1. Neoplasia

2. What is a “neoplasm”?
Lay term of “tumor” conveys usual connotations – ie a new growth or mass
Definition revolves around these features:
Monoclonal proliferation of cells with specific mutations
Excessive and unregulated growth of these cells, often at the expense of surrounding normal tissue

3. Tumor classified into two categories; benign and malignant.
Tumor is an abnormal mass of tissue, the growth of which is virtually autonomous and exceeds that of normal tissue.
The growth of tumor persist after cessation of the stimuli that initiated the changes.
Tumor classified into two categories; benign and malignant.
All tumors have two basic component:
The transformed neoplastic cells.
The supporting stroma composed of non transformed elements such as connective tissue and blood vessels.

4. Benign tumors. In general benign tumors end with suffix oma .
Examples lipoma, fibroma, angioma and leiomyoma (mesenchymal tumor).
The nomenclature of benign epithelial tumors is somewhat complex and is based on both histogenesis and architecture.
Adenoma-arise from glands or forming glandular pattern.
Cystadenoma- adenoma producing large cystic masses.
Papilloma- epithelial tumor forming microscopic or macroscopic finger like projections.

5. Malignant tumors Often called cancers and divided into two categories.
Carcinoma- arising from epithelial cells.
Sarcoma- arising from mesenchymal cells.
Nomenclature based on their appearance and presumed histogenetic origin.
Malignant epithelial tumor with glandular growth termed adenocarcinoma.
Sarcoma of smooth muscle cells called leimomyosarcoma.

6. Classification continued
Tumors of lymphocytes are always malignant – called lymphoma
Tumors of melanocytes
Benign – nevus
Malignant - melanoma

7. Some tumors have more than one parenchymal cell type, two important members:
Mixed tumors: derived from one germ cell layer that differentiate into more than one parenchymal type, as mixed salivary gland tumor contain epithelial cells as well as myxoid stroma and cartilage like tissue, all elements arise from altered differentiation of ductal epithelial cells.
Teratomas: made up of variety of parenchymal cell types represented of more than one germ cell layer, usually all three endodermal, ectodermal and mesenchymal, such tumor present principally in ovary and testis.

8. Characteristic of benign and malignant neoplasms.
Based on appearance (morphology) and ultimately on behavior (clinical course) using four criteria.
Differentiation and neoplasia.
Rate of growth.
Local invasion.
Metastasis.

9. Differentiation and neoplasia
Differentiation is the extent to which tumor cells resemble comparable normal cells.
Cells within most benign tumors closely mimic corresponding normal cells.
Thyroid adenoma composed of normal looking thyroid acini and cells in lipoma mimic normal adipose tissue.
Malignant tumors in general less well differentiated than their benign counterparts.

10. Malignant tumors display pattern of differentiation ranging from well differentiated to poorly differentiated.
Lack of differentiation called also anaplasia.
Cytological features of poorly differentiated or anaplastic tumors.
Nuclear and cellular pleomorphism-wide variation in shape and size of cells and nuclei.
Hyperchromasia- darkly stained nuclei that frequently contain prominent nucleoli.
Nuclear/cytoplasmic ratio-approach 1:1 instead of 1:4 or 1:6 reflecting nuclear enlargement.

11. Microscopic features of tumors
Pleomorphism – variation in size and shape of cells within the neoplasm

12. 4. Abnormal mitosis- reflect proliferative activity, mitotic figures may be abnormal.
5. Tumor giant cells- contain a single large polypoid nucleus or multiple nuclei.
Poorly differentiated anaplastic tumor demonstrate also total disarray of tissue architecture.
Well differentiated tumor whether benign or malignant tend to retain the functional characteristics of their normal counterparts such as production of hormones.

13. Microscopic features of tumors
Mitotic activity - Increased in more malignant tumors and often abnormal in shape

14. Here are three abnormal mitoses
Here are three abnormal mitoses. Mitoses by themselves are not indicators of malignancy. However, abnormal mitoses are highly indicative of malignancy. The marked pleomorphism and hyperchromatism of surrounding cells also favors malignancy.

15. Dysplasia Refer to disorderly but non neoplastic growth.
Characterized by pleomorphism, Hyperchromasia and loss of normal orientation.
Usually encountered in epithelia, especially in uterine cervix.
When changes are marked and involve entire thickness of epithelium, the lesion considered a preinvasive neoplasm and referred to as carcinoma insitu.
Mild dysplasia do not always lead to cancer and are often reversible when inciting cause removed.

16. Rate of growth
Most malignant tumors grow more rapidly than benign tumors.
Some cancers grow slowly for years, however, and then enter a phase of rapid growth, others expand rapidly from the onset.
Growth of cancer arising from hormone sensitive tissue, such as the uterus, may be affected by variation in hormones level associated with pregnancy and menopause.
Rapidly growing malignant tumor often contain central areas of ischemic necrosis because of blood supply fail to pace with O2 needed for expanding cells.

17. Local invasion; characterized by
Most benign tumors grow as cohesive expansible masses that develop a rim of condensed connective tissue or capsule at periphery.
They do not penetrate capsule or surrounding normal tissue.
The plane of cleavage between capsule and surrounding tissue facilitate surgical enucleation.
Malignant tumors are invasive infiltrating and destroying normal surrounding tissue.

18. Well defined capsule and plane of cleavage are lacking , making enucleation difficult or impossible.
Surgical treatment of such tumors require removal of considerable margin of healthy tissue.

19. Gross (macroscopic) features of two breast neoplasms
Benign – circumscribed, often encapsulated, pushes normal tissue aside
Malignant – infiltrative growth, no capsule, destructive of normal tissues

20. Metastasis
Involve invasion of the lymphatics, blood vessels and body cavities by the tumor.
Follow by transport and growth of secondary tumor cell masses that are discontinuous with the primary tumor.
This distinguish benign from malignant tumors.
Distant metastasis occur by three routes.

21. Spread into body cavities: occur by seeding of surfaces in peritoneal, pleural, pericardial and subarachnoid spaces.
Invasion of the lymphatics: follow by transport of tumor cells to regional lymph nodes and ultimately other parts of the body.
Hematogenous spread: this is typical of all sarcoma but also is the favor routes of certain carcinoma such as kidney originating tumor.

22. Neoplasms can spread by seeding along body cavities, and this pattern is more typical for carcinomas than other neoplasms.
Note the multitude of small tan tumor nodules seen over the peritoneal surface of the mesentery shown here.

23. Both lymphatic and hematogenous spread of malignant neoplasms is possible to distant sites.
Here, a breast carcinoma has spread to a lymphatic in the lung.

25. Benign
Malignant

27. Epidemiology : Geographic and environmental factors:
In USA cancer responsible for approximately 23% of all deaths annually.
In men lung, colon and prostate cancer are leading cause of death.
In women lung, breast and colon cancer are leading cause of death.
increase risk of certain cancers with exposure to asbestos and vinyl- chloride.
Association of oropharynx, larynx and lung cancer with cigarette smoking.

28. 2. Age.
Cancer is most common in those older than 55 y of age.
Certain tumors are particular common in children younger than 15 y old as leukemia, neuroblastoma, wilm’s tumor, retinoblastoma and bone sarcoma.
3. Hereditary.
Play a role in the development of cancer even in the presence of clearly defined environmental factors.
Hereditary form can be classified into three categories:-

29. Inherited cancer syndrome:
Inheritance of single mutant gene that greatly increase the risk of developing a certain type of tumors.
The predisposing to tumor is thus autosomal dominant trait as familial retinoblastoma.
These tumors associated with inheritance of single mutant allel of cancer suppression gene.
2. Familial cancer:
Characterized by familial clustering of specific forms of cancer, but the transformation pattern is not clear in an individual case.

30. Familial form of common cancers for examples, breast, ovary, colon are recorded.
3. Autosomal recessive syndromes of defective DNA repair:
are characterized by chromosome or DNA instability that greatly increase the predisposition to environmental carcinogens.

31. 4. Acquired preneoplastic disorders
Certain clinical conditions are associated with the increase risk of developing cancer.
Cirrhosis of liver-hepatocellular carcinoma.
Atrophic gastritis-stomach cancer.
Chronic ulcerative colitis- colon carcinoma.
Leukoplakia of oral cavity and genital mucosa- squamous cell carcinoma.
Certain benign tumors associated with subsequent development of cancer-villous adenoma of colon often develop in to cancer

32. Molecular basis of cancer
Cancer is a genetic disease; genetic injury may be acquired in somatic cells by environmental agents or inherited in germ line.
Tumors develop as clonal progeny of single genetically damaged progenitor cell.
Four classes of genes are the target of genetic damage.
Growth promoting proto-oncogenes.
Growth inhibiting tumor suppressor gene.
Gene that regulate apoptosis.
Gene that regulate DNA repair.
carcinogenesis is a multistep process

33. Oncogene and cancer
Oncogenes and proto-oncogenes are defined as follows:
Oncogenes are gene whose products are associated with neoplastic transformation.
Protooncogenes are normal cellular gene that affect growth and differentiation. They can be transformed into oncogenes by
Transduction into retrovirus (v-onc)- most human tumors not caused by this type.
Change insitu that affect their expression, function or both there by converting them into c-onc.

34. Protein products of oncogenes
Growth factor: some Protooncogenes (c-sis) code for growth factor as PDGF, many tumors that produce growth factors are also responsive to growth promoting effect of secreted growth factors and hence autocrine stimulation.
Growth factor receptor: several oncogenes encode for growth factor receptors, both structural alteration (mutation) and over expression of receptor gene has been found in association with malignant transformation.

35. Signals transducing proteins: these proteins are biochemically heterogeneous and grouped into two major categories.
Guanosine triphosphate (GTP) binding protein- e.g: colonic carcinoma.
Non receptor associated tyrosine kinase- e.g: chronic myeloid leukemia.
Nuclear transcription protein: the product of myc and myb oncogenes are nuclear proteins, expressed highly in normal cell proliferation, their oncogene version associated with persistent expression, e.g; Burkett's lymphoma.
Cyclins and cyclin dependent kinase (CDK): these regulate progression of cells through cell cycle.

36. Activation of oncogenes
Protooncogenes can be transformed into oncogenes by one of three mechanism.
Point mutation.
Chromosomal rearrangement.
Gene amplification.

37. Point mutation. The ras Protooncogenes activated by point mutation.
Approximately 15 % of human tumors associated with mutated H-ras or K-ras oncogenes.
One possible mechanism of these mutation is exposure to cancer causing chemicals.

38. Chromosomal rearrangement.
Placement of gene next to strong promoter/enhancer elements of Ig or T-cell receptor loci in lymphoid cells- Burkitt lymphoma t(8;14).
Fusion of the gene with new genetic sequences, in CML t(9;22).

39. Gene amplification
Reduplication of proto-oncogenes can lead to increase expression or activity.
Example-N-myc amplification in neuroblastoma, amplification of c-erb-2 gene in 30-40% of breast cancer.

40. Cancer suppressor genes
Cancer may arise not only by activation of growth promoting oncogenes, but also by inactivation of gene that normally suppress cell proliferation (antioncogenes).
The Rb gene is prototypic cancer suppressor gene.

41. Protein products of tumor suppressor genes
P53: is mutated in greater than 50% of all human cancers, those who inherit mutant copy of P53 gene are at high risk of developing malignant tumor by inactivation of the second normal allel in somatic cells,the normal function of P53 gene is to prevent propagation of genetically damage cells.
BRCA-1&BRCA-2: mutation in these can account for 80% of breast cancers.
APC gene: those with one mutant allel of this gene develop hundreds of adenomatous polyps in the colon.

42. Gene that regulate apoptosis
The prototypic gene in this group, bcl-2 prevent apoptosis.
Over expression of bcl-2 extend cell survival , and if the cells are genetically damaged, the continue to suffer additional mutations in oncogenes and cancer suppressor gene.
Most common example B- cell lymphoma of follicular type.

43. Gene that regulate DNA repair.
The DNA repair gene do not contribute directly to cell growth or proliferation.
They act indirectly by correcting error in DNA that occur spontaneously during cell division or those that follows exposure to mutagenic chemicals or irradiation.
Patient with hereditary non polyposis colon cancer are born with one defective copy of one of several DNA repair gene.

44. Biology of tumor growth