Autopsy & Neoplasm

8/6/2019 Autopsy & Neoplasm

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AUTOPSY - external examination after death- 2 main types:

A. CLINICAL AUTOPSY

Where the cause of death is known (or often incorrectly thought tobe known)

The examination is held to confirm the diagnosis (dx) & to discoverthe extent of the lesions, for academic interest, teaching &research purposes

B.MEDICO-LEGAL AUTOPSY

Whose function (fx) is to discover some/all of the ff facts:1) The identity of the body2) Cause of death3) The nature & # of injuries4) Time of death5) Presence of poison6) The expectation of duration of life for insurance purposes7) The interpretation of any other unnatural conditions,

including those associated w/ surgical/medical procedures

The performance of an autopsy should ideally be only carried out by apathologist

Poorly performed autopsy may be worse than no autopsy @ all

Most common faults: to read conclusions into some supposed findings that

are unjustified/inaccurate

- Most important points in autopsy:

Dead body must be definitely identified before autopsy

In suspicious death: the body should be photographed, examinethe body w/ clothing in place, examine any injury/stabwounds/gunshot wounds

For specimen collection: blood should be taken from the cut end of large vein, such as axillary/iliac, or from the distal end of the

jugular

• Heart/visceral blood should not be used for toxicology(maybe contaminated post mortem from thestomach/intestine)

• Urine-preferably by syringe from the exposed fundus of the bladder

• For toxicology: stomach contents, intestinal contents,liver kidney/brain

• For alcohol analysis: collected into a tube containing NaF(sodium fluoride), to inhibit microorganisms w/c caneither destroy/produce alcohol in vitro after the blood istaken

Internal examination must be complete & always include the brain.It is very bad practice only to examine the organs w/c the historysuggests might contain the fatal lesion

The materials needed for autopsy:

Scalpel w/ blade

Different knives: cartilage knife, rib knife, long knives

Hand saw/electric oscillating (orthopedic) saw Mayo type scissors

Forceps (toothed/untoothed)

Probes (blunt ended)

Wooden board

Different sizes of specimen bottle (plastic/glass)

Weighing scales

AUTOPSY DECORUM

Morgue should be kept clean & tidy, w/ instruments neatly put away

Respect the human dead body

Any specimen/s that are taken/borrowed from the morgue should have

permission from the pathologist & should be return after Wear the proper attire (lab gown, mask, gloves, etc)



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NEOPLASM

• Origin: literally means “new growth”“Tumors”, refers to the swelling noted in neoplasm“Oncos”, Greek word for tumor, & is the study of tumors/neoplasmCancer is the common term for all malignant tumors. Latin word is

“crab”.• Definition: a neoplasm is an abnormal mass of tissue, the growth of

w/c exceeds & is uncoordinated w/ that of normaltissues & persists in the same excessive manner aftercessation of the stimuli w/c evoked the change.

• Also: abnormal mass is purposelesspreys on the hostautonomous (however depends on the host for nutrition & vascularsupply)

• Nomenclature:a. Nomenclature is based on the parenchymal component of the neoplasm.b. Two (2) basic components of all tumors.

b.1. parenchyma: composed of the proliferating neoplasticcells.b.2. supporting stroma: made up of CT & blood vessels (BV)

e.g. Fibroadenoma

Parenchyma: proliferating ducts lined w/glandular epith

Stroma: fibrous CTc. Benign Tumors:

‘oma’ -suffix attached to the cell of origin-applied usually to mesenchymal cells

e.g. Fibroma – benign tumor from fibroblastsChondroma – from chondrocytes (cartilage)Osteoma – from osteoblasts

For epithelial tumors:

Adenoma : benign epithelial neoplasm that forms glandularpatternsPapillomas : benign epithelial neoplasms producing

micro/macroscopically visible finger-like projections fromepithelial projections.

Cystadenomas: those forming large cystic massesPapillary cystadenomas : tumors that produce papillary patterns that

protrude into cystic spacesPolyp : benign neoplasm producing visible projection above a

mucosal surface & projects, e.g. into gastric & coloniclumen.

Polypoid cancer : term from malignant polyps

d. Malignant Tumors

sarcomas : malignant tumors of mesenchymal origin

e.g. fibrosarcoma : for fibrous tissue cancerliposarcoma : for fatty tissue cancerleiomyosarcoma : for smooth muscle cancer

carcinomas : malignant neoplasms of epithelial cellorigin : derived from any of the 3 germ layers.

Adenocarcinomas: carcinomas w/ a glandular growth pattern.Squamous cell carcinoma: carcinoma producing recognizable squamous

cells arising in any epithelium of the body.e. Miscellaneous:

Teratomas : arise from totipotential parenchymal cell typesrepresentative of more than 1 germ layer, usually all 3.

These totipotential cells differentiate producing tissuesthat can be identified as skin, muscle, fat, gutepithelium, tooth structures, & any tissue of the body.

Dermoid cyst : cystic teratoma of the ovary w/c in the pcs. of differentiation create a cystic tumor lined by skinreplete w/ hair, sebaceous gland & tooth structures.

CHARACTERISTICS OF BENIGN & MALIGNANT NEOPLASMS

Comparisons : Benign vs. Malignant TumorsCHARS. BENIGN MALIGNANT

Differentiation

OrAnaplasia

Well differentiated Lack

of differentiation w/anaplasia

Structure typical of tissue of origin

Structure often atypical

Rate of Growth

Progressive & slow; may cometo stand still &/or a regress

Mitotic figures rare & normal

Erratic (slow to rapid)Mitotic figures numerous

& abnormal

Local invasion

Cohesive & expansiveWell demarcated massesDo not invade/infiltrate

surrounding tissues

Locally invasiveInfiltrate surrounding

normal tissue

Metastasis Absent Frequently present

1. Differentiation & Anaplasia: The terms differentiation & anaplasia apply to parenchymal cells of

neoplasms.

Differentiation: refers to the extent to w/c parenchymal cells resemblecomparable normal cells, both in morphology & in function.

Well differentiated tumors: composed of cells resemblingthe mature normal cells of tissue of origin of neoplasm.Chracteristic of most benign tumors.e.g. Leiomyoma – resemble mature smooth muscle

Poorly differentiated/undifferentiated tumors:-have primitive appearing cells-Malignant neoplasms range from well differentiated toundifferentiated.

Anaplasia/lack of differentiation is characteristic of undifferentiated cells. Anaplasia is the “hallmark” of malignant

transformation.



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Anaplasia: “to form backward”, implying a reversion from a highlevel of differentiation to a lower level.

Morphologic changes in anaplasia:

a. Pleomorphism – variation in size & shape of cells

b. Hyperchromasia – dark staining nucleic. Nuclear:Cytoplasmic ratio – 1:1

(normal is 1:4 or 1:6)d. increased mitoses, reflecting higher proliferative activity

of the parenchymal cells.(note: mitoses not always a sign of malignancy)e.g. Bone Marrow (BM)

e. tumor giant cell formation (do not confuse w/ Langhans orforeign body giant cells; in tumors g.c., there ishyperchromasia & large nuclei in relation to the giantcell)f. orientation of anaplastic cells is markedly disturbed,where the cells grow in disorganized pattern.

exception dysplasia – term used to describe disorderly but non-neoplastic proliferation. Encountered in epithelium.Dysplasia may progress to carcinoma/may notnecessarily progress to cancer.

2. Rate of Growth:

In general, the growth rate of tumors correlates w/ their level of differentiation, & thus most malignant tumors grow more rapidly than dobenign lesions

3. Local invasion:

Nearly all benign tumors grow as cohesive expansile masses, which remainlocalized to their site of origin & do not have the capacity to infiltrate,invade/metastasize to distinct sites.

The growth of cancers is accompanied by progressive infiltration, invasion& destruction of the surrounding tissue.

Next to metastases, invasiveness is the most reliable feature thatdifferentiates malignant from benign.

4. Metastasis:

Metastases are tumor implants not continuous w/ the primary tumor. Metastasis marks a tumor as malignant, because benign neoplasms do not

metastasize.

w/ few exceptions, all cancers can metastasize.

Invasiveness of cancers permits them to penetrate into BV, lymphatics &body cavities, providing opportunities for spread.

In general, the more aggressive, the more rapidly growing, the larger theneoplasm, the greater the likelihood for metastasis.

5. Pathways of Spread :a. direct seeding of body cavities

Peritoneal cavity – most often involved

Pleural, pericardial, subarachnoid, joint spaces

b. Lymphatic spread:

Most common pathway for the initial dissemination of carcinomas, & in some cases sarcomas.

The pattern of lymph node involvement follows thenatural routes of drainage.e.g. breast carcinomas – usually arises in the upperouter quadrants of the breast, & disseminate 1st toaxillary lymph nodes.

c. Hematogenous spread:

Most common pathway for spread of sarcomas, but in

some cases by carcinomas also. w/ venous invasion, the cancer cells follow the venous

flow, & the liver & lungs are the most frequentlyinvolved secondarily.

EPIDEMIOLOGY:1. Cancer incidence:

expressed by nat’l incidence & mortality rate.e.g. Cancer Incidence by site & sex:

Organ MaleDeath

Rate

Prostate 32% 13%Lung 16% 33%

Colon &rectum

12% 10%

Organ FemaleDeathRate

Breast 32% 18%Lung 13% 23%

Colon &rectum

13% 11%

2. Geographic & environmental factors:a. death rate of stomach carcinoma in both male & female is 7 to 8x

higher in Japan than in the US.b. skin cancer deaths (melanocarcinoma) are 6x more frequent in

New Zealand than in Iceland, probably attributable to differences insun exposure.

c. it is believed that these geographical differences are theconsequences of environmental influences.

e.g. death rate of stomach CA is higher in Japan than inmigrant Japanese to the USA. The death rate amongmigrant Japanese is higher than California whites. Thispoint strongly to environmental & cultural diff ratherthan genetic predisposition.

3. Age:a. age is an important influence on the likelihood of being afflicted w/

CA.b. most carcinomas occur in the later years of life (55 years & over)c. each group has its own predilection to certain forms of cancer.

e.g. 35 – 54 : Lung CA, most common typeBreast CA, most common cause of death

55 – 74 : Lung CA, most common type



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Lung CA ff by breast CA, the most commoncause of death

4. Hereditary: Table: Inherited Predisposition to CA:a. Inherited CA syndrome (autosomal dominant)

o inherited predisposition indicated by strong family historyof uncommon CA &/or asso. marker phenotype.e.g. Familial retinoblastoma

Familial adenomatous polyps of colon

b. Familial CA:o evident familial clustering of CA, but role of inherited

predisposition may not be clear in an individual case.e.g. Breast CA

Ovarian CAColon CA other than familial adenomatous

polyps

c. Autosomal recessive syndromes of Defective DNA Repair:e.g. Fanconi’s anemia

ACQUIRED PRENEOPLASTIC DISORDERS:1. “not to be born” is the only way of avoiding CA; to live is to incur the risk.

The risk is greater than average however, under may circumstances.

2. certain clinical conditions are also of importance.e.g. well defined asso. bet:o certain forms of endometrial hyperplasia & endometrial

CAo cervical dysplasia & cervical carcinoma

o bronchial metaplasia & dysplasia & bronchogeniccarcinoma

o liver cirrhosis & 80% of hepatocellular CA

3. Precancerous conditions (non-neoplastic disorders w/ well defined asso w/CA, w/c in majority of cases no malignant neoplasm emerges. It callsattention however to the increased risk.

Chronic atrophic gastritis of pernicious anemia

Solar keratosis of the skin

Chronic ulcerative colitis

Leukoplakia of the oral cavity, vulva & penis

FLOWCHART Depicts simplified Scheme of CA Pathogenesis

1. Oncogenes : are CA-causing genes, are derived from proto-oncogenes.2. Proto-oncogenes : cellular genes that promote normal growth &differentiation. These were 1st discovered as “passengers” w/inthe genome of acute transforming retroviruses, w/c cause rapidinduction of tumors in animals.

Proto-oncogenes become oncogenic by the ff:a. retroviral transduction (v-ons)b. or by influences that alter their behavior in situ,

thereby converting them into cellular oncogenes (c-oncs).

3. Oncoproteins : proteins encoded by oncogenes, w.c resemble normalproducts of proto-oncogenes, w/ the exception thatoncoproteins are devoid of important regulatoryelements & their production in the transformed cells does notdepend on the growth factors or other external signals forgrowth.

4. Principal targets of genetic damage:a. the growth-promoting proto-oncogenesb. the growth-inhibiting CA suppressor genes (anti-oncogenes)

BIOLOGY OF TUMOR GROWTH:

1. Natural history of most malignant tumors can be divided into 4 phases:a. malignant change in the target cell, referred to as transformationb. growth of transformed cellsc. local invasiond. distant metastases

2. Factors that influence tumor growth:a. kinetics of tumor cell growthb. tumor angiogenesisc. tumor progression & heterogeneity

CARCINOGENIC AGENTS:

Induce genetic damage & neoplastic transformation.

Acquired envi’talFactors: Inherited mutations

Chemical radiation (geneticfactors)

Viruses

Clonal expansion

Additional mutations (progression)

Heterogeneity

Mutations in the

genome of

somatic cells

Activation

of growth

promoting

oncogenes

Alterations

of genes

that

regulate

Inactivati

on of CA

suppress

or genes

Expression of altered gene products &

loss of regulatory gene products

Malignant Neoplasm



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1. Chemical carcinogens:a. Direct acting carcinogens:

Alkylating Agents:β-propiolactoneDimethyl sulfateDiepoxybutaneAnticancer drugs (cyclophosphamide, chlorambucil, nitoureas,etc)

Acylating Agents:

1-Acetyl-imidazoleDimethylcarbamylchloride

b. Procarcinogens that require metabolic activation:

Polycyclic & heterocyclic aromatic hydro-c: Benz(a)anthraceneBenzo(a)pyreneDibenz(a,h)anthracene3-methylcholanthrene7,12-Dimethylbenz(a)anthracene

Aromatic amines, amides, azo dyes2-naphthylamine (β-naphthylamine)Benzidine2-acetylaminofluoreneDimethylaminoazobenzene (butter yellow)

Natural plant & microbial productsAflatoxin B1Griseofulvin safroleCycasin betel nuts

OthersNitrosamine &amidesVinyl chloride, nickel, chromiumInsecticides, fungicidesPolychlorinated biphenyls

2. Radiation carcinogens:

Radiant energy (UVrays, ionizing radiation, particulate radiation) can

transform virtually all cell types in vitro & induce neoplasms in vivo in bothhumans & experimental animals.

a. UVrays from the sun:

UVA 320 to 400 nm

UVB 280 to 320 nm, responsible for induction of cutaneous

CAs

UVC 200 to 280 nm, a potent mutagens, is not significantbecause it is filtered out by the ozone shield around earth.

e.g. squamous cell CA, basal cell CA, melanocarcinoma

b. Ionizing radiation:

The ff are all carcinogenic:

EMRs (electromagnetic radiation like x-rays, gamma rays)

Electromagnetic particulate (α & β particles, protons, neutrons) Even therapeutic radiation

e.g. victims of A-bomb in Nagasaki & Hiroshima leading toleukemia & solid tumors radiation fallout in Marshall island

Frequency of CA incidence in decreasing order: LeukemiaCA of the thyroid (young patients)CA of the breast, lungs & salivary glands

3. Viral Carcinogens:

DNA ONCOGENIC Viruses:a. Human Papilloma virus:

Benign squamous papilloma (warts) in humans due toHPV types 1, 2, 4, & 7

85% of invasive squamous cell CA of cervix, due to HPVtypes 16 & 18 in majority of cases

Genital warts w/ low malignancy – HPV 6 & 11b. Epstein-Barr virus:

Member of the herpes family, implicated in the ff:b.1. African form of Burkitt’s lymphomab.2. B-cell lymphoma in the immunosuppressed

esp. after HIV infection & organ transplantation.b.3. some cases of Hodgkin’s dse.b.4. Nasopharyngeal carcinomas

c. Hepatitis B virus:close asso. w/ dev’t of Hepatocellular carcinoma.

PNA ONCOGENIC Viruses:a. HTLV – 1:

This is the only human retrovirus firmly implicated in the causation of CA.

Asso w/ T-cell leukemia/lymphoma in certain parts of Japan & Caribbean basin, &sporadically in USA.

Infection w/ HTLV – 1 infection of T lymphocytes in necessary for leukemogenesis.Leukemia: malignant neoplasm of T lymphocytes

TUMOR ANTIGENS:1 Tumor specific antigens (TSA) present on tumor cells & not on normal cells.

e.g. 40% of melanomas20% of breast carcinomas

30%, small cell CA of lungs

2 Tumor asso antigens (TAA): these are human tumor antigenspresent in both tumor & certain normal cells. 3 categories of TAAs:

a. TACAs (tumor asso carbohydrate antigens)b. Oncofetal antigens, or embryonic antigens

e.g. α-fetoproteincarcinoembryonic antigen

c. Differentiation antigens:

Peculiar to the differentiation state at w/c the CA cells arearrested.e.g. CD10 (CALLA Ag) w/c is an Ag expressed only be

lymphocytes, & is expressed in B-cell leukemias &lymphomas.

ANTITUMOR EFFECTOR MECHANISMS:1 Cytotoxic T lymphocytes

Express a TSAcalled melanoma

Ag – 1[ MAGE – 1 ]



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2 NK cells – lymphocytes capable of destroying tumor cells w/o priorsensitization. Provide the 1st line of defense against many tumors.3 Macrophages: this cell collaborate w/ T cells in antitumor reactivity,

because interferon gamma (IFN - γ ), a T cell derived cytokine, is a potentactivator of macrophages.4 Humoral mechanisms: participates in tumor cell destruction by 2mechanisms:

a. activation of complementb. induction of ADCC by NK cells

IMMUNOSURVEILLANCE:1 The strongest evidence for immunosurveillance is the increased incidenceof tumors in immunodeficient hosts.

Lymphomas: (B – cell lymphomas), most common form of CA inimmunocompromised hosts.

CLINICAL FEATURES OF TUMORS:1 Effects of tumors on hosts:

a. location & impingement on adjacent structuresb. functional activity such as hormone synthesisc. bleeding secondary to infections when they ulcerate through

adjacent natural surfacesd. initiation of acute symptoms caused either by rupture/infarctions.

2 Local & Hormonal effects: (not very common)e.g. pituitary adenoma – expansile growth of the tumor can destroy the

remaining pituitaryneoplasms in the GUT – cause obstructionbenign B cell adenoma of pancreatic islets – can produce sufficient

insulin to cause fatalhypoglycemia.

3 CA cachexia:a. patients w/ CA suffer progressive loss of body fat & lean body

mass accompanied by profound weakness, anorexia, & anemia. This wasting syndrome is called cachexia.4 Paraneoplastic syndromes:

Def: symptom complexes in CA bearing patients that cannot be readilyexplained, either by local/distant spread of the tumor/by theelaboration of hormones indigenous to the tissue from w/c the tumor

arose. Occur only in 10% of patients w/ advanced malignant dse. The ff are some ex.:

a. endocrinopathies (ectopic hormone production)e.g. Cushing’s syndrome – most common endocrinop.

b. hypercalcemia – most common paraneoplastic syndromec. neuromyopathic paraneoplastic syndromesd. acanthosis nigricans

Gray-black patches of verrucous hyperkeratosis on theskin. This lesion is asso in 50% of cases w/ some form of CA.

e. Clubbing of fingers & hypertrophic osteoarthropathy

Seen in 1-10% of px w/ bronchogenic carcinomas.

GRADING & STAGING OF TUMORS:

1 Grade: to express the differentiation of the tumor cells & the # of mitosisw/in the tumor as presumed evidence of the tumor’s aggressiveness.

2 Stage: the extent of spread of a CA w/in the pxStaging is based on the size of the primary lesion, its extent of

spread to regional lymph nodes & the presence/absence of bloodborne metastases.

3 2 major grading systems used:a. UICC (Union Internationale Contre CA)

TNM system: gen principle based on increasing sizes: T - for primary tumor T0 - in situ lesion T1 - T4 - based on increasing size

N - for regional lymph node involvementN0 - no nodal involvementN1 - N3 - denote involvement of increasing # &

range of nodes.

M - for metastasesM0 - no distant metastasesM1 - M2 - indicate blood borne metastases

b. AJC (American Joint Committee)

Divides CAs into stages 0 to IV, incorporating w/in each of thesestages the size of the primary lesion as well as the presence of nodal spread & distant metastases.

4 staging & grading of neoplasms has assumed importance in the selection of the best form of therapy for the patient.

LABORATORY DIAGNOSIS OF CA:

1 Histologic & cytologic methods:a. FNA – fine needle aspiration biopsyb. Papanicolau smears

2 Immunocytochemistry

Specific monoclonal antibodies to identify cell products/surfacemarkers for tumors.

a. Hormones:

a.1. HCG (trophoblastic tumors)a.2. calcitonin (medullary CA of thyroid)a.3. catecholamines & metabolitesa.4. ectopic hormones(paraneop syndromes)

b. Oncofetal antigens:b.1. α-fetoprotein Liver cell CAb.2. carcinoembryonic antigen CA of colon, breast,

pancreas, lung,stomach

c. Isoenzymes:c.1. prostatic acid phosphatase prost. CAc.2. neuron specif ic enolase small cell CA of lung

d. Specific proteinsd.1. immunoglobulins multiple myelomas



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d.2. prostate-specific antigen prostatic CA

3 Flow Cytometrycan rapidly & quantitatively measure several individual cell

characteristics, such as membrane antigens, & DNA content of tumorcells.

4 Tumor Markers:biochemical indicators of the presence of a tumor. They include

cell surface antigens, cytoplasmic proteins, enzymes & hormones. Tumor markers cannot be considered as primary modalities for the

diagnosis of CA.

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Autopsy & Neoplasm