NEOPLASIA -new growth Neoplasm- abnormal mass of tissue the growth of which exceeds & is uncoordinated with that

of the normal tissues & persists in the same excessive manner after the cessation of the stimuli which evoked the change. state of autonomous cell division cells are said to be transformed because they continue toreplicate behave as parasite and competes with normal cells & tissues for their metabolic needs may flourish in patients who are otherwise wasting increases in size regardless of their local environment & the nutritional status of the host depends on the host for its nutrition & blood supply referred as tumor in common medical usage Oncology study of tumors (ONCOS) DIVISION OF NEOPLASMS (based on the potential clinical behavior) BENIGN Localized the margins of the tumor are well defined & cell growth is entirely local Non-invasive cannot spread to other sites Amenable to local surgical removal Patient generally survives MALIGNANT o -collectively referred to as Cancer (crab) o -spreading to distant sites (metastasis) o -Invasive destroying adjacent structures TUMOR NOMENCLATURE Two Basic Components of Tumors 1) Parenchyma - made up of transformed or neoplastic cells - determines the biologic behavior - the component from which the tumor derives its name 2) Stroma - non-neoplastic - carries the blood supply - provides support for the growth of parenchymal cells - crucial to the growth of the neoplasm - does not aid in the separation of benign from malignant T UMO R NOMENC LA T UR E : BE N IGN T U MO R S Generally designated by attaching the suffix oma to the cell type or connective tissue from which the tumor arises A benign tumor arising in fibrous tissue is a FIBROMA; a benign cartilaginous tumor is a CHONDROMA. The nomenclature of benign epithelial tumors is MORE COMPLEX. They are classified sometimes on the basis of their microscopic pattern and sometimes on the basis of their macroscopic pattern. Others are classified by their cells of origin. Benign neoplasms of surface epithelia, ex. Skin, are termed papillomas. This term is preceded by the cell of origin, ex. Squamos papilloma of the skin . PAPILLOMA produces microscopic or macroscopic finger-like fronds ADENOMA- is applied to benign epithelial neoplasms producing gland patterns and to neoplasms derived from glands but not necessarily exhibiting gland patterns POLYP is a mass that projects above a mucosal surface, as in the gut, to form a macroscopically visible structure CYSTADENOMAS -are hollow cystic masses typically seen in the ovary TUMOR NOMENCLATURE: MALIGNANT TUMORS The nomenclature of malignant tumors essentially follows that of benign tumors, with certain additions and exceptions. Malignant neoplasms arising in mesenchymal tissue or its derivatives are called SARCOMAS. are designated by their histogenesis (i.e., the cell type of which they are composed A cancer of fibrous tissue origin is a FIBROSARCOMA, and a malignant neoplasm composed of chondrocytes is a CHONDROSARCOMA Malignant neoplasms of epithelial cell origin are called carcinomas. Tumors are preceded by the cell type of origin, ex. Squamos cell carcinoma. It must be remembered that the epithelia of the body are derived from all three germ-cell layers; a malignant neoplasm arising in the renal tubular epithelium (mesoderm) is a carcinoma, as are the cancers arising in the skin (ectoderm) and lining epithelium of the gut (endoderm).

Carcinomas that grow in a glandular pattern are called adenocarcinomas, and those that produce squamous cells are called squamous cell carcinomas Sometimes the tumor shows little or no differentiation and must be called poorly differentiated or undifferentiated carcinoma. NOMENCLATURE OF OTHER TUMORS (MIXED TUMORS) The parenchymal cells in a neoplasm, whether benign or malignant, resemble each other, as though all had been derived from a single progenitor In some instances, however, the tumor cells may undergo divergent differentiation , creating so-called mixed tumors example is mixed tumor of salivary gland which have diverse elements that are thought to derive from epithelial cells, myoepithelial cells, or both in the salivary glands, and the preferred designation of these neoplasms is pleomorphic adenoma Fibroadenoma of the female breast is another common mixed tumor The multifaceted mixed tumors should not be confused with a teratoma, which contains recognizable mature or immature cells or tissues representative of more than one germ-cell layer and sometimes all three Teratomas originate from totipotential stem cells such as those normally present in the ovary and testis and sometimes abnormally present in sequestered midline embryonic rests. Such cells have the capacity to differentiate into any of the cell types found in the adult body and so, not surprisingly, may give rise to neoplasms that mimic, in a helter-skelter fashion, bits of bone, epithelium, muscle, fat, nerve, and other tissues. *** Teratoma - is an encapsulated tumor with tissue or organ components resembling normal derivatives of all three germ layers. The tissues of a teratoma, although normal in themselves, may be quite different from surrounding tissues and may be highly disparate; teratomas have been reported to contain hair, teeth, bone and, very rarely, more complex organs such as eyes, [1][2] torso,[3][4] and hands, feet, or other limbs.[5] NOMENCLATURE REMINDERS Some glaring inconsistencies may be noted. For example, the terms lymphoma, mesothelioma, melanoma, and seminoma are used for malignant neoplasms. These inappropriate usages are firmly entrenched in medical terminology. There are other instances of confusing terminology: Hamartoma is a malformation that presents as a mass of disorganized tissue indigenous to the particular site. One may see a mass of mature but disorganized hepatic cells, blood vessels, and possibly bile ducts within the liver, or there may be a hamartomatous nodule in the lung containing islands of cartilage, bronchi, and blood vessels There are other instances of confusing terminology: choristoma. This congenital anomaly is better described as a heterotopic rest of cells. For example, a small nodule of well-developed and normally organized pancreatic tissue may be found in the submucosa of the stomach, duodenum, or small intestine. This heterotopic rest may be replete with islets of Langerhans and exocrine glands. The term choristoma, connoting a neoplasm, imparts to the heterotopic rest a gravity far beyond its usual trivial significance ** Choristomas, forms of heterotopia , are closely related benign tumors. These tumors also contain normal tissues but are found in abnormal locations **Heterotopia (medicine), the displacement of an organ from its normal position

- may come to standstill or regress Malignant tumors - erratic & may be slow to rapid most grow much faster, spreading locally & to distant site ( metastasizing) & causing death - The rate of growth of malignant tumors correlates in general with their level of differentiation. - the notion that they emerge out of the blue is not true C. Local Invasion Benign Tumors - remains localized at its site of origin - does not have the capacity to infiltrate, invade, or metastasize to distant sites - most develop an enclosing capsule that separates them from host tissue - not all benign neoplasms are encapsulated Malignant Tumors - grow by progressive infiltration, invasion, destruction, and penetration of the surrounding tissue - do not develop well- defined capsule - microscopic examination reveals tiny, crablike feet penetrating the margin & infiltrating adjacent structures - next to the development of metastases, local invasiveness is the most reliable feature that distinguishes malignant from benign tumors D. Metastasis - connotes the development of secondary implants(metastases) discontinuous with the primary tumor possibly in remote tissues - unequivocally identify a neoplasm as malignant - not all cancers have equivalent ability to metastasize Examples are basal carcinoma of the skin & most primar tumors of the CNS(highly invasive in their primary sites of origin but rarely metastasize.) - generally the more anaplastic & the larger the primary neoplasm, the more likely is metastatic spread but exceptions abound CHARACTERISTICS OF BENIGN & MALIGNANT NEOPLASMS A. Differentiation and Anaplasia refer only to the parenchymal cells that constitute the transformed elements of neoplasms. The differentiation of parenchymal cells refers to the extent to which they resemble their normal forebears morphologically and functionally. The stroma carrying the blood supply is crucial to the growth of tumors but does not aid in the separation of benign from malignant ones. The amount of stromal connective tissue does determine, however, the consistency of a neoplasm ** Anaplasia refers to a reversion of differentiation in cells and is characteristic of malignant neoplasms(tumors). Sometimes, the term also includes an increased capacity for multiplication. [1]Lack of differentiation is considered a hallmark of aggressive malignancies. The term anaplasia literally means "to form backward Benign neoplasms composed of well-differentiated cells closely resembling their normal counterparts mitoses are extremely scant in number and are of normal configuration. Malignant neoplasms are characterized by a wide range of cell differentiation, from well differentiated to completely undifferentiated.. Anaplasia (lack of differentiation) is a hallmark of malignancy. The cells: display pleomorphism (marked variation in size & shape) nuclei are hyperchromatic & large, variable & bizarre in size & shape nuclear-cytoplasmic ratio may approach 1:1 ( normal is 1:4 or 1:6) chromatin is coarse & clumped & nucleeoli may be astounding size mitoses are often numerous & atypical DYSPLASIA, a term used to describe disorderly but nonneoplastic proliferation. loss in the uniformity of individual cells and in their architectural orientation When dysplastic changes are marked and involve the entire thickness of the epithelium, the lesion is referred to as carcinoma in situ, a pre-invasive stage of cancer Although dysplastic changes are often found adjacent to foci of malignant transformation, and long-term studies of cigarette smokers show that epithelial dysplasia almost invariably antedates the appearance of cancer, the term dysplasia without qualifications does not indicate cancer, and dysplasias do not necessarily progress to cancer B. Rate of Growth Benign tumors -it is generally true that most benign tumors increase in size slowly over the span of months to years MODES OF SPREAD OF MALIGNANT NEOPLASMS Seeding within body cavities occurs when neoplasms invade a natural body cavity is particularly characteristic of cancers of the ovary, which often cover the peritoneal surfaces widely. Here is an instance of the ability to reimplant elsewhere that seems to be separable from the capacity to invade. Lymphatic spread More typical of carcinomas pattern of lymph node involvement depends principally on the site of the primary neoplasm and the natural pathways of lymphatic drainage of the site Neoplastic cells are conducted to lymph nodes where they become trapped & set up secondary tumors e.g. * breast cancer spreading to lymph nodes in the axilla * carcinoma of the tongue spreading to lymph nodes in the neck A "sentinal lymph node" is defined as the first lymph node in a regional lymphatic basin that receives lymph flow from a primary tumor It can be delineated by injection of blue dyes or radiolabelled tracers. Biopsy of sentinal lymph nodes allows determination of the extent of spread of tumor, and can be used to plan treatment. Hematogenous spread or vascular spread Most feared consequence of a cancer Favored pathway for sarcomas but carcinomas use it as well arteries are penetrated less readily than are veins With venous invasion, the blood-borne cells follow the venous flow draining the site of the neoplasm, with tumor cells often stopping in the first capillary bed they encounter All portal area drainage flows to the liver, All caval blood flows to the lungs(the most frequently involved secondary sites) EPIDEMIOLOGY o Cancer Incidence Overall, it is estimated that about 1.4 million new cancer cases will occur in 2006, and 565,000 people will die of cancer in the United States Geographic and Environmental Factors 65% of common cancers are due to environmental causes

26% to 42% - heritable factors Geography Death rates breast cancer fourfold to fivefold higher in the USA & Europe compared with Japan stomach carcinoma 7 times higher in Japan than in USA Liver carcinoma is infrequent in the US but is the most lethal in Africa (natives) Environmental influences workplace food personal practices like cigarette smoking, chronic alcohol consumption, age at first intercourse and number of sex partners Frequency of cancer increases with age due to the accumulation of somatic mutations associated with the emergence of cancer decline in immune competence that accompanies aging Most cancer mortality occurs between ages 55 & 75 years Rate declines after age 75 Cancer causes more than 10% of all deaths among children younger than 15 years major lethal cancers in children are leukemia, tumors of the CNS, lymphomas, soft tissue sarcomas and bone sarcomas

Age

e.g. xeroderma pigmentosum DNA repair is defective 5% to 10% of all human cancers fall into one ofthe three categories ACQUIRED PRENEOPLASTIC DISORDERS - clinical conditions which are predisposed to develop malignant neoplasia o Persistent regenerative cell replication ( e.g. squamous cell carcinoma in the margins of a chronic skin fistula or in a long-unhealed skin wound; hepatocellular carcinoma in cirrhosis of the liver) o Hyperplastic & dysplastic proliferations ( e.g. Endometrialcarcinoma in atypical endometrial hyperplasia; bronchogenic carcinoma in the dysplastic bronchial mucosa of habitual cigarette smokers) o Chronic atrophic gastritis ( e.g. gastric carcinoma in pernicious anemia) o Chronic ulcerative colitis ( e.g. an increased incidence of colorectal carcinoma in long-standing disease) o Leukoplakia of the oral cavity, vulva, or penis (e.g., increased risk of squamous cell carcinoma) o Villous adenomas of the colon (e.g., high risk of transformation to colorectal carcinoma) ETIOLOGY OF CANCER: CARCINOGENIC AGENTS Chemicals Radiant energy Microbial agents Chemical Carcinogens DIRECT ACTING AGENTS require no metabolic conversion to become carcinogenic e.g. Alkylating agents Anticancer drugs (cyclophosphamide, chlorambucil) for leukemia, lymphoma, Hodgkin disease & ovarian carcinoma later form a second cancer usually leukemia INDIRECT-ACTING AGENTS - refers to chemicals that require metabolic conversion before they become active Radiation Carcinogenesis Radiation is an established carcinogen Sources: UV rays of sunlight, x-rays, nuclear fission, radionuclides Examples Pioneers of roentgen x-rays developed skin cancers Miners of radioactive elements have suffered increased incidence of lung cancer Increased incidence of leukemia after a latent period of 7 years in survivors of atomic bombs dropped in Hiroshima & Nagasaki High cancer incidence in the surrounding areas of Chernobyl in Russia as a result of nuclear power accident Therapeutic irradiation like the development of papillary thyroid cancers in 9% of individuals exposed during infancy & childhood to head & neck irradiation Radiation is oncogenic The effect of ionizing radiation is related to its mutagenic effects: it causes chromosome breakage, translocations less frequently point mutations Natural UV radiation derived from the sun can cause skin cancers (melanomas, squamos cell carcinomas & basal cell carcinomas) Cancers of the exposed skin are common in Australia & New Zealand Nonmelanoma skin cancers are associated with total cumulative exposure to UV radiation, whereas melanomas are associated with intense intermittent exposure as with sunbathing UV light has biologic effects on the cells like the ability to damage DNA by forming pyrimidine dimers DNA damage is repaired by a complex set of proteins that effect nucleotide excision repair UV light causes mutations in the TP53 gene

Mortality rate of lung cancer has been shown to be 4 times greater among non-smoking relatives (parents & siblings) of lung cancer patients than among nonsmoking relatives of controls THREE CATEGORIES OF HEREDITARY FORMS OF CANCER 1. Inherited Cancer Syndromes - inheritance of a single mutant gene greatly increases the risk of a persons developing a tumor. e.g. Retinoblastoma - (Rb) is a rapidly developing cancer that develops in the cells of retina, the light-detecting tissue of the eye 40% are familial carriers of the gene have a 10,000 fold increased risk of developing retinoblastoma (bilateral) Increased risk of developing second cancer particularly osteogenic sarcoma Cancer suppressor gene implicated in thepathogenesis of this tumor e.g. Familial Adenomatous polyposis of the colon individuals who inherit the gene will have innumerable polypoid adenomas of the colon at birth or soon thereafter 100% of patients develop carcinoma of the colon by age 50 Associated with specific marker phenotype e.g. presence of multiple benign tumors in familial polyposis & multiple endocrine neoplasia 2. Familial Cancers e.g. carcinomas of colon, breast, ovary & brain Features that characterize familial cancers early age at onset tumors arising in two or more close relatives sometimes multiple or bilateral tumors Familial cancers are not associated with specific marker phenotypes e.g. familial colonic cancers do not arise in preexisting benign polyps Transmission pattern is not clear Certain familial cancers can be linked to the inheritance of mutant genes 3. Autosomal Recessive Syndromes of Defective DNA Repair Autosomal recessive disorder is characterized by DNA or chromosomal instability

Heredity

Three other disorders of DNA repair & genomic instability that are characterized by an increased risk of cancer: 1) ataxiatelangiectasia 2) Fanconi anemia 3) Bloom syndrome Viral and Microbial Oncogenesis RNA ONCOGENIC VIRUSES Human T-Cell Leukemia Virus Type 1 (HTLV-1) associated with a form of T-cell leukemia/lymphoma that is endemic in certain parts of Japan & the Carribean basin human infection requires transmission of infected T cells via sexual intercourse, blood products or breast feeding Leukemia develops in only 1% of infected individuals after a latent period of 20-30 years DNA ONCOGENIC VIRUSES Human Papilloma Virus (HPV) Types 1, 2, 4 & 7 cause benign squamos papillomas (warts) in humans Has been implicated in the genesis of squamos cell carcinoma of the cervix, anal, perianal, vulvar and penile cancer 20% of oropharyngeal cancers are HPVassociated Types 16 & 18 are found in 75% to 100% invasive squamos cell cancers Genital warts with low malignant potential are associated with HPV-6 and HPV-11 Infection with high-risk HPV simulates the loss of tumor suppressor genes, activates cyclins, inhibits apoptosis & combats cellular senescence Infection with HPV itself is not sufficient for carcinogenesis Epstein-Barr Virus (EBV) Has been implicated in the pathogenesis of : Burkitt lymphoma which is endemic in certain part of Africa Post-transplant lymphoproliferative disease primary CNS lymphoma in AIDS patients a subset of Hodgkin lymphoma nasopharyngeal carcinoma which is endemic inSouthern China Hepatitis B Virus (HBV) Strongly linked to hepatocellular carcinoma likeHepatitis C virus (HCV) which is not a DNA virus Mechanism of HBV-related cancer chronic liver cell injury and regeneration predisposes cells to mutation disruption of normal growth of liver cells secondary arrangement of chromosomes HELICOBACTER PYLORI causes peptic ulcer, gastric lymphoma and gastric carcinoma Gastric lymphomas o B-cell in origin o called MALTomas (marginal zone associated lymphomas) o Pathogenesis- initial chronic gastritis that causes lymphoid follicles to develop in the gastric mucosa Gastric carcinoma o Pathogenesis initial development of chroni gastritis, followed by gastric atrophy, intestinal metaplasia of the lining cells, dysplasia & cancer

CLINICAL ASPECTS

Takes decades to complete & occurs in only 3% of infected patients Patients with duodenal ulcers almost never develop gastric carcinoma OF NEOPLASIA

Effects of Tumor on Host Location & impingement on adjacent structures A small (1-cm) pituitary adenoma can compress & destroy the surrounding normal gland & give rise to hypopituitarism A 0.5-cm leiomyoma in the wall of renal artery may lead to renal ischemia & hypertension Small carcinoma within a common bile duct may induce fatal biliary tract obstruction Functional activity ( Hormone Synthesis) seen in benign & malignant neoplasms arising in endocrine glands adenomas & carcinomas arising in the cells of the islets of the pancreas often produce hyperinsulinism, sometimes fatal Production of bleeding & secondary infections when the lesion ulcerates through adjacent surfaces tumor that protrudes into the gut lumen may lead to ulceration & obstruction CANCER CACHEXIA A wasting syndrome where there is progressive loss of body fat and lean body mass accompanied by profound weakness anorexia and anemia There is in general some correlation between the size & extent of spread of the cancer & the severity of the cachexia Small, localized cancers are generally silent & produce no cachexia PARANEOPLASTIC SYNDROMES These are symptom complexes that occur in patients with cancer & that can not be readily explained by local or distant spread of the tumor or by the elaboration of hormones indigenous to the tissue of origin of the tumor Appear in 10% to 15% of patients with cancer Example- Clinical Syndrome Underlying Cancer hypercalcemia breast carcinoma

renal carcinoma Three classes of normal regulatory genes are the principa targets of genetic damage: 1) growth- promoting protooncogenes 2) growth-inhibiting cancer suppressor genes (antioncogenes) 3) genes that regulate programmed cell death Oncogenes which are the mutant alleles of protooncogenes are dominant because they transform cells despite the presence of their normal counterpart th 4 category - genes that regulate repair of damaged DNA which are pertinent in carcinogenesis DNA repair genes affect cell proliferation or survival indirectly by influencing the ability of the organism to repair nonlethal damage in other genes A disability in the DNA repair genes can predispose to widespread mutations Carcinogenesis is a multistep process at both the phenotypic and the genetic levels

The phenotypic attributes of a malignant neoplasm which are acquired in a stepwise fashion are: excessive growth, local invasiveness & the ability to form distant metastases. This phenomenon is called tumor progression. At the molecular level progression results from the accumulation of genetic lesions which are favored by defects in DNA repair. Cancer cells bypass the normal process of aging which limits cell division. Examples of cancer associated genes 1. P53 tumor suppressor gene one of the most commonly mutated genes in human cancers guardian of the genome- assists in DNA repair regulates apoptosis 2. RB gene loss of this gene is a common event in breast cancer, small cell cancer of the lung & bladder cancer 3. ADENOMATOUS POLYPOSIS COLI (APC) gene exerts antiproliferative effects loss of this is common in colon cancer Grading and Staging of Cancer Grading attempts to establish some of cancers estimate aggressiveness or level of malignancy based on the: cytologic differentiation of tumor cells number of mitoses within the tumor degree of variability in cellular shape & size The cancer may be classified as grade I, II, III or IV in order of increasing anaplasia Broders Classification- one of of CA Differentiaated Cells Grade I 100 75% Grade II 75 - 50% Grade III 50 25% Grade IV 25 0% the most widely used grading system Undifferentiated Cells 0 25% well differentiated 25- 50% medium differentiation 50-75% poorly differentiated 75-100%

Prostate-specifc antigen (PSA) in metastatic deposits indicate definitive diagnosis of a primary tumor in the prostate Estrogen receptors & HER-2 (neu) indicate breast cancers Flow cytometry Used routinely in the classification of leukemias and lymphomas Useful in assessing DNA content of the tumor cells BIOCHEMICAL ASSAYS For tumor- associated enzymes, hormones and other tumor markers in the blood Prostatic carcinoma can be suspected when elevated levels of PSA are found in the blood Benign prostatic hyperplasia may have an elevated PSA levels Elevations in PSA are not diagnostic of cancer

Staging of cancers is based on the size of the primary lesion its extent of spread to regional lymph nodes the presence or absence of metastases Staging is usually based on clinical and radiographic examination (computed tomography and magnetic resonance imaging) & in some cases surgical exploration. Compared with grading, staging has proved to be of greater clinical value Two Methods of Staging 1. TNM system (T, primary tumor; N, regional lymph node involvement; M, metastases) 1. AJC (American Joint Committee) Cancers are divided into stages 0 to IV, incorporating the size of primary lesions & the presence of nodal spread & of distant metastases TNM System T1, T2, T3 and T4 describe the increasing size of the primary lesion N0, N1, N2 and N3 indicate progressively advancing node involvement M0 and M1 reflect the absence and presence of distant metastases Example of TNM method of breast cancer staging: T0= breast free of tumor N0= no axillary nodes involved T1= local lesion <2 cm in size N1= mobile nodes involved T2= lesion 2-5 cm in diameter N2=fixed nodes involved T3= lesion >5 cm in diameter N3=ipsilateral internal T4= skin &/or chest wall mammary node involved involved M0 = no metastases M1 = demonstrable metastases MX = suspected metastases Cytologic (Papanicolaou) smears Used widely for the discovery of carcinoma of the cervix Used also with other forms of suspected malignancy like endometrial carcinoma, bronchogenic carcinoma bladder & prostate tumors & gastric carcinomas For identification of tumor cells in abnominal, pleural, joint & cerebrospinal fluids Immunocytochemistry Powerful adjunct to routine histology

Cancers Seven Warning Signals 1. 2. 3. 4. 5. 6. 7. 8. 9. Change in bowel or bladder habits A sore throat that does not heal Unusual bleeding or discharge Thickening or lump in the breast or elsewhere Indigestion or difficulty in swallowing Obvious change in wart or mole Nagging cough or hoarseness of voice Unexplained anemia or paleness Sudden unexplained weight loss