1

AUTOPSY - external examination after death - 2 main types: A. CLINICAL AUTOPSY Where the cause of death is known (or often incorrectly thought to be known) The examination is held to confirm the diagnosis (dx) & to discover the 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 body 2) Cause of death 3) The nature & # of injuries 4) Time of death 5) Presence of poison 6) The expectation of duration of life for insurance purposes 7) 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 a pathologist 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, examine the body w/ clothing in place, examine any injury/stab wounds/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 the stomach/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 can either destroy/produce alcohol in vitro after the blood is taken Internal examination must be complete & always include the brain. It is very bad practice only to examine the organs w/c the history suggests might contain the fatal lesion

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)

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

e.g.

fibrosarcoma : for fibrous tissue cancer liposarcoma : for fatty tissue cancer leiomyosarcoma : for smooth muscle cancer

NEOPLASM

Origin:

literally means new growth Tumors, refers to the swelling noted in neoplasm Oncos, Greek word for tumor, & is the study of tumors/neoplasm Cancer is the common term for all malignant tumors. Latin word is crab.

carcinomas : malignant neoplasms of epithelial cell origin : 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 types representative of more than 1 germ layer, usually all 3. These totipotential cells differentiate producing tissues that can be identified as skin, muscle, fat, gut epithelium, 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 skin replete w/ hair, sebaceous gland & tooth structures. CHARACTERISTICS OF BENIGN & MALIGNANT NEOPLASMS Comparisons CHARS. : Benign vs. Malignant Tumors BENIGN Well differentiated Structure typical of tissue of origin Progressive & slow; may come to stand still &/or a regress Mitotic figures rare & normal Cohesive & expansive Well demarcated masses Do not invade/infiltrate surrounding tissues Absent MALIGNANT Lack of differentiation w/ anaplasia Structure often atypical Erratic (slow to rapid) Mitotic figures numerous & abnormal Locally invasive Infiltrate surrounding normal tissue Frequently present cells of

Definition: a neoplasm is an abnormal mass of tissue, the growth of w/c exceeds & is uncoordinated w/ that of normal tissues & persists in the same excessive manner after cessation of the stimuli w/c evoked the change. Also: abnormal mass is purposeless preys on the host autonomous (however depends on the host for nutrition & vascular supply)

a. b.

c.

Nomenclature: Nomenclature is based on the parenchymal component of the neoplasm. Two (2) basic components of all tumors. b.1. parenchyma: composed of the proliferating neoplastic cells. b.2. supporting stroma: made up of CT & blood vessels (BV) e.g. Fibroadenoma Parenchyma: proliferating ducts lined w/ glandular epith Stroma: fibrous CT Benign Tumors: oma -suffix attached to the cell of origin -applied usually to mesenchymal cells e.g. Fibroma benign tumor from fibroblasts Chondroma from chondrocytes (cartilage) Osteoma from osteoblasts For epithelial tumors: Adenoma patterns Papillomas : benign epithelial neoplasm that forms glandular

Differentiation Or Anaplasia Rate of Growth Local invasion Metastasis 1.

: benign epithelial neoplasms producing micro/macroscopically visible finger-like projections from epithelial projections. Cystadenomas: those forming large cystic masses Papillary cystadenomas : tumors that produce papillary patterns that protrude into cystic spaces Polyp : benign neoplasm producing visible projection above a mucosal surface & projects, e.g. into gastric & colonic lumen. Polypoid cancer : term from malignant polyps d. Malignant Tumors sarcomas : malignant tumors of mesenchymal origin

Differentiation & Anaplasia: The terms differentiation & anaplasia apply to parenchymal neoplasms. Differentiation: comparable

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

Well differentiated tumors: composed of cells resembling the 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 to undifferentiated. Anaplasia/lack of differentiation is characteristic of undifferentiated cells. Anaplasia is the hallmark of malignant transformation.

Anaplasia: level of

to form backward, implying a reversion from a high differentiation to a lower level.

Morphologic changes in anaplasia: a. Pleomorphism variation in size & shape of cells b. Hyperchromasia dark staining nuclei c. 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 or foreign body giant cells; in tumors g.c., there is hyperchromasia & large nuclei in relation to the giant cell) f. orientation of anaplastic cells is markedly disturbed, where the cells grow in disorganized pattern. exception dysplasia term used to describe disorderly but nonneoplastic proliferation. Encountered in epithelium. Dysplasia may progress to carcinoma/may not necessarily progress to cancer.

Most common pathway for the initial dissemination of carcinomas, & in some cases sarcomas. The pattern of lymph node involvement follows the natural routes of drainage. e.g. breast carcinomas usually arises in the upper outer quadrants of the breast, & disseminate 1st to axillary 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 frequently involved secondarily.

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 do benign lesions Local invasion: Nearly all benign tumors grow as cohesive expansile masses, which remain localized 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 that differentiates malignant from benign. 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 the neoplasm, the greater the likelihood for metastasis. Pathways of Spread: a. direct seeding of body cavities Peritoneal cavity most often involved Pleural, pericardial, subarachnoid, joint spaces b. Lymphatic spread:

EPIDEMIOLOGY: 1. Cancer incidence: expressed by natl incidence & mortality rate. e.g. Cancer Incidence by site & sex: Death Organ Male Rate Prostate 32% 13% Lung 16% 33% Colon & 12% 10% rectum Organ Breast Lung Colon & rectum 2. Female 32% 13% 13% Death Rate 18% 23% 11%

3.

4. 5.

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 in sun exposure. c. it is believed that these geographical differences are the consequences of environmental influences. e.g. death rate of stomach CA is higher in Japan than in migrant Japanese to the USA. The death rate among migrant Japanese is higher than California whites. This point strongly to environmental & cultural diff rather than genetic predisposition. 3. CA. Age: a. b. c. age is an important influence on the likelihood of being afflicted w/ most carcinomas occur in the later years of life (55 years & over) each group has its own predilection to certain forms of cancer. e.g. 35 54 : Lung CA, most common type Breast CA, most common cause of death 55 74 : Lung CA, most common type

cause of 4.

Lung CA ff by breast CA, the most common death Hereditary: Table: Inherited Predisposition to CA: a. Inherited CA syndrome (autosomal dominant) o inherited predisposition indicated by strong family history of 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 CA Colon CA other than familial adenomatous polyps Autosomal recessive syndromes of Defective DNA Repair: e.g. Fanconis anemia

Expression of altered gene products & loss of regulatory gene products

Malignant Neoplasm

c.

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 CA o cervical dysplasia & cervical carcinoma o bronchial metaplasia & dysplasia & bronchogenic carcinoma Acquired envital o liver cirrhosis & 80% of hepatocellular CA Factors: Precancerous conditions (non-neoplastic disorders w/ well defined asso w/ Inherited mutations 3. Chemical (genetic CA, w/c in radiation majority of cases no malignant neoplasm emerges. It calls factors) however to the increased risk. attention Viruses 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 Mutations in the genome of somatic cells

1. Oncogenes : are CA-causing genes, are derived from protooncogenes. 2. Proto-oncogenes : cellular genes that promote normal growth & differentiation. These were 1st discovered as passengers w/in the genome of acute transforming retroviruses, w/c cause rapid induction 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, converting them into cellular oncogenes (c-

thereby oncs).

3. Oncoproteins : proteins encoded by oncogenes, w.c resemble normal products of proto-oncogenes, w/ the exception that oncoproteins are devoid of important regulatory elements & their production in the transformed cells does not depend on the growth factors or other external signals for growth. 4. Principal targets of genetic damage: a. the growth-promoting proto-oncogenes b. the growth-inhibiting CA suppressor genes (anti-oncogenes)

BIOLOGY OF TUMOR GROWTH: 1. Natural a. b. c. d. Factors a. b. c. history of most malignant tumors can be divided into 4 phases: malignant change in the target cell, referred to as transformation growth of transformed cells local invasion distant metastases that influence tumor growth: kinetics of tumor cell growth tumor angiogenesis tumor progression & heterogeneity

2. Activation of growth promoting oncogenes Alterations Clonal expansion of genes that Additional mutations regulate apotosis Heterogeneity Inactivati on of CA suppress (progression) or genes

CARCINOGENIC AGENTS:

Induce genetic damage & neoplastic transformation.

1.

Chemical carcinogens: a. Direct acting carcinogens: Alkylating Agents: -propiolactone Dimethyl sulfate Diepoxybutane Anticancer drugs (cyclophosphamide, chlorambucil, nitoureas, etc) Acylating Agents: 1-Acetyl-imidazole Dimethylcarbamylchloride b. Procarcinogens that require metabolic activation: 3.

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

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

Polycyclic & heterocyclic aromatic hydro-c: Benz(a)anthracene Benzo(a)pyrene Dibenz(a,h)anthracene 3-methylcholanthrene 7,12-Dimethylbenz(a)anthracene Aromatic amines, amides, azo dyes 2-naphthylamine (-naphthylamine) Benzidine 2-acetylaminofluorene Dimethylaminoazobenzene (butter yellow) Natural plant & microbial products Aflatoxin B1 Griseofulvin safrole Cycasin betel nuts Others Nitrosamine &amides Vinyl chloride, nickel, chromium Insecticides, fungicides Polychlorinated biphenyls 2. Radiation carcinogens:

Viral Carcinogens: DNA ONCOGENIC Viruses: a. Human Papilloma virus: Benign squamous papilloma (warts) in humans due to HPV types 1, 2, 4, & 7 85% of invasive squamous cell CA of cervix, due to HPV types 16 & 18 in majority of cases Genital warts w/ low malignancy HPV 6 & 11 b. Epstein-Barr virus: Member of the herpes family, implicated in the ff: b.1. African form of Burkitts lymphoma b.2. B-cell lymphoma in the immunosuppressed esp. after HIV infection & organ transplantation. b.3. some cases of Hodgkins dse. b.4. Nasopharyngeal carcinomas c. Hepatitis B virus: close asso. w/ devt 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 melanomas Express a TSA 20% of breast carcinomas called melanoma 30%, small cell CA of lungs Ag 1 [ MAGE 1 ] 2 Tumor asso antigens (TAA): these are human tumor antigens present in both tumor & certain normal cells. 3 categories of TAAs: a. TACAs (tumor asso carbohydrate antigens) b. Oncofetal antigens, or embryonic antigens e.g. -fetoprotein carcinoembryonic antigen c. Differentiation antigens: Peculiar to the differentiation state at w/c the CA cells are arrested. 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

Radiant energy (UVrays, ionizing radiation, particulate radiation) can transform virtually all cell types in vitro & induce neoplasms in vivo in both humans & experimental animals. a. UVrays from the sun: UVA UVB 320 to 400 nm 280 to 320 nm, responsible for induction of cutaneous 200 to 280 nm, a potent mutagens, is not significant filtered out by the ozone shield around earth. squamous cell CA, basal cell CA, melanocarcinoma

CAs

UVC because it is b. e.g.

Ionizing radiation: The ff are all carcinogenic: EMRs (electromagnetic radiation like x-rays, gamma rays) Electromagnetic particulate ( & particles, protons, neutrons) Even therapeutic radiation

2 NK cells lymphocytes capable of destroying tumor cells w/o prior sensitization. Provide the 1st line of defense against many tumors. 3 Macrophages: this cell collaborate w/ T cells in antitumor reactivity, because interferon gamma (IFN - ), a T cell derived cytokine, is a potent activator of macrophages. 4 Humoral mechanisms: participates in tumor cell destruction by 2 mechanisms: a. activation of complement b. induction of ADCC by NK cells IMMUNOSURVEILLANCE: 1 The strongest evidence for immunosurveillance is the increased incidence of tumors in immunodeficient hosts. Lymphomas: (B cell lymphomas), most common form of CA in immunocompromised hosts. CLINICAL FEATURES OF TUMORS: 1 Effects of tumors on hosts: a. location & impingement on adjacent structures b. functional activity such as hormone synthesis c. bleeding secondary to infections when they ulcerate through adjacent natural surfaces d. 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 pituitary neoplasms in the GUT cause obstruction benign B cell adenoma of pancreatic islets can produce sufficient insulin to cause fatal hypoglycemia. 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 readily explained, either by local/distant spread of the tumor/by the elaboration 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. b. c. d. e. endocrinopathies (ectopic hormone production) e.g. Cushings syndrome most common endocrinop. hypercalcemia most common paraneoplastic syndrome neuromyopathic paraneoplastic syndromes acanthosis nigricans Gray-black patches of verrucous hyperkeratosis on the skin. This lesion is asso in 50% of cases w/ some form of CA. Clubbing of fingers & hypertrophic osteoarthropathy Seen in 1-10% of px w/ bronchogenic carcinomas.

the extent of spread of a CA w/in the px Staging 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 involvement N0 - no nodal involvement N1 - N3 - denote involvement of increasing # & range of nodes. M - for metastases M0 - no distant metastases M1 - M2 - indicate blood borne metastases b. AJC (American Joint Committee) Divides CAs into stages 0 to IV, incorporating w/in each of these stages the size of the primary lesion as well as the presence of nodal spread & distant metastases.

Stage:

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 biopsy b. Papanicolau smears Immunocytochemistry

a.

Specific monoclonal antibodies to identify cell products/surface markers for tumors. Hormones: a.1. HCG (trophoblastic tumors) a.2. calcitonin (medullary CA of thyroid) a.3. catecholamines & metabolites a.4. ectopic hormones(paraneop syndromes) Oncofetal antigens: b.1. -fetoprotein Liver cell CA b.2. carcinoembryonic antigen CA of colon, breast, pancreas, lung, stomach Isoenzymes: c.1. prostatic acid phosphatase prost. CA c.2. neuron specific enolase small cell CA of lung Specific proteins d.1. immunoglobulins multiple myelomas

b.

c.

GRADING & STAGING OF TUMORS: 1 Grade: w/in the to express the differentiation of the tumor cells & the # of mitosis tumor as presumed evidence of the tumors aggressiveness. d.

d.2. 3

prostate-specific antigen

prostatic CA

Flow Cytometry can rapidly & quantitatively measure several individual cell characteristics, such as membrane antigens, & DNA content of tumor cells. 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.