lipoma, liposarcoma
Smooth muscle: leiomyoma, leiomyosarcoma
What is the nomenclature (benign, malignant) for the following cells dervied from the mesodermal germ layer?
- Skeletal muscle
- Bone
- Cartilage
- Blood
Skeletal muscle: rhabdomyoma, rhabdomyosarcoma
Bone: osteoma, osteosarcoma
Cartilage: chondroma, chondrosarcoma
Blood: hemangioma, angiosarcoma
What are the three types of hematolymphoid neoplasms?
- Lymphoid neoplasms
- Myeloid neoplasms
- Histiocytic neoplasms
What is the pathogenesis of the following neoplasms of hematolymphoid origin?:
- Lymphoid neoplasms
- Myeloid neoplasms
- Histiocytic neoplasms
- Lymphoid neoplasms: cell resembles normal stage of lymphocyte differentiaiton (non-hodgkin lymphomas, hodgkin lymphoma)
- Myeloid neoplasms: arise from progenitor cells that give rise to granulocytes, RBCs, and platelets (acute myeloid leukemia)
- Histiocytic neoplasms: proliferative lesions of macrophages and dendritic cells (langerhans cell histiocytosis)
What is the origin of melanocytes? What are they called when they’re benign vs malignant? How does their appearance differ?
Neural crest origin
Benign: nevus - homogenous in color with a defined border
Malignant: melanoma - hyperpigmented areas with light areas nearby, irregular border
What is the different in appearance, growth rate, and invasivity of benign (tumor) vs. malignant (cancer) neoplasms?
Benign (tumor):
- “oma”
- resembles normal tissue but often larger than normal tissue
- Slow growth rate
- non-invasive, encapsulated
- does NOT metastasize
Malignant (cancer):
- “carcinomas” or “sarcomas”
- variable morphology
- variable growth rate
- Invasive growth pattern (non-encapsulated)
- Capable of metastasizing (may now, but CAN)
What is often seen on histology of a malignant tissue?
Irregular pattern, cells grow in different orientations.
Presence of atypical mitotic figures.
What are characteristics are used to determine if something is benign vs. malignant?
Differentiation and anaplasia
Rate of growth
Local invasion (malig)
Mets (malig)
Define “differentiation and anaplasia” and how it pertains to determining whether tumor histology is normal or malignant?
Extent to which tumor cells morphologically and functionally resemble the normal tissue counterpart.
Benign tumors are almost always well-differentiated (looks like normal tissue counterpart)
Malignant tumors vary from well to poorly differentiated/anaplastic
What are characteristics of well-differentiated tissues?
Resemble normal histology
Evidence of maturation
Evidence of functionality
What are some histological features that are associated with malignancy?
- Cellular and nuclear pleomorphism (cells at different stages)
- Coarsely clumped chromatin
- Hyperchromatic nuclei
- High nuclear to cytoplasmic ratio (N/C ratio) (normal nuclei are all same-ish size- in malig. nucleus is bigger)
- Large nucleioli
- Atypical, bizarre mitosises (mitotic figures)
- Loss of tissue polarity
- Tumor giant cells
How can you tell that this is a picture of a malignancy?
Nuclear pleomorphism: HUGE nuclei with a ton of chromatin packed along the nuclear membrane
Nuclei with coarsely clumped chromatin.
What leads you to believe that this tissue is malignant?
High nucleus/cytoplasm ratio (large nucleus)
Large nucleoli
What is displayed in this picture? How do these occur?
Nuclear pleomorphism with tumor giant cells
Can happen because of cells continuing to divide without cytokinesis or by cell fusion.
What is tissue polarity? What occurs with in malignant tissue?
When nuclei line up, basal orientation, apical cytoplasm (ie you can tell the top from the bottom).
Malignant tissue: loss of polarity (see image), nuclei off of the basal lamina, hyperchromatic cells. Cells undergoing mitosis/apoptosis.
Describe the matruration in normal mucosa?
Cells are born at the bottom and mature upwards.
What are the features of malignancy on cytology and histology?
Cytological atypia
Histological dysplasia:
- loss of polarity
- loss of maturation
- loss of architecture
- loss of organization
What is a adenoma?
A benign epithelial tumor of the glandular epithelium
What is a squamous papilloma?
A benign epithelial tumor of the squamous epithelium.
What is an adenocarcinoma?
A malignant epithelial tumor.
What is a leiomyoma? What is a hemangioma?
Leiomyoma: A benign mesenchymal tumor of smooth muscle
Hemangioma: A benign mesenchymal tumor of blood vessels
What is a benign mixed tumor? What is an example?
A tumor with multiple morphological components such as:
- epithelial and mesenchymal
What is a malignant mixed mullerian tumor (MMMT)?
A carcinoma or the endometrium that invades the myometrium superficially and pushes apart the cervical canal.
Bone-like material is layed down and epithelial cells are mixed in. Highly aggressive.
What are teratomas?
Predominantly benign tumors composed of tissues derived from multiple germ layers- totipotent cells (as opposed to previous tumors)
What are two tumor-like conditions that may mimic tumors clinically?
- Hamartoma: mass of disorganized, mature tissue which is specific to the site of development (exp. lung hamartoma contains misarranged mature lung tissue)
- Choriostoma: ectopic tissue with normal, organized morphology in a foreign location (ie piece of tissue in a part of the body where it shouldn’t be)
Describe in situ vs. invasive cancer? What are the types of invasive cancer?
In situ: neoplasm growing above basal membrane that hasn’t broken through
Invasive:
- locally invasive: breaks through BM into the parenchyma or stroma, potentially curable
- metastatic: unlikely curable
What is carcinoma in situ (CIS)?
Pre-invasive lesion frequently seen in proximity to invasive tumor.
Malignant cells do not penetrate beyond basement membrane. Full thickness dysplasia (disordered growth)
What is the process by which tumors invade the extracellular matrix?
1. Loosening of intercellular junctions
- inactivation of E-cadherin
- activation of beta catenon
- SNAIL or TWIST TF expression
2. Degredation of BM via matrix metalloproteinases (MMP)
3. Change in attachment of tumor cells
4. Migration
What is metastasis? What are common site sof metastases?
Spread of tumor - a criterion for malignancy (benign tumors do NOT metastasize)
Each tumor has a penchant for specific metastatic sites based on chemokines, adhesion molecules, and blood flow.
Common sites: lymph nodes, lungs, liver, bone (vertebrae), brain
What is hematogenous metastitic spread? What places are commonly invaded?
Spread through the bloodstream, veins more so than arteries.
Portal, vena caval, and paravertebral plexus are most commonly invaded leading to liver, lung and vertebral mets respectively.
What is the most common pathway for carcinoma spread? What type of involvement is predicatable?
Lymphatic metastatic spread (rare with sarcomas)
Lymph node involvement predictable based on drainage: sentinal lymph nodes are the first lymph nodes to drina the tumor and are often affected.
Besides lymphatic and hematologic spread, where else can tumor spread? What is an example?
They can directly seed body cavities and surfaces.
Peritoneal cavity commonly involved in ovarian cancer.
What is cancer staging?
The proces of determining how much cancer is in the body and where it’s located.
Describes the severity of a cancer, the magnitue/size of the cancer, and the extent of spread.
What are the three components of TNM staging of cancer?
T - tumor size
N - nodal involvement
M - mets
STAGE IS NOT GRADE
Management of cancer is determined by _____?
Stge
What is the host reaction to cancer?
- Local effects such as compression of viral structures and ulceration (bleeding, infection)
- Cachexia (weight loss) from cytokine release and TNF
- Hematologic abnormalities such as anemia and hypercoagulability
What are paranyeoplastic syndromes? How common are they?
When tumors secrete hormonal and non-hormonal molecules that cause endocrine abnormalities (cushings, hypercalcemia, etc.)
10% of cancer pts get these.
What is the difference between targeted therapy and traditional chemotherapy?
Targeted therapy targets the cancer directly and not the entire body.
What would you do if you’re trying to treat lung adenocarcinoma with targeted therapy? What is the purpose of this and how long does it take?
MoIDX testing: state of the art algorithm for treating adenocarcinoma
Looks for mutations in epidermal growth factor receptor and gene translocations in ROS1 or ALK.
Takes 10 working days.
What is the gold standard to determine treatment of adenocarcinoma?
Two parallel testing workflows:
Cytogenetic testing looking for translocations in ROS1 and ALK
Next generation sequencing of the epidermal growth factor gene
What are the two most common mutations in non-small cell lung cancer (NSCLC)?
KRAS (24%)
EGFR (13%)
What does EGFR mutations result in?
Alteration in EGFR kinase activity.
What mutatations can activate EGFR? How common is this and what does this predict?
A deletion in exon 19
A small nucleotide substitution in exon 21
Together these make up 85% of all EGFR mutations and predict a good response to drug.
What can mutations in exom 20 predict?
Drug resistance
Describe EGFR dideoxy sequencing (sanger) and how long it takes? How sensitive is it?
2 day workflow, multiple steps and labor intensive:
- Sample prep
- PCR
- Sequencing
- Interprat/analyze
Insertions/deletions can be difficult to interpret.
Requires 8ng DNA, Sensitivity about 20%
What is the purpose of targeted sequencing?
Looks at a range of gene mutations and uses technology called next gen sequencing to generate a report with hundreds of reads about nucleotide of interest.
What is variant reporting? What is the clinical importance?
Genetic variants given clinical meaning via next gen sequencing
Generates clnical report with three components: drugs predicted to work, drugs predicted to not work based on genetics, drugs shonwn in other tumor types with the same variation
Important because the type of variant will predict therapy.
What are the two types of mutant EGFR?
1. Inaccessible target
- exon 20 insertion
- exon 20 T790M
2. Accesible target
- exon 19 deletion
- exon 20 L858R
What is the therapy for an inaccessibly mutated EGFR? What mutations make it an inaccessible target?
Exon 20 insertion, exon 20 T790M
Cytotoxic therapy (more side effects)
What is the therapy for an accessible mutated EGFR? What mutations make it an accessible target?
EGFR Tyrosine kinase inhibitor
Exon 19 insertion, exon 20 L858R
What first-line treatment has been shown to be superior to tradiational chemotherapy in treating patients with an EGFR mutation? What second line treatment?
First line: EGFR tyrosine-kinase inhibitor: Erlotinib or Getfitinib
Second line: EGFR tyrosine-kinase inhibitor: Afatinib
*these are for EGFR exon 19 deletions or EGFR L858R mutations (activating mutations)*
Tumor plasticity and selective pressure can cause what to happen?
Tumor adaptation and resistance to EGFR tyrosine-kianse inhibitors.
If someone has a T790M mutation in exon 20 (resistant mutation), what drug should you use to treat them?
Osimertinib (third gen)
