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    Neoplasia

    Dr Suvarna Nalapat

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    Alterations in cell growth physiologic (normal responses to stimuli) or

    pathologic. alterations of cell growth are potentially reversible and include:

    Hypertrophy: increase in cell size. Increase inskeletal muscle fiber size is a physiologic responseto exercise, but the cardiac hypertrophy above is a

    pathologic response to abnormally elevated blood pressure.

    Hyperplasia: a increase in number of cells.Postpartum breast lobules undergo hyperplasia for lactation, endometrial hyperplasia in

    postmenopausal woman is abnormal

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    Growth disturbances

    increase in tissue size isnot necessarily neoplasia

    increase in the size of themyocardial fibers inresponse to an increased

    pressure load fromhypertension

    cells increase in size, butnot in number

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    large fronds of endometrium are a resultof hyperplasia. resultedfrom increased estrogen.With hyperplasia, there isincrease in cell numberscells are normal inappearance. Sometimeshyperplasias can be"atypical" and the cells not

    completely normal. Suchconditions can be premalignant.

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    cellular transformation.

    The two forms of cellular transformation that are potentially reversible, but may be steps toward aneoplasm, are

    metaplasia: the exchange of normal epithelium for another type of epithelium. Metaplasia isreversible when the stimulus for it is taken away.

    Dysplasia: a disordered growth and maturation of an epithelium, which is still reversible if thefactors driving it are eliminated

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    metaplasia of normalrespiratory laryngealepithelium on the rightto squamousepithelium on the leftin response to chronicirritation of smoking

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    biopsy of the lower esophagus in a patientwith chronicgastroesophageal refluxdisease shows columnar metaplasia (Barrett'sesophagus), and the gobletcells are typical of anintestinal type of epithelium. Squamous

    epithelium typical of thenormal esophagus appearsat the right

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    next step towardneoplasia. Here, there isnormal cervical squamousepithelium at the left, but

    dysplastic squamousepithelium at the right.Dysplasia is a disorderlygrowth of epithelium, butstill confined to the

    epithelium. Dysplasia isstill reversible

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    the normal cervicalsquamous epitheliumat the left merges intothe dysplasticsquamous epitheliumat the right in whichthe cells are moredisorderly.

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    Some epithelia areaccessible, such as thecervix, that cancer screening can be done bysampling some of the cells

    and sending them to thelaboratory. cervical Papsmear in which dysplasticcells are present that havelarger and darker nucleithan normal squamouscells with small nuclei andlarge amounts of cytoplasm

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    When entire epithelium isdysplastic and no normalepithelial cells are left, the

    process is beyonddysplasia and is neoplasia.If the basement membraneis still intact, as shownhere, then the process iscalled "carcinoma in situ"

    because the carcinoma is

    still confined to theepithelium.

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    This is a neoplasm. Neoplasia is uncontrollednew growth. Note mass of abnormal tissue on surfaceof cervix. term "tumor"used synonymously withneoplasm, but "tumor" canmean any mass effect,whether inflammatory,hemodynamic, or

    neoplastic. Once aneoplasm, it is notreversible.

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    microscopic appearanceof neoplasia, or uncontrolled newgrowth. Here, theneoplasm is infiltratinginto the underlyingcervical stroma. Of course, there can becarcinoma in situ inwhich a full-fledged

    neoplasm is present, buthas not yet invaded

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    squamous cellcarcinoma. Note thedisorderly growth of the squamousepithelial cells in theselarge nests with pink keratin in the centers

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    neoplasms can be benignas well as malignant,.Here is a benign lipomaon the serosal surface of

    the small intestine. It hasthe characteristics of a

    benign neoplasm: it is wellcircumscribed, slowgrowing, and resembles

    the tissue of origin (fat).

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    At low power magnification, a lipoma of the stomach is seen to bewell demarcated from themucosa at the lower center-right. Thisneoplasm is so well-differentiated that, exceptfor its appearance as alocalized mass, it is

    impossible to tell fromnormal adipose tissue

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    Here is the lipoma athigh magnification.This is a goodexample of how a

    benign neoplasmmimics the tissue of origin.

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    Benign neoplasms can bemultiple, leiomyomas of

    varying size, but all benign and well-

    circumscribed firm whitemasses. most commonneoplasm is a benign

    nevus (pigmented mole)of the skin, and most

    people have several. As a

    general rule, benignneoplasms do not give riseto malignant neoplasms.

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    microscopicappearance of aleiomyoma indicatesthat the cells do notvary greatly in sizeand shape and closelyresemble normalsmooth muscle cells.

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    Multiple adenomatous polyps of the cecumare seen here in a caseof familial polyposis

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    This schwannoma wasresected from a nerve.

    Note thecircumscribed nature

    of this benignneoplasm.

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    schwannoma is seenmicroscopically to becomposed of spindlecells (like most

    neoplasms of mesenchymal origin),

    but the cells are fairlyuniform and there is

    plenty of pink cytoplasm.

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    small fibroadenoma of the breast, a benign neoplasmmore commonly found inyounger women of

    reproductive age. The bluedye was injected during aradiographic procedure tomark the location of theneoplasm so the surgeon

    could find it.

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    the most commonneoplasm is a benignnevus (pigmented mole)of the skin, and most

    people have several, asseen here over the skin of the chest. As a generalrule, benign neoplasms donot give rise to malignant

    neoplasms

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    small hepatic adenoma, anuncommon benignneoplasm, but one thatshows how well-demarcated an benignneoplasm is. It alsoillustrates how function of the normal tissue ismaintained, because theadenoma is making bile

    pigment, giving it a greencolor.

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    In contrast, thishepatocellular carcinomais not as wellcircumscribed (note the

    infiltration of tumor off tothe lower right) nor asuniform in consistency. Itis also arising in acirrhotic (nodular) liver.

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    renal cell carcinomademonstrates distortionand displacement of therenal parenchyma by the

    tumor mass in the lower pole. This malignantneoplasm is variegated oncut surface, with yellow towhite to red to brown

    areas.

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    excision of skindemonstrates amalignant melanoma,which is much larger and more irregular than a benign nevus.

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    example of metastases tothe liver. Note that the tan-white masses are multipleand irregularly sized. Likemany large metastaticlesions, there is centralnecrosis. A primaryneoplasm is more likely to

    be a solitary mass. The presence of metastases arethe best indication that aneoplasm is malignant.

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    This abdominal CT scandemonstrates multiplevariegated mass lesions,some with dark central

    necrosis, in a patient withwidespread metastaticcarcinoma. A normal sizedspleen is seen at the lower left.

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    metastaticadenocarcinoma isseen in a lymph nodehere. It is common for

    carcinomas tometastasize to lymphnodes. The first nodesinvolved are thosedraining the site of the

    primary neoplasm

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    Both lymphatic andhematogenous spreadof malignantneoplasms is possibleto distant sites. Here, a

    breast carcinoma hasspread to a lymphaticin the lung.

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    chest radiographreveals the presence of multiple roundedmasses in all lungfields. These aremetastases.

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    Neoplasms can spread byseeding along bodycavities, and this pattern ismore typical for

    carcinomas than other neoplasms. Note themultitude of small tantumor nodules seen over the peritoneal surface of

    the mesentery shown here.

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    microscopic evidenceof the spread of a

    carcinoma via bodycavities. A focus of

    metastatic breastcarcinoma is present

    along the pleuraoverlying the lung.

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    small focus of metastaticcarcinoma to theepicardium .key feature of neoplasms--angiogenesis.

    Note the proliferation of many small capillariesadjacent to the neoplasticcells. Neoplasms can

    produce factors that promote vascular growthto provide a vascular supply and continueduncontrolled growt

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    Malignant neoplasmsare also characterized

    by the tendency toinvade surroundingtissues. Here, a lungcancer is seen to bespreading along the

    bronchi into the

    surrounding lung.

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    squamous cellcarcinoma of the lung.It is a bulky mass thatextends intosurrounding lung

    parenchyma.

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    chest CT scandemonstrates a largesquamous cell carcinomaof the right upper lobe that

    extends around the rightmain bronchus and alsoinvades into themediastinum and involveshilar lymph nodes.

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    infiltrating ductalcarcinoma of the breastsurrounding breast.centralwhite area is very hardand gritty, because theneoplasm is producing adesmoplastic reaction withlots of collagen. This isoften called a "scirrhous"appearance. There is alsofocal dystrophiccalcification leading to thegritty areas

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    the infiltrating ductalcarcinoma extendsirregularly through thetissue as cords and

    nests of neoplasticcells with interveningcollagen. There is a

    purplishmicrocalcification at

    the lower center right.

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    the infiltrating ductalcarcinoma of breasthas pleomorphic cellsinfiltrating through thestroma.

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    invadingadenocarcinoma can

    be seen here. Normalgastric epithelium at

    the left merges into thecarcinoma at the right,and irregular neoplastic glandsinfiltrate downward

    into the submucosa.

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    Branches of peripheralnerve are invaded bynests of malignantcells. This is oftenwhy pain associatedwith cancers isunrelenting

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    The concept of differentiation isdemonstrated by this smalladenomatous polyp of the

    colon. Note the differencein staining quality between the epithelialcells of the adenoma at thetop and the normalglandular epithelium of the colonic mucosa below.

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    normal colonic epitheliumat left contrasts withatypical epithelium of adenomatous polyp(tubular adenoma) at right.

    Nuclei darker moreirregularly sized closer

    together in theadenomatous polyp thanin normal mucosa. overalldifference between themis not great, so this benignneoplasm mimics normal

    tissue and is, well-differentiated.

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    colonoscopy of adenocarcinoma colon.

    bulky mass spreads over colonic mucosal surface. Ithas red areas because it is

    bleeding, and this led to positive occult blood instool (screening methodfor detection). Neoplasmsmay not maintain thestructure of normaltissues, there is irregular growth with necrosis and

    hemorrhage, in larger aggressive neoplasms.

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    The infiltrating glands of this colonicadenocarcinomademonstrate lessdifferentiation than theadenomatous polyp,although they stillresemble glands. Ingeneral, lessdifferentiation of aneoplasm means a greater likelihood of malignant

    behavior. This is the basisfor grading.

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    gastric adenocarcinoma is positive for cytokeratin byimmunoperoxidase.typical staining reactionfor carcinomas and helpsto distinguish carcinomas

    from sarcomas andlymphomas.Immunoperoxidasestaining helpful todetermine cell type of neoplasm when degree of

    differentiation, or morphology, does notallow exact classification

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    By electron microscopy,features of carcinoma

    seen. adenocarcinomademonstrates severalfeatures typical of neoplasm of epithelialorigin, including

    junctional complex (tight junction at the asterisk andthe desmosomes atcrosses). The mucingranule (M) and lumenalmicrovilli at upper rightalso typical for adenocarcinoma.

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    normal squamousepithelium at left mergesinto squamous cellcarcinoma at right,

    infiltrating downward.neoplastic squamous cellsare still similar to normalsquamous cells, but areless orderly. This is awell-differentiatedsquamous cell carcinoma.

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    a moderatelydifferentiated squamouscell carcinoma in whichsome, but not all, of the

    neoplastic cells in nestshave pink keratin. Ingeneral, neoplasms withless differentiation aremore aggressive.

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    At high magnification,

    squamous cell carcinomademonstrates enoughdifferentiation to tell thatcells are of squamousorigin. cells are pink and

    polygonal with

    intercellular bridges (seenas desmosomes or "tight

    junctions" by electronmicroscopy). neoplasticcells show pleomorphism,with hyperchromaticnuclei. A mitotic figure

    present near center.

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    Features of a carcinomaare seen in this electronmicrograph. Thissquamous cell carcinoma

    demonstrates manydesmosomes, along withcytoplasmic tonofilamentsstreaming to the left.

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    This neoplasm is so poorlydifferentiated that it isdifficult to tell what thecell of origin is. It is

    probably a carcinoma

    because of the polygonalnature of the cells. Notethat nucleoli are numerousand large in this neoplasm.

    Neoplasms with nodifferentiation are said to

    be anaplastic.

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    Neoplasia in the pediatricage range is not common.Childhood malignanciesare rare, but those that

    occur often have theappearance of primitive"small round blue celltumors" such as theneuroblastoma seen here

    Childh d li

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    Childhood Malignancy

    Leukemia

    Neuroblastoma

    Medulloblastoma

    Retinoblastoma

    Wilms tumor

    Ewing sarcoma

    Blood, marrow, lymphnodes Adrenal, extra-adrenal

    ganglia Cerebellum Eye

    Kidney

    bone

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    Aneuploidy by flow cytometry-ca breast

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    A mitotic figure in center,surrounded by poorly

    differentiated squamouscell carcinoma with pleomorphic cells thathave minimal pink keratinization incytoplasm., mitoses are

    more likely to be seen inmalignant neoplasms.Remember,, that normallycells are actively dividingin many tissues of body,including skin, bonemarrow, gonads, andgastrointestinal tract.

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    Here are three abnormalmitoses. Mitoses bythemselves are notindicators of malignancy.However, abnormal

    mitoses are highlyindicative of malignancy.The marked

    pleomorphism andhyperchromatism of surrounding cells alsofavors malignancy.

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    large fleshy mass inretroperitoneum Sarcomasarise from mesenchymaltissues. "malignant fibroushistiocytoma" awastebasket term for sarcomas that do notresemble striated muscle(rhabdomyosarcoma),

    smooth muscle(leiomyosarcoma), fat(liposarcoma), bloodvessels (angiosarcoma),

    bone (osteosarcoma),cartilage(chondrosarcoma).Sarcomas tend to be bigand bad.

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    computed tomographic(CT) scan of the abdomenat the level of the kidneysin which there is a largemass in theretroperitoneum that

    proved to be a sarcoma.The mass is just anterior to the right kidney andmedial to the right lower lobe of liver.

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    fleshy mass arising in thesoft tissues of the lower leg. The tibia and thefibula are seen in crosssection. This neoplasm

    proved to be a malignantfibrous histiocytoma.Sarcomas tend to invadelocally, as can be seenhere by the ill-definedmargins of the mass.

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    Sarcomas tend to havea spindle cell pattern.

    Note that some of thecells are much larger and very pleomorphic.

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    sarcoma seen at mediummagnification is composedof very pleomorphic cells.The cell of origin of sarcomas is often difficultto determine because of their tendency to be poorlydifferentiated or evenanaplastic.

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    magnetic resonanceimaging (MRI) scan of the left leg, with alarge sarcoma arising

    posterior to the knee,seen here at the levelof the lower femur.

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    Vimentin-infiltrating to normalmuscle is a sarcoma

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    liposarcoma

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    large bizarre lipoblasts

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    Paraneoplastic syndromes

    A paraneoplastic syndrome occurs when aneoplasm elaborates a substance that results in aneffect that is not directly related to growth,invasion, or metastasis. Most paraneoplasticsyndromes result from elaboration of hormone-like substances, but a variety of effects are

    possible. Sometimes the paraneoplastic syndromemay precede diagnosis of the neoplasm and may

    give a clue to its presence.

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    Syndrome

    Cushing's

    Mechanism

    ACTH-like

    Example

    Lung (oat

    Hypercalcemia

    Parathormone-like

    Lung(squamous

    Hyponatremia InappropriateADH

    Lung (oat

    Polycythemia Erythropoietin-like

    Renal cellcarcinoma

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    process of neoplasia begins with celltransformation. A variety of chemical carcinogensas diverse as benzene, cigarette smoke, and nitritescan initiate and/or promote this process. Radiation,either as low level long-term environmentalgamma rays or as higher dose therapeuticradiation, can also produce genetic mutations.Infectious agents such as human papillomavirus

    can lead to cellular transformation as well

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    Genetic damage with DNA alterations leads to point mutations of genes, translocations of geneticmaterial between chromosomes, and genereduplication with amplification. These alterationstransform proto-oncogenes into oncogenes. The

    proto-oncogenes may play a role in growth promotion and regulation in normal cells, perhapsin embryogenesis, but are typically "turned off" in

    adults. They are "turned on" by transformation.

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    or uncontrolled cellular proliferation, canresult either from mutations that "turn on"the oncogenes that stimulate growth, or

    from mutations that result in loss of tumor suppressor genes and their products thatinhibit growth.

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    Thank you