Module 5 - Neoplasia Flashcards

Question

What are the 5 characteristics of Benign and Malignant Neoplasms?

Answer 1

1) Differentiation & Anaplasia 2) Rate of Growth 3) Invasion 4) Metastasis

Answer 2

- Differentiation =Extent to which tumor cells resembles normal counterpart (morphologically & functionally). - well, moderately or poorly differentiated - benign tumors are well differentiated. - Lack of differentiation = Anaplasia [The term anaplasia is used with respect to an invasive (see below) neoplasm]. Features of Anaplastic (undifferentiated) cells: - Variable cell size & shape (cellular pleomorphism). - Variable nuclear size & shape (nuclear pleomorphism). - Hyperchromatic nuclei. - Increased mitosis and atypical mitosis. - Loss of polarity - Tumour giant cell. Functional differentiation - correlate roughly with structural differentiation. - Poorly differentiated tumours are less functionally active e.g., Keratin production by squamous cell carcinoma; well differentiated endocrine tumours produce more hormones

Answer 3

- benign tumors are slow growing - malignant tumors are fast growing, Exception: - Growth of leiomyoma during pregnancy - Rate of growth correlates with blood supply - Rate of growth inversely correlates with differentiation - Poorly differentiated tumors grow faster

Answer 4

Next to metastasis, invasion is a reliable feature of malignancy. - Benign tumors are circumscribed and do not invade. They grow by expansion and show a rim of compressed stromal and connective tissue (capsule). - However the absence of a capsule is not always equivalent to malignancy (e.g. benign tumors such as hemangioma or dermatofibroma do not have capsules). - Most carcinomas begin as localized growth originating from a single cell (monoclonal origin) and are confined to the epithelium of their origin - As long as the basement membrane is intact, they are termed carcinoma in situ (severe dysplasia) Malignant tumors invade and destroy the tissue. They secrete proteases to facilitate invasion.

Answer 5

Metastasis is defined as a tumor implant discontinuous from the primary tumor. - Metastasis is an unequivocal sign of malignancy Pathways of metastasis: - seeding via body cavities - lymphatic - hematogenous a) Seeding via body cavities: - peritoneal cavity - most common - pericardial/pleural/subarachnoid cavities. - E.g. ovarian carcinoma b) Lymphatic Spread - most common initial dissemination. - follows natural drainage. c) Hematogenous Spread - favoured by sarcoma, but carcinomas also use it. - liver and lung are frequent sites.

Answer 6

1. Benign: a) Differentiation/Anaplasia - Well-differentiated; structure may be typical of tissue of origin b) Rate of Growth - Usually progressive & slow c) Local Invasion - Usually cohesive & expansile, well- demarcated masses that do not invade or infiltrate the surrounding normal tissues. d) Metastasis - Absent 2. Malignant: a) Differentiation/Anaplasia - Some lack of differentiation with anaplasia b) Rate of Growth - Erratic and may be slow to rapid, mitotic figures may be numerous and abnormal c) Local Invasion - Locally invasive, infiltrating the surrounding normal tissues d) Metastasis - Frequently present

Answer 7

Natural history of malignant tumor consists of four phases 1. Transformation → A normal cell changed to a malignant cell (carcinogenesis) 2. Growth of transformed cell 3. Local invasion 4. Distant metastases

Answer 8

Most human tumors are derived from a single transformed cell (monoclonal in origin). The tumor cells may not be subject to normal growth and differentiation control - They show - self sufficiency in growth signal - insensitivity to growth-inhibitory signal - resistance to apoptosis - defective DNA repair - unrestricted proliferation - angiogenesis, invasion and metastasis

Answer 9

Time required for a tumor to double in volume or mass depends on: - growth fraction = # of cycling cells / # of total cells - cell loss factor - in tumors there is excess cell production over loss producing a rapid growth. - cells are lost due to apoptosis, ischemia and host defense mechanisms. - tumor cells go through cell cycle phases similar to normal cells - doubling time of tumor cells are similar to or sometimes more than normal counterpart - earlier majority of the cells are in the proliferative pool. - tumors with high growth fractions are susceptible to chemotherapy. Minimum size for clinically detectable tumor is 1cm3 (1gm) which is equivalent to 108 to 109 cells. This translates to 30 doubling from a single cell not including the cell loss. Ten population doublings from this stage will lead to a tumor size of 1kg (lethal).

Answer 10

-Blood supply a major factor modifying tumor growth. Angiogenic factors: - Produced by tumor cells - Produced by inflammatory cells infiltrating tumor. o - Chemotactic & mitogenic for endothelial cells. - Induce production of proteolytic enzyme. - E.g.: Fibroblast growth factors (FGFs), vascular endothelial growth factor (VEGF)

Answer 11

- Over period of time tumors develop various subpopulation of cells. - The sub population may vary in antigenicity, invasiveness, metastatic potential, growth factor requirement, etc. The sub population "beat the odds" and survive.

Answer 12

As the tumor grows, certain subclones acquire more metastatic potential than others. Two phases of metastasis are of importance, which are: 1) invasion of extracellular matrix. 2) vascular dissemination & homing of tumor cells.

Answer 13

Cancer cells are less adherent to each other due to lack of cell adhesion molecules - They degrade basement membrane by secretion of proteolytic enzymes that dissolve matrix proteins, e.g., collagenase, cathepsin B (Benign tumors secrete little or no such enzymes.) - They attach to the basement membrane through laminin receptors and integrins - Tumor cells trigger production of cytokines, such as autocrine motility factors and cleavage products of matrix component

Answer 14

Single or many tumor cells form emboli by aggregating with platelets & WBC. They form adhesion with endothelium and finally exit through basement membrane - Site of metastasis may be predicted by vascular or lymphatic drainage Metastasis may be related to: - presence or absence of endothelial adhesive molecules in some sites. - chemoattractant. - unfavourable environment (e.g.: skeletal muscle).

Answer 15

1) Effect of Tumour on Host - Local effects - Hormonal effects - Cancer Cachexia - Paraneoplastic syndrome 2) Grading and Staging of Cancer - Grading - Staging 3) Lab Diagnosis of Cancer - Tissues - Sampling Methods - Tissue processing - FNAB - Cytologic smear - Cytology of Body Fluids - Additional Techniques - Biochemical tumour markers

Answer 16

a) Local effects: Effects may be varied depending on location and infringement. Local effects are seen in both benign & malignant neoplasm. - benign submucosal leiomyoma - bleeding. - neoplasms (benign or malignant in gut) → obstruction. - pituitary adenoma → expansile growths destruction of remaining gland. - gastrointestinal tumors/urogenital tumors → bleeding - ovarian tumors → torsion. *Tumor may undergo infraction, rupture, ulceration and secondary infection. b) Hormonal effects: - β cell adenoma in pancreas → insulin → hypoglycemia, may be lethal. - adrenal cortex adenoma → steroid → secondary effects. - carcinoid tumor - hormones → carcinoid syndrome c) Cancer Cachexia - Definition: Progressive loss of fat & lean body mass with weakness, anorexia & anemia. Several factors may be responsible. - reduced food intake - abnormalities of taste & central control. - reduced synthesis & storage of fat, increased mobilization of fatty acids fromadipocytes. - probable candidate tumor necrosis factor α (TNF ). d) Paraneoplastic Syndrome: - Definition: symptom complex in cancer bearing patients that cannot readily be explained, either by local or distant spread of the tumor or by the elaboration of the hormones indigenous to the tissue of origin. Importance: - may be earliest manifestation of an occult neoplasm. - may cause significant even lethal clinical problem. - may mimic metastatic disease. * May produce: - endocrine symptoms - neurological symptoms - blood cell abnormalities - renal symptoms For example Bronchogenic Carcinoma may cause: - Cushing's Syndrome - Syndrome of inappropriate antidiuretic hormone secretion. - Hypercalcemia - Myesthesia - Acanthosis Nigricans - Hypertrophic osteoarthropathy - Venous thrombosis

Answer 17

a) Grading is an estimate of aggressiveness of the neoplasm and based on the level of differentiation - Variable criteria are used in various neoplasms. - Commonly based on differentiation, mitosis, and necrosis - Commonly described as well, moderately or poorly differentiated tumors. b) Staging is of greater clinical importance than grading - Staging is based on tumor size, lymph node spread, and metastasis to other organs - There is clinical and pathological staging - Clinical staging is based on evidence acquired prior to the decision as to definitive treatment - Pathological staging includes information obtained at surgery and from examination of tissues by the pathologists - Staging is based on size of the primary lesion, extent of spread to regional lymph nodes, and the presence or absence of blood-borne metastases - There are two major systems. The TNM (T-tumor, N-nodes, M- metastases) system was developed by the Union Internationale Centre Cancer (UICC) - The system used by the American Joint Committee (AJC) on Cancer Staging divides tumors into stages O to IV using factors similar to the TNM system

Answer 18

Clinical information is of great importance. Without clinical information an incorrect diagnosis is easily reached a) Tissues - fresh - formalin fixed - other fixatives - gluteraldehyde - fine needle aspirations - cytology smear. b) Sampling methods - biopsy. - excision. - fine needle aspiration biopsy - smear. - body fluid. c) Tissue Processing - formalin fixative. - dehydration in graded alcohol. - xylene. - paraffin embedding. - sections cut & stained with hematoxylin & eosin d) Fine Needle Aspiration Biopsy - useful for palpable lesions. - office procedure - thyroid, breast, salivary glands. - deeper tissues (liver) - imaging guided. - smear, cell blocks e) Cytologic Smear - cervical cancer detection. - can be adapted for other lesion. f) Cytology of Body Fluids - pleural & peritoneal fluid. - CSF. - sputum - urine. g) Additional Techniques - immunocytochemistry. - electron microscopy. - flow cytometric analysis; marker, DNA ploidy - molecular diagnosis - cytogenetics. h) Biochemical Tumour Markers - PSA (prostate specific antigens); prostatic adenocarcinoma - They are not diagnostic as they may be elevated in inflammatory conditions - Used in screening.

Answer 19

1) Predisposing factors | 2) Carcinogenesis

Answer 20

a. Geographic Factors - age adjusted death rate for breast cancer: US - 27, England - 36, & Japan -7. - stomach cancer - 7 times higher in Japan than US - hepatocellular carcinoma  infrequent in US, some African populations #1 lethal cancer b. Environmental Influence - smoking - sunlight c. Age - in general increases with age - Peak 55-75 yrs Exceptions: - sarcomas younger age group (osteosarcoma) - childhood cancers: occurs exclusively in children; neuroblastomas, Wilms tumor (kidney), retinoblastoma d. Hereditary: There is definite hereditary predisposition i) Inherited Cancer Syndromes (autosomal dominant) - MEN (Multiple Endocrine Neoplasia) ii) Familial Cancers: - shows clustering but hereditary predisposition in individual cases is notclear. e.g. breast/colon/ovary. iii) Hereditary Preneoplastic Conditions - DNA repair defect (autosomal recessive). e.g. xeroderma pigmentosa e. Acquired Preneoplastic Conditions - Barrett’s esophagus (intestinal metaplasia) -> adenocarcinoma

Answer 21

Cancer is a genetic disease. The genetic damage can be caused by chemicals, biological or physical agents. Carcinogenic agents causing genetic damage may be: - chemicals. - physical agents such as radiation. - oncogenic virus. - bacteria. a) Chemical Carcinogens - Diverse natural & synthetic products are of importance. - They may be direct acting or indirect acting (following conversion in the body) from pre-carcinogens to carcinogens in the body. - They are highly reactive molecules which reacts with RNA or DNA or proteins. Several chemical carcinogens may act together or along with other virus or radiation b) Radiation Carcinogenesis: - Radiant energy, whether in the form of ultraviolet (UV) rays of sunlight or as ionizing electromagnetic and particulate radiation can transform virtually all cell types - Acts by DNA damage via direct ionization of cellular macromolecules or indirectly by generating free radicals and damage to critical molecules. E.g: - UV rays – squamous cell carcinoma - Ionizing radiation – leukemia c) Viral Oncogenesis: - A large number of viruses have proved to be oncogenic in animals - Only few have been linked with human cancer. - Oncogenic viruses fall into two classes: i) DNA Oncogenic Viruses: - HPV (Human papilloma virus) - More than 50 subtypes have been identified. Types 16, 18, 31 are associated with cervical cancer. - EBV (Epstein-Barr virus): Nasopharyngeal Ca; Burkitt's lymphoma - HBV (hepatitis B virus): Hepatocellular Ca ii) RNA Oncogenic Viruses: Human T-cell leukemia virus (HTLV-1) - human T cell leukemia/lymphoma. d) Bacterial Infection: - H. pylori infection is associated with B cell lymphoma in the Mucosa Association Lymphatic Tissues (MALToma).

Answer 22

1. Genetic Change in Tumors 2. Oncogenes and Cancer 3. Tumor Suppressor Genes 4. Apoptosis Regulating Genes 5. Mutator (Caretaker) Genes 6. Telomeres 7. Epigenetic 8. Molecular Basis of MultiStep Carcinogenesis

Answer 23

The genetic changes in tumors may be subtle (point mutations) or large, to be detected as chromosomal changes Karyotypic Changes: - balanced translocation → CML-t (9,22) - deletion → retinoblastoma → del 13q14 - gene amplification: neuroblastoma → N-MYC. Point Mutations: - RAS in colon carcinoma: * Carcinogenesis affects several classes of genes such as: - oncogenes. - tumor suppressor genes - apoptosis regulating gene - mutator (caretaker) genes *Carcinogenesis is a multi-step process.

Answer 24

Proto-oncogenes are normal genes that play key roles in controlling cell proliferation and differentiation. Oncogenes are deregulated or altered proto-oncogenes that lead to development of cancer. Activation of Oncogenes: - The activation of oncogene can be secondary to change in gene structure or due to a change in regulation of gene expressions. The changes are secondary to the following mechanisms. a) Point Mutation: RAS mutation is the most common mutation in human cancer. b) Translocation: e.g. t(9,22) in chronic myeloid leukemia. c) Gene Amplification - NMYC in neuroblastoma. Protein Products of Oncogenes: - Oncogenes encode for protein products called oncoproteins - They are devoid of regulatory elements - Oncogenes may lead to the development of tumor by acting at different levels of signal transduction

Answer 25

These genes acts as an inhibitor of cell proliferation. - When mutated the inhibition is lost. Examples: P53 → lung, colon, breast, ovary & other cancers BRCA1, BRCA2 → Breast carcinoma RB → retinoblastoma

Answer 26

Genes that prevent or induce apoptosis may also be important in carcinogenesis. - E.g. BCL2 in lymphoma.

Answer 27

These are DNA repair genes. They are not oncogenic by themselves - However, when mutated, they allow mutation in other genes in normal cell division. - E.g. MSH2, MLH2 in hereditary non-polyposis colon cancer

Answer 28

Present at the end of the chromosome, are progressively shortened with age. Cancer cells make the enzyme telomerase which maintain their ability to replicate

Answer 29

DNA methylation, histone acetylation and de-acetylation microRNA alteration play important roles in carcinogenesis

Answer 30

Carcinogenesis is a multistep process. Multiple oncogene as well as one or multiple tumor suppressor genes works together to produce cancer