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Basics of Neoplasia

 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 benign
 Benign: slow growth, non-invasive, no metastasis  Malignant: 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

Oncology Terminology
 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)

Oncology Terminology
 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

Oncology Terminology
 Sarcoma : cancer that affects connective, supportive and soft tissue (bone, cartilage, muscle or fat)
 Osteosarcoma bone  Chondrosarcoma cartilage  Leiomyosarcoma smooth muscle

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

Oncology Terminology
 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

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)

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

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

Mechanisms of invasion and metastasis

Invasion of the extracellular metastasis
a. Loosening up of tumor cells from each other: Eadhering 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.

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

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

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

 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

 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 Kaposis sarcoma, certain lymphomas, and anal cancer  Pharmacologic agents: estrogens-uterine and breast cancer  Diet : breast, colon and stomach

Diagnosis and Staging

 Histologic Diagnosis - Invasive Biopsy
 Morphology, invasiveness, molecular markers

 Tumor staging - Clinical or Pathological

 Clinical : Imaging studies  Pathological : 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 Grade Grade : well differentiation, low malignancy : middle differentiation, middle malignancy : poor differentiation, high malignancy

TNM method for Staging of Tumor

 T - score: size and extent of invasion of the primary tumor  N - score: number and location of histologically involved regional lymph nodes  M - 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