TA Reviews

Neoplasia

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M2

Pathology

TA Reviews

Neoplasia Lecture Handout

Jill Conway, 9/1/00

Neoplasia: uncontrolled new growth unresponsive to normal growth control mechanisms like contact inhibition. Neoplasia can occur in any cell, unlike hyperplasia which requires dividing cells. Best official definition: "A neoplasm is an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissues and persists in the same excessive manner after cessation of the stimuli that evoked the change."[1] This points out some of the key features of neoplasms: loss of growth control, irreversibility, and apparent disassociation with other tissue. In advanced metastatic cancer, the patient may appear cachexic, while tumor growth continues unabated.

Classification: Benign and malignant are terms that describe certain features of neoplasms. In general, benign tumors do not invade or metastasize, tend to grow more slowly, have fewer abnormal mitotic figures, and better resemble their tissue of origin than malignant ones. However, only the existence of metastases truly distinguishes malignant tumors from benign ones. Under a light microscope, it may not be possible to tell benign and malignant tumors apart.

Differentiation: denotes the degree to which neoplastic tissue resembles its tissue of origin both structurally and functionally. Benign tumors tend to be well differentiated and therefore, they function as the tissue of origin. Therefore, a benign adenoma of the thyroid will probably secrete the thyroid hormone associated with its original cell type.

Malignant tumors may be well-differentiated or totally anaplastic, which refers to "backward growth" or tissue that arises from stem cells and fails to undergo the normal differentiation of that tissue. Anaplastic tumors are completely undifferentiated neoplastic parenchyma. Biochemical convergence indicates that anaplastic cells resemble other anaplastic cells more than they do their tissue of origin. Diagnosis of tissue of origin may require testing for presence of cellular markers.

As cells get more anaplastic, you will see more:

pleomorphism, hyperchromasia, high N/C ratio, increased mitotic activity with atypical mitotic figures (tripolar and quad spindles), tumor giant cells, loss of polarity, some necrosis possible.

Growth rate generally increases with increasing anaplasia.

Local Invasion: Benign tumors are generally well encapsulated, surrounded by a fibrous capsule created via compression of normal tissue as the tumor expands.

The capsule demarcates the tumor from the normal tissue, making surgical removal fairly easy. In contrast, malignant tumors tend to project into surrounding tissue (infiltration), invade it, and cause tissue destruction. Surgical resection must always occur with a wide margin of normal tissue to attempt to remove all the neoplastic cells. Only the presence of metastases better distinguishes benign from malignant tumors than local invasiveness.

Carcinoma in situ = presence of indicators of malignancy in cytology (hi N/C ratio, abnormal mitotic figures, etc.) without local invasion. Most will invade with time unless removed.

Development of Metastases:

Development of distant spread requires the ability of a tumor cell to break free from primary tumor, invade through basement membrane and get into the lymphatic or blood supply, enter the circulation, survive there, enter a host tissue, anchor, establish a blood supply, and divide excessively to form a metastatic site. Tumor cells may secrete laminin which can bridge them to the BM, type IV collagenase to degrade the BM, elastase, or have more laminin receptors than a normal cell, etc.

Millions of tumor cells may enter the circulation each day from a primary tumor, yet few will produce secondary tumors as many genetic alterations are necessary in combination to allow spread to occur.

Tumors may decrease production of E-cadherins and integrins which are believed to help bind cells together normally and bind to the ECM and down regulation loosens the cells from the surrounding stroma. Normal cells express receptors that attach to BM only on one surface, whereas cancerous ones present this receptor all over the cell, allowing it to attach more readily to the ECM at a distant site. Ability to adhere to laminin seems to be significant in determining the invasiveness of cells. Malignant cells often overexpress collagenases, especially those that degrade type IV collagen of the BM. Cathespin D breaks down many ECM components

(fibronectin, laminin, etc.) and seems to be significant for prognosis of tumor aggressiveness. Most tumor cells that reach the circulation migrate as single cells.

Where they attach and invade depends partially on routes of drainage, but also on surface receptors expressed by the cell and target organ.

Malignant tumors must be capable of angiogenesis as tumors cannot grow beyond 1-2 mm without being vascularized. Angiogenic factors may be elaborated from the tumor cells or secreted by surrounding connective tissue. VEGF and bFGF seem to be most important and are expressed by many tumor cells. Angiogenic factors are balanced by certain antiangiogenic proteins, including endostatin, angiostatin, and thrombospondin-1. Most tumors exist for years before inducing angiogenesis and growing rapidly. Normal p53 seems to increase thrombospondin-1 (antiangiogenic) and thus decrease spread. Deletion of both p53 alleles makes angiogenesis more likely.

Benign tumors never metastasize and therefore, any tumor with distant mets is by definition cancerous. 30% of those diagnosed with solid tumor ca already have metastasis. Spread occurs via direct seeding of body cavities (ovarian ca and peritoneum), spread through blood or lymphatic channels.

Hematogenous Spread: typical of sarcomas, usually occurs through veins. Tumor expansions typically follow the route of venous drainage, meaning that liver and lungs are frequent sites of metastasis.

Lymphatic Spread: typical of carcinomas, usually follows patterns of drainage

SUMMARY OF BENIGN/MALIGNANT FEATURES:

Most benign tumors grow slowly and are encapsulated, and show fewer atypical cells. Most are well differentiated and show no signs of local invasion. Benign tumors do not metastasize.

Most malignant tumors invade, are not encapsulated, grow quickly, are capable of angiogenesis, and metastasize. Malignant tumors may be well-differentiated or anaplastic and usually show lots of cellular atypia with hi N/C ratios, hyperchromasia, abnormal mitotic figures.

Nomenclature:

Benign neoplasms are named with the suffix -oma, such as a leiomyoma (fibroid) in the uterus. Adenomas refer to benign tumors of epithelial origin that resemble glandular structures, or those tumors derived from glands. Papillomas project with finger like areas raised from an epithelial surface. Polyps are benign, macroscopically visible projections from a mucosal surface.

Malignant tumors are named with the suffix -carcinoma for those of epithelial cell origin, and -sarcoma for those derived from mesenchymal tissue.

Note exceptions to nomenclature: teratoma (benign or malignant), hepatoma, seminoma (testis), and melanoma are all malignant, whereas hamartoma=benign proliferations of normal tissue in an organ Adenocarcinoma: these arise from glandular tissue or resemble glandular tissue Carcinoma: malignant tumor arising from epithelial origin, tends to spread via lymphatics. Those that resemble glands are called adenocarcinomas, and those with visible squamous cells are called squamous cell carcinomas.

Sarcoma: malignant neoplasm arising from mesenchyme, tends to spread hematogenously (especially to liver and lungs since most often invades into venous drainage and these organs are exposed to most venous drainage).

Most tumors are originally monoclonal, deriving from one cell line. Exceptions include pleomorphic adenomas, such as the mixed tumor of salivary gland origin, that includes components derived from two different cell lines (epithelial and myoepithelial). Teratomas include cell types of more than one germ cell line, usually all three and usually arise in germ cell tissue such as testis and ovary.

Classification of Malignant Tumors: grading and staging

Differentiation = both structural and functional resemblance to tissue of origin and number of mitoses present, determined by grading from I to IV, with IV being less well differentiated

Staging: size, spread, and mets

Two methods: TNM, T= size of primary tumor, 0 = in situ, 4 = big N=nodal involvement, 0=none, 3=many, M=mets, M0 = no mets, M1 and M2, distant mets of varying degrees

Or staging by the I to IV method: I =one lymph node or region, II= lymphatics on same side of diaphragm, III= lymphatics on both side of diaphragm, IV= organ mets

Epidemiology of Cancer:

In the USA, about one in five will die from cancer with an estimated 564,000 in 1998. This accounts for 23% of mortality, second only to cardiovascular disease.[2]

The major cause of death from cancer in men and women is from lung cancer, although breast ca is more common in women and prostate ca is more common in men than lung ca.

About 90% of ca may be related to environment and lifestyle.

Risk factors for developing various forms of cancer include advancing age, certain inherited mutations, familial dispositions, smoking, and alcohol intake.

Heredity: Predispositions to cancer may be inherited in an autosomal dominant or recessive fashion. Dominant patterns of inheritance involve presence of a single mutant gene that greatly increases risk of ca such as familial retinoblastoma or familial adenomatous polyposis (FAP).

Familial cancers are those that clearly occur in familial clusters but do not have a confirmed genetic heritable basis and they include breast cancer and colon cancer other than those of FAP.

Autosomal recessive defects in repair of DNA predisposes to the development of certain cancers such as xeroderma pigmentosum.

In addition, acquired "precancerous" conditions such as hyperplastic nodules in cirrhotic liver, bronchial metaplasia from cigarette smoke, ulcerative colitis, certain benign neoplasms, and many other conditions provide an environment in which cancer arises more frequently than in healthy tissue.

MOLECULAR BASIS OF CANCER

Basic Principles:

Cancer arises from nonlethal genetic damage which can be transmitted to cell progeny. Most tumors initially develop as monoclonal, arising from a single mutated cell.

Three kinds of genes are targets for carcinogenic transformation:

  1. proto-oncogenes promote cell growth and require the alteration of only one allele to create out of control cellular growth (dominant gene)
  2. tumor suppressor genes inhibit cell growth and require the alteration of both alleles to affect cell growth (recessive oncogenes), DNA repair genes are similar
  3. genes that regulate apoptosis may be dominant or recessive but influence the ability of the cell to target itself for destruction following cell damage

Tumor progression refers to the ability of transformed cells to acquire further abnormal characteristics over time, independent of tumor size. These include ability to invade, metastatic spread, further anaplasia. It is believed that these characteristics are acquired through mutations within the tumor leading to subgroups of cells with varying characteristics. At the time of diagnosis, most tumors are heterogenous and have multiple cell lines present. The absence of p53 in many human tumors may contribute to the increased instability of DNA in tumors.

ONCOGENES

Proto-oncogenes are normal cellular genes that regulate cell growth, division, and differentiation. Oncogenes are cancer-causing genes derived from proto-oncogenes by mutation, retroviral transduction, gene amplification, or dislocations. Oncogenes occur as transformations of genes that normally regulate expression of growth factors and receptors, signal transducing proteins, nuclear transcriptions factors, and cyclins and their associated proteins.

Classes of Oncogenes:

Growth Factors: Genes that encode growth factors may become oncogenic. For example, cells that produce PDGF may also develop receptors for it and become permanently turned on via autocrine stimulation. Usually, the PDGF gene (sis) is normal, but oncogenes such as ras cause PDGF to be overexpressed.

Excess growth factor itself cannot completely transform a cell, but in conditions of excessive growth and cell division, other mutations become more likely.

Growth Factor Receptors: most are transmembrane proteins that cause phosphorylation of proteins on the cytoplasmic side when activated. Normally, the cytoplasmic side gets transiently turned "on" and then rapidly deactivated. Oncogenic receptors exist in a prolonged "on" state, even in the absence of bound growth factor. Point mutations in the ret protooncogene (codes for receptor associated with glial cells) are associated with MEN and familial medullary thyroid carcinoma.

Growth factor receptors may also be overexpressed. c-erb1 codes for an EGF receptor overexpressed in many squamous cell cas, and c-erb 2 in the adenocas of the breast, ovary, lung and others.

Signal Transducing Proteins: these proteins exist on the inner plasma membrane and following activation work to phosphorylate cytoplasmic proteins. Ras, a GTP cleaving protein receptor associated transducing protein, is the prototype and mutated versions of the ras proteins are present in 10-20% of human cancers.

The normal GTPase activity of ras protein is accelerated when in association with GAPs (GTPase-activating proteins). Ras normally works to activate MAP (mitogen activated protein) kinase that increase nuclear transcription factors. Mutated forms of ras bind GAP normally, but the GTPase activity of GAP fails to occur.

Translocation of the signal transducing protein (non-receptor associated) c-abl on chromosome 9 to the bcr region of chromosome 22 activates it to increase cell growth. This translocation is associated with CML.

Nuclear Transcription Proteins: these proteins influence DNA synthesis in the nucleus. C-myc, forms a heterodimer with max protein, and the myc-max combination activates transcription. Mad, a similar protein to myc, may also combine with max to turn off transcription and is therefore a tumor-suppressor gene.

Cyclins and CDKs: CDKs are present within the cell at all times and help the cell through the cell cycle. Cyclins are synthesized and then rapidly degraded and work to activate the CDKs. CDKIs regulate the activity of CDKs. CDK4 mutation seems to be implicated in melanomas and other cancers.

Methods of Activation of Oncogenes:

  1. Point mutations: typical ofras proteins
  2. Chromosomal rearrangements: translocation may associate a growth factor or receptor with an actively transcribed area, or result in the formation of an active hybrid protein. EX: philly chromosome c-abl-bcr has hybrid activity
  3. Gene Amplification: duplication, multiplication of DNA sequences in the genome. Associated with N-myc in neuroblastoma and c-erb 2 in breast ca.

Tumor Suppressor Genes

Tumor suppressor genes are normal cell genes that "brake" cell division and cycling at various point in the cell cycle. They work through similar mechanisms to proto-oncogenes, through signal transduction, through cell surface receptors and nuclear transcription regulators.

Suppressor genes are "recessive" and require loss of both copies of the normal before cancer becomes likely, the "two-hit" model of carcinogenesis.

Retinoblastoma models this behavior and exists as 60% sporadic and 40% familial, but occurs much earlier if familial. The theory is that both alleles of Rb must be ineffective before tumor suppression is lost. In the familial forms, all somatic cells have inherited one defective allele, and only one cell must lose its other allele to become predisposed to produce tumors. pRb works to prevent cells in G1 from advancing to S phase. This is an extremely sensitive transition since no further growth factors are required to complete mitosis following progression into S phase. pRb normally exists in an active, hypophosphorylated state and when phosphorylated, it releases the brakes and allows cell division to progress. Most likely, Rb forms tumors in the retina and osteosarcoma because deletion of both active alleles should trigger apoptosis. But, for reasons not fully understood, retinoblasts fail to die following transformation. p53, a protein exclusive to the nucleus, is the most common transformed gene in human cancer, presenting in over 50% of human tumors. p53, designated "guardian of the genome," acts in the nucleus to stop replication of damaged cells. Following damage, p53 gets rapidly up regulated and its accumulation triggers increased transcription of DNA repair proteins and those that stop the cell cycle. If repair occurs, the cell cycle resumes. If not, p53 plays a role in triggering apoptosis. Loss of both normal alleles of p53 causes the cell cycle to continue with the mistakes in DNA transcription intact. p73 has recently been discovered and appears to work by similar mechanisms.

Other tumor suppressor genes include NF-1, NF-2, VHL, and WT-1.

Suppressors of apoptosis involved in ca include bcl-2 , which inhibits apoptosis and is transformed in most B cell lymphomas. Growth arises from decreased cell death rather than increased cell proliferation. The bax and bad gene accelerates cell death and opposes bcl-2.

Defective DNA repair genes are implicated in the development of cancers as they may allow cell division despite mutated DNA. HNPCC (hereditary nonpolyposis colon cancer) illustrates a cancer associated with defects in DNA repair. These genes are not considered oncogenic but favor conditions that allow mutations in normal oncogenes. XP also arises from defects in DNA repair genes.

CARCINOGENESIS:

Carcinogenesis is a multi-step process and may involve mutations in growth promoting proto-oncogenes, and growth-inhibiting cancer suppressor genes (anti-oncogenes) and the genes that regulate apoptosis. Every human cancer studied shows loss of two or more antioncogenes and activation of several oncogenes.

No single mutation is sufficient for malignant transformation. The sequence in which mutations are acquired seems to affect the potential malignancy of a cell.

Tumor cells may cycle continuously, but the time it takes them to divide is not any faster than that of normal cells. Growth fraction, the % of cells in a given pool currently replicating may be much higher than in normal tissue. However, even in the fastest growing tumors, most cells are resting in G0 and only about 20% are involved in replication. Cell production must outpace cell loss for the tumor to grow. Growth fraction must be high for most chemotherapeutic agents to be effective.

Tumors are clinically evident only after about 30 population doublings or about 1 gm of tumor with about 109 cells present. By this time, many of the tumor cells have stopped cycling. However, although it may take years to reach clinical detectability, rapidly growing tumors may double in size with 2-3 months.

Chemical Carcinogenesis:

Initiator=carcinogenic agent that changes DNA irreversibly, with a change that can be passed on to cell progeny. Promoter can produce a tumor in previously initiated cells only and is reversible.

Many carcinogens must be activated first (procarcinogen -> ultimate carcinogen). This process often occurs with the P450 liver oxygenase system.

Initiators include alkylating agents, polycyclic aromatic hydrocarbons, B-napththylamine, aflatoxin B1, nitrate, asbestos.

Promoters include agents such as hormones that encourage cell division.

Radiation: Exposure to UV light, especially UVB, increases the risk of basal cell ca, squamous cell ca, and maybe melanoma. UV light increases the formation of pyrimidine dimers in DNA which often gets repaired by DNA repair mechanisms. Xeroderma pigmentosum, a hereditary dysfunction of the nucleotide excision repair pathway, results in a much increased risk of skin cancer. UVB may also cause mutations in oncogenes and tumor suppressor genes.

Ionizing radiation predisposes to the development of certain kinds of cancer, especially leukemias and thyroid cancers (in the young). Following a long latency period, survivors of atomic bomb fallout have also developed increased incidence of breast, colon, and lung cancers.

Viral Oncogenensis:

DNA viruses: These viruses integrate into cellular DNA and in doing so, interrupt the sequence necessary for viral replication. Viral genes normally expressed early in the replication process play a role in transforming cells.

Associations between viruses and human cancers include the following:

HPV (especially 16, 18, and 31) and cervical ca. HPV 6 and 11 are *not* associated with the development of cancer.

EBV is present in 100% of nasopharyngeal ca, 90% of African Burkitt's lymphoma, some B cell lymphomas, especially those in HIV infected or otherwise immunosuppressed patients. EBV infection immortalizes B cells.

HBV and hepatocellular ca. HBV causes chronic liver insult and therefore increased numbers of dividing hepatocytes. HBV codes for Hbx protein which may interfere with p53 function.

RNA viruses:

All are retroviruses and only HTLV-1 causes a human tumor. HTLV-1 infects CD4+ cells preferentially and may lead to leukemia after many years via stimulating T-cell replication.

Microbes: H. pylori may be implicated in the development with gastric B-cell lymphomas.

Host defenses

TSA=tumor specific antigens cause an immune response and are present only on tumor cells. These may activate a cytotoxic T-cell response through presentation by class I MHC molecules. Some tumor-specific shared antigens have been identified that are silent in all normal adult tissue but may be expressed on tumor cells.

For example, MAGE proteins are present only in the adult testis, but are not expressed on the cell surface. Various MAGE proteins are associated with a number of cancers, including lung cas and melanoma.

TAA=tumor associated antigens may be on tumor and normal cells so do not cause an immune response but can help diagnosis or treatment of existing neoplasms.

For example, PSA levels may indicate extent of prostate cancer, AFP may be expressed by liver and testicular cancers, and CEA is expressed by many colorectal,pancreatic, gastric, and breast cas.

NK cells are lymphocytes (non-T, non-B) that can destroy tumor cells without being sensitized first, upon activation by IL-2. Considered the first line of defense against most tumors. They also participate in ADCC, where they can bind the Fc portion of IgG attached to cells and lyse them.

Cytotoxic T cells (antibody dependent) can be sensitized specifically to attack neoplastic cells (this happens especially in HPV induced cancers).

Macrophages can attack tumor cells when activated by IFN-gamma released by T cells. Macrophages secrete TNF-alpha.

It is not clear exactly how this works, although the number of cas (especially lymphomas) in immunosuppressed patients would seem to indicate that immunosurveillance normally occurs.

Cachexia is seen in advanced ca and includes body wasting, weakness, anorexia, and anemia. It is *not* caused by the tumor's nutritional needs, although the larger the tumor, the worse it is. Both fat and protein are consumed equally. Cause unknown, but some relation to TNF-alpha and perhaps to a newly isolated protein-mobilizing factor, which, when injected into healthy mice causes rapid weight loss despite maintenance of caloric intake.

Paraneoplastic syndromes: this includes many signs and symptoms that arise from sources other than local tumor effects, consequences from distant mets, or production of hormones native to the tissue of origin. These syndromes include endocrinopathies from ectopic hormone production, in which tumor cells secrete excessive quantities of endocrine hormones. Small cell ca of the lung is often associated with elaboration of ACTH. Hypercalcemia arises from either osteolysis by primary tumors or production of PTHrP that may act as PTH at various sites. Hypercalcemia is especially associated with carcinomas of breast, kidney, ovary, and squamous cell ca of the lung. DIC, migratory thrombophlebitis, neuromyopathies are also associated with various forms of advanced cancer.

[1] British oncologist Willis, quoted in Robbins Pathologic Basis of Disease, Sixth Edition, p. 261.

[2] From Robbins Pathologic Basis of Disease, Sixth Edition, p. 260.

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