Pathology Trans 3A Neoplasia I PDF

PATHOLOGY | TRANS 3A LE Neoplasia I DR. JOSELLI RUEDA-CU, RN, LLB, DTM&H, MHA, MPH, MD, FPSP | 09/20/2024 | Versio...

PATHOLOGY | TRANS 3A LE Neoplasia I DR. JOSELLI RUEDA-CU, RN, LLB, DTM&H, MHA, MPH, MD, FPSP | 09/20/2024 | Version #1 02 OUTLINE → Reactive stroma made up of connective tissue, blood I. Neoplasia V. Staging and Grading vessels, and variable number of cells of adaptive and II. Types of Neoplasia A. Staging innate system A. Benign Neoplasms B. Grading ▪ Tumor’s growth and spread are critically dependent B. Malignant Neoplasms VI. Appearances of Neoplasm on the stroma. III. Benign VS Malignant A. Carcinoma ▪ In other cases, parenchymal cells stimulate formation A. Differentiation B. Sarcoma of a lot of collagenous stroma, known as B. Anaplasia C. Blastoma C. Desmoplasia D. Neoplasms With More desmoplasia (stony hard or scirrhous), noted in D. Metaplasia than One Cell Type carcinoma of the breast tissue. E. Dysplasia VII. Non-Neoplastic Growth II. TYPES OF NEOPLASIA F. Carcinoma In-Situ (CIS) A. Hamartomas G. Local Invasion B. Choristoma A. BENIGN NEOPLASMS H. Functional Differential VIII. Supplemental Videos Characteristics I. Rate of Growth IX. Sample questions → Slow growth J. Metastasis X. References → Resemblance to tissue of origin (well-differentiated) IV. Neoplastic Spread XI. Appendix → Solitary Must Lecturer Book Previous Youtube → Circumscription → Lack of invasion or metastases ❗️ Know 💬 📖 📋 Trans 🔺 Video In general, does not result in death of a patient, except: → If located in critical tight areas like pituitary adenoma in SUMMARY OF ABBREVIATIONS sella turcica → problems through mass effect CA Cancer → Secretory tumors (e.g., endocrine tumors) EMT Epithelial-Mesenchymal Transition Can be cured by surgery alone PDGF Platelet-Derived Growth Factor EGFR Epithelial Growth Factor Receptor Gross description of a benign tumor is circumscription TGF-α Tumor Growth Factor Alpha → Benign tumors grow and expand slowly with VEGF Vascular Endothelial Growth Factor development of a small rim of compressed tissue, called FGF Fibroblast Growth Factor capsule, that separates them from the host tissue LEARNING OBJECTIVES ✔ Define, classify, and illustrate the nomenclature of neoplasia. ✔ Describe, distinguish, demonstrate, categorize, evaluate the characteristics of benign and malignant neoplasm as to: o Differentiate and anaplasia o Local invasion o Metastasis ✔ Describe, discuss, explain, apply, analyze, appraise, and assess the grading/ staging of tumors. I. NEOPLASIA Literally means new growth Abnormal mass of tissue growing autonomously and uncoordinated with surrounding normal tissue. → Neoplastic cells are transformed (i.e. continue growing without regard for normal control). → Neoplastic cells are mostly autonomous (without control) but still depend on host cells for blood supply Figure 1. Circumscription.[Lecturer’s PPT] (some are endocrine dependent). NOMENCLATURE Oncology: Study of neoplasm (onco - tumor; logos - Nomenclature of benign tumors are more complex study) → Some are classified based on their cells of origin Two Fundamental Features of Neoplasm: → Others on their microscopic pattern → Unregulated growth Usually with a suffix of -oma, especially stromal tumors → Clonal genetic defects Adenoma ▪ Derived from single cells with all cells within the → Epithelial in origin derived from glands 📋 neoplasm, clonally related. Two Basic Components of Tumor → Neoplastic cells that constitute tumor parenchyma ▪ Renal tubular adenoma: forming gland-like structures is renal tubular cells in form of small glands ▪ Basis for classification of tumors and biologic ▪ Adrenal cortical adenoma: from adrenal cortical behavior cells growing in solid sheet → May or may not form glandular structure Fibroma: Fibrous tissue LE 2 TG 23 | Mendoza, M.J., Mendoza, R., Mercado, TE | Mercado, A AVPAA | Lee, A. PAGE 1 of 20 TRANS 3A A., Mercado, H., Millares, P., Morales, K. VPAA | Fabros, P. PATHOLOGY | LE 2 Neoplasia I | Dr. Joselli Rueda Cu , RN, LLB, DTM&H, MHA, MPH, MD, FPSP Leiomyoma: Smooth muscle tissue B. MALIGNANT NEOPLASMS Lipoma: Adipose tissue From latin word, crab Cystadenoma: Hollow cystic mass in ovary → Tend to adhere to any part in an obstinate manner → Papillary cystadenoma: papillary patterns that → Usually fixed and non-movable, and hard protrude into cystic spaces Collectively known as cancers Papilloma Characteristics: → Microscopic or macroscopic finger-like frond projects on → Rapid increase in size epithelial surface → Anaplasia Polyp ▪ Looks different from the cells of origin. → Benign or malignant neoplasm macroscopically ▪ Lack of differentiation producing visible projection above a mucosal surface → Tendency to spread by invasion into gastric or colonic lumen → Destroy local structures ▪ Adenomatous polyp: if the polyp has glandular → Metastases tissue ▪ Go to distant structures from the primary growth Osteoma: Bone SPREAD OF MALIGNANT NEOPLASMS Chondroma: Cartilage Metastasis Table 1. Nomenclature exceptions to -oma suffix → Spread to distant, non-contiguous sites via: Benign Description ▪ Invasion Hepatoma Malignant transformation of hepatocytes − Direct extension into surrounding tissues Melanoma Malignancy of skin; involving the − There is a particular site in the capsule where the melanocytes malignant cells invade. Mesothelioma Malignancy of lungs ▪ Lymphatic spread (nodes) Lymphoma Malignancy of the lymph nodes − Lymph channels to lymph nodes Sarcoma Malignancy of soft tissues − Typical of carcinomas Seminoma Malignant tumors of undescended testis − Multiple nodules indicates metastatic lesion MUST KNOW 📋 ▪ Hematogenous spread (lung, liver, bone, brain) − Through the bloodstream → lung, liver, bone, Malignant tumors that can also end in "-oma" which are brain exceptions to the general rule: − Typical of carcinomas or sarcomas ○ Seminoma: malignant tumors of undescended testis ▪ Implantation (Seeding) in body cavities ○ Melanoma: melanocytes or melanin-carrying basal − Typical of neoplasms in the peritoneal cavity cells − Characteristic of malignancy of appendix or ○ Lymphoma: lymph nodes ovarian carcinomas seeding into the serosal ○ Hepatoma: hepatocytes surfaces with their mucin secretion filling the ○ Sarcoma: soft tissues peritoneal cavity, and is known as pseudomyxoma ○ Mesothelioma: lungs peritonei. (See Figure 7) "So Much Love: High School Musical" Invasion and metastasis: hallmarks of malignancy Usually results in death. Figure 2. Squamous cell papilloma. Finger-like frond tissue Figure 4. Direct/contiguous invasion (follicular carcinoma of extruding through the mucosal surfaces made up mostly of the thyroid). Note the rows of cells penetrating the margins, squamous cells.[Lecturer’s PPT] and infiltrating adjacent structures.[Lecturer’s PPT] Figure 5. Hematogenous route. (L) Liver studded with multiple umbilicated nodules with depression at the center, a characteristic of metastatic lesions.[Lecturer’s PPT] Figure 3. Papilloma of glandular structure.[Lecturer’s PPT] PATHOLOGY Neoplasia I PAGE 2 of 20 PATHOLOGY | LE 2 Neoplasia I | Dr. Joselli Rueda Cu , RN, LLB, DTM&H, MHA, MPH, MD, FPSP Epithelium adenoma adenocarcinoma Liver Cell Hepatic Hepatocellular adenoma carcinoma Urinary Tract Transitional cell Transitional cell Transitional papilloma carcinoma Cell Connective Fibroma Fibrosarcoma Tissue Lipoma Liposarcoma Chondroma Chondrosarcoma Osteoma Osteosarcoma Endothelium Hemangioma Hemangiosarcoma Meningioma Invasive Figure 6. Lymphatic Spread. Lymph node with metastatic Hemangioma spread of glandular and aplastic cells.[Lecturer’s PPT] Smooth Muscle Leiomyoma Leiomyosarcoma Skeletal Rhabdomyoma Rhabdomyosarcoma Muscles Not all malignant neoplasms have benign counterparts: → Hematopoietic and lymphoid cells (as in bone marrow and lymph nodes) give rise to leukemias and lymphomas. → Gliomas (astrocytomas, oligodendrogliomas, glioblastoma multiforme, etc.) arise from glial cells in the CNS Figure 7. Peritoneal Spread (Seeding). The serosal surface SARCOMA of the intestinal tract is seeded by numerous malignant arise from soft tissue (connective tissues such as nodules. Characteristic of malignancy originating from the cartilage, bone, fascia, smooth or skeletal muscle, blood appendix or ovaries, they seed on serosal surfaces with vessels, lymph vessels, coverings of organs such as mucin secretion filling the peritoneal cavity. known as mesothelium. pseudomyxoma peritonei.[Lecturer’s PPT] In general they are composed of very pleomorphic NOMENCLATURE spindle-shaped cells. Sarcoma: Solid mesenchymal tumor generally big and bad → Fibrosarcoma: soft tissue malignancy of fibrous tissue Malignancies arising from mesoderm are usually → Chondrosarcoma: malignancy of cartilage sarcomas → Leiomyosarcoma: malignancy of smooth muscle tissue → Leiomyosarcoma: arise from smooth muscle. → Rhabdomyosarcoma: malignancy of skeletal muscle → Chondrosarcoma: arise from cartilage Leukemia: Those arising from white blood cells → Osteosarcoma: arise from bone Lymphoma: Tumors of lymphocytes or their precursors → Liposarcoma: arise from adipose tissue Carcinoma: Malignancy from epithelial cell origin REVIEW OF ORGANS DERIVED FROM GERM LAYERS → From any of the three germ cell layers: Endoderm ▪ Ectoderm: Epidermis → Lining of Epithelia: Gastrointestinal tract, middle ear, ▪ Mesoderm: Renal tubules respiratory tract, gallbladder, duct system, pancreatic ▪ Endoderm: Lining of the gastrointestinal tract ducts, urinary bladder except trigone, female urethra → Further subclassification of carcinoma: except posterior wall, male urethra except posterior ▪ Squamous cell carcinoma: resembles stratified wall of prostatic part, greater part of vagina, vestibule squamous epithelium and inner surface of labia minora. ▪ Adenocarcinoma: glandular pattern → Endocrine Glands: Thyroid, parathyroid, thymus, ▪ Undifferentiated malignant tumor: unknown tissue islets of langerhans. of origin → Exocrine Glands: Liver, pancreas, glans in GIT, Table 2. Summary of Nomenclature: Benign vs Malignant prostatic glands and its female homologues. BENIGN MALIGNANT Mesoderm Squamous Papilloma Squamous cell → All connective tissue: Loose areolar tissue, superficial Cells carcinoma and deep fascia, ligaments, tendons, aponeuroses, Basal Cells Basal cell carcinoma dermis. → Specialized connective tissue: Adipose, reticular, Glands Adenoma Adenocarcinoma cartilage, bones Adeno Cystic → All muscles: Smooth, striated, cardiac-except Cystadenoma adenocarcinoma musculature of iris. Lung: Bronchial Bronchogenic → Heart, all blood and lymphatic vessels, blood cells Respiratory adenoma carcinoma → Kidneys, ureters, trigone of bladder, parts of male and Passages female urethra, inner prostatic glands. Neuroectoderm Nevus Melanoma → Ovary, uterus, uterine tubes, upper part of vagina. Renal Reba tubular Renal tubular → Testis, epididymis, ductus deferens, seminal vesicle, PATHOLOGY Neoplasia I PAGE 3 of 20 PATHOLOGY | LE 2 Neoplasia I | Dr. Joselli Rueda Cu , RN, LLB, DTM&H, MHA, MPH, MD, FPSP ejaculatory duct. abnormal) → Lining mesothelium of pleural, pericardial and Local Cohesive,expansile, Locally invasive peritoneal cavities, tunica vaginalis. Invasion well demarcated Infiltrating → Lining mesothelium of bursae and joints. masses surrounding → Substance of cornea, sclera,choroid, ciliary body and DO NOT invade or tissue iris. infiltrate normal (sometimes Ectoderm surrounding tissues. maybe → Lining of Epithelia: Skin, lips, cheeks, gums, part of misleading floor of mouth, parts of palate, nasal cavities, paranasal cohesive and sinuses, lower part of anal canal, terminal part of male expansile) urethra, labia majora, epithelium of cornea, conjunctiva, Metastasis Never / Absent Frequent ciliary body, iris, outer layer of tympanic membrane and Large and membranous labyrinth undifferentiated → Exocrine Glands: Sweat glands, sebaceous glands, primary tumors parotid, mammary and lacrimal. → Others: Hair, nails, enamel of teeth, lens of eye, A. DIFFERENTIATION musculature of iris, nervous system. Refers to the parenchyma of the neoplasm The extent to which neoplastic cells resemble their III. BENIGN VS MALIGNANT normal forebears, morphologically and functionally. Four Parameters to differentiate Benign vs Malignant: BENIGN NEOPLASM → Differentiation and Anaplasia ▪ Differentiation: how different from are one another Typically well-differentiated, histologically similar to the ▪ Anaplasia: how different they look from the original cells of origin → Rate of Growth Mitoses - rare and normal in appearance ▪ How fast is the rate of growth? → Local Invasion ▪ Do they invade contiguous tissue or not? → Metastases ▪ Do they have the ability to travel distant from their original location? Table 3. Characteristics that Differentiate Benign and Malignant Neoplasms BENIGN MALIGNANT Differentiation Well differentiated Lack / Anaplasia Most of the time differentiation Figure 8. Gross specimen of well delineated breast tumor with typical Atypical structure from the surrounding stroma.[Lecturer’s PPT] structure (often) Structure Structure often Cells usually of typical dedifferentiation toward anaplasia Cellular Variable degree of Structure often Differentiation normal greatly altered Manner of By expansion, By invasion and Growth usually destruction, encapsulated poorly demarcated, not encapsulated Rate of Usually progressive Erratic Growth and slow May be slow; Figure 9. Microscopic View: Fibroadenoma of Breast May come to a usually (Benign).[Lecturer’s PPT] standstill or regress rapid and Mitotic figures rare unrestricted Examples: and normal Numerous and → Lipoma: Mature fat-laden cells abnormal mitotic → Chondroma: Mature cartilage cells figures (often → Leiomyoma: Mature bundles of spindled smooth abnormal) muscle CAUTION: Don’t be misled by normally high mitotic index → Polyp: neoplastic protrusion from an epithelial surface in tissues such as gut, lymph nodes, bone marrow that projects into the lumen Progression Erratic Relentless of growth May be slow; progression B. ANAPLASIA usually rapid and toward eventual Loss of structural and functional differentiation of unrestricted; death normal cells. numerous and Failure of differentiation of malignant cells abnormal mitotic Hallmark of malignancy (as far as histologic feature is figures (often concerned) PATHOLOGY Neoplasia I PAGE 4 of 20 PATHOLOGY | LE 2 Neoplasia I | Dr. Joselli Rueda Cu , RN, LLB, DTM&H, MHA, MPH, MD, FPSP CYTOLOGIC FEATURES OF → prominent nucleoli within the nuclei. MALIGNANT(ANAPLASTIC) NEOPLASMS → mitoses (especially irregular or bizarre mitoses), Pleomorphism - marked variation in size and shape reflecting the high proliferative activity of the parenchymal cells. All of these features are "atypical". Atypia implies a change for the worse from normal. Figure 10. Variation in nuclear or cell size (pleomorphism). increased nuclear size (with increased nuclear/cytoplasmic ratio--N/C ratio).[Lecturer’s PPT] N/C RATIO: constant proportionality between the volume of nucleus and cytoplasm characteristic of any given type of cell Nuclear Hypochromasia (very dark) Figure 13. Anaplasia.[Lecturer’s PPT] Anaplasia; cells lose the morphological characteristics of mature cells and their orientation with respect to each other and to endothelial cells. Figure 11. Hyperchromatism.[Lecturer’s PPT] Hyperchromatism: increased nuclear DNA content with subsequent dark staining on H&E slides Nuclear Enlargement → Increased Nuclear/Cytoplasmic ratio Figure 14. Abnormal Mitosis (1).[Lecturer’s PPT] Mitoses by themselves are NOT indicators of malignancy. However, abnormal mitoses(centrally located) are highly indicative of malignancy. The marked pleomorphism and hyperchromatism of surrounding cells also favors malignancy. Figure 12. Prominent nucleoli. one of the indicators of increased cellular activities. Nucleoli (blue arrows)[Lecturer’s PPT] Bizarrely shaped Nuclei Cytologic features of malignant (anaplastic) neoplasms → increased nuclear size that may approach 1:1 rather than the normal 1:4 or 1:6 (with increased nuclear/cytoplasmic ratio--N/C ratio). → variation in nuclear or cell size (pleomorphism). → lack of differentiation (anaplasia). → increased nuclear DNA content with subsequent dark Figure 15. Abnormal Mitosis (2).[Lecturer’s PPT] staining on H and E slides (hyperchromatism). PATHOLOGY Neoplasia I PAGE 5 of 20 PATHOLOGY | LE 2 Neoplasia I | Dr. Joselli Rueda Cu , RN, LLB, DTM&H, MHA, MPH, MD, FPSP Mitoses by themselves are not indicators of malignancy. C. DESMOPLASIA However, abnormal mitoses(centrally located) are highly Fibrous stroma induced by malignant neoplasm indicative of malignancy. The marked pleomorphism and Produces a very hard lump hyperchromatism of surrounding cells also favors Scirrhous Neoplasm malignancy. Commonly seen in Breast Cancer Note those indicated by the arrows which are the abnormal mitotic figures MALIGNANT NEOPLASM Malignant Neoplasm vary from well differentiated to poorly differentiated or anaplastic Anaplastic refers to poorly differentiated neoplasms Some malignant neoplasms are so well differentiated they are hard to distinguish from benign growths Figure 19. Desmoplasia. Hyalinized fibrocollagenous tissue.[Lecturer’s PPT] D. METAPLASIA (RECALL) Metaplasia: replacement of one type of cell with another type which is more resistant to offending stimulus. → Nearly always found in association with tissue damage, Figure 16. Well Differentiated Squamous Cell Carcinoma. repair and regeneration keratin formation (arrow)[Lecturer’s PPT] → Replacing tissue better suited to the local environment. e.g. esophagus stratified squamous epithelium changing into gastric glandular mucosa in gastroesophageal reflux more suited to acidic environment. E. DYSPLASIA Dysplasia: disordered growth in epithelia with loss in uniformity of individual cells and loss in their architectural orientation. In squamous epithelium, tall cells in the basal layer to flattened squames on the surface may fail in part or entirely with replacement by basal-appearing cells with hyperchromatic nuclei. Mitotic figures are noted at all levels including surface cells Loss of Cellular uniformity and architectural Figure 17. Anaplastic Cells in rhabdomyosarcoma (1).[Lecturer’s orientation PPT] This is a phenomenon seen in epithelial cells Not Neoplastic change Mitotic figures are confined to the basal layer of stratified squamous epithelium → Dysplastic epithelium has mitoses throughout Stratified squamous epithelium has a normal maturation from base to top → Dysplastic epithelium has architectural anarchy Antedates the appearance of Cancer → Smoker bronchi → Uterine cervix Dysplasia is not cancer Dysplasia is not an adaptive response Dysplasia is reversible Pre-invasive neoplasm/Carcinoma in situ: marked dysplastic changes involving full thickness of the epithelium but does not penetrate the basement Figure 18. Anaplastic Cells (2).[Lecturer’s PPT] membrane. PATHOLOGY Neoplasia I PAGE 6 of 20 PATHOLOGY | LE 2 Neoplasia I | Dr. Joselli Rueda Cu , RN, LLB, DTM&H, MHA, MPH, MD, FPSP Some may persist for years before it becomes invasive Severe dysplasia in bronchial lining epithelium among chronic cigarette smokers and Barrett esophageal dysplasia usually progresses to cancer. However, some may not always progress to cancer. With removal of inciting cause in mild to moderate dysplasia, architecture may revert to normal Once tumor goes beyond the basement membrane it is invasive F. CARCINOMA IN-SITU (CIS) Full thickness dysplasia Pre-invasive stage of cancer A misnomer because Carcinoma In-Situ is a not cancer - YET- It is NOT a carcinoma It will become a cancer 99.999% of the time → Walker’s Law Fails Figure 21. “Pseudoencapsulated” masses.[Lecturer’s PPT] Histologic exam shows rows of cells penetrating the margins and infiltrating adjacent structures as noted here in the follicular carcinoma of the thyroid Figure 20. Carcinoma In-Situ.[Lecturer’s PPT] G. LOCAL INVASION Growth of cancers is by progressive infiltration, invasion Figure 22. Malignant tumors.[Lecturer’s PPT] and destruction of surrounding tissue Malignant tumors are poorly demarcated from the Poorly demarcated from the surrounding tissue lacking the surrounding normal tissue and a well defined cleavage well defined cleavage plane is noted in benign. structure (capsule) is lacking. They grow by progressive Slowly developing malignant tumor may develop pseudo infiltration, invasion, destruction, and penetration of the encapsulation but on histologic examination, shows rows surrounding tissue. of cells penetrating adjacent structures INVASIVENESS, next to metastases, is the most reliable feature that differentiates cancers from benign tumors making surgical extirpation difficult, hence wide resection is done Benign tumors grow as cohesive expansile masses and remain localized to site of origin. It doesn’t infiltrate, invade, or metastasize to distant sites. The slow expansive growth compress fibrous tissue cause hypoxic damage activating fibroblasts and depositing extracellular matrix forming a capsule that separates the normal tissue → Malignant neoplasms invade and metastasize by definition → Most develop a surrounding fibrous capsule → Exceptions to every rule such as in hemangioma which is unencapsulated and often unresectable Figure 23. Breast Cancer.[Lecturer’s PPT] Microscopic examination: Malignant tumors are poorly demarcated from the surrounding normal tissue. They do not form capsules. Hence, surgeons do Wide Excisions. PATHOLOGY Neoplasia I PAGE 7 of 20 PATHOLOGY | LE 2 Neoplasia I | Dr. Joselli Rueda Cu , RN, LLB, DTM&H, MHA, MPH, MD, FPSP H. FUNCTIONAL DIFFERENTIAL SEEDING OF BODY CAVITIES The more differentiated the neoplasm, the more like its CA of the Colon invades the pericolonic fat and breaks free normal counterpart into the peritoneal cavity → Endocrine adenomas make the same hormones CA of the Ovary is another big peritoneal spreader → Some malignant endocrine neoplasm make hormones → Squamous Cell CA makes Keratin LYMPHATIC SPREAD Benign Neoplasms may produce excessive normal More typical of carcinomas (epithelial origin) rather substances than sarcomas (hematogenous, mesenchymal origin) Thyroid Adenomas produce too much thyroid hormone → But this is a vast generalization, through an important Some malignant neoplasms become like fetal cells one → Make fetal cell products → It is the rationale for lymph node dissection in many Some make products the normal counterpart doesn’t make Carcinomas → Ectopic hormone production Most common transport pathway for initial dissemination of Bronchogenic carcinoma: produce corticotropin, carcinomas is lymphatic. Less common for Sarcomas parathyroid-like hormone, insulin, glucagon -> Skip bypass of local lymph nodes may occur due to paraneoplastic syndromes venous-lymphatic anastomosis or obliteration of lymphatic Rapidly growing anaplastic tumor are less likely to have channels brought about by venous lymphatic anastomosis specialized functional activity Sentinel lymph node: the first node in a regional The more anaplastic and rapidly growing, the less likely to lymphatic basin that receives lymph flow from the primary have specialized functions tumor, hence it is utilized for detecting spread of melanomas, colon cancer and other tumors by injecting I. RATE OF GROWTH radiolabeled tracers or colored dyes during frozen Benign neoplasms biopsy → Slow growth Serve as an effective barrier to further dissemination of Malignant neoplasms tumor cell debris/tumor antigens and they elicit immune → Fast growth response -> reactive change within the node -> There are exceptions to this rule. hyperplasia which may not be due to dissemination of The faster the growth, the more anaplastic the primary lesion. malignant neoplasm The pattern of nodal spread reflects the normal lymph These fast growers often have necrotic centers drainage Neoplasms frequently evolve over years Breast Ca - axillary nodes Spread of Malignant Neoplasms → Follow the normal lymphatic drainage, hence upper → Direct extension (Invasion) into surrounding tissues outer quadrant mass of the breast, the usual location, → Through lymph channels to lymph nodes (lymphatic metastasize to axillary nodes. For the breast inner outer spread) - typical of carcinomas quadrant, it drains in nodes along the internal mammary → Via the bloodstream (hematogenous spread) - typical arteries -> infraclavicular and supraclavicular nodes. of carcinomas or sarcomas → Determining involvement of axillary nodes is important → Within body cavities (Seeding) - typical of neoplasms in in the assessment the course of illness and selection of peritoneal cavity therapeutic regimen J. METASTASIS Lung Ca - bronchial nodes - tracheal nodes The development of secondary implants discontinuous → Carcinomas of the lungs from the major respiratory with primary Malignant neoplasm and possibly in remote passage -> perihilar tracheobronchial and mediastinal tissues nodes Malignant Neoplasm invade and metastasize by HEMATOGENOUS SPREAD definition Sarcomas predominate but carcinomas may also spread There are variation in theses abilities, but all can do it via this route Metastasis: spread of tumor to sites that are Arteries are rarely invaded physically discontinuous with the primary tumor, Veins are the route of hematogenous spread marking the tumor as malignant. → Arteries have thicker walls hence less readily → Invasiveness penetrates into blood vessels, lymphatics penetrated than the veins. However, when tumor cells and body cavities pass through the pulmonary capillary beds or pulmonary → Some tumors rarely metastasize such as gliomas from arteriovenous shunts or when pulmonary metastases glial cells of CNS and basal cell carcinoma of the skin themselves give rise to tumor emboli, this pattern of About 50% of all patients with newly diagnosed solid vascular spread can occur with interplay of several malignant neoplasms have metastases (20% are occult) other factors → Walkers Law Liver and lungs are the usual endpoints of The more anaplastic the neoplasm, the more likely to have hematogenous spread Metastases Portal flow to liver and caval flow to lungs 📖 Exceptions to every rule 30% of newly diagnosed solid tumors (excluding skin cancer other than melanoma), they are present with Renal Cell Ca has a propensity to invade the renal vein Venous invasion follows the venous flow, draining the site of the neoplasm with the tumor cells resting at the first metastases available capillary bed. Liquid tumors: leukemia, lymphoma The liver and lungs are the most frequently involved, all Metastasis could be: Seeding in body cavities, Lymphatic portal area drainage flows to the liver, and all caval blood spread, Vascular spread, or spread through surgical flows to the lungs. instruments PATHOLOGY Neoplasia I PAGE 8 of 20 PATHOLOGY | LE 2 Neoplasia I | Dr. Joselli Rueda Cu , RN, LLB, DTM&H, MHA, MPH, MD, FPSP Renal vein invasion, inferior vena cava, right side, or When the entire epithelium is dysplastic and no normal hepatocellular ca, the portal and hepatic radicle, main epithelial cells are left, the process is beyond dysplasia venous channels, carry a bad prognosis. and is now neoplasia. If the basement membrane is still intact, the process is called “carcinoma-in-situ” since the carcinoma is still confined to the epithelium Figure 27. Schematic diagram of microinvasion.[Lecturer’s PPT] Figure 24. Liver Metastases.[Lecturer’s PPT] Once the tumor cells reach the basement membrane, it is LEIOMYOMA VS. LEIOMYOSARCOMA already invasive. Figure 28. Microinvasion. Upper left image (pointed by arrow): Malignant cell that has gone beyond the basement Figure 25. Myometrium: Benign vs. Malignant Tumor.[Lecturer’s membrane. Other pics show extension of anaplastic cells into PPT] the underlying tissue.[Lecturer’s PPT] Check table in appendix for table differentiating benign and malignant tumors. Don’t be misled by normally high Metastasis: from primary site to site discontinuous with mitotic index in tissues such as gut, lymph nodes, and the primary tumor bone marrow STAGES OF METASTASIS IV. NEOPLASTIC SPREAD Local invasion: spread within the organ of origin or to The spread of malignant neoplasms determines the stage contiguous structures. In-situ: epithelial malignancies confined to the epithelium Local metastases: contiguous spread of the neoplasm without going through the basement membrane. within the organ of origin or to the lymph nodes closest to Microinvasion: spread of epithelial malignancies beyond the organ of origin. the point of origin through the basement membrane. Distant metastases: spread to other organs or to far away lymph nodes Figure 26. Carcinoma in situ.[Lecturer’s PPT] PATHOLOGY Neoplasia I PAGE 9 of 20 PATHOLOGY | LE 2 Neoplasia I | Dr. Joselli Rueda Cu , RN, LLB, DTM&H, MHA, MPH, MD, FPSP V. STAGING AND GRADING For malignant neoplasms, to determine the treatment and the prognosis In general, the higher the stage, the larger and more aggressive a neoplasm is and the farther it has likely spread. Grading is an assessment for how different the cell is from normal like increase of nucleus size, presence of nucleoli, etc. A. STAGING The most common systems for staging employ the TNM classification. → A "T" score is based upon the size and/or extent of invasion. → The "N" score indicates the extent of lymph node involvement. Figure 29. Local Invasion of Melanoma. Black melanoma → The "M" score indicates whether distant metastases are tumor spreading to its contiguous site.[Lecturer’s PPT] present. TNM STAGING SYSTEM Table 4. Staging of Malignant Neoplasms T Score Stage Definition Tis In situ, non-invasive; confined to epithelium T1 Small, minimally invasive w/in primary organ site T2 Larger, more invasive w/in primary organ site T3 Larger and/or invasive beyond margins of T4 primary organ site Very large and/or very invasive (≥ 4cm spread to adjacent organs 💬 ), TX* Tumor cannot be measured Figure 30. Local Metastasis. note the invasion of poorly N Score differentiated cancer cells, which are destroying the normal lymph node architecture.[Lecturer’s PPT] Stage Definition N0 No lymph involvement Local Metastases: As cancer cells gain the ability to N1 Regional lymph node involvement metastasize, they may escape the local tissue and enter N2 Extensive regional lymph node involvement the lymphatic vessels. N3 More distant lymph node involvement Once in the lymphatic circulation, they drain toward the nearest regional lymph node, where they can lodge and NX* More distant lymph node involvement develop a secondary implant. M Score Stage Definition M0 No distant metastases M1 Present distant metastases MX* Metastasis cannot be measured The TNM system is the most widely used cancer staging system. Most hospitals and medical centers use the TNM system as their main method for cancer reporting. → You are likely to see your cancer described by this staging system in your pathology report, unless you have a cancer for which a different staging system is used. Examples of cancers with different staging Figure 31. Distant metastases (spread to other organs or to systems include brain and spinal cord tumors and blood far away lymph nodes).[Lecturer’s PPT] cancers. Tumor growth at a primary site When your cancer is described by the TNM system, there Local invasion & EMT will be numbers after each letter that give more details Intravasation & dissemination about the cancer—for example, T1N0MX or T3N1M0. DTC fate determined within vascular sub-niches T (Primary Tumor) Extravasation to pre-metastatic niches → Based upon the size and/or extent of invasion of the Indicators that a neoplasm is malignant are: main tumor/primary tumor → Metastases (best indicator) → TX: Main tumor cannot be measured → Invasion (next best indicator) → T0: Main tumor cannot be found → T1, T2, T3, T4: Refers to the size and/or extent of the main tumor PATHOLOGY Neoplasia I PAGE 10 of 20 PATHOLOGY | LE 2 Neoplasia I | Dr. Joselli Rueda Cu , RN, LLB, DTM&H, MHA, MPH, MD, FPSP ▪ The higher the number after the T, the larger the OTHER STAGING CLASSIFICATION tumor or the more it has grown into nearby tissues → May be further divided to provide more detail (i.e., T3a Reference from the National Cancer Institute of Health and T3b) (NIH) N (Regional Lymph Nodes) Less detailed than TNM Classification → Indicates the extent of lymph node involvement Table 6. Cancer Staging Classification → NX: Cancer in nearby lymph nodes cannot be measured Stage Description → N0: There is no cancer in nearby lymph nodes 0 Presence of abnormal cells but have not spread → N1, N2, N3: Refers to the number and location of to nearby tissues lymphnodes that contain cancer. A.K.A. “Carcinoma in situ (CIS)” ▪ The higher the number after the N, the more lymph CIS is not a cancer but can develop into one nodes that contain cancer 1, 2, 3 Cancer is present M (Distant Metastases) The larger the number, the larger the cancer → Indicates whether distant metastases are present 4 The cancer has spread to distant parts of the → MX: Metastasis cannot be measured body → M0: Cancer has not spread to other parts of the body → M1: Cancer has spread to other parts of the body B. GRADING A cellular assessment of how different a cell is from normal → Microscopic appearance The higher the grade, the higher the probability that the stage is also high Used to measure cell anaplasia or reversal differentiation Base on the resemblance of the tumor to the original tissue Parameters of cellular malignancy: → Increase in size of the nucleus → Presence of nucleoli → Abnormal mitotic figures, etc. Table 7. Grading of Malignant Neoplasms Grade Description I Well-differentiated Figure 32. Lung cancer illustration staging.[Lecturer’s PPT] Cells look very similar to tissue of origin Table 5. Lung cancer Stages and its Notations II Moderately differentiated Lung cancer Illustration Staging Slightly looks like the tissue of origin Stage Explanation of various stage III Poorly differentiation Tis smallest, within basement membrane No longer looks like the tissue of origin Hard to determine the origin of the tissue T1 slightly bigger tissue, one part of organ IV Nearly Anaplastic T2 gone beyond to other part of organ Indistinguishable from the tissue of origin T3 gone outside of the organ Sometimes called “undifferentiated” N1 small perihilar nodes N2 into regional draining lymph nodes N3 more distant nodal filtration M1 gone beyond the confines of the lungs Figure 34. Well Differentiated Adenocarcinoma.[Lecturer’s PPT] Figure 34: Looks very similar to the origin the the individual epithelial cell lining the gland show features of malignancy: → Hyperchromicity & irregular border of the nuclei Figure 33. Staging.[Lecturer’s PPT] PATHOLOGY Neoplasia I PAGE 11 of 20 PATHOLOGY | LE 2 Neoplasia I | Dr. Joselli Rueda Cu , RN, LLB, DTM&H, MHA, MPH, MD, FPSP VI. APPEARANCES OF NEOPLASM ▪ Tumor of unknown tissue origin Neoplasms may mimic the tissue origin, but not always HEPATOCELLULAR CARCINOMA Larger masses tend to undergo central necrosis Not as well-circumscribed nor as uniform in consistency in Differentiation contrast to tumor in the cervix (Fig 36) → Extent to which neoplastic parenchymal cells resemble Arising in a cirrotic (nodular liver) the corresponding normal parenchymal cells morphologically and functionally Single Large Mass → Usually the primary site Multiple Masses → Indicates metastases → Usually look similar to the primary, but not always It is not always possible to tell benign from malignant based upon histologic or cytologic criteria alone The biologic behavior of a neoplasm may not always correlate with the appearance, making choice of treatment more difficult Neoplasia → Uncontrolled new growth Tumor → Can mean any mass effect, whether it is inflammatory, Figure 36. Hepatocellular Carcinoma. Note the infiltration of hemodynamic, or neoplastic in origin the tumor off to the lower right.[Lecturer’s PPT] → Once a neoplasm has started, it is not reversible RENAL CELL CARCINOMA → Figure 35 Demonstrates distortion and displacement of the renal parenchyma by the tumor mass in the lower pole Variegated on cut surface, with yellow to white to red to brown areas Figure 35. Mass of abnormal tissue in the cervix.[Lecturer’s PPT] A. CARCINOMA Most common type of cancer Found on epithelial tissues of skin or lining of internal organs such as the liver and kidney Figure 37. Renal Cell Carcinoma.[Lecturer’s PPT] Malignancy from epithelial cell origin, from any of the B. SARCOMA three germ cell layers: → Ectoderm: Epidermis Arise from mesoderm / mesenchymal / soft tissues → Mesoderm: Renal tubules → connective tissues such as cartilage, bone, fascia, → Endoderm: Lining of the gastrointestinal tract smooth or skeletal muscle, blood vessels, lymph Malignancy of epithelial surfaces of gastrointestinal tract, vessels, coverings of organs such as mesothelium respiratory tract, urogenital tract, biliary tract, skin, and Made up of pleomorphic spindle-shaped cells organs with epithelial-lined ducts such as: Typically large and dangerous: “Big and Bad” → breast Malignancies arising from mesoderm are usually → pancreas sarcomes → liver → Leiomyosarcoma → endocrine gland → Chondrosarcoma → testis → Osteosarcoma → ovary → Liposarcoma Composed of polygonal-shaped cells Features Further subclassification of carcinoma: → Tend to invade locally as characterized by the ill-defined → Squamous cell carcinoma margins of the mass ▪ Resembles stratified squamous epithelium ▪ Example: Malignant Fibrous Histiocytoma ▪ Solid nests of cells that have distinct borders, Histology (Figure 38): intercellular bridges, and pink keratinized cytoplasm → Spindle cell pattern → Adenocarcinoma ▪ Some cells are large and pleomorphic ▪ Form glandular patterns/ configurations → Abnormal nuclear morphology → Undifferentiated malignant tumor → Mitosis and loss of polarity is observed PATHOLOGY Neoplasia I PAGE 12 of 20 PATHOLOGY | LE 2 Neoplasia I | Dr. Joselli Rueda Cu , RN, LLB, DTM&H, MHA, MPH, MD, FPSP → Cell of origin is difficult to determine due to poor differentiation and anaplasia Figure 40. High magnification of Liposarcoma.[Lecturer’s PPT] OSTEOSARCOMA Large, bulky mass arises in the cortex of the bone and extends outward (Figure 41) Histologic examination (Figure 42): → Composed of spindle cells ▪ Show some degree of pleomorphism → Pink osteoid formation is seen– consistent with differentiation that suggests osteosarcoma Figure 38. Histologic Examinations of Sarcoma.[Lecturer’s PPT] Table 8. Nomenclature of Sarcomas Sarcoma Tissue Figure 41. Osteosarcoma.[Lecturer’s PPT] Rhabdomyosarcoma Striated muscle Leiomyosarcoma Smooth muscle Liposarcoma Fat Angiosarcoma Blood vessels Chondrosarcoma Cartilage Osteosarcoma Bone Fibrosarcoma Connective fibrous tissue LIPOSARCOMA Common sites: Retroperitoneum and thigh Occur in middle aged to older adults Figure 42. Osteosarcoma.[Lecturer’s PPT] Figure 39: → Specimen is yellowish, resembling adipose tissue and is MALIGNANT FIBROUS HISTIOCYTOMA well-differentiated Used interchangeably with undifferentiated pleomorphic Histologic Examination (Figure 40): sarcoma → Large bizarre hypoblasts → Usually large: 10 to 20 cm gray white fleshy tumor Though indolent, it continues growing to reach a large size A wastebasket term for sarcomas that do not resemble High recurrence rate following incomplete excision mesenchymal cells → Best treated surgically, because most respond poorly to → Rhabdomyosarcoma: striated muscle chemotherapy or radiation → Leiomyosarcoma: smooth muscle Liposarcoma has enough differentiation to determine the → Liposarcoma: fat cell origin, but there is still significant pleomorphism of the → Angiosarcoma: blood vessels neoplastic cells. → Osteosarcoma: bone → Chondrosarcoma: cartilage Figure 43. Malignant Fibrous Histiocytoma. (L) Large fleshy Figure 39. Liposarcoma.[Lecturer’s PPT] sarcoma mass in the retroperitoneum. (R) Fleshy mass arising in the soft tissues of the lower leg. Sarcomas tend to invade locally, as can be seen here by the ill-defined margins of the mass.[Lecturer’s PPT] PATHOLOGY Neoplasia I PAGE 13 of 20 PATHOLOGY | LE 2 Neoplasia I | Dr. Joselli Rueda Cu , RN, LLB, DTM&H, MHA, MPH, MD, FPSP C. BLASTOMA Neoplasms ending in “blastoma” resemble primitive embryonic tissues. These are usually the aggressive malignant tumors. → Retinoblastoma (arising from the retina) → Neuroblastoma (arising from neural cells) → Hepatoblastoma (arising in the liver) → Medulloblastoma (arising from the medulloblastoma tissues in the brain) D. NEOPLASMS WITH MORE THAN ONE CELL TYPE MIXED TUMORS Neoplasms with more than one cell type arising from one clone or germ layer capable of producing both epithelial and myoepithelial cells Proliferation of glandular cells along with myoepithelial Figure 45. Teratoma: Dermoid tumor of ovary. Gross components appearance shows hair, sebum, and teeth. Microscopic Example: features show benign squamous epithelium, and its → Benign mixed tumor ( pleomorphic adenoma) of salivary appendage-like sebaceous gland and hair follicles.[Lecturer’s PPT] gland ▪ Epithelial components scattered within a myxoid stroma that may contain islands of cartilage or bone Figure 46. Teratoma: Testis. The usual gross appearance for malignant neoplasms is that the stroma is solid, not cystic. The microscopic appearance likewise shows malignant transformation of the cells.[Lecturer’s PPT] Figure 44. Pleomorphic adenoma of the salivary gland. There is a neoplastic proliferation of the parenchymal glandular cells with myoepithelial components (biphasic: epithelial and mesenchymal).[Lecturer’s PPT] Figure 44. Pleomorphic adenoma of the salivary gland → Upper left figure: arrows are pointing to the epithelial mesenchymal component → Lower left figure: arrows are pointing to the epithelial component lining the glands TERATOMAS Neoplasms arising from more than one germ layer Common in the ovary (Dermoid cyst/ovarian cystic teratoma) Figure 47. Malignant Teratoma. Transformation of lining → Differentiates along ectodermal lines to create a cystic epithelium of glands (left), chondrocytes/ cartilage (center), tumor lined by skin replete with hair, sebaceous glands and stratified squamous epithelium (right).[Lecturer’s PPT] and tooth structures Originates from totipotential germ cells normally present VII. NON-NEOPLASTIC GROWTH in the ovary and the testis, sometimes in abnormal midline A. HAMARTOMAS embryonic rests. Disorganized benign masses indigenous to the site → Can differentiate into any of the cell types found in the → These tissues are native to the organ where it has body, hence can contain bone, epithelium, muscle, fat, arisen nerve, and other tissues. Considered neoplasm since many have clonal chromosomal aberrations acquired through somatic mutations PATHOLOGY Neoplasia I PAGE 14 of 20 PATHOLOGY | LE 2 Neoplasia I | Dr. Joselli Rueda Cu , RN, LLB, DTM&H, MHA, MPH, MD, FPSP Localized haphazard tumor growth of tissues normally Integrins tell the cell about the type of environment they found at a given site are in and keep the cell instruction about what to do. In Pulmonary hamartoma has jumbled cartilage, bronchial the case of cancer, particular integrins can send signals epithelium, and connective tissue that tell cancer cells to invade the surrounding tissue. Sometimes, the invading tumor cells may reach a blood vessel, squeeze in and enter the bloodstream. The cancer cell takes a bumpy journey to a distant part of the body. Sometimes, they are able to squeeze out of the blood vessel, into the healthy tissue - where they can start forming secondary tumors. → Metastasis - ability of cancer cells to invade and spread around the body. Represents the biggest challenge in treating cancer. 🔺 ABNORMAL SIGNAL TRANSDUCTION Abnormal signal transduction results in uncontrolled cell proliferation. Normal cells require signals usually delivered by ligands, to stimulate their growth and to tell them when Figure 48. Hamartoma.[Lecturer’s PPT] to stop growing. It can be in the form of → Growth factors and inhibitors B. CHORISTOMA → Extracellular matrix components or cell adhesion Heterotopic rest of cells molecules Ectopic tissue that is not normal to the site of origin These signals are transmitted into the cell through Examples: proteins found on the surface of the cell called → Normal pancreatic tissue noted on submucosa of receptors. Each ligand binds to its own specific stomach, duodenum, or small intestine receptor. → Pancreatic tissue in choristoma of gallbladder Receptors often consist of 3 domains: During embryogenesis, some of these cells may be → Extracellular ligand-binding domain plucked off from the organ, and deposited in some other → Transmembrane domain organs → Intracellular domain Binding of the ligand to the extracellular domain activates the receptor tyrosine kinase, which activates other proteins by phosphorylation (adding phosphate to) of the amino acid tyrosine on a protein inside the cell. When a ligand binds to a receptor, a signal goes to the intracellular domain - activating the associated enzyme and initiating a cascade of signals to the nucleus that tell the cell to grow and divide or to stop growing. Malignant cells generate many of their own growth signals which allows them to divide with reduced external growth stimulation. Autocrine stimulation - able to produce their own growth factor and stimulate their own growth. Figure 49. Choristoma in pancreatic tissue noted in → Example: Glioblastomas express platelet-derived gallbladder..[Lecturer’s PPT] growth factor (PDGF); Sarcomas express tumor VIII. SUPPLEMENTAL VIDEOS growth factor alpha (TGF-α) and epidermal growth 🔺 CANCER GROWTH SPREAD factor receptor (EGFR) In normal cells, the production of cell surface receptors Solid tumors, like every tissue in our body, need a blood is limited by cellular restraints on gene expression and supply to survive and grow. As a tumor grows, it protein translation. releases chemical messengers into the environment In tumor cells, mutations in the genes and coding for that cause new blood vessels to sprout from the the receptors disrupts this finely tuned regulation, existing once. resulting in gene amplification. This phenomenon leads These new blood vessels are drawn towards the tumor, to excessive transcription and production of receptors. where they feed the cancer cells and allow them to → Gene amplification - many copy of the genes are grow. produced Each time the cancer cells divide, more mutations are → End result: Overexpression of receptors on the built up in their genomes. Because different parts of the tumor cell surface → increased potential to be tumor acquire different mutations, they behave triggered into the growth phase by the binding of differently. Sometimes one region of the tumor will grow ligands into the excess receptors. faster and more aggressively than the others - causing → More receptors expressed, more binding sites the cancer to spread. available for the ligands. All cells in the body including cancer cells must attach to → Overexpression of receptors / Structural changes the network of proteins that surrounds them. This is of receptors → Ligand-independent signaling done by proteins called integrins. PATHOLOGY Neoplasia I PAGE 15 of 20 PATHOLOGY | LE 2 Neoplasia I | Dr. Joselli Rueda Cu , RN, LLB, DTM&H, MHA, MPH, MD, FPSP ▪ Ligand-independent signaling - receptors are 🔺LOSS OF APOPTOSIS absent in the absence of stimulating molecules. Solid tumors, like every tissue in our body, need a blood ▪ Example: Truncated versions of the EGFR, where supply to survive and grow. As a tumor grows, it much of the intracellular domain is missing, is releases chemical messengers into the environment constitutively active. that cause new blood vessels to sprout from the EGF receptor (HER 1 or c-ErbB-1) is a member of the existing once. sub-family of type 1 receptor tyrosine kinases. Found in These new blood vessels are drawn towards the tumor, the normal epithelial cells from: where they feed the cancer cells and allow them to → Skin, breast, colon, lungs, etc. grow. EGF receptor and its ligands play a central role in the Each time the cancer cells divide, more mutations are regulation of cell proliferation, differentiation, and built up in their genomes. Because different parts of the survival. Overexpressed EGFR arised from the colon, tumor acquire different mutations, they behave rectum, head and neck. differently. Sometimes one region of the tumor will grow When a specific ligand binds to its receptor, this leads to faster and more aggressively than the others - causing changes in the receptor that transmit a specific signal the cancer to spread. into the cell. (e.g. Receptor TK is activated and initiates All cells in the body including cancer cells must attach to a signaling pathways specific to that receptor - signal the network of proteins that surrounds them. This is transduction) done by proteins called integrins. Signal transduction pathway creates a complex chain Integrins tell the cell about the type of environment they of events in the cytoplasm that eventually leads into the are in and keep the cell instruction about what to do. In cell nucleus, where the transcription of genes regulating the case of cancer, particular integrins can send signals cell cycle production are stimulated - resulting in cell that tell cancer cells to invade the surrounding tissue. proliferation. Sometimes, the invading tumor cells may reach a blood RAS-RAF mitogen activated protein/ MAP kinase vessel, squeeze in and enter the bloodstream. The pathway - one of the major cascades implicated in cancer cell takes a bumpy journey to a distant part of cancers. the body. Sometimes, they are able to squeeze out of → PI3K/Akt/mTOR pathway - another interesting the blood vessel, into the healthy tissue - where they pathway. can start forming secondary tumors. → These pathways are linked to each other and other → Metastasis - ability of cancer cells to invade and signal transduction pathways in the cell. spread around the body. Represents the biggest → T regulation (loss of normal control in these challenge in treating cancer. pathways) is thought to be present in all human tumors. 🔺 TISSUE INVASION AND METASTASIS Once the signal reaches the nucleus, transcription Malignant tumors can metastasize at any point factors are activated. These factors (e.g. growth factors Ability to invade affects the function of the normal tissue necessary to allow the cell to continue to proliferate) Multifactorial process, interaction between tumor cells transcribe the genes that are translated into the protein. EGFR pathway Tumor DNA replication and cell division - end result → Signals enter cell of growth factor receptor signal transduction pathway. → Transcription of genes regulating cell cycle → If mitosis continues, two tumor cells become four - progression and cell growth is stimulated with exponential growth potential. ▪ Matrix metalloproteinase (MMP) is produced → On tissue level: increased tumor growth and → Tumor cell breaks off and enters extracellular space increased tumor size. → MMP is secreted which degrades the collagenase Many components of the signal transduction pathway ECM, breaking through the basement membrane are potential targets of anti-cancer therapies. → This allows tumor cells to migrate into the blood and Target of anti-cancer therapies: lymph to other tissues → Ligands Metastatic tumor cells target certain cells more than → Receptors others but reason is poorly understood → Intracellular second messengers Migration of tumor cells is like the recruitment of WBC to → Nuclear transcription factors - tumor growth injured tissues Ligands can be neutralize before they bind to the Initially, there is weak adhesion of the tumor to the receptors endothelial cells, then it rolls along the vessel lining until → Example: Bevacizumab/ Avastin - humanized a stronger bond is formed. Once securely attached, they monoclonal antibody targeting circulating VEGF, leave the vessel and enter the tissue PDGF and FGF. They leave an open pathway that lets less aggressive The receptors on the surface of normal and tumor tumor cells invade and grow. cells can be inhibited directly. → Example: Cetuximab / Erbitux - chimeric antibody 🔺 CANCER- FROM A HEALTHY CELL TO A CANCER CELL that binds directly into EGFR and competitively More than 60,000 billions cells make up the human inhibits the binding of EGF and other ligands body (TGF-alpha) → units that build up the tissues which make up the Another way to block receptors' function is through organs small molecule inhibitors of receptor phosphorylation When the body needs it, cells split into two (mitosis) associated with them. and replace cells that are defective or dying. → Example: EGF receptors have a TK that can be → this makes our cells capable of preserving their blocked by the molecules Gefitinib and Erlotinib. shape and functions PATHOLOGY Neoplasia I PAGE 16 of 20 PATHOLOGY | LE 2 Neoplasia I | Dr. Joselli Rueda Cu , RN, LLB, DTM&H, MHA, MPH, MD, FPSP → Every cell is programmed to multiply and die. Cancerous tumors form when cells abnormally divides This program is controlled by the nucleus which without control contains chromosomes containing many genes made Immune system is capable of detecting and killing up of DNA abnormal cells Sometimes, genes undergo change In serious diseases, it surpasses the immune system → due to it, the nucleus make abnormal orders (e.g., and tumors continue to grow uncontrolled multiplication) How tumors get nutrients → Each new cells contain the same defect → Tumors release a growth factor (PLGF) which binds → continuous proliferation eventually forms a tumor. to receptors on blood vessels → This process may be short but is often long. 10-30 → Capillary networks expand through the tumor, years may separate the birth of first abnormal cell to providing blood supply and stimulating growth the appearance of the tumor of about 1cm3 → Can be blocked by PLGF antibodies which slow The tumor forms many blood vessels (angiogenesis) down tumor growth by preventing the capillary → Supply the tumor with oxygen and nutrients. networks from providing the tumor with blood supply The tumor only becomes dangerous when the With PLGF antibodies the cancer killing system can cancerous cells begin to invade through the vessels to work faster than the rate of tumor cell division adjacent areas and spread to surrounding organs (metastasis). 🔺 CANCER GROWTH SPREAD Cancer or cancerous cells are cells that have lost the → These cells can then invade other parts of the body; ability to follow the normal control that the body exerts multiply and produce new tumors on all cells. In our body we have billions of cells that Factors that contribute to development of tumor cells have different functions under incredibly phenomenal → Hereditary genetic anomalies control. → Exposure to some viruses → If something goes wrong in that control is lost, a ▪ HIV particular set of cells escape the normal control ▪ Hepatitis B,C,D mechanisms and they continue to grow and spread. ▪ Papilloma virus Those cells are what we call a tumor ▪ EBV Cancer is a malignant tumor → Exposure to toxic agents, chemical products, → We call it malignant because not only can it invade to radiation, sun adjacent organs, it can also spread to other tissues → Unhealthy behaviors (smoking, drinking) that can be life threatening → Diet rich in fat, low in fru