basics of neoplasia

Basics of Neoplasia

Objectives

Understand significant cellular and genetic events that cause cancer and clinical features of neoplastic disease

Differentiate types of cancer/neoplasia by histological origin and staging system

What is cancer?

Abnormal cell growth (neoplasia)

Malignant as opposed to benignBenign: slow growth, non-invasive, no

metastasisMalignant: rapid growth, invasive, potential

for metastasis

Oncology Terminology

Neoplasia (new growth) abnormal proliferation of cells in a tissue or

organ, used as synonymous to tumor Hyperplasia proliferation of cells within an organ , result in gross

enlargement in response to a physiological stimulus, remains under normal regulatory control mechanisms, breast during pregnancy

Hyperthrophy increased in cell size, as in weight training and steroid

therapy


Dysplasia early form of pre-cancerous transformation detected in

a Biopsy or Pap-smear. Cells are different from the tissue of origin

Carcinoma “in situ” “cancer in place”, cells have lost their tissue identity,

growth is rapid and without regulation, however remains localized to a specific area or organ

Invasive Carcinoma invading beyond the original tissue layer or location,

may be able to spread to another parts of the body (Metastasize)


Metaplasia

- changes in response to chronic physical or chemical irritation such as cigarette smoking that causes the mucus secreting Ciliated epithelium to be replaced by Simple Squamous epithelium; benign change, reversible to certain limit

Some cells go from:

- Metaplasia-Dysplasia-Neoplasia


Sarcoma : cancer that affects connective, supportive and soft tissue (bone, cartilage, muscle or fat)Osteosarcoma – boneChondrosarcoma – cartilageLeiomyosarcoma – smooth muscle


Adenoma

collection of growth(-oma) of glandular origin, benign but may compress other structures (mass effect) or produce large amounts of hormones (para-neoplastic syndromes), may become malignant called Adeno-carcinomas


Paraneoplastic Syndromes : mediated by humoral factors (hormones and cytokines) excreted by tumor cells or by immune response against the tumor. Symptoms may show before diagnosis of malignancy SIADH – small cell lung cancer and CNS

malignancies Hypercalcemia – Breast and Lung cancer due to

production of PTHrp

Phenotype of a cancer cell

The Hallmarks of Cancer Cells 1) Self-sufficient growth signals

Constitutively activated growth factor signalling

2) Resistance to anti-growth signals Inactivated cell cycle checkpoint

3) Immortality Inactivated cell death pathway

Phenotype of a cancer cell (cont'd)

4) Resistance to cell death Activated anti- cell death signalling

5) Sustained angiogenesis Activated VEGF signalling

6) Invasion and metastasis Loss of cell-to-cell interactions

Biology of tumor growth

The natural history of malignant tumors can be divided into four phase:

A. Transformation

B. Growth of transformation cells

C. Local invasion

D. Distant metastases

Tumor growth

(1) Rate of growth

Benign: slowly years to decades

Malignant: rapidly moths to years

(2) Pattern of growth

① Expansile

a. Well-demarcated and encapsulated

b. Gradual progression

c. Easy enucleation

d. Particular growth pattern of benign tumors

Expansile Growth pattern(offered by Song W.Wong)

② Invasive

a. Progressive infiltration, invasion, and destruction of the surrounding tissue

b. Ill-defined and non-encapsuled

c. The particular growth pattern of malignant tumors

d. Surgical enucleated difficult

Invasive growth pattern

The steps and mechanism of invasion

i. Cancerous cells attaching basement membrane

Cancerous cells have more receptors of lamina and fibronectin

ii. Local proteolysis

iii. Locomotion

Metastasis

Definition-development of secondary implants discontinuous with the primary tumor, possibly in remote tissue

Mechanisms of invasion and metastasis

① Invasion of the extracellular metastasis

a. Loosening up of tumor cells from each other: E-adhering expression is reduced

b. Attachment to matrix components: cancer cells have many more receptors of lamina and fibronectin

c. Degradation of extra cellular matrix:

Tumor cells can secrete proteolytic enzymes or induce host cells to elaborate proteases.

① Lymphatic metastasis

a. most common pathway for initial dissemination of carcinoma.

b. Tumor cells gain access to an afferent lymphatic channel and carried to the regional lymph nodes.

In lymph nodes, initially tumor cell are confined to the subcapsular sinus; with the time, the architecture of the nodes may be entirely destroyed and replaced by tumor.

c. Through the efferent lymphatic channels tumor may still be carried to distanced lymph rode, and enter the bloodstream by the way of the thoracic duct finally.

d. Destruction of the capsule or infiltration to neighboring lymph nodes eventually causes these nodes to become firm, enlarged and matted together.

Lymphatic metastasis

② Hematogenous metastasis

a. Typical of sarcoma,also used by carcinoma

b. Process: tumor cells →small blood vessels→ tumor emboli→ distant parts→ adheres to the endothelium of the vessel→ invasive the wall of the vessel→ proliferate in the adjacent tissue→ establish a new metastatic tumor.

Pathways to Cancer

Exposure to environmental carcinogens

Dysregulated DNA repair

Random replication errors

Hereditary germline mutations in a cancer gene

c. follow the direction of blood flow. Tumors entering the superior or inferior vena cava will be carried to the lungs tumors entering the portal system will metastasize to the liver

d. Some cancers have preferential sites for metastases lung cancer metastasize to brain, bones, and adrenal glands.

Prostate cancer - bones.

Blood metastasis

③ Implantation metastasis

a. Tumor cells seed the surface of body cavities

b. Most often involved is the peritoneal cavity

c. But also may affect pleural, pericardial, subarachnoid, and joint space.

Molecular genetics of metastases

At present, no single “metastasis gene” has been found

a. High expression of nm23 gene-low metastatic potential

b. KAI-I gene, located on 11pn-2, expressed in

normal prostate but not in metastasis prostate cancer

Genes responsible for cancer

Oncogenes

Tumor-Suppressor Genes

Stability Genes

Epidemiology

Cancer incidence rates - number of new cases per 100,000 people

Age group specific risk, or lifetime risk - describes the risk of developing a particular type of cancer in a specific population

Survival rates expressed as relative survival rate: % of people with the disease who are alive 5 years after the diagnosis

Epidemiology

Prevalence of a disease: number of people living with the disease

Survival rates are poorer in African -Americans in the US

Survival rates are higher for “limited Ds” than for “regional” than for “metastatic” disease

Cancer Etiologic factors

Tobacco : lung, esophagus, head and neck, stomach, pancreas, kidney, bladder and cervix

Alcohol : squamous cell cancer of the oral cavity, pharynx, Larynx, esophagus, liver, rectal, and breast cancer

Asbestos : mesothelioma, lung

Cancer Etiologic factors

Infectious agents: Hepatitis B and C virus-liver cancer, HPV-cervical and anal cancer, HIV induced immunodeficiency associated with Kaposi’s sarcoma, certain lymphomas, and anal cancer

Pharmacologic agents: estrogens-uterine and breast cancer

Diet : breast, colon and stomach

Diagnosis and Staging

Histologic Diagnosis - Invasive BiopsyMorphology, invasiveness, molecular

markers

Tumor staging - Clinical or PathologicalClinical : Imaging studiesPathological : follows Tumor(T), Node(N),

Metastasis(M) (TNM method).

Grading and staging of tumor

Grading -attempts to establish some estimate of its aggressiveness or level of malignancy based on the differentiation of tumor cells and number of mitoses within the tumor.

Grade Ⅰ: well differentiation, low malignancy

Grade Ⅱ: middle differentiation, middle malignancy

Grade Ⅲ: poor differentiation, high malignancy

TNM method for Staging of Tumor

TT - score: size and extent of invasion of the primary tumor

NN - score: number and location of histologically involved regional lymph nodes

MM - score: presence or absence of distant metastasis.

Tumor Staging

TNM scores are group into categories from I - IV reflecting increasing burden of the disease

Has prognostic and therapeutic implications

Staging -based on the size of the primary lesion, its extent of spread to regional lymph Medes, and metastases.

Widely used is a so-called TNM system.

T: primary tumor

N: regional lymph node involvement

M: metastases

Tumor Staging

Example of tumor staging: T2-N1-M0 (stage III) Colon cancer

Resected Colon Cancer that invades the muscularis propia, involves 2 of the 16 lymph nodes but has no distant metastasis

Tumor recurrence is 40-50% Six months of chemotherapy is recommended

Tumor markers

Serum levels of proteins used for diagnosis of tumors

Carcino-Embryonic Antigen (CEA) for colon cancer

Alpha feto protein in testicular and liver cancer

basics of neoplasia

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