NEOPLASIA-G PATHOLOGY {S1}

1. NEOPLASIA-G PATHOLOGY {S1} BY RANJEET RAMAN

2. Neoplasm is clonal proliferation of cells with somatic genetic alterations and autonomous ​regulation of growth. Usually form tumors, but not if in situ (“pre-invasive”). Neoplasia = dysplasia. • Malignant neoplasms are called cancer, and occur when neoplasms invade adjacent tissues and ​metastasize into distant tissues. • Some cancers injure patients mechanically, such as lung tumors blocking superior vena cava.

3. Uncontrolled population growth • Cancer cells ignore external controls. Many cancer-causing mutations occur in genes that regulate ​regulation. For instance, Rb, p16, and p53 regulate cell growth, but all lowered in cancer. ​EGFR is a growth factor signal which stimulates overgrowth.

4. Cancer cells also have reduced apoptosis in unfavorable environments, such as detachment and ​DNA damage. They resist apoptosis signal genes such as p53and BAX, and overexpress ​protective genes such as bcl2. This makes therapies difficult, because therapies can target ​proliferating cells, but may not be able to target cells that won’t die.

5. Invasion and Metastasis • First step is invasion of BM and degradation of ECM. This occurs with proteolytic enzymes such ​as metalloproteinase's. Tumor cells also may also bind and destroy ECM components ​such as fibronecting, laminin, and collagen. Cells frequently invade lymphatics because ​they lack a BM.

6. Second step is vascular or lymphatic dissemination. Cells often can survive detached from ECM, ​which is not normal. This may depend on loss of e- cadherin. They then adhere and ​extravasate at distant sites. • Third step is growth at a distant site. GI cancers commonly metastasize to lymph nodes and liver, ​whereas most other cancers spread to the lungs and brain.

7. Site of metastasis depends on two things: • ​natural pathways of vascular and lymphatic drainage ​--cancer cells express chemokine receptors, and the corresponding chemokines are often ​found in new metastatic site. Thus, cancer cells migrate in a similarly to leukocytes.

8. Modifying the host environment • Tumors must create a new stroma and blood vessels. • First modification is angiogenesis. Cancers produce angiogenic substances such as VEGF and ​FGF, which generate new endothelial vessel linings. Some tumors also produce anti-​angiogenic factors such as angiostatin.

9. There is also the possibility of vasculogenic ​mimicry, in which tumor cells themselves form a vascular lining and channel. • Second modification are the systemic effects, such as secretion of humoral factors. These may​include ectopic hormones such as ACTH and Cachexia factors such as TNF.

10. Such humoral factors cause the paraneoplastic syndromes Extended replication Normally, cells can only replicate so many times. The Hayflick Principle states that cellular ​senescence is related to shortening of DNA telomeres with each replication. Telomerase, which maintains telomeres, is expressed only during renewal.

11. Cancers express increased telomerase, although many cancers still have short telomeres. Detecting and inhibiting telomerase may help find and destroy cancer, but that’s a problem ​because you also need it for renewal.

12. Genomic instability • Most cancers are aneuploid (abnormal chromosome numbers/replications/inversions/deletions) ​because of continuous dividing. Shortening of telomeres contributes to genomic instability. • Sometimes there are mutations in mitotic checkpoint genes, which regulate segregation.

13. Morphologically, cancers are hyperchromatic and have abnormal mitoses. • Genomic instability gives cancers new phenotypic properties, including drug resistance.

14. Clonal evolution and carcinogenesis. “Multistep carcinogenesis” • Clonal evolution makes cancer. Sequential genetic changes and clonal expansion of progeny. In this way a given cell can accumulate multiple mutations, because it inherits past “hits.”

15. Although they are clonal, cells are genetically unstable and become genetically heterogeneous. • Injury to tissue promotes growth, and perhaps tumor potential. • There are three steps to carcinogenesis: • ​initiation (an irreversible DNA mutation, initiated by mutagens) ​--promotion (stimulation of initiated cell to clonally proliferate, creating neoplasm) ​--conversion (converts to malignancy, undergoes autonomous clonal proliferation)

16. Carcinomas in situ are basically hyperplasia's with major nuclear atypia. • Benign tumors have the suffix –oma. For example, benign glandular epithelial tumors are ​adenomas, and benign smooth muscle tumors are Leiomyomas. EXCEPTIONS are ​hepatoma, melanoma, and astrocytoma, all of which are malignant tumors.

17. Malignant tumors have the suffix –carcinoma if they refer to glandular epithelial tumors. • Malignant tumors have the suffix –sarcoma if they refer to stromal (connective tissue) tumors. • Hematopoetic neoplasms are called leukemia or lymphoma, depending on if in blood or lymph.

18. Tumors with mixed epithelial and mesenchymal/stromal differentiation are called a ​fibroadenoma if benign, and a carcinosarcoma if malignant. • Tumors that involve multiple germ cell layer are called a teratomas.

19. There are five major patterns of differentiation, each with different subtypes. These are named ​for they’re site of origin, not embryological origin: • ​​epithelial (squamous, glandular, basal, transitional/urothelial) ​--mesenchymal/stromal/connective ​--hematopoetic ​--melanocytic ​--Glial

20. Some benign tumors have a borderline or “low malignant” potential. One such neoplasm are ​carcinoid tumors. These tumors have neuroendocrine functions and occur in the ​respiratory and digestive systems. May range from benign to malignant. • Almost all neoplasms form tumors unless they are in situ.

21. Differentiating benign and malignant tumors Architecturally, only benign tumors are well circumscribed or encapsulated. Malignancy is seen ​when there is local invasion and vascular/lymphatic neogenesis. • Cytologically, there are numerous signs:

22. Benign cells • Malignant cells • normal sized nuclei • very large nuclei • round nucleus, even chromatin • irregular nucleus and chromatin distribution clear cellular polarity and differentiation loss of polarity and differentiation mitoses limited to the basal layer mitoses not limited to basal layer

23. The clinical situation is also very important for the diagnosis. • ​1. Site of tumor. For instance, Leiomyomas and follicular thyroid adenomas won’t ​become malignant, whereas an adenoma of the colon may become malignant. • ​2. Gender. Teratomas in the ovary are usually benign, but the same cancer in the testis ​will likely be aggressively metastatic. • ​3. Age. Teratomas in the adult male testis are dangerous, but usually not in children.

24. Grading and Staging Neoplasia • Grade = degree to which cells have malignant features. Poorly differentiated neoplasm has ​irregular cytology and architecture, and is considered high grade. Well differentiated ​tissue is low grade. • Nuclear features are the major criteria for grading. However, grading is normally not very ​predictive of clinical behavior.

25. Stage = extent of spread of the cancer. Staging, which ranges from 1 to 4, is used to predict ​clinical behavior. • Staging has three criteria, which are weighted and judged differently depending on the cancer: • ​T (for tumor size and spread into nearby tissue) ​--N (for spread into lymph nodes) ​--M (for metastasis to distant organs)

26. Stage 0 has a tumor in situ, nothing more. • Stage 1 has a growing tumor in situ. • Stage 2 may have a larger tumor, but most importantly there is spread to the lymph system. • Stage 3 may have a larger tumor, but has extensize spread through lymph system. • Stage 4 may have a larger tumor, but has metastasized to distant organs.

27. Ancillary techniques for diagnosis • Immunohistochemistry: for instance, diagnosing prostate cancer where there is a basal cell layer ​that only stains for p63 in normal tissue. Cancer won’t stain. Also, different cytokeratins ​are expressed on different tissues, and this can be used to track origin of metastatic cancer.

28. Molecular markers: such as PSA for prostate cancer. PSA is made by epithelium. It has the ​best positive predictive value of any cancer biochemical marker. • ​Another example is measuring estrogen receptor in breast cancer, since ER positive ​breast cancers have better prognosis than ER negative cancers.

29. PATHOLOGY OF HUMAN NEOPLASIA • Neoplasia = clonal proliferation of cells w/genetic alterations that confer disregulation of growth chart. • Benign tumors have the suffix –oma following the name or tissue from which the cancer arose • Ex: benign glandular epithelial tumors = adenomas: benign smooth muscle tumors = Leiomyomas. EXCEPTIONS = hepatoma, melanoma, and astrocytoma, are malignant tumors.

30. Malignant tumors have the suffix –carcinoma if they are epithelial origin have the suffix –sarcoma if they are mesenchymal (stromal) origin. • Hematopoietic neoplasms are called leukemia or lymphoma, depending on if in blood or lymph. • Tumors with mixed epithelial and mesenchymal/stromal differentiation are called a fibroadenoma if benign, and a carcinosarcoma if malignant.

31. Tumors that involve multiple germ cell layer are called a teratomas. • Five major patterns of differentiation (named for site of origin not embryological), ​​1. epithelial (Squamous =epidermoid, glandular, basal, transitional/ urothelial) ​2. mesenchymal/ stromal/connective ​3. hematopoietic ​4. melanocytic ​5. Glial Subtypes include terms papillary, cystic, polypoid, mucinous, annular (around a lumen)

32. Some benign tumors have a borderline or “low malignant” potential. • ​Ex: carcinoid tumors = have neuroendocrine functions found in respiratory and digestive systems. • May range from benign to malignant behaviour. • Almost all neoplasms of sold tissue form tumors unless they are in situ (tough to see w/naked eye)

33. Differentiating benign and malignant Tumors • Benign Tumors • ( Circumscribed, organized, capsulate) • Malignant Tumors • (Invasive, metastatic) normal sized nuclei very large nuclei round nucleus, even chromatin irregular nucleus and chromatin distribution clear cellular polarity and differentiation loss of polarity and differentiation mitoses limited to the basal layer mitoses not limited to basal layer

34. Clinical Features important for Diagnosis ​1. Site of tumor. • Ex: Leiomyomas (uterus) and follicular thyroid adenomas are benign, whereas • Adenoma of the colon may become malignant and thus called leiomyosarcoma • ​2. Gender. • Ex: Teratomas are benign in ovary but malignant in testis despite similar histology • 3. Age. • Ex: Teratomas usually benign in boys but malignant the adult male testis/

35. GRADING AND STAGING OF NEOPLASIA • Grade = degree to which cells have malignant features. • Low grade have normal nuclei and are well differentiated -High grade have large, irregular nuclei, abnormal mitosis and are poorly differentiated Nuclear features are the major criteria for grading but grading not always predictive of clinical behavior • ​Example: Useful for mesenchymal tumors, but useless for colon cancer

36. Stage = extent of spread of the cancer. (1 to 4) is used to predict clinical behavior. • Staging has three criteria, which are weighted and judged differently depending on the cancer: • ​T (for tumor size and spread into nearby tissue) ​--N (for spread into lymph nodes) ​--M (for metastasis to distant organs)

37. Combine above for clinical management, grouped staging uses the numbers 0 and I-IV Stage 0 has a tumor in situ, nothing more. • Stage 1 has a growing tumor in situ. • Stage 2 may have a larger tumor, but most importantly there is spread to the lymph system. • Stage 3 may have a larger tumor, but has extensive spread through lymph system. • Stage 4 may have a larger tumor, but has metastasized to distant organs.

38. ANCILLARY TECHNIQUES FOR DIAGNOSIS • Immunohistochemistry: Although no one marker to differentiate benign from malignant, can be helpful -Diagnosing prostate cancer: Normal tissue will stain for p53 in basal-cell layer • Cancer won’t stain for p53 but has ↑ a-methyl acylCoA racemase (AMACR) -Different cytokeratins expressed on specific tissues can be used to track origin of metastatic cancer. • ​Ex: CK 20 in cancers from colon, and CK7 in cancers from breast/lung

39. Molecular markers: (immunological) Detection of Proteins (tumor-specific antigens) secreted by the cancer • Ex: 1)PSA for prostate cancer. • PSA is made by epithelium and has best +ve predictive value of any cancer biochemical marker. • ​ 2) Estrogen receptor in breast cancer • ER +ve breast cancers have better prognosis and response to anti-E therapy than ER -ve cancer • 3) DNA w/ H-ras mutations shed by colorectal neoplasms and found in stool • 4) Mutations of EGF receptor (Her-2 neu) forms basis of lung cancer response to ┤of EFG-R

40. Subclassification of Cancer According to Molecular Features -gene expression array analysis, but still not of practical use • Example: Hematopoietic neoplasm's: • specific genetic ∆characterize classes of leukemia/lymphoma w/particular clinical properties

41. Early Detection/Monitoring • Problem: PSA à can lead to over diagnosis • RNA: unstable • DNA: stable and defining of neoplasia • Cancer specific mutation • Cancer specific methylation patterns