chapter 6: neoplasia

neoplasm

(or tumor), is a cellular growth that no longer responds to normal genetic controls

• cell continue to reproduce without need for them, which deprives other cells of nutrition

tumor

swelling caused by number of conditions; used to define a mass of cells arising due to overgrowth + also referred to as neoplasm "(new growth)”

neoplasm consist of:

atypical or immature cells

characteristics of each tumor depends on:

• type of cell arises on

• unique structure and growth pattern

cancer

derived from greek word “crab” — “karkinoma”; and is another name for maligant tumor + uncontrol of cell proliferation

neoplasia

process itself of abnormal unregulated cell and tissue growth

principles used to classify benign and maligant neoplasms

• cell characteristics: appearance + behavior of cells

• rate of growth: how fast cells multiply + increase in size

• manner of growth: pattern by which tumor expands + develops

• capacity to invade + metastasize other parts of body: ability of cell to spread into nearby + distant parts

• potential for causing death: likelihood disease become life-threatening

benign neoplasms - cell characteristics, rate of growth, mode of growth, and metastasis:

• cell characteristics: well differentiated, with cells resembling tissue of origin

• rate of growth: usually progressive and slow; may come to standstill or regress

• mode of growth: grows by expansion without invading surrounding tissues; usually encapsulated (enclosed in capsule)

• metastasis: doesn’t spread by metastasis

malignant neoplasms - cell characteristics, rate of growth, mode of growth, and metastasis:

• cell characteristics: cells undifferentiated, with anaplasia + atypical structure that bears little resemblance to cells in tissue of origin

• rate of growth: variable + depends on level of differentation; more undiff = more rapid rate of growth

• mode of growth: grows by invasion, sending out processes that infiltrate surrounding tissues

• metastasis: gains access to blood + lymph channels to metastasize other areas of body

benign vs malignant neoplasms

benign neoplasms:

• well-differentiated

• cells resemble tissues of origin, but lost ability to control cell proliferation

• grows by expansion, but enclosed in fibrous capsule

• not cause death unless location is such that interrupts vital body functions

malignant neoplasms:

• less differentiated

• lost ability to control both cell proliferation and differentiation

• grows in disorganized + uncontrolled manner, and invades surrounding tissue

• cells break loose + travel to distant sites to form metastases

• causes death unless growth controlled through treatment

benign tumors are named according to: + examples

tissues from which they arise + include suffix -”oma”

• lipoma: benign tumor of fat tissue

• leiomyoma: b. tumor of smooth muscle

• papilloma: b. tumor of epithelial tissue

malignant tumors are named according to: + examples

tissues which they arise

• carcinomas: malignant epithelial tumors (ex: adenocarcinoma arise in ducts or glands)

• sarcomas: malignant connective tissue tumors

• lymphomas: cancers of lymphatic tissue

clonal proliferation or expansion occurs:

• cancer cell progeny can accumulate faster than nonmutant neighbors

• due to mutation = cell aquires characteristics allowing it to have selective adv. over nbrs

  • ex: increased growth rate of decreased apoptosis

• angiogenesis involved

angiogenesis

mutant cells secrete growth factor

• stimulates development of new capillaries in tumor

malignant transformation

process during which normal cell becomes cancer cell

• important to consider that multiple mutations required before cancer develops

  • mutations: alteration in DNA affecting expression or function of gene

  • gene amplification: rep. dupes of chromosome 10s or 100s of gene copies made

chromosome translocation

large changes in chromosome structure → pieces of 1 chromosome translocated into another

chromosome translocation is associated with cancers such as:

burkitt lymphoma, and chronic myelogenous leukemia

burkitt lymphoma

myc proto-oncogene (which encodes growth single protein), is translocated from normal position on chromosome 8 to chromosome 14

myelogenous leukemia (CML)

translocation involving chromosome 9 and 22, resulting in formation of abnormal fusion protein, which is a hybrid oncogenic protein (bcr-abl) that promotes cell proliferation (philadelphia chromosome)

cancer-associated genes classified into 3 categories:

proto-oncogenes, oncogenes, tumor-suppressor genes

proto-oncogenes

normal nonmutant gene that codes for normal cellular growth

oncogenes

mutated proto-oncogenes that promote excessive cell growth

tumor-suppressor genes

prevent uncontrolled cell growth + help maintain genomic stability (aka anti-oncogenes)

3 key genetic mechanisms have role in human carcinogenesis

• activation of oncogenes

• inactivation of tumor suppressor genes

• defects in DNA repair genes

activation of oncogenes

mutations of proto-oncogenes can convert them into oncogenes, promoting uncontrolled cell growth and proliferation

inactivation of tumor-suppressor genes

loss/alteration of tumor-suppressor genes removes important controls on cell division, DNA repair, and apoptosis

defects in DNA repair genes

mutation in genes responsible for repairing DNA damage allow additional mutations to accumulate, increasing cancer risk

carcinogenesis

process by which carcinogenic (cancer-causing) agents cause normal cells to become cancer cells

multistep mechanism of carcinogenesis that can be divided into 3 stages:

1. initation → 2. promotion → 3. progression

first step in carcinogenesis:

initiation - exposure of cells to carcinogenic agent causes alterations in DNA, affecting genes that regulate cell growth, DNA repair, or apoptosis

second step in carcinogenesis:

promotion - allows growth + proliferation of cells triggered by multiple growth factors & chemicals

• reversible if promoter substance removed

third step in carcinogenesis:

progression: process when tumor cells acquire malignant phenotypic changes (becomes malignant + aggressive)

is cancer a single disease/have a single cause?

cancer is not a single disease + not single cause = occurs due to interaction among multiple risk factors or repeated exposure to single carcinogenic agent

cancer predisposing factors:

heredity, hormonal factors, immunologic mechanisms, environmental agents (chemicals, radiation, cancer-causing viruses)

heredity involvement in cancer

gene predisposition is identified in 50 types of cancers

• ex: breast cancer common among women w/ history of it in first-degree relative

• people carrying BRCA1 & BRCA2 genes identified in genetic susceptibility to breast + ovarian cancer

• people carrying BRCA mutation have lifetime risk of 80% developing breast cancer

carcinogenesis

agent capable of causing cancer + produces genetic mutations that can transform normal cell into initiated cell

• classified into 2 groups: direct-reacting and indirect reacting agents

direct-reacting agents in carcinogens

agents that dont require activiation in body to become carcinogenic

• can bind directly to DNA & cause mutations

indirect-reacting agents in carcinogens

agents (parcinogens or initiators) which become active only after metabolic conversion

• activated metabolites bind to DNA, causing mutations

carcinogens vs tumor promoters + roles in multistep process of carcinogenesis

carcinogens:

• produce genetic mutations that transform normal cell to initiated cell

  • ex: cig smoke directly associated w/ lung and laryngeal cancer

promoter:

• not cause mutations but encourages growth + division of previously mutated cells

  • ex: inflammation caused by H. pylori increase risk of gastric cancer

tumor cell markers

substance produced by benign or malignant cells which are found in tumor cells + secreted into body fluids (blood, spinal fluid, urine) → hormones, enzymes, antigens, antibodies

tumor markers are used to:

screen and identify individuals at high risk for cancer, and diagnose specific types of tumors + follow clinical course of cancer

liver and germ cell tumors:

secretes alpha fetoprotein (AFP) into blood

prostate tumors:

secrete prostate-specific antigen (PSA)

• used for screening, risk assessment, evaluation of suspected prostate cancer, and monitoring treatment or recurrence

ovarian epithelial tumors:

secrete cancer antigen - 125 (CA-125)

• used for monitoring treatment response + detecting recurrence of ovarian cancer

• not good screening test: CA-125 be elevated in benign conditions

tumor invasion is + what favors it:

the local spread of cancer, which is a pre-requisite for metastasis + first step in metastatic process & requires cancer attach to specific receptors + survive specific environment

• factors promoting it:

  • epithelial-like characteristics are lost (ex: polarity, adhesion to basement membrane)

  • migratory capacity increases (causing cancer cells to secrete protease)

    • digests extracellular matrix + basement membranes, and creates pathways through which cells move

  • resistance to apoptosis increases

  • dedifferentiation to stem cell-like state favors growth in foreign microenvironments + establishment of metastatic disease

tumor metastasis is:

spread of cancer cells from site of original tumor to distant tissues + organs through body & its a complex process requiring cells to have many new abilities

• hematologic and lymphatic metastasis are 2 major routes by which cancer spreads from its primary site to distant locations

lymphatic metastasis

often earliest detectable spread in epithelial cancers

• first destination: regional lymph

• sentinel lymph node biposy is important in detecting

• ex: breast cancer frequently spreads first to axillary lymph nodes

hematologic metastasis

cancer cells spread through the blood, associated with more advanced disease

• first destination: organs with rich blood flow (ex: lungs, liver, bone, brain)

• ex: osteosarcoma commonly spreads to lungs via bloodstream, renal cell carcinoma often metastasizes hematologic to lungs + bones

common clinical manifestations of cancer

grouped into local effects and systemic effects

• local effects: cancer disrupts tissue integrity → compresses + erodes blood vessels, causing ulceration, necrosis, and bleeding

  • infiltrate + destroy normal tissues, leading to inflammation & pain

• systemic effects: seen in advanced stages

cancer cachexia

syndrome with progressive weight loss, loss of skeletal muscle + fat, weakness, and anorexia

common local effects of tumors include:

• pain: may be absent until late stages, which occurs when tumor is well advanced + severity depends on type of tumor

• obstruction: tumor compresses duct or passageway (digestive tract, bronchi); blood supply or lymphatic flow may be restricted

• tissue necrosis & ulceration: may lead to bleeding or infection around tumor

common systemic effects of tumors include:

• weight loss: due to increase demands from tumor cells on body; anorexia, fatigue, pain, stress

• anemia: due to blood loss at tumor site + nutritional deficits may reduce hemoblogin synthesis

• severe fatigue: due to inflammatory changes, cachexia, anemia

• effusions: inflammation causes fluid buildup in body cavities

paraneoplastic syndrome

not directly related to tumor invasion or metastasis, often caused by etopic hormone production or immune mechanisms

• ex: squamous cell carcinoma of lung can secrete parathyroid hormone, resulting in hypercalcemia

tumor grade

how closely tumor cells resemble normal tissue from which they arose (degree of differentiation)

low-grade tumors

• well differentiated

• looks similar to normal cells

• grows and spreads more slowly

high-grade tumors

• poorly differentiated or undifferentiated

• markedly abnormal appearance

• higher mitotic activity

• tend to behave more aggressively

stages in tumors are + involve:

size, degree in which invaded, and extent of spread

• stage 1: tumor confined to organ of origin

• stage 2: tumor locally invasive

• stage 3: tumor advanced to regional structures

• stage 4: tumor has spread to distant sites

TNM system used in staging (from WHO)

• tumor (T): number equals size + local extent

  • T0: organ free of tumor

  • Tis: carcinoma in situ

  • T1: lesion <2 cm in size

  • T2: lesion 2-5 cm

• nodes (N): lymph nodes involvement; higher number means more nodes involved

  • N0: no lymph nodes involved

  • N1: regional lymph nodes involved

  • N2: more lymph nodes involved

• metastases (M): extent of distant metastases

  • M0: no metastases

  • M1: distant metastases present

carcinoma in situ (CIS)

pre-invasive cancer in which abnormal cells present only in epithelium

• cells not crossed basement membrane or invaded surrounding tissues

• no invasion into underlying tissue and is considered stage 0 cancer in many organs

• if untreated = CIS progresses to invasive carcinoma

adequate margins

tumor should be completely removed along with sufficient amount of surrounding health tissue + surgeons must provide critical staging information

palliative surgery

performed not to cure disease, but to relieve symptoms + improve quality of life

• colostomy: creates alternative pathway for stool to bypass an obstructing colorectal tumor to relieve bowel obstruction

surgery

selected high-risk diseases, which surgery can play role in prevention of cancer

• colectomy: removal of colon (APC gene = 100% lifetime risk of colon cancer)

• prophylactic mastectomy: removal of breast

• bilateral salpingo-oophorectomy: removal of ovaries + uterine tubes

  • p + b = women w/ BRCA ½ mutations = sig. increase in breast and ovarian cancer

radiation

used to kill cancer cells + minimize damage to normal structures; it uses radiation to damage DNA of cancer cells, preventing growth/division = cell death

• external beam: radiation delivered from machine outside body

• brachytherapy: radioactive source placed inside/near tumor

chemotherapy

uses cytotoxic drugs to destroy cancer cells and inhibit growth + division; can be single agent or combo chemotherapy

• induction chemotherapy: causes shrinkage or disappearance of tumors

• adjuvant chemotherapy: administered after surgical excision w/ goal of eliminating micrometastases

• neoadjuvant chemotherapy: administered before localized (surgical or radiation) treatment

cancer prognosis

predicted course + outcome of cancer, including: likelihood of recovery, recurrence, progression, survival

factors affecting cancer prognosis include:

type of cancer, stage of cancer, grade of tumor, size and location, presence of metastasis

cancer-free state

generally defined as 5-year survival without recurrence

• childhood leukemia generally cured after 10-year cancer-free period

• 5-year survival rate is percent of people who are alive 5 years after being diagnosed