Neoplasia Outline PDF

Cytologic (atypia) Nuclear enlargement Nuclar pleomorphism Nuclear hyperchromasia Prominent nucleoli If cells LOOK GOOD, they are probably going to BEHAVE GOOD If cells LOOK BAD, they are probably going to BEHAVE BAD Invasion of tumor cell into normal tissue  Cli...

Cytologic (atypia) Nuclear enlargement Nuclar pleomorphism Nuclear hyperchromasia Prominent nucleoli If cells LOOK GOOD, they are probably going to BEHAVE GOOD If cells LOOK BAD, they are probably going to BEHAVE BAD Invasion of tumor cell into normal tissue  Clinical malignancy Meningioma Natural History Of Malignant Tumors 1. Malignant change in the target cell, referred to as transformation 2. Growth of the transformed cells 3. Local invasion 4. Distant metastases.  Differentiation Well differentiated neoplasm – Resembles mature cells of tissue of origin Poorly diffentiated neoplasm – Composed of primitive cells with little diffrerentiation Undifferentiated or “anaplastic” tumor Correlation with biologic behavior – Benign tumors are well differentiated – Poorly differentiated malignant tumors usually have worse prognosis  “ANAPLASIA” n Pleomorphism n Size n shape n Abnormal nuclear morphology nHyperchromasia nHigh nuclear cytoplasmic ratio nChromatin clumping nProminent nucleoli n Mitoses n Mitotic rate n Location of mitoses n Loss of polarity metastasis! The diagram shows the cycle of events during which epithelial cells are transformed into mesenchymal cells and vice versa. The different stages during EMT (epithelial–mesenchymal transition) and the reverse process MET (mesenchymal–epithelial transition) are regulated by effectors of EMT and MET, which influence each other. Important events during the progression of EMT and MET, including the regulation of the tight junctions and the adherens junctions, are indicated. A number of markers have been identified that are characteristic of either epithelial or mesenchymal cells and these markers are listed in Box 1 and Box 2. E-cadherin, epithelial cadherin; ECM, extracellular matrix; FGFR2, fibroblast-growth-factor receptor-2; FSP1, fibroblast-specific protein-1; MFs, microfilaments. During embryonic development, epithelial cells (purple cells) undergo partial or complete epithelial–mesenchymal transition (EMT) (pink cells). EMT is an important component of various morphogenic events, such as gastrulation, neural-crest formation and branching of the three germ-layer-derived tubes (blue cells). The reverse process, during which mesenchymal cells (green) undergo mesenchymal–epithelial transitions (METs), also has an important role during embryonic development. Most animals gastrulate using a full EMT, including fruitflies (Drosophila melanogaster), most amphibians (such as urodeles), fish, birds, reptiles and mammals. However, there are some notable exceptions, such as the African clawed frog (Xenopus laevis) — in this organism individual mesenchymal cells are not formed during gastrulation, but rather a mass of epiblast cells penetrate the blastocoel cavity (involution) and converge–extend to form the axial mesoderm (notochord and somites). This mechanism, however, implies that gastrulating cells must exchange rapidly with their neighbours to form an elongated structure.  The microenvironment of the tumour–host interface Lance A. Liotta and Elise C. Kohn Nature 411, 375-379(17 May 2001) Invasive carcinoma is viewed as a pathology of multiple cell societies inhabiting the epithelial/mesenchymal stromal unit. Transition to invasive carcinoma is preceded by the activation of host fibroblasts, immune cells and endothelial cells. Invasion occurs in a localized zone of cross-talk and cooperation between the stromal cells and the premalignant epithelium (depicted as zones demarked by dashed lines). Cytokine and enzyme exchange between the participating cells stimulates migration of both cell types towards each other and modifies the adjacent extracellular matrix/basement membrane. The result is a breakdown of normal tissue boundaries.  The microenvironment of the tumour–host interface Lance A. Liotta and Elise C. Kohn Nature 411, 375-379(17 May 2001) Example mediators are shown. Motility and invasion is a bi-directional process. Fibroblasts produce chemoattractants such as SF/HGF, which stimulates motility of tumour cells by binding to the Met receptor (c-Met). Tumour cells produce angiogenesis factors such as VEGF and bFGF, which bind to receptors on stromal vascular cells and cause increased vascular permeability, endothelial proliferation, migration and invasion. Fibroblasts and endothelial stromal cells elaborate latent enzymes, including MMPs and uPA, which dock on the surface of the carcinoma invadopodia and become activated, thereby degrading the ECM, and clearing a pathway. ECM degradation releases bound growth factors such as TGF- and EGF, which bind to cognate receptors (TGF- R and uPAR) on the carcinoma cell. ECM proteolysis also exposes cryptic RGD sites, which are recognized by integrins. Cross- talk between signal pathways within the carcinoma cells links motility, proliferation and pro-survival signals. For example, phosphorylation of FAK through Met and integrin signalling transduces signals through Ras, PI(3)K, -catenin and MLCK, causing cytoskeletal remodelling, ERK activation of mitogenesis, and sustainment of survival through phosphorylation of Akt. Schematic diagram of the main cell properties affected in a transient versus stable epithelial–mesenchymal transition (EMT) process. Cells that underwent EMT during tumour invasion are characterized by the loss of cell–cell adhesion and polarity accompanied by cytoskeleton rearrangements and increased cell motility. Sometimes, cells that had previously undergone EMT could transiently re-acquire an epithelioid phenotype by reverse mesenchymal–epithelial transition (MET) as the result of new interactions with the tumour microenvironment. EMT could also have an active role during metastatic spreading by promoting other malignant properties such as tumour cell intravasation16, and stable MET can occur at established secondary metastases2. Schematic of the potential interplay of CDH1 repressors and the microenvironment during tumour progression. Hypoxia- and TGF -derived signals could promote the interplay of Snail, Zeb and bHLH factors that orchestrate CDH1 repression and epithelial–mesenchymal transition (EMT) during tumour progression. SNAI1 could be implicated in the initial migratory phenotype and considered as an early marker of EMT that sometimes contributes to the induction of other factors. By contrast, SNAI2, ZEB1, ZEB2 and/or TWIST could be responsible for the maintenance of migratory cell behaviour, malignancy and other tumorigenic properties. Pink cells indicate intra-tumoral stromal-like cells. Thyroid adenoma Thyroid adenoma  Thyroid Normal thyroid adenoma Leiomyoma Chondroma Oral papilloma Oral papilloma  Head Stalk Colon polyp Colon polyp Colon polyp Ovarian cystadenoma Ovarian cystadenoma Ovarian cystadenoma Neoplasia Outline Tumor nomenclature Definitions Benign tumors Malignant tumors  Malignant Tumors Carcinomas – arise in epithelial tissue adenocarcinoma – malignant tumor of glandular cells squamous cell carcinoma – malignant tumor of squamous cells Sarcomas – arise in mesenchymal tissue chondrosarcoma – malignant tumor of chondrocytes angiosarcoma – malignant tumor of blood vessels rhabdomyosarcoma – malignant tumor of skeletal muscle cells Adenocarcinoma Squamous cell carcinoma Chondrosarcoma Angiosarcoma Rhabdmyosarcoma Neoplasia Outline Tumor nomenclature Definitions Benign tumors Malignant tumors Mixed tumors  Mixed Tumors “Mixed” tumors show divergent differentiation Examples pleomorphic adenoma – glands + fibromyxoid stroma fibroadenoma – glands + fibrous tissue Not to be confused with teratomas Pleomorphic adenoma Neoplasia Outline Tumor nomenclature Definitions Benign tumors Malignant tumors Mixed tumors Confusing terms  Confusing Terms Malignant tumors that sound benign lymphoma mesothelioma melanoma seminoma Non-tumors that sound like tumors hamartoma – mass of disorganized indigenous tissue choristoma – heterotopic rest of cells Names that seem to come out of nowhere nevus leukemia hydatidiform mole  Dysplasia n Literally means abnormal growth n Malignant transformation is a multistep process n In dysplasia some but not all of the features of malignancy are present n Dysplasia may develop into malignancy n Uterine cervix n Colon polyps n Graded as low-grade or high-grade n Dysplasia may NOT develop into malignancy  INTRAEPITHELIAL NEOPLASIA Premalignant dysplastic changes occurring within an epithelium (not invasive, not yet cancer) Precursor to squamous cell carcinoma  CERVICAL INTRAEPITHELIAL NEOPLASIA Spectrum of cervical intraepithelial neoplasia (CIN): normal squamous epithelium for comparison  HUMAN PAPILLOMA VIRUS (HPV) Sexually transmitted disease implicated in epidemiology of cervical cancer - Early age at first intercourse - Multiple sexual partners - Male partner with many previous sexual partners - HPV DNA is detected in 85% of cervical cancers, and in 90% of cervical condylomata and precancerous lesions Responsible for squamous proliferations (benign, premalignant, and malignant) High risk (16, 18) and low risk (6, 11) types