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Neoplasia Neoplasia

Dr suvarna nalapat



Definition

• Neoplasia is new, uncontrolled growth; a"tumor" or "mass lesion" is simply a "growth"or "enlargement" which may not be neoplastic

(such as a granuloma). The term "cancer"implies malignancy, but neoplasms can besubclassified as either benign or malignant.

• Sir rupert willis”neoplasm is an abnormalmass of tissue ,the growth of which exceeds

and is uncoordinated with that of normal tissueand persists after cessation of the stimuli”



Normal vs neoplastic cells

Autonomous –independent of growth factors and

regulatory mechanisms

Excessive-

Disorganised-

Key words-tumour (swelling)-benign ,malignant

Cancer-malignant tumour

Oncology oncos-greek for the latin tumour-thescince dealing with study of tumours.



Benign Neoplasms• slow growth, resemblance to tissue of origin (well

differentiated), circumscription, lack of invasion or metastases.

• solitary (e.g., lipoma of colon, meningioma of dura), but may be multiple (e.g., leiomyomata of uterus,intradermal nevi on skin). cause problems through mass

effect, particularly in tight quarters (pituitary adenomain sella turcica).

• hamartoma benign ,localized but haphazard growth of tissues normally found at a given site (pulmonaryhamartoma has jumbled cartilage, bronchial epithelium,and connective tissue).another eg a mole

• choristoma benign tissue not normal to the site of origin(e.g., salivary gland choristoma of the middleear,pancreatic choristoma in stomach or liver,ectopic brain tissue in nasal cavity.



Malignant Neoplasms

• rapid increase in size, lack of differentiation(anaplasia), tendency to spread by invasion or metastases.

• Cytologic features of malignant neoplasms increasednuclear size (with increased nuclear/cytoplasmic ratio-- N/C ratio).

• variation in nuclear or cell size (pleomorphism).

• lack of differentiation (anaplasia).

• increased nuclear DNA content with subsequent dark staining on H and E slides (hyperchromatism).

• prominent nucleoli within the nuclei.• mitoses (especially irregular or bizarre mitoses).

• All of these features are "atypical". Atypia implies achange for the worse from normal.



Spread of Malignant

Neoplasms

By direct extension (invasion) into surrounding

tissues.

Through lymph channels to lymph nodes

(lymphatic spread)--typical of carcinomas.

Via the bloodstream (hematogenous spread)--

typical of carcinomas or sarcomas.

Within body cavities (seeding)--typical of

neoplasms in peritoneal cavity



The spread of malignant

neoplasms determines the

stage

In-situ (refers to epithelial malignancies

confined to just the epithelium withoutgoing throug the basement membrane).

Microinvasion (spread of epithelial

malignancies just beyond the point of

origin through the basement membrane).



Local invasion (spread

within the organ of originor to contiguous

structures).

Local metastases (non-

contiguous spread of the

neoplasm within the organof origin or to the lymph

nodes closest to the organ

of origin).

Distant metastases (spread

to other organs or to far

away lymph nodes)

•



The indicators that a neoplasm is

malignant are:

Metastases (best indicator) and Invasion (next best indicator



Grading of neoplasms

• Based upon: differentiation (the degree to which theneoplasm resembles the tissue of origin) along withthe degree of atypia.

• well-differentiated--looks very similar to normal tissue

• moderately differentiated--looks something likenormal

• poorly differentiated--hardly looks like normal tissue

• anaplastic--virtually no similarity to normal tissue

• Both staging and grading schemes are devised toclassify malignant neoplasms for determiningappropriate treatment and to try and determine the prognosis. In general, the higher the stage or thehigher the grade, the worse the prognosis.



Appearances of Neoplasms

• Desmoplasia the proliferation of non-neoplasticconnective tissue in association with neoplasia (givestumors a firm, fibrous, "scirrhous" appearance) andmay distort surrounding tissues.

• Neoplasms mimic tissue of origin, but not always.Larger masses tend to undergo central necrosis.

Metastases usually look similar to primary, but notalways.

• primary site is ususally a single large mass in anorgan, while multiple masses in an organ usuallyindicate metastases.

• It is not always possible to tell benign from malignant based upon histologic or cytologic criteria alone. biologic behavior of neoplasm may not alwayscorrelate with appearance, making choice of treatmentmore difficult.



• The process of

neoplasia is

represented

symbolically

•Oncogenesis



Nomenclature of Neoplasia

• Based upon origin:

• Maligant neoplasms arising from tissueembryologically derived from ectoderm or

endoderm are usually carcinomas. Examplesinclude:

• Squamous cell carcinoma of cervix

• Adenocarcinoma of stomach

• Hepatocellular carcinoma• Renal cell carcinoma



Malignancies arising from mesoderm are

usually sarcomas. Examples include:

Leiomyosarcoma

Chondrosarcoma

Osteosarcoma

Liposarcoma



• Neoplasms with more than one cell type but

arising from only one germ layer are called

"mixed tumors". The best example is the

benign mixed tumor (also called pleomorphicadenoma) of salivary gland.

• Neoplasms with more than one cell type and

arising from more than one germ layer are

called teratomas. Such neoplasms are commonin the ovary.



Neoplasms ending in "-

blastoma"• resemble primitive embryonic tissues:

• Retinoblastoma

• Neuroblastoma• Hepatoblastoma

• Medulloblastoma



Not all malignant neoplasms have benigncounterparts:

Hematopoietic and lymphoid cells (as in bone

marrow and lymph node) give rise to leukemiasand lymphomas. They have no benigncounterpart.

Gliomas (astrocytomas, oligodengrogliomas,glioblastoma multiforme, etc) arise from glialcells in the CNS. They have no benigncounterpart



Carcinomas

• Arise from epithelial surfaces (in gastrointestinal tract,in respiratory tract, in urogenital tract, in biliary tract,in skin) and in organs with epithelial-lined ducts(breast, pancreas, salivary gland, liver). Endocrine

glands, including testis and ovary, may also give riseto carcinomas. In general, carcinomas are composedof polygonal-shaped cells.

• Carcinomas that form glandular configurations arecalled adenocarcinomas.

• Carcinomas that form solid nests of cells with distinct borders, intercellular bridges, and pink keratinizedcytoplasm are called squamous cell carcinomas.



Sarcomas

• Arise from soft tissues (connective tissues

such as cartilage, bone, or fascia, smooth or

skeletal muscle, blood vessels, lymph vessels,

coverings of organs such as mesothelium). Ingeneral, sarcomas are composed of very

pleomorphic spindle-shaped cells. Sarcomas

are generally big and bad.



Biology of Neoplasia

• This subject attempts to determine what gives

rise to neoplasms and what controls their

growth.

Causes of Neoplasia

• The origin for many neoplasms is obscure.

However, there are several theories of origin



Environmental causes:

• Chemicals (aniline dyes and bladder cancer), drugs(cigarette smoke and lung cancer), and naturalcompounds (aflatoxins and liver cancer) carcinogenic.

• Oncogenic viruses human papillomavirus (HPV)implicated in most squamous cell carcinomas of cervix and anogenital squamous papillomas, Epstein-Barr virus (EBV) implicated in African Burkitt'slymphoma, and hepatitis B virus (HBV) implicated indevelopment of hepatocellular carcinomas.

• Radiation (such as ultraviolet light and skin cancers;gamma radiation and leukemia, thyroid, lung, colon,and breast cancers). Ultraviolet light induces pyrimidine dimers in DNA. Ionizing radiation inducesmutations in DNA



Hereditary causes:

• Chromosomes which have absent or defective anti-

oncogenes that control growth (retinoblastoma results

from defective chromosome 13)• Obscure defects: racial predilections (American

women have breast cancer more often than Japanese

women; Japanese men have stomach cancer far more

often than American men).

• Age: older persons have a greater propensity todevelop neoplasms from lack of effective control

mechanisms.



Altered DNA:

• All the above mediated by the cause, producing a

mutation in, or damage to, cell DNA

• mutations involving tumor suppressor genes (such as

p53),. The majority of human neoplasms probablyarise via this mechanism.

• In some cases these mutations are probably mediated

by proto-oncogenes (genes which control cellular

growth) that undergo mutation to oncogenes which

give rise to neoplasia. Proto-oncogenes can beactivated by point mutations, translocations, and by

gene amplification



• An example of this is chronic myelogenous leukemia

(CML) which is a neoplastic proliferation of white

blood cells. All cases of CML have the "Philadelphia

chromosome" which is a translocation betweenchromosomes 9 and 22. This translocation juxtaposes

the proto-oncogene ABL with the breakpoint cluster

region (BCR) on chromosome 22. The chimeric ABL-

BCR gene leads to production of a mutant protein with

enhanced tyrosine kinase activity. This protein may

play a role in regulation of cell growth in CML.



• About 15 to 20% of human cancers have been linkedto oncogenic activity. The ras oncogene is thetransforming gene found most frequently in humancancers.

• Oncogenic viruses may bring oncogenes with them,so-called viral oncogenes (typical of RNA containing"retroviruses" such as human T-lymphotropic viruses(HTLV's).

• Growth factors such as epidermal growth factor

(EGF), platelet-derived growth factor (PDGF) andcolony-stimulating factor-1 (CSF-1) assist oncogeneactivity. Transforming growth factor (TGF-alpha) also promotes tumor growth.



Tissue evidence of

carcinogenic factors at work Metaplasia: an initial change from normal cells to

a different cell type (such as chronic irritation of cigarette smoke causing ciliated pseudostratified

epithelium to be replaced by squamousepithelium more able to withstand the insult

Dysplasia: an increasing degree of disorderedgrowth or maturation of the tissue (often thoughtto precede neoplasia) such as cervical dysplasia

as a result of human papillomavirus infection.Dysplasia is still a reversible process. However,once the transformation to neoplasia has beenmade, the process is not reversible



Metaplasia - dysplasia -

Neoplasia. best evidenced inuterine cervix and respiratory

tract



Chemical carcinogenesis

initiation and promotion

• initiating carcinogenic agent irreversibly damages cellDNA (mutagenic). Examples : alkylating agents likecyclophosphamide, polycyclic aromatic hydrocarbonslike epoxides found in smoked foods, aromatic amines

or azo dyes used in food coloring, aflatoxins in moldy peanuts, nitrosamines in pickled foods.

• promoting agent (may be the same as the carcinogen)then acts (reversibly) to cause proliferation of neoplastic cell clone, but there appears to be a "dose-

threshold" concentration of promoter below whichneoplasia will not occur. Examples of promotersinclude: hormones such as estrogen, drugs such asdiethylstibesterol, and chemicals such as cyclamatesused as sweeteners



Malignant neoplasms do not tend to arise from benign neoplasms (e.g., malignant melanomas donot come from benign nevi) though in some cases

such as adenomas of the colon, the appearance of the benign neoplasm is a step toward possiblemalignancy.

There are "pre-cancerous" conditions in whichmalignant neoplasia is more likely to occur (but

not in every case): liver cirrhosis, chroniculcerative colitis, atrophic gastritis, epidermalactinic keratosis, oral leukoplakia



Clonality

Neoplastic cells tend to be monoclonal, or similar in genetic makeup, indicating origin from atransformed cell. Non-neoplastic proliferations

(such as reactions to inflammation) have cellsthat are polyclonal in origin.

The concept of "tumor progression" holds thatsubclones may arise over time from the originalmalignant clone. These subclones may differ

from the original clone in characteristics such asinvasiveness, metastatic potential, and responseto therapy



Tumor Genetics

• Neoplasms have a greater tendency to

karyotypic abnormalities such as

translocations, deletions, and gene

amplifications (which are also activators of proto-oncogenes). Leukemias and lymphomas

are famous for this, as with the Philadelphia

(Ph1) chromosome of chronic myelogenous

leukemia and the t(8:14) translocation inBurkitt's lymphomas



Tumor growth

less differentiated a neoplasm, faster it grows.

cell cycle of neoplastic cells is not shortened,

rather the growth fraction of cells proliferating is

increased. This is offset by neoplastic cell death.Tumor growth is expressed as a "doubling time"

or the time to increase twice in volume (e.g.,

from 1 to 1.3 cm diameter). An aggressive

malignant neoplasm doubles in 1 to 3 months,while benign neoplasms double in years.



Some neoplastic growth is influenced by host

factors. Estrogenic hormones aid growth of

breast fibroadenomas or carcinomas and uterine

leiomyomas because the tumor cells havehormone receptors.

Growth is also dependent upon the ability of the

tumor to develop a blood supply. Factors secreted

by neoplastic cells promote angiogenesis andfibroblast proliferation.



Characteristics of

Transformed (Neoplastic)

Cells

Neoplastic cell growth is not inhibited by contactwith surrounding cells and is not dependent on

anchorage to a solid surface. Neoplastic cells may attain "immortality" or the

ability to keep dividing indefinitely.

They are discohesive and transplantable--favoring invasion and metastasis.

Tumor cells can bind to laminin and fibronectinin connective tissues, then secrete collagenases or

proteases, and then invade



Epidemiology of Neoplasia

• Neoplasms can be characterized by:

• Their incidence (how often they occur).

• Their death rate (how many deaths are caused

by them).• A neoplasm such as basal cell carcinoma of

the skin can be quite common, yet it almostnever kills the patient. On the other hand,gliomas of the brain are uncommon butvirtually always kill the patient. One in 5Americans dies of cancer.



Men Women

Prostate 317,000 Breast 184,000

Lung 112,000 Colon-rectum 82,000

Colon-rectum 68,000 Lung 78,000

Bladder 38,000 Endometrium 34,000

Lymphomas 35,000 Lymphomas 26,000

Incidence of Neoplasia

(estimated new cases for 1996 for malignant neoplasms in the U.S.)



Deaths from Neoplasia

(top death-causing malignant neoplasms in the U.S. estimated for 1996)

Men Women

Lung 94,000 Lung 64,000

Prostate 41,000 Breast 44,000

Colon-Rectum 27,000 Colon-Rectum 28,000

Pancreas 14,000 Ovary 15,000

Lymphomas 13,000 Pancreas 14,000



• These data indicate that some cancers such as prostate

and breast are more amenable to therapy than lung or

pancreas. Another measure of therapeutic

effectiveness is the so-called "5-year survival".

Treatments can be compared based upon who survived

the longest.

• The incidence of some tumors in the U.S. is increasing

(lung) while others are decreasing (stomach).

Environmental factors influence incidences fromlocation to location and race to race.



Important to remember:

• the incidence of cancer varies greatly with age.

Testicular cancers and Hodgkin's disease are

seen mostly in young adult males, while

prostate cancers are more frequent in older men. Of malignant neoplasms in children,

leukemias and brain tumors are most frequent.



Effects of neoplasia on the

body

Mass effect: impinging on a vital area (airway,nerve, blood vessel, hollow viscus) to obstruct or destroy it, or lead to infarction or infection.

Local destruction: invasion or lysis of epithelialsurfaces or vascular channels, leading toulceration, bleeding, and infection.

Cachexia: either caloric intake is decreased (lack of appetite or inability to eat) or the neoplasm

alters normal metabolism (tumor necrosis factor);cancers do not "eat" the calories themselves.



Functional activity: production of a hormone or substance that has an untoward effect. Many of these are so-called "paraneoplastic" syndromes

(such as an oat cell lung cancer secreting ACTHor a renal cell carcinoma secreting erythropoietinor an islet cell tumor producing insulin).

Hypercalcemia often accompanies cancers and isdue either to: (1) osteolysis from metastases to

bone or (2) production of parathormone-likesubstance (often in squamous cell carcinomas).



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