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Introduction to Neoplasia – Pathology 1) Cellular Adaptations of Growth and Differentiation a) Many mechanisms for cellular adaptation i) Induced by factors from environment or autostimulation ii) Activation of surface receptors and downstream pathways b) Respond to increased demand and external stimulation by i) Hyperplasia (1) Increase in number of cells in organ or tissueusu. Increased volume of organ/tissue (2) Often occurs together with hypertrophy (may be triggered by same external stimulus) (a) E.g. in uterus hormones cause both in smooth muscle and epithelium (3) Takes place when cell population is capable of synthesizing DNAmitotic division (a) Alternatively hypertrophy=growth w/o division (4) Can be pathologic or nonpathologic (5) Physiologic Hyperplasia (a) Divided into: (i)Hormonal hyperplasia 1. increases functional capacity of tissue when needed 2. exemplified by a. proliferation of glandular epitheilium in breast during puberty and during pregnancy b. physiologic hyperplasia in pregnant uterus (ii)Compensatory hyperplasia 1. increases tissue mass after destruction or partial resection 2. Classic illustrations a. Liver regrowth after partial resection b. Remaining kidney growth after unilateral nephrectomy (b) Mechanisms of hyperplasia (i)generally caused by 1. increase in local production of growth factors 2. increase in growth factor receptor density in tissue 3. activation of particular intracellular signaling pathways (ii)all causes generally lead to changes in transcription factor production 1. activate genes a. encoding growth factors b. growth factor receptors c. cell cycle regulators 2. net resultcellular proliferation (iii)In compensatory hyperplasia, mechanisms not well defined 1. source of growth factors somewhat unclear 2. proliferation of remaining cells occurs 3. also, generation of new cell lines from stem cells (c) Pathologic hyperplasia (i)most forms caused by excessive hormonal stimulation or growth factor action 1. Common examples a. Endometrial hyperplasia i. Usu. Estrogen and pituitary hormones stim. Burst of regrowth after menstrual period. Regrowth halted by progesterone 10-14 days pre menstrual. ii. Some cases balance of estrogen and progesterone is off iii. Increased estrogen leads to overgrowth of endometrium b. Benign prostatic hyperplasia i. Excess androgens (ii)although pathologic hyperplasia is abnormal, restoration of normal hormone or growth factor control will resolve hyperplastic condition response to normal regulatory control mechanisms that distinguishes b/t pathologic hyperplasia and cancer 2. hyperplastic conditions are, however, breeding grounds for cancer (iii)important in wound healing and hyperplastic response to viruses such as HPV ii) Hypertrophy (1) Refers to cell size increaseincrease in size of organ (a) No new cells, just larger cells (2) Size increase is due to production of new subcellular components, not swelling (3) Nondividing cells cannot undergo hyperplasia, so must only undergo hypertrophy (4) Caused by increased functional demand on cells (5) Can be: (a) Physiologic hypertrophy (i)Building skeletal muscle 1. repeated strain causes hypertrophy so increases mass of cellular structural componants can share load 2. new equilibrium in larger muscle cell, allowing it to function at higher capacity 3. estrogen on uterine smooth muscle during pregnancy 4. progesterone and prolactin on breast during lactation (b) Pathologic hypertrophy (i)Cardiomyocytes are capable of massive hypertrophy (ii)stimulus is usu. Chronic hemodynamic overload 1. hypertension 2. faulty valves (iii)hypertrophy creates greater functional capacity to meet greater need, while not increasing the functional capacity per unit volume (6) Traditional view of cardiac and skeletal muscle is that they are uncapable of proliferation, new data shows that they may be capable of limited proliferation and repopulation (7) Mechanisms of hypertrophy (a) Much of understanding based on heart (b) Signal transduction cascades (i)turn on many genes that lead to increased protein production 1. transcription factors (c-fos c-jun) 2. growth factors (TGF-β, IGF-1, FGF) 3. vasoactive agents (α-adrenergic agonists, endothelin-1, angiotensin-II) (c) What triggers changes? (i)Mechanical triggers 1. stretch (ii)Trophic triggers 1. growth factors (IGF-1) 2. vasoactive substances (above) (d) Size of cells regulated by nutritional state and environmental cues (i)involve several transduction pathways (currently being researched) (e) regardless of mechanism, cell size has an upper limit, after which heart failure ensues (i)number of degenerative changes occur 1. lysis 2. loss of myofibrillar contractile elements (ii)myocyte death can occur by apoptosis or necrosis (iii)limiting factors of hypertrophy and causes of cardiac dysfunction poorly understood 1. may be due to a. limited vascular supply to enlarged fibers b. diminished oxidative capabilities of mitochondria c. alterations in protein synthesis and degradation d. cytoskeletal alterations iii) Metaplasia 1. (1) One adult cell type (epithelial or mesenchymal) is replace with another (a) May be adaptive replacement of sensative cell types with those that are better able to withstand adverse conditions (2) Most common epithelial metaplasia is columnar to squamous (a) Occurs in respiratory tract in response to chronic irritation (i)Chronic cigarette smoking (ii)norm. ciliated columnar cells in trachea or bronchi are replaced focally or widely by stratified squamous (b) stones in salivary, pancreatic, bile ducts cause replacement of ciliated columnar by nonfunctioning stratified squamous (c) vitamin A deficiency induces squamous metaplasia in respiratory epithelium (d) in all instances, more rugged stratified squamous can live whereas columnar would have died (i)although cell structure survives, fucntions can be lost 1. e.g. mucous secretion in respiratory 2. makes metaplasia undesirable (e) inlfuences that induce squamous metaplasia, if chronic, can predispose to malignant transformation in metaplastic epithelium (i)i.e. squamous cell carcinoma is malignant result in areas of metaplasia (3) Metaplasia from squamous to columnar (a) Barrett esophagus (i)chronic reflux of gastric acid (ii)esophageal squamous epithelium changes to intestine-like columnar (iii)cancers can arise, typically glandular (adeno)carcinomas (4) connective tissue metaplasia (a) formation of cartilage, bone, or adipose tissue (b) Myositis ossificans (i)formation of bone in muscle after bone fracture (occasionally) (c) difficult to construe as adaptive (5) Mechanisms of metaplasia (a) Not change in phenotype of existing cells, reprogramming of stem cells (i)stem cell change is brought on by 1. cytokines 2. growth factors 3. ECM components (ii)tissue specific signaling molecules (iii)factors initiate cascadetranscription factors for specific genes desired differentiation (b) mechanism of change from normal differentiation to metaplasia not clear 2) Neoplasia a) General i) 2000=10 million new cancer cases, 6 million deaths ii) Cancer mortality + morbidity is declining b) Definitions i) Neoplasia, neoplasm: literal: new growth ii) Tumor once meant inflamitory swelling, now syn. Neoplasm iii) Cancer is net for all malignant neoplasms (1) Cancer, from crab: cancer takes hold of anything it can find and refuses to let go iv) Neoplasm: “an abnormal mass of tissue the growth of which excceds and is uncoordinated with that of the normal tissue and persists in the same excessive manner after cessation of the stimulus which evoked the change.” v) Tumors are clonal: all tumor cells arise from one cell that incurred a genetic change which allowed excessive and unregulated proliferation and renders the cells autonomous (unregulated by normal physiologic mechanisms) c) Nomenclature i) All tumors have two components (1) Parenchyma: proliferating neoplastic cells (a) Represent cutting edge of neoplasm (b) Determine behavior and pathologic consequences (c) Cancer is named based on character of parenchyma (2) Stroma: supportive connective tissue and blood vessels (a) Growth and survival are critically dependant on stromal support (b) Adequate blood supply in needed for fuel (c) Connective tissue is needed for framework (d) Differing degrees of stromal support (i)some tumors soft and fleshy (ii)sometimes abundant collagenous stroma: desmoplasia (iii)sometimes rock hard (e.g. breast): scirrhous (3) There is cross-talk b/t stroma and parenchymadirectly influences growth ii) Benign tumors (1) Generally, attach –oma to name of cell type (a) Works for mesenchymal tumors (fibroma, chondroma, osteoma) (2) Epithelial naming more complex (a) Can be based on (i)Cell of origin (ii)Microscopic structure (iii)Macroscpic patterns (b) Adenoma is applied when tumor produces or arises from glandular tissue (c) Produce micro/macroscopic finger-like warty projections are papillomas (d) Cystadenomas form large cystic masses (e.g. ovary) (i)some have warty projections into cystic spaces: papillary cystadenomas (e) benign or malignant projection from mucosa into lumen = polyp (i)better nomenclature: polypoid cancer for malignant iii) Malignant tumors (1) Essentially same as that for benign (2) Arise in mesenchyme = sarcoma (a) Little stromal support, so fleshy (sar=fleshy) (b) Examples (i)fibrosarcoma (ii)liposarcoma (iii)leiomyosarcoma (smooth muscle) (iv)rhabdomyosarcoma (differentiates toward skel. muscle) (3) Epithelial origin (any of the three germ layers)= Carcinoma (a) further qualification (i)glandular pattern= adenocarcinoma (ii)squamous cell producing= squamous cell carcinoma (4) preferable, if possible, to attach name of organ of origin (renal cell adenocarcinoma) (a) if not possible, designated as poorly/undifferentiated malignant tumor (5) Usually parenchyma cells are all very similar owing to their single cell origin, but it is possible for a cell line to divergently differentiate into a new tissue (a) Called mixed tumor (b) E.g. mixed tumor of salivary gland origin (i)epithelial parenchyma dispersed within a myxoid stroma (ii)islands of cartilage or even bone (iii)all thought to arise from epithelial or myoepithelial cells of salivary gland (iv)preferably called pleomorphic adenoma (6) Vast majority of cancers represent cells of a single germ layer (even mixed) (a) Exception: teratoma (i)usually cells from all three germ layers (ii)arise from totipotent stem cells 1. usually encountered in gonad 2. sequestered primitive cells elsewhere (rare) (iii)differentiate along different cell lines that can be identified 1. any tissue of the body possible 2. particularly common: cystic teratoma a. (dermoid cyst) b. Differentiates primarily along ectodermal lines c. Creates cystic tumor i. Lined with skin ii. Hair iii. Sebaceous glands iv. Teets v. Fucking sick! (7) Some problematic naming (a) Melanoma should be melanocarcinoma (b) Testicular tumors probably should not be called seminomas (c) Hepatocellular carcinomas “ “ hepatomas (d) Etc. (8) Nomenclature is impt. b/c specific designations have specific clinical implications (a) Even tumors of the same tissue (b) E.g. in Testes (i)seminoma 1. testicular carcinoma 2. spreads to lymph nodes along iliac arteries and aorta 3. extremely radiosensitive and can be eradicated 4. rarely deadly (ii)embryonal carcinoma of the testis 1. not radiosensitive 2. tends to invade locally beyond the confines of the testes and spread throughout the body 3. bad news (iii)also other neoplasms of testes with variable clinical pictures (iv)therefore, the term testicular cancer tells little of its clinical signficiance d) Biology of Tumor Growth: Benign and Malignant Neoplasms i) Natural history has 4 phases (1) Malignant change in the target celltransformation (2) Growth of the transformed cells (3) Local invasion (4) Distant metastasis ii) Differentiation and Anaplasia (1) Differentiation: the extent to which neoplastic cells resemble normal cells functionally and morphologically (a) Well differentiated: composed of cells resembling mature normal cells of origin (i)leiomyoma: almost indiscriminate from normal, only massing points to neoplasm (b) Poorly differentiated: primitive-appearing, unspecialized cells (2) Anaplasia: lack of differentiation (3) Malignant neoplasms range from well differentiated to undifferentiated (a) Composed of undifferentiated= anaplastic (i)hallmark of malignant transformation (ii)some cancers= reversion from high differentiation to low differentiation (iii)substantial evidence that most cancers do not “reverse differentiation” but arise from stem cell 1. well differentiated cancer: evolve from maturation or specialization of undifferentiated cells as they proliferate 2. undifferentiated: proliferation without differentiation in transformed cells (4) Morphologic changes in anaplasia (a) Pleomorphism (i)variation in size and shape (ii)seen in nucleus and cell as a whole (iii)some cells v. large, some v. small + primitive (b) abnormal nuclear morphology (i)abundance of DNA (ii)v. dark staining (hyperchromatic) (iii)disproportionately large 1. nuc. to cytoplasm ratio approaches 1:1 (norm. 1:4 or 6) (iv)variable shape (v)chromatin clumped at adges (vi)large nucleoli (c) Mitoses (i)large # mitoses (ii)not definitive (iii)atypical, bizarre mitotic figures (tri, quadri, or multipolar spindles) (d) Loss of polarity (i)orientation is markedly disturbed (ii)sheets/masses (iii)disorganised (e) Other (i)Tumor giant cells: some w/single huge polymorphic hyperchromatic nuc. others have multiple nuc. (ii)often vascular stroma is scant, many central areas undergo ischemic necrosis (5) in-between two extremes of differentiation= moderately well differentiated (6) Dysplasia (a) Literally: disordered growth (b) Principally in epithelia (c) loss of uniformity of individual cells (d) loss of architectural orientation (e) considerable pleomorphism (f) hyperchromatic, abnormally large nuclei (g) overly abundant, otherwise normal, mitotic figures (h) in stratified, mitosis occurs in all layers (Abnorm) (i) carcinoma in situ (i)dysplastic changes are marked (ii)involve the entire epithelium (iii)confined to normal tissue (iv)once moves beyond normal confinesinvasive (j) does not necessarily progress to cancer (7) better the differentiation more retention of normal capabilities (a) well defined carcinomas and benign neoplasms of endocrine glands (i)maintain hormone producing capability (ii)over secrete hormone (iii)good test for detection and monitoring (b) poorly differentiated neoplasms can gain novel functions (i)express fetal proteins and antigens (ii)express inappropriate hormones: ectopic hormones (iii)more rapidly growing and anaplastic the tumor, the less likely it is to have a specialized function iii) The cells of benign tumors are almost always well differentiated. iv) Cancer cells are more or less differentiated, but some loss of differentiation is always present 3) Clinical Features of Tumors a) General i) Neoplasms essentially parasites ii) All tumors (even benign) cause morbidity and mortality iii) With a few exceptions, all masses require anatomic evaluation b) Effects of tumors on hosts i) Cancer/benign can both cause host problems (1) Location and impingement on adjacent structures (2) Functional activity such as hormone synthesis (3) Bleeding and secondary infections when they ulcerate through normal tissue (4) Initiation of acute symptoms caused by rupture or infarction ii) Local and hormonal effects (1) Pituitary adenoma (a) Benign and non-hormone producing (b) Expansile growth can destroy remaining pituitary and lead to severe endocrinopathy (2) Cancers of or metastatic to an endocrine gland can cause insufficiency by destruction (3) Gut neoplasm= obstruction (a) Peristalsis can drag lesion and gut segment downstream…nasty, like eating yourself iii) Cancer Cachexia (1) Wasting syndrome of cancer (a) Progressive loss of body fat +lean body mass (b) Profound weakness (c) Anorexia (i)common problem in patients with cancer (ii)reduced intake due to abnormalities of taste and control of hunger (central) 1. not sufficient to explain anorexia (iii)caloric expenditure high and BMR elevated, despite reduced intake 1. normally starvation would lower BMR (iv)fat loss =muscle loss 1. in starvation fat loss >>>> muscle loss (v)basis of abnormalities not fully understood 1. administration of TNF mimics loss of apatite and alterations in fat metab a. suspected culprit of cachexia 2. cytokines synergize with TNF 3. evidence for other factors (d) Anemia (2) Obscure origins (3) Not caused by nutritional demands of tumor (a) Soluble agents such as cytokines (b) Host response to tumor iv) Paraneoplastic Syndromes (1) Symptom complexes that cannot be explained by local or distant spread of tumor or by elaboration of hormones expressed in tumor’s native tissue (2) 10% of patients w/ malignant disease (3) Important for several reasons (a) Represent earliest manifestation of occult neoplasm (b) Cause significant or even lethal problems (c) Mimic metastatic diseaseconfound treatment (4) Classified based on their presumed origins (a) Table 7-12 pp.334 (5) Syndromes of interest (a) Endocrinopathies (i)from ectopic hormone production by cancer cells (ii)cushing syndrome most common 1. 50% patients have small cell carcinoma of the lung 2. excessive production of corticotropin or corticotropin-like peptides a. precursor POMC levels high in lung cancer, not in pituitary excess (b) Hypercalcemia (i)most common (ii)overtly symptomatic form is most often from cancer, not hyperparathyroidism (iii)associated cancer processes 1. osteolysis: a. primary in bone (e.g. multiple myeloma) b. metastatic in bone 2. production of calcium humoral substances by extraosseous neoplasm (iv)hypercalcemia owing to skeletal metastasis is not a paraneoplastic syndrome (v)factors implicated in hypercalcemia of malignancy 1. parathyroid related hormone (PTRH) a. normally produced in small amounts, prob. to reg. calcium transport across placenta and in lactating breast b. overproduction associated with i. osteolytic bone disease ii. bone metastasis iii. humoral hypercalcemia (vi)most often found in tumors of breast, lung, kidney, ovary (c) neuromyopathic paraneoplastic syndrome (i)peripheral neuropathies (ii)cortical cerebellar degeneration (iii)polymyopathy resembling polymyositis (iv)myasthenic syndrome sim. to myasthenia gravis (v)poorly understood (vi)antibodies to tumor may cross-react with neuronal cells (d) Acanthosis nigricans (i)grey-black patches of verrucous hyperkeratosis on skin (ii)can be rare genetic condition (iii)sometimes skin changes noted before discovery of neoplasm (e) Hypertrophic osteoarthropathy (i)1-10% bronchiogenic carcinomas (ii)rare from other cancers (iii)Characteristics 1. new bone formation at distal ends of long bones 2. arthritis of adjacent joints 3. clubbing of the digits (iv)cause unknown (f) vascular & hemorrhagic manifestations (i)migratory thrombophlebitis seen with some deep seated cancers (carcinomas of pancreas or lung) (ii)disseminated intravascular coagulation v) Grading and Staging of Tumors (1) Look for similarities b/t cancers for prognosis of course of disease and to determine efficacy of treatments (2) level of differentiation = grade (a) measure level of differentiation of tumor cells (b) measure # mitoses in tumor (c) presumed correlates of neoplasm’s aggressiveness (d) Grades I-IV (e) Do our best, but correlation b/t histologic appearance and biologic behavior is less than perfect (f) Has less clinical value than staging (3) extent of spread of cancer = stage (a) based on (i)size of primary lesion (ii)spread to regional lymph nodes (iii)presence or absence of blood borne metastasis (b) two major systems in use (i)UICC (international) 1. uses TNM (primary Tumor, regional Nodes, Metastasis) 2. 0-4 indicating greater severity (ii)AJC (American) 1. has stages 0 to IV for all cancer types 2. incorporates all staging aspects into single stages (4) Staging has massive clinical significance, very important to selection or proper therapy (5) Can be aided by PET, among imaging modalities vi) Laboratory diagnosis of cancer (1) Ever increasing in complexity, sophistication, and specialization (2) Histologic and Cytologic methods (a) Two ends of spectrum not diagnostically difficult (b) Grey area requires caution (c) Need an adequate, representative, and well preserved sample (i)modes of sampling 1. excision or biopsy a. sometimes excision not possible b. must select proper site for biopsy of mass i. edges not representative ii. center necrotic c. proper preservation and analysis is crucial to accurate diagnosis 2. needle aspirate a. suck up part of tumor and associated fluid b. examine stained smear c. used in easily palpable lesions (breast, thyroid, lymph nodes) d. now can be done in deep-seated regions with interventional radiology e. less invasive and more rapid than biopsy 3. cytologic smears a. Pap smear i. Discovery of carcinoma of cervix often at in situ stage b. Possible for other neoplasms, were swab possible (gut, genital, lymph, etc.) c. Analysis of cells shed by cancer, cannot tell architectural abnormalities (3) Immunohistochemistry (a) Categorization of undifferentiated malignant tumors (i)malignant tumor cells are often difficult to differentiate because of poor differentiation 1. e.g. certain anaplastic carcinomas, malignant lymphomas, mealnomas, and sarcomas may look similar 2. they must, however, be differentiated b/c their treatment and prognosis are different (ii)immunohistochemistry can help, as certain proteins may be expressed even in poorly differentiated cells that give a clue to their origin 1. antibody stains for intermediate filaments have proven helpful in determining the origin of tumor cells (b) Categorization of leukemias and lymphomas (i)immunohistochem useful in identifying tumors arising from T & B Lymphocytes and mononuclear-phagocyte cells (c) Determination of site of origin of metastatic tumors (i)some patients present with metastatic disease and no obvious original neoplasm (ii)immunohistochemistry can be used to identify tissue specific antigens in metastatic deposits (iii)e.g. PSA is indicative of prostatic origin, thyroglobulinthyroid origin (d) Detection of molecules that have prognostic or therapeutic significance (i)e.g. detection of hormone receptors in breast cancer cells is significant b/c it renders the cancer susceptible to antiestrogen therapy. (ii)e.g. breast cancers with overexpression of ERBB2 have poorer prognosis (4) Molecular diagnosis (a) Can be used to diagnose and predict the behavior of tumors (b) Diagnosis of malignant neoplasms (i)not primary modality of diagnosis (ii)use tests such as FISH or PCR based assay for specific translocations (iii)can diagnose neoplasms resulting from very specific molecular abnormalities (c) Prognosis of malignant neoplasms (i)Also FISH or PCR assays (ii)Certain molecular abnormalities (translocations) associated with poor prognosis (d) Detection of minimal residual disease (i)can be used to identify residual cancer after treatment or incumbent relapse in cancers with specific translocations (ii)PCR based amplification of sequence e.g. BCR-ABL in CML (e) Diagnosis of heridatary predisposition to cancer (i)use molecular genetic techniques to identify mutations in tumor suppressor genes, etc. (f) DNA microarray analysis and proteomic (i)obtain gene expression profile (molecular profile) of cancer cells (5) Flow cytometry (a) Can rapidly and quantitatively several individual cell characteristics (i)membrane antigens 1. widely used to identify leukemias and lymphomas (ii)DNA content of tumor cells 1. abnormal DNA content (e.g. aneuploidy) is associated with poor prognosis in a variety of cancers (Breast, bladder, lung, colorectal, prostate) (6) Tumor Markers (a) Are biochemical indications of the presence of a tumor (i)cell surface antigens (ii)cytoplasmic proteins (iii)enzymes (iv)hormones (b) usually refers to molecule that can be detected in the plasma (c) cannot be relied upon as a primary modality for diagnosis (i)supportive evidence (ii)determine response to therapy (iii)relapse warning (d) many identified, few proved reliable in long term (i)CEA 1. normally produced in embryonic tissue 2. found elevated in some cancers (colorectal, pancreatic, gastric, breast carcinomas) 3. also found elevated in other conditions 4. lack both sensitivity and specificity for early diagnosis (ii)AFP 1. glycoprotein normally synthesiszed in early fetal life 2. elevated levels found in certain cancers (cancers of the liver and testis, colon, lung, pancreas carcinomas) 3. also elevated in non-malignant conditions 4. not very specific test, but relatively sensative 5. good marker for quantitative analysis of response to treatment (iii)Few other widely used markers 1. PSA & PSMA (prostate) 2. CA125 (ovarian) 3. APC, p53, RAS in stool (colorectal) 4. mutant p53 in sputum (lung) 5. mutant p53 in urine (bladder) (iv)Table 1. HCGtrophoblastic tumors, nonseminomatous testicular tumors 2. 3. Calcitoninmedullary carcinoma of the thyroid Catecholamine and metabolitesPheochromocytoma, etc.
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