Neoplasia Notes

Chapter 5 - Neoplasia   











Neoplasms have certain degree of autonomy but rely on their environment Malignant tumor = lesion that can invade and destroy adjacent structures and spread (metastasize) to cause death Tumor composed of: o Parenchyma: neoplastic cells, transformed cells o Stroma: supporting host cells, not neoplastic (ex. Blood vessels, inflammatory cells, CT) Benign tumors: Have the –oma suffix. Ex: o Adenoma  From gland origin even if it doesn’t have gland pattern  Has gland pattern even if not from glandular origin o Papilloma: benign epithelial neoplasm looks like a finger Malignant tumor: o Tumors are of monoclonal origin but may undergo divergent differentiation.  Created mixed tumors.  Salivary gland tumors are often mixed  Fibroadenoma of the female breast is another common mixed tumor  Fibrous + ductal (but only the fibrous part is neoplastic) o Sarcoma: from mesenchyme o Carcinoma: from epithelium  All tumors from epithelia (no matter the germ layer) are carcinomas. Epithelium can come from any of the three germ layers. Ex. Renal tubule epithelium (mesoderm), skin (ectoderm) and gut lining (endoderm).  Adenocarcinoma: grow in glandular pattern  Squamous cell carcinomas: produce squamous cells  Carcinomas can be poorly differentiated or undifferentiated o Teratomas:  Have mature or immature cells from two or three germ layers.  Originate from totipotential stem cells.  From ovary, testis, or midline embryonic rests Hamartoma: mass of mature but disorganized indigenous tissue. o Not malignant tumors. o Ex. Mass of mature but disorganized liver cells in the liver. Choristoma: Tissue from one part of the body found in another o Not a malignant tumor. o “heterotropic rest of cells” – not neoplastic, a congenital anomaly. Factors that determine if a tumor is benign or not o Differentiation and anaplasia  Refers only to the transformed elements, the parenchyma  Differentiation: How much they resemble their forebears  Stromal cells don’t help distinguish benign from malignant tumors.  Benign: cells resemble normal cells from their original tissue and mitosis is scant.



o o

o

Malignant: Cells range from completely undifferentiated to very well differentiated.  Tumors may secrete product that normal cells of their origin produce or may secrete a foreign product (even fetal products)  Certain lung canciromas can produce ACTH, insulin, glucagon, parathyroid like hormone, etc.  The more anaplastic and rapid-growing a tumor, the less likely it is to secrete anything  Anaplasia = undifferentiated  Pleomorphism: variation in size and shape.  Nuclei hyperchromatic and large  1:1 cytoplasm to nuclear ratio  Giant cells (larger, with larger nuclei or more than one)  Dysplasia: Loss of uniformity and architectural orientation. More mitosis than usual and occurs at top layers instead of just bottom.  Desmoplasia = abundant fibrous stroma induced by cancer cells, makes the tumors hard “Schirrhous tumors” Rate of growth  Cancers usually grow faster than benign tumors but the opposite can be true. Local invasion  Benign tumors are usually encapsulated  Malignant tumors can appear to have capsule but under microscope you can see tiny penetrating feet towards stroma Metastasis  Some highly invasive tumors rarely metastasize  Some metastasize fast  Ways of metastasizing:  Seeding – as in ovarian cancer  Hematologic – favored in sarcomas o Liver and lungs are the most frequently involved secondary sites in hematogenous dissemination  Lymphatic – typical of carcinomas

A “sentinal lymph node” is the first lymph node in a regional lymphatic basin that receives lymph flow from a primary tumor. Environmental factors that cause somatic mutations are predominant cause of common sporadic cancers. Major childhood cancers o Leukemia o CNS tumors o Lymphomas o Soft tissue sarcomas o Bone sarcomas o

 









    









Inherited cancer syndromes include cancers in which inheritance of a single mutant gene increases the risk of developing a tumor. o Specific marker phenotypes (cancerous polyps come from benign polyps) Familial Cancers o Features that characterize familial cancers  Include early age at onset,  Tumors arising in two or more close relatives of the index case,  And sometimes multiple or bilateral tumors o No specific marker phenotypes (cancerous polyps don’t come from benign polyps) Preneoplastic disorders predispose people to certain cancer o Villous adenomas of colon  high risk of transforming to colorectal carcinoma. o Myoleimyomas of uterus  Extremely rate become malignant. Nonlethal genetic damage lies at the heart of carcinogenesis. o Growth promoting proto-oncogenes o Growth inhibiting tumor suppressing genes o Genes that regulate apoptosis o Genes involved in DNA repair. Tumor progression increase in size and more Even though most malignant tumors are monoclonal in origin, by the time they become clinically evident, their constituent cells are extremely heterogeneous. Oncogenes promote autonomous growth of cancer cells o Resembles normal proto-oncogene except that it doesn’t respond to regulatory signals Cancer cells make their own growth factors  autocrine signaling. Can also overexpress growth factor genes. Receptor mutations o Mutant receptors can deliver growth signal without stimuli. o Overexpression of receptor  ERBB1  EGF receptor Signaling proteins mutation can cause cancer o RAS  most commonly mutated proto-oncogene. o ABL  translocate from chromosome 9 to 22 Mutation of transcription factors o MYC  most implied in human cancers.  Activates: growth promoting genes  Represses: CDK inhibitors Cell cycle: CDK-cyclin complexes drive the cell through the cell cycle. o Common mishap: errors in CYCLIN D or CDK4  Overexpressed genes in many cancers  Amplifications in some cancers o P-number proteins are CDK inhibitors  Deleted or silenced in many cancers Tumor suppressing genes o EX. RB for retinoblastoma  Both alleles need to be deactivated (two hit)



o

o o

o













Familial when one bad gene inherited and only one somatic mutation needed for tumor  Sporadic when both copies are lost to somatic mutation. Two hit hypothesis also implied in  Breast cancer  Bladder cancer  Retinoblastoma Virus cases damage RB by making it hypophosphorylated (inactive) so the cells divide erratically. P53 prevents tumors by inducing  Quiescence  Senescence  Apoptosis Normally P53 has a short life  Targeted for destruction by MDM2  When cell is stressed it frees from MDM2  It is a transcription factor for cell cycle arrest and apoptosis genes. Is a primary response to DNA damage P53 damaged allele can rarely be inherited P53 can be damaged by viruses

o o o TGF-B o Forms a dimer and promotes CDK inhibitors. o Mutations of TGF-B pathway cause cancer o TGF-B mutated in 100% of pancreatic cancers and 83% of colon cancers!! APC o Rare and hereditary o Adenomatous polyps  high transformation rate o APC is an antiproliferative gene.  Regulates levels of cytoplasmic B-Catenin o APC damaged in 80% of colonic cancers o Remaining 20% have APC-unresponsive B-Catenin. Evasion of Apoptosis o BCL2 protects tumor cells from apoptosis o Common in lymphomas.  Avoidance of cell death, not explosive proliferation. Unlimited replication requires telomere lengthening by o Up regulation of Telomerase (up to 95% of cancers) o DNA recombination Sustained Angiogenesis o Provides nutrients AND growth factors o Route for metastasis o More production of angiogenesis factors or loss of angiogenesis inhibitors o P53 blocks angiogenesis Metastasis

o







Loosening of cells  E-cadherin is intercellular glue, lost in all epithelial cancers. Normally transmit antiproliferative signal by sequestering B-Catenin. o Degradation of basement membrane and CT  May produce proteases themselves or induce other cells to produce proteases.  Products of collagen type IV cleavage can have many carcinogenic effects. o Changes in attachment of tumor cells to ECM proteins  Would normally produce apoptosis but not in tumors cells  Cleavage from ECM proteins attachment generates NOVEL sites that promote migration. o Locomotion  Autocrine motility factors  Cleavage products of matrix components have chemotactic properties. o Vascular dissemination and homing of tumor cells  Can form emboli with platelets  Invade next capillary bed [organ] encountered o Molecular stuff about metastasis  SNAIL and TWIST encode transcription factor to promote EMT  EMT  epithelial to mesenchymal transition. Genomic instability: Defects in DNA repair cause cancer. o Mismatch repair deficiency  Hallmark  Microsatellite instability  EXAMPLE: Hereditary Nonpolyposis Cancer Syndrome o Excision repair deficiency  Excision repair damaged and so body cannot fix pyrimidine residues crosslinking causes by UV light.  EXAMPLE: Xeroderma Pigmentosum o DNA Repair by homologous recombination  Sensitivity to ionizing radiation  EXAMPLE: Bloom Syndrome  EXAMPLE: Ataxia-telangiectasia  Sensitivity to DNA crosslinking agents  EXAMPLE: Fanconi anemia  BRCA1 and BRCA2 mutations  Mutations in BRCA1: higher risk of woman breast cancer, epithelial ovarian cancer. Men - Prostate cancer.  Mutations in BRCA2: breast cancer in men and women, ovary and prostate cancer, cancer of pancreas, bile ducts, stomach and melanocytes. MicroRNA “Oncomirs” o Are single stranded, 22-nucleotide long RNAs that regulated gene expression o Can cause cancer by overexpressing oncogenes or blocking tumor suppressor genes. Individual tumors accumulate average of 90 mutant genes.











In certain cancers, specific abnormal karyotypes are common. Some common effects of karyotype changes are o Balanced translocations: Hematopoietic cells very prone to this kind of abnormality. o Deletions: Most common damage in non-hematopoietic cells. o Cytogenic manifestation of gene amplification  Example: MYC amplification o Epigenetic changes  Silencing by methylation of tumor suppressing gene promoter can cause cancer.  Hypomethylation can also cause tumors. Carcinogens o Direct acting agents  are carcinogenic per se, don’t need metabolic conversion to become so.  Some medicines, including cancer medicines can be direct acting carcinogens. o Indirect acting agents  require metabolic conversion to be carcinogenic.  Products of cigarette smoking. Radiation - all radiation can cause cancer o UV Radiation can cause two types skin cancers:  Non-melanoma: cumulative short exposures  Melanoma: less time, highly intense sessions o UV Radiation creates pyrimidine dimers Oncogenic RNA viruses – HTLV-1 o Attacks CD4+ T cells. o Long 20-50 years latent period o Has pX retroviral genes that produces TAX protein:  Stimulates cytokine production.  Activates cyclins to go through cell cycle.  Blocks tumor suppressor genes (such as p53) o Endemic to Japan and Caribbean. Sporadic elsewhere. Oncogenic DNA viruses o Human Papilloma Virus  Some cause benign warts  Some implicated to cancer  E6 and E7 are early viral gene products that interact with protooncogenes and tumor suppressor genes. o Epstein-Barr Virus  Burkitt Lymphoma  Endemic to some Africa regions  Produces LMP-1 genes o Mimics B cell activation via CD40 receptor  Has a vIL-10 (pirated from host) that keeps T-cell from activating.  LMP-1 recognized by immune system so in normal individuals MYC takes the roles of LMP1  In immunosuppressed patients, LMP-1 prevails. o Hepatitis B and Hepatitis C Viruses











 Causes most liver carcinomas.  Constant inflammation  cell destruction and regeneration  tumor  HBx  activates transcription factors  hepatocellular cancer  HCV core protein  activates growth promoting signals Oncogenic bacteria: H. pylori o Gastric adenocarcinomas and gastric lymphomas o CagA toxin  injected in cells and starts cascades that mimics lots of growth factor stimulation Tumor immunity o Cytotoxic T cells are major defense against tumors. o Unique tumor antigens arise from products of β-catenin, RAS, p53, and CDK4 genes, which frequently are mutated in tumors. o NK cells are first line of defense against tumors, don’t need to be sensitized first to recognize it. o Macrophages – shown to attack tumors in vitro. Engulfing or secretion of TNF. o Tumors secrete TGF-B, an immunosuppressant Clinical effects o Cachexia: high metabolic rate but anorexia due to cytokines made by tumor and host. TNF suppresses appetite. Proteolysis inducing factor promoted the break down skeletal muscle. o Paraneoplastic syndromes: experimented with cancer but cannot be readily explained by the tumor.  Hypercalcemia – synthesis of parathyroid hormone related protein by tumor cells.  Cushing syndrome – ectopic production of ACTH or analogues, as in small cell cancer of lung.  Thrombotic endocarditis – hypercoagulability  venous thrombosis and nonbacterial thrombotic endocarditis. Grading and Staging of cancer o Grading: establishes aggressiveness or level of malignancy.  Cytological differentiation  Low=similar to cell of origin  High = anaplastic = al garete  Number of mitoses o Staging: based on size of primary lesion, extent of spread to regional lymph nodes and presence or absence of metastases. o Staging done by imagining or surgery  has more clinical value. Laboratory diagnosis of cancer o Some tests have low specificity and sensitivity so they are not good for early detection of cancer but are good to detect recurrence of cancer.

Other pearls about neoplasia  Colon cancer and size o Right colon  larger, therefore cancer goes asymptomatic longer



 

 

o Left colon  smaller, therefor can cause obstruction, detection earlier Colonic polyps o Most likely to transform: villous adenoma o Less likely to transform: hyperplastic polyp Hilar mass is very likely squamous cell carcinoma. Dysplasia: o Full thickness of epithelium = carcinoma in situ o Invasion of lamina propia = invasive carcinoma Metaplasia o Change from one cell type to another Dysplasia and metaplasia are both reversible.

Chap 6 - Childhood Neoplasia Benign Tumors  Three most common tumors of childhood o Hemangiomas (#1) o Lymphangiomas o Sacrococcygeal teratomas  Hemangiomas: most common tumor childhood o Cavernous and capillary  Capillary can appear more worrisome than they are o Port wine stains  larger lesions o Most lesions on skin and scalp o Cosmetic problem, regresses spontaneously.  Lymphangiomas o Lymphatic counterpart of Hemangiomas o Deeper regions of neck, axilla, mediastinum and retroperitoneum.  Sacrococcygeal Teratomas o Most common germ cell tumor of childhood (40%) o 10% associated with congenital anomalies. o Most benign teratomas found early, malignant found later. Malignant Tumors  Unique histological appearance “Small, round, blue cell tumor” o Tend to have embryonal rather than pleomorphic-anaplastic histology o Tend to exhibit features of organogenesis (specific to origin site)  Neuroblastoma o Neuroblastic tumor, second most common solid malignancy. o Spontaneous regression and spontaneous or therapy induce maturation. o ALK gain of function in familial and sporadic Neuroblastoma. o Most come from adrenal medulla.

o





Histology: small primitive looking cells with large dark nucleus and scant cytoplasm, poorly defined borders and growing in sheets. Background has fibrillary material (neuropil). Forms Homer Wright pseudo rosettes. o Ganglioneuroma when Neuroblastoma maturate and form mature ganglion cells, with no remaining neuroblasts. They grow Schwann cells in their stroma. o Very good prognosis. Better for younger children. Better when Schwann cells are present. Better for patients with less NMYC amplification. Worse for patients with deletions in chromosome 1, gain in chromosome 17 and expression of telomerase. o In babies, causes blueberry muffin lesions. o Tumors produce catecholamines, important in diagnosis. Retinoblastoma o Most common primary intraocular malignancy of children. o 40% associated with germline mutation of RB1. 60% sporadic.  Familial  multiple bilateral tumors.  Sporadic  Unilateral and unifocal. o Histology: Tumor made of undifferentiated retinoblasts. Small round cells with dark blue nucleus and scant cytoplasm. Flexner-Wintersteiner rosettes. o Usually presents around 2 years, but can be present at birth. o Untreated is fatal, but early treatment has good prognosis. o Patients with familial RB have higher risk of osteosarcoma and other soft tissue tumors. WIlms Tumor o Also known as nephroblastoma. Occurs in children from 2-5 years old o Three congenital malformations associated with WIlms Tumor.  WAGR syndrome **  Denys-Drash Syndrome **  Beckwith-Wiedemann Syndrome ** o Different stages of nephrogenesis can be recognized in a tumor. o Nephrogenic rests are considered to be precursor lesions for Wilms tumors. o Readily palpable abdominal mass that may cross midline or go down to the pelvis.

Chap 20 – Rhabdomyosarcomas - Soft tissue tumors  Most soft tissue tumors arise without antecedent causes (Exposures)  Most occurs in lower extremities, especially the thigh.  Lipoma – benign lipid cell mass  Liposarcoma – malignant, very recurrent lipid cell tumor.  Fibromatoses o Superficial: superficial fascia. Can cause deformity. o Deep: desmoid tumors in abdominal wall. Aggressive and recurrent**  Rhabdomyosarcoma – most common soft tissue sarcoma of childhood and adolescence (appears before 20) o Occurs at site of very little skeletal muscle (head and genitourinary tract) o Swirling histology. o Three forms  Embryonal: seen in children

 

Alveolar: seen in teens Pleomorphic: seen in adults