What is neoplasia?
New growth from uncontrolled or autonomous proliferation due to genetic mutations.
- results in a mass or neoplasm
- neoplasm = benign or malignant depending on clinical behavior or aggressiveness
What is a tumor?
- originally a result of swelling due to inflammation
- also may be a benign or malignant neuplasm that produces a swelling
Characteristics of benign neoplasms/tumors
- Slow growing neoplasms that stay put
- Do not invade surrounding tissues
- Do not metastasize (travel to other organs)
Characteristics of cancer/malignant neoplasms
- Do invade surrounding tissues
- Do metastasiize (travel to other organs)
What is metaplasia?
- Non-neoplastic change in type of tissue at a site of injury or irritation; a form of reaction to injury
- assoc. w/ chronic irritations and explains cancers arising from cells not normally found in those sites
- ex. squamous epithelium replaces glandular epithelium = squamous metaplasia
What is dysplasia?
- Neoplastic mutations which result in abnormal features in some but not all original or metaplastic cells sothet there is a mix of abnormal and normal cells
What is carcinoma-in-situ?
Neoplastic mutations which result in replacement of all the normal epithelial cells w/ abnormal cells w/out invasion of basement membrane
What is carcinoma?
Invasion through the basement membrane and or metastases
Lung Cancer: ex. of metaplasia
- smoking changes ciliated columnar epithelium to benign squamous epithelium (non-neoplastic change) --> dysplasia (neoplastic change) -->carcinoma-in-situ --> invasive squamous cell carcinoma (among most common types of lung cancer)
Cervical Cancer: ex. of metaplasia
- chronic HPV infection changes endocervical epithelium to squamous epithelium --> dysplasia --> carcinoma-in-situ --> invasive squamous cell carcinoma (most common type of cervical cancer)
Esophageal Cnacer: ex. of metaplasia
- chronic reflux of gastric acid into distal esophagus changes squamous lining into gastric glandular epithelium --> dysplasia --> adenocarcinoma-in-situ --invasive adenocarcinoma (most common type of esophageal cancer in US)
What is the significance of accumulation of mutations?
- neoplastic cells often have genetic instability allowing for additional mutations altering the tumor and often making it more aggressive; i.e progression from dysplasia to metaplaisia
- a larger population of tumor cells increases the tumor's chance of surviving and accumulating additional mutations = allow mutational experimentation despite loss of many cells that develop unsuccessful mutations
What is differentiation?
The degree to which neoplastic cells resemble normal cells and structure (morphologically and functionally)
What are the grades/degrees of differentiation?
- Low grade (well differetiated): look the same or nearly the same as tissue of origin
- Intermediate grade (moderately differentiated: some resemblance to tissue of origin
- High grade (poorly differentiated or anaplastic): little or no similarity to origin of tissue
**Grade/degree of anaplasia relates well to aggressiveness of the tumor
Grades or degrees of benign vs. malignant tumors
- Benign tumors are almost always well differentiated, not aggressive, and very rarely graded
- Malignant tumors - behavior predicted by grade; the uglier/ less lke its tissue of origin the WORSE it behaves
What is the grade/degree of anaplasia or lack of differentiation determined by?
- Cellular and nuclear pleomorphism (varied size and shape)
- Hyperchromatic staining or hyperchromasia (increased nuclear DNA)
- Increased nuclear/cytoplasmic ratio (usually from larger nuclei)
- Prominent nucleolus or nucleoli
- Increased mitotic activity
- Disorganized growth: failure to produce structures ( glands or keratin)
What are some characteristics of growth for neoplasms?
- Benign usually grow slow while malignant grow more rapidly
- growth is measured byt doubling time - time required for tumor to double in size
- the higher the grade, the faster the growth and the shorter the doubling time
How does cell cycle relate to doubling times in a tumor?
- Cell cycle is usually NOT shorter
- cancer grows faster b/c cells produced exceeds cells lost; fewer cells are lost to permanet terminal maturation (non-replicating stage) or apoptosis
- therefore, there are more cells capable of re-entering the cell replicative cycle
What does the stage of a neoplasm refer to?
- Stage = extent of spread
- low stage = tumor limited to site of origin; good prognosis
- high stage = spread to other organs; poor prognosis
- TNM cancer staging system:
* T = size or local extent of primary tumor
* N = number and distribution of lymph node metastases
* M = presence and extent of distant metastases
What is invasion and what are its steps?
- progressive inflitration and destruction of surrounding tissues (usually malignant tumors)
1) Less cell-to-cell adhesion
2) Binding of malignant cells to ECM by activation of adhesion molecules
3) Migration of tumor cells int degraded zone of ECM
What causes less cell-to-cell adhesion
- Due to down regulation of:
* Epithelial (E) cadhedrin = fewer bridges btwn cells which anchor cells to catenins
- catenins - membrane attacment sides under the plasma membrane; unbound or free catenins also induce cellular proliferation
What are some adhesion molecules that are activated by malignant cells?
- Immunoglobulin supergene family (expression correlates w/ aggressiveness)
* ICAM (intercellular adhesion molecule)
* VCAM (vascular cell adhesion molecule)
*bind to basement membrane and/or matrix proteins as laminin or fibronectins
* transmembrane molecules for signal conduction; increase and initiate BM penetration by secreting proteolytic enzymes = matrix degradation
What are some cells/enzymes activated by integrins?
* Serine proteinase - activates plasmin
* Collagenases (metalloproteins)
#Type IV collagen of BM and Type I collagen of stroma
* Cystein proteinase (cathepsin B)
- Activates fibroblasts resulting in:
* Desmoplastic rxn
* Type I collagenase production = penetration of fibrous stroma by tumor cells
What allows tumor cells to migrate into ECM?
- Autocrine motile factor (AMF) causes pseudopodia of tumor cells rich in receptors for laminin and fibrinectin
What is metastasis and how is it spread?
- separate sites of tumor which are discontinuous with primary neoplasm b/ tumor cells were separted and traveled to other sites via:
* direct seeding of body cavities or surfaces
* spread through lymphatic or blood (hematogenous) vessels
- not all organs (ex. spleen) are equally susceptible to metastases
What are the steps in formation of metastases
- invasion of blood/lymphatic vessels by malignant cells
- cells transported by embolization or mechanical means
- lodging and growth in new location (lung, liver, bone, etc) requiring angiogenesis to support new growth
What are the most important angiongenic factors and how are they produced?
- vascular endothelial growth factor (VEGF) and basic fibroblast growth factor or (bFGF)
*Produced by either:
#tumor cells directly or benign stromal cells in response to signals from tumor cells
**Suppression of normal anti-angiogenic factors (ex. thrombospondin-1) must occur for angiogenesis to take place.
What is the Walburg Effect?
- altered glycolysis: most tumor cells
* don't use mitochondria for glycolysis (20 ATPs from 1 glucose)
* but use direct aerobic glycolysis (2 ATPs from 1 glucose) therefore tumor cells take up more glucose than most normal cells
- Use Walburg effect by CT/PET scans to detect increased uptake of radioactive labelled glucose (fludeoxyglucose, 18Fm to detect tumor, particularly metastases)
What are the components of neoplasms?
1) parenchyma or neoplastic cells: proliferating malignant cells of the neoplasm; nomenclature usually based on parenchymal component
2) Stroma: benign supporting framework of CT and blood vessels (adequate blood supply is critical to tumor growth); derived from non-neoplastic cells
How are neoplasms classified?
** based on histogenesis (cell of origin) of parenchymal component and behavior (benign or malignant
- most benign neoplasms = suffix "-oma"
- most malignancies = suffix "-carcinoma" or "-sarcoma"
- exceptions: some malignancies by convention end with "oma" = lymphoma, mesothelioma, melanoma, seminoma
What are Epithelial Neoplasms?
- carcinomas: malignancies of epithelial cells (cells w/ BMs) typically spread by lymphatic channels
- may be carcinoma in-situ or invasive carcinoma
- may be ectodermal (skin and brain), mesodermal (kidney and endometrium, or endodermal (gut) origin
What are some tumors of non-glandular epithelium?
- Stratified squamous epithelium
*Benign: squamous papilloma
* Malignant: squamous cell carinoma
- Basal cells of skin
* Malignant: basal cell carcinoma
- Transitional epithelium
* Benign: Transitional papilloma
* Malignant: Transitional cell carcinoma
What are neoplasms of glandualr/ductal epithelium?
Benign: Adenoma or Papilloma
Malignant: Adenocarcinoma or Papillary adenocarcinoma
What are mesenchymal neoplasms?
- arise from stromal or supporting tissues (CT, muscles, bld vessels)
- generally nambed for mature tissue they most closely resemble but some malignancies are sufficiently undifferentiated making subclassification difficult
- benign: end w/ "-oma"
- malignant: end w/ "-sarcoma" - typically spread by blood (hematogenously)
What are some CT neoplasms [benign (B) or malignant (M)]?
- Fibrocytes: fibroma (B); fibrosarcoma (M)
- Adipocytes: lipoma (B); liposarcoma (M)
- Chondrocytes: chondroma (B); chondrosarcoma (M)
- Osteocytes (bone): osteoma (B); Osteosarcoma (M)
What are some muscle neoplasms?
- Smooth muscles: Leiomyoma (B); Leiomysarcoma (M)
- Skeletal muscles: Rhabdomyoma (B); Rabdomyosarcoma (M)
What are some endothelial cell neoplasms?
- Blood vessels: hemangioma (B); angiosarcoma (M)
- Lymph vessels: lymphangioma (B); lymphangiosarcoma (M)
What are mesothelial cell neoplasms called?
- Benign/malignant mesothelioma
What are some neoplasms of the Nervous system (derived from neuroectoderm)?
- Support/glial cells
* Astrocytes: astrocytoma (M) - lower grades; glioblastoma (M) - high grade
* oligodendrioglia: oligodendroglioma (M)
* Nerve sheath: benign/malignant schwannoma
- Nerve cells: Neuroma/ganglioma (B); Neuroblastoma/medulloblastoma (M)
- Retina: Retinoblastoma (M)
- Melanocytes in skin (neural crest origin): nevus (benign mole); melanoma (malignant mole)
What are germ cell neoplasms?
- arise from pleuripotent stem cells; can differentiate into cell lines of >1 dermal (ecto-, meso-. and/or endodermal) origin and thus contain one or more types of mature tissues
What are some examples of germ cell neoplasms?
- Germ cells w/out differentiation: Seminoma (M) in males; Dysgerminoma (M) in females
- Placenta: hydatidiform mole (B); choriocarcinoma (M)
- mature tissues (mix of brain, gut, skin and/or lung): mature teratoma (B); immature teratoma (M)
Hematopoietic malignancies: What are leukemias?
- malignant neoplasms of the myeloid or lymphoid hematopoietic stem cells (granulocytes, lymphocytes, monocytes, RBCs and/or megakaryocytes)
- diffusely replae bone marrow and often spill over into peripheral bld
What is the difference between acute and chronic leukemias?
- Acute: composed of very immature cells (blasts) and rapidly progressive (ex. acute lymphoblastic/myeloblastic leukemia)
- Chronic: more mature and clinical cours is usually indolent or prolonged (ex. chronic lymphocytic/myelogenous leukemia)
Hematopoietic malignancies: What are lymphomas?
- malignancies of lymphocytes that form solid tissue masses and usually DO NOT spill over into peripheral blood although frequently invlolve bone marrow
- Divided into two main groups: Hodgkin's and Non-Hodgkin's lymphoma
What is Hodgkin's Lymphoma?
- always malignant and accounts for 20% of lymphomas
- primarily involves lymph nodes
- has Reed-Sternberg (RS) cells = giant usually multinucleated cells w/ large red nucleoli of lymphocytic origin (owl-eyed)
-histologic changes in lymph nodes mostly due to non-neoplastic host response (benign, small lymphs, eosinophils, plasmacytes)
- usually depression of T-cell fxn (cellular immunity)
What is Non-Hodgkin's lymphoma?
- Malignancies of lymphocytes w/ NO Reed-Sternberg cells
- 80% of lymphomas
- most involve lymph nodes but 1/3 of cases have primary sites in other tissues (ex. oropharynx, gut, bone marrow, or skin)
- morphological features of malignant cells recapitulate (repeat) various stages of normal lymphocyte transformation (small to giant lymphs)
- usually furthur characterised by immunologic methods into:
* B cell (80%) - cause depression of humoral immunity
* T cell (20% of non-Hodgkin) - cause depression of cellular and humoral immunity
Hematopoietic Malignancies: What is multiple myeloma?
- Malignant proliferation of plasma cells (transformed B cells)
- usually remains in the bone marro and causes lytic lesions (holes) in the bones
- plasma cells secrete monoclonal immunoglobulin (M-protein); usually IgG or IgA
- Sometimes produces Bence-Jones proteins: component of monoclonal kappa or lamda light chain which is small enough to pass into urine
- Amyloidosis of AL type - assoc. w/ myelomas that produce Bence-Jones proteins
- Most pts die of infection b/c of
1) depression of humoral immunity = infection
2) renal failure b/c proteins plug up renal tubules and/or amyloidosis