Assessment of Oncologic Diseases PDF

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Assessment of Oncologic Diseases (Staging) Oncogenes & Tumor-Suppressor Genes Tumor Staging ▪ Method of determining and classifying a tumor according to its spread throughout the body. ▪ Staging of the tumor is typically more important than the grade in determining the prognosis. ▪ Staging systems o TNM and AJCC systems are most commonly used. TNM Classification ▪ T: size or direct extent of the primary tumor o T cis Carcinoma in situ (no basement membrane penetration - no infiltration of submucosa) o T1-4 based on the size and/or extent of the primary tumor o T4 refers to infiltration of neighboring organs ▪ N: Involvement of Regional Lymph Nodes o N0: No lymph node involvement o N1-3 based on type of tumor and lymph node involvement ▪ M: Presence of distant metastasis o M0: No distant metastasis o M1: Presence of distant metastasis o Mx: Unknown if distant metastasis is present or not By adding a "C" to any category, it's possible to express the certainty of the diagnosis. ▪ C1: Routine procedure (clinical examination, x-ray) ▪ C2: Special procedure (e.g. ERCP, CT) ▪ C3: Based on biopsy, cytology or surgical exploration ▪ C4: Based on surgery and additional histopathological workup ▪ C5: ▪ Based on autopsy and histopathological workup

By adding a prefix to TNM it's possible to indicate additional diagnostic or clinical information. ▪ cTNM: Staging based on clinical criteria ▪ pTNM: Histopathological staging T, N, and M have independent prognostic values. N and M are typically the most important determinants of prognosis Tumor Grading ▪ Process of classifying tumors based on their histological appearance (degree of differentiation). ▪ Indicators of poor differentiation

AJCC Grading System ▪ Most commonly used grading system for nonhematological malignancies ▪ Can be applied to a wide range of tumors

Cancer-specific Grading Systems 1. Gleason score: Prostate Cancer • Gleason X: The Gleason score cannot be determined. • Gleason 6 or Lower: The cells are well differentiated, meaning they look similar to healthy cells. • Gleason 7: The cells are moderately differentiated, meaning they look somewhat similar to healthy cells. • Gleason 8, 9, or 10: The cells are poorly differentiated or undifferentiated, meaning they look very different from healthy cells. 2. Nottingham grading system: Breast Cancer • Grade I Tumors o Total score of 3-5. o Well Differentiated.

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o Mostly resembles normal tissue and usually has a good prognosis • Grade II Tumors o Total score of 6-7. o Moderately Differentiated. o Intermediate forms of tumor with both good and bad prognosis • Grade III Tumors o Total score of 8-9. o Poorly Differentiated. o Tumors spread easier than other tumor's, and their prognosis is a little worse than for others. Cancer Staging ▪ Stage 0 - Cancer in Situ o still located in the place they started and have not spread to nearby tissues. o often highly curable, usually by removing the entire tumor with surgery. ▪ Stage I - Early-stage Cancer o small cancer or tumor that has not grown deeply into nearby tissues. o not spread to the lymph nodes or other parts of the body ▪ Stage II and Stage III o Indicate larger cancers or tumors that have grown more deeply into nearby tissue. o May also spread to lymph nodes but not to other parts of the body. ▪ Stage IV - Advanced or Metastatic Cancer. o cancer has spread to other organs or parts of the body For staging after treatment or after cancer recurrence/progression: ▪ Restaged after neoadjuvant therapy (or other therapy). ✓“y” might be used in front of the category ✓E.g., ycT1 or ypT2 ▪ Restaged after recurrence or progression of the cancer, ✓ “r” might be used in front of the category ✓ E.g., rcT1 or rpT2 Importance of Cancer Staging 1. Determines treatment. 2. Helps predict the chances of recovery. 3. Sets expectations and starts discussions. 4. Help identify clinical trials that may be right for the patients. 5. Changes as we learn more.

Cancer Classifications 1. Carcinoma • a malignant neoplasm of epithelial origin or cancer of the internal or external lining of the body. • Two major subtypes: I.Adenocarcinoma - develops in an organ or gland, II.Squamous Cell Carcinoma - originates in the squamous epithelium. 2. Sarcoma • originates in supportive and connective tissues such as bones, tendons, cartilage, muscle, and fat • most common sarcoma often develops as a painful mass on the bone • usually resemble the tissue 3. Myeloma • originates in the plasma cells of bone marrow 4. Leukemia • "liquid cancers" or "blood cancers “ • are cancers of the bone marrow (the site of blood cell production) 1. Myelogenous or granulocytic leukemia 2. Lymphatic, lymphocytic, or lymphoblastic leukemia 3. Polycythemia vera or erythremia 5. Lymphoma • "solid cancers’’ • Develop in the glands or nodes of the lymphatic system • Extranodal lymphoma o Lymphomas in specific organs such as the stomach, breast or brain • subclassified into two categories: o Hodgkin lymphoma and Non-Hodgkin lymphoma. o Reed-Sternberg cells diagnostically distinguishes Hodgkin lymphoma from Non-Hodgkin lymphoma. Tumor markers Tumor markers are biological substances that can be detected in the blood, urine, or body tissue of some tumor patients. Although some tumor markers may aid in the diagnosis of cancer, they are primarily used for monitoring treatment response and detecting cancer recurrence. Tumor markers are not reliable screening or diagnostic markers due to their low sensitivity (i.e.,

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not elevated in all cancer patients) and low specificity (i.e., also elevated in benign, noncancerous conditions or otherwise healthy patients). The majority of tumor markers that are used in the clinical setting can be detected in the blood. A number of tumor markers can be detected on tissue histopathology. They are also referred to as immunohistochemical markers and can be detected using immunohistochemical techniques. Gene mutations and patterns of gene expression are also increasingly being used as tumor markers.

Endothelium and Mesothelium

Overview Definition: substances (hormones, enzymes, antigens, immunoglobulins, glycoproteins) that can be detected in the blood, urine, or body tissue of some cancer patients

Blood and Lymphoid Cells Tissue Benign Tumors

Clinical use: 1. Detect cancer (does not confirm diagnosis!) 2. Predict therapeutic responses 3. Monitor the effectiveness of cancer treatment 4. Detection of cancer recurrence and screening Limitations: 1. Not all patients with cancer have elevated tumor markers (low sensitivity) 2. Not all patients with elevated tumor markers have cancer! (low specificity) • Tumor markers may also be elevated in patients with noncancerous conditions or otherwise healthy individuals. ! Tumor markers are generally not used to screen for or diagnose cancer. However, once cancer has been diagnosed via biopsy, tumor markers can be used to predict therapeutic responses and monitor the effectiveness of cancer treatment! Connective Tissue Tissue Adult fibrous tissue Embryonic (myxomatous) fibrous tissue Fat Cartilage Bone Notochord Connective tissue, probably fibrous

Benign Tumors Fibroma

Fibrosarcoma

Myxoma

Myxosarcoma

Malignant Tumors

Tissue Blood vessels Lymph vessels

Mesotheli um

Benign Tumors Hemangioma, hemangioperic ytoma Lymphangioma

Malignant Tumors

—

Mesothelioma

Hematopoietic cells

Hemangiosarcoma, angios arcoma Lymphangiosarcoma

"Preleukemias", "myeloproliferative disorders" Plasmacytosis

Lymphoid tissue

Muscle Tissue Smooth muscle Striated muscle

Malignant Tumors Leukemia, of various types aleukemic leukemia Plasmacytoma; multiple myeloma; Hodgkin lymphoma and NonHodgkin lymphoma

Benign Tumors Leiomyoma Rhabdomyoma

Malignant Tumors Leiomyosarcoma Rhabdomyosarcoma

Benign Tumors Papilloma Seborrheic keratosis and some skin adnexal tumors Adenoma 1. Hepatic adenoma 2. Renal tubular adenoma 3. Bile duct adenoma Transitional cell p apilloma Hydatidiform mole —

Malignant Tumors Squamous cell carcinoma; epidermoid carcinoma and some malignant skin adnexal tumors Adenocarcinoma 1. Hepatoma: hepatoc ellular carcinoma 2. Renal cell carcinoma; hyperne phroma 3. Cholangiocarcinoma Transitional cell carcinoma Choriocarcinoma

Epithelial Tissues Tissue Stratified squamous

Glandular epithelium 1. Liver 2. Kidney 3. Bile duct

Transitional epithelium Placenta Testis

Seminoma; embryonal cell carcinoma

Common tumor markers in peripheral blood Lipoma Chondroma Osteoma — Fibrous histiocytoma

Liposarcoma Chondrosarcoma Osteosarcoma Chordoma Malignant fibrous histiocytoma

Tumor marker Alpha fetoprotein (AFP)

Associated conditions Hepatocellular carcinoma (HCC) Hepatoblastoma Yolk sac tumor (endodermal sinus tumor) Mixed germ cell tumor Ataxia-telangiectasia

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β-HCG

Carcinoembryonic antigen (CEA)

Prostate-specific antigen (PSA)

Calcitonin Alkaline phosphatase

AFP is normally produced by the fetus → transient elevation of maternal AFP levels ↑ AFP: abdominal wall defects, neural tube defects ↓ AFP: associated with trisomy 21, 18, and 13 (see prenatal diagnostics for details) Testicular germ cell tumors (choriocarcinoma, embryonal cell carcinoma, mixed germ cell tumor, seminoma) Ovarian cancer: choriocarcinoma (gestational trophoblastic disease) If detectable in urine Pregnancy marker (produced by the syncytiotrophoblast in the placenta) Molar pregnancy (hydatidiform mole) Highly nonspecific marker; elevated in most adenocarcinomas Colorectal cancer Pancreatic cancer Breast cancer Lung cancer (especially in non-small cell cancers) Gastric cancer Endometrial cancer Medullary thyroid cancer Smokers Prostate cancer Benign prostatic hyperplasia Prostatitis Medullary thyroid cancer (both sporadic and associated with MEN 1 and MEN 2) Metastases to bone or liver Paget disease of the bone

Lactate dehydrogenase

Neuron specific enolase (NSE)

Levels correlate with tumor burden, reflects growth and invasiveness of cancer Ovarian cancer (dysgerminoma) Testicular germ cell tumors (both seminoma and nonseminoma) Lymphomas Ewing's sarcoma Hepatitis Hemolysis Myocardial infarction Neuroendocrine tumors Small cell lung cancer Carcinoid tumor Neuroblastoma

CA 19–9 CA 15–3 and CA 27–29 CA 125 CA 72-4 Chromogranin A S-100 protein (S100A) and (S100B) β2 microglobulin (β2M) Thyroglobulin

Monoclonal immunoglobulins

NSE is released secondary to brain injury Pancreatic adenocarcinoma Gastric cancer Breast cancer Ovarian carcinoma Ovarian carcinoma Gastric cancer Neuroendocrine tumors Medullary thyroid cancer Malignant melanoma Multiple myeloma Chronic lymphocytic leukemia Renal disease Papillary thyroid carcinoma Follicular thyroid carcinoma Multiple myeloma Waldenstroms macroglobulinemia Monoclonal gammopathy Infections Certain autoimmune conditions (e.g., rheumatoid arthritis)

Gene mutations and changes in gene expression Abnormal patterns of gene expressions and gene mutations from tissue samples are increasingly being used as tumor markers. Gene ALK rearrangement

gene

EGFR gene mutation

HER2neu

receptor

Conditions Non-small cell lung cancer Anaplastic large cell lymphoma Non-small cell lung cancer Certain head and neck cancers Breast cancer

Estrogen and progesterone receptors

Immunohistochemical Markers Definition: Antigens on the surface of cells that can be detected via tissue histopathological evaluation. Clinical relevance 1. Immunohistochemical information about

markers provide the origin and

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immunohistochemical characteristics of tumor cells (e.g., distribution of protein expression). 2. The presence or absence of certain immunohistochemical markers can help establish the prognosis of disease. Marker and Natural occurrence Vimentin ▪ Intermediate filament in the cytoskeleton of mesenchymal cells (e.g., macrophages, fibroblasts, endothelial cells)

Desmin ▪ Intermediate filament

Occurrence in Tumors Sarcomas ▪ Ewing sarcoma ▪ Osteosarcoma ▪ Chondrosarcoma ▪ Soft tissue sarcomas (e.g., GIST, angiosarcoma, liposarcoma) Endometrial carcinoma Renal cell carcinoma Meningioma Mesothelioma Rhabdomyosarcoma Leiomyosarcoma

in the cytoskeleton of smooth and skeletal muscle cells

Mesothelin ▪ Membranebound glycoprotein

Cytokeratin ▪ Intermediate filament in cytoskeleton epithelial cells Neurofilaments ▪ Neurons

the of

Chromogranin A and Synaptophysin ▪ Secretory granules of neuroendocrine cells

S-100 ▪

Neural cells

crest

Mesothelioma Pancreatic, esophageal, and gastric carcinoma ▪ Squamous cell carcinoma (e.g. of the skin or lung) ▪ Basal cell carcinoma ▪ Neuroendocrine tumors (e.g., carcinoid tumor) ▪ Neuroblastoma ▪ Medulloblastoma ▪ Small cell lung cancer (SCLC) ▪ Neuroendocrine tumors (e.g., carcinoid tumor) ▪ Small cell lung cancer (SCLC) ▪ Medullary thyroid cancer Schwannoma Melanoma

Langerhans histiocytosis GFAP ▪ Intermediate filament in the cytoskeleton of neuroglia (e.g., oligodendrocytes, astrocytes, Schwann cells) PSA Prostate epithelium TRAP Tartrate-resistant acid phosphatase CD20 B lymphocytes

Glioblastoma Astrocytoma

CD3 T lymphocytes

T cell lymphoma

cell

Prostate cancer Hairy cell leukemia

B cell lymphoma

CD8 T killer cells (cytotoxic T lymphocytes) CD4 T helper cells

Oncogenes and Tumor-Suppressor Genes Oncogene ▪ Gain-of-function mutation converts a protooncogene into an oncogene which leads to overexpression of signaling proteins and growth factors → uncontrolled cellular proliferation. ▪ Only one allele of proto-oncogene needs to be damaged to form an oncogene. ▪ A gene that is often present in cancer cells. Proto-oncogene ▪ Genes that encode proteins that are important in normal cell division and cell differentiation. ▪ The protein products of proto-oncogenes stimulate cell growth and division ▪ Examples include: o Protein kinases, e.g., protein kinase B (PKB) o Ligand-directed transcription factors (intracellular hormone receptors) o GTP-binding proteins o Tyrosine kinase receptors o Growth factors and cytokines

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BRAF (7q34) Gene Products: ▪ Serine/Threonine Kinase Associated Malignancies: ▪ Melanoma, Non-Hodgkin lymphoma, Papillary thyroid carcinoma BCR-ABL t(9;22) (q34.1;q11.21) Gene Products: ▪ Tyrosine kinase Associated Malignancies: ▪ CML t(9;22), ALL JAK2 (9p24.1) Gene Products: ▪ Tyrosinase Kinase Associated Malignancies: ▪ Chronic myeloproliferative disorders HER2/neu (c-erbB2) (17q12) Gene Products: ▪ Receptor tyrosine kinase Associated Malignancies: ▪ Breast Cancer ▪ Gastric Cancer ALK (2p23.2-p23.1) Gene Products: ▪ Receptor tyrosine kinase Associated Malignancies: ▪ Lung adenocarcinoma RET (10q11.21) Gene Products: ▪ Receptor Tyrosine Kinase Associated Malignancies: ▪ Papillary thyroid cancer ▪ MEN 2A and MEN 2B c-KIT(4q12) Gene Products: ▪ Cytokine receptor Associated Malignancies: ▪ Gastrointestinal stromal tumors L-myc-1 (MYCL1) (1p34.2) Gene Products: ▪ Transcription Factors Associated Malignancies: ▪ Lung cancer (SCLC)

N-myc (MYCN) (2p24.3) Gene Products: ▪ Transcription Factors Associated Malignancies: ▪ Neuroblastoma c-myc (8q24.21) Gene Products: ▪ Transcription Factors Associated Malignancies: ▪ Burkitt lymphoma t(8;14) KRAS (12p12.1) Gene Products: ▪ GTPase Associated Malignancies: ▪ Colorectal cancer ▪ Lung cancer ▪ Pancreatic cancer BCL-2 (18q21.33) Gene Products: ▪ Antiapoptotic molecule Associated Malignancies: ▪ Follicular lymphoma t(14;18) ▪ Diffuse large B cell lymphoma CCND1 (11q13.3) Gene Products: ▪ Cyclin D protein (regulatory protein of the cell cycle) Associated Malignancies: ▪ Mantle cell lymphoma t(11;14) ERBB1 (7p11.2) Gene Products: ▪ Epidermal growth factor receptor Associated Malignancies: ▪ Squamous cell carcinoma of the lung Tumor Suppressor Genes ▪ A gene that normally controls and suppresses cell proliferation. ▪ Loss of function or inactivation leads to an increased risk of developing cancer. Both alleles need to be mutated in order for complete loss of function of the gene. ▪ Involved in DNA repair mechanisms and inhibiting transcription factors that try to push the cell along in the cell cycle

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TP53 (17p13.1) Gene Products: ▪ p35 Protein ▪ Causes cell apoptosis (by activating proapoptotic gene such as BAX) and cell cycle arrest at the G1 phase (by activating p21) ▪ Inhibits entry in the S phase via inhibition of pRb phosphorylation Associated Malignancies: ▪ Most Human Cancers ▪ Lifraumeni Syndrome

▪ An intracellular protein that acts as a transcription factor to influence cellular proliferation. In normal cellular physiology, the Wnt signaling pathway mediates the destruction of this protein via the tumor suppressor protein APC. Failure of this regulatory process is implicated in colorectal cancer. Associated Malignancies: ▪ Familial adenomatous polyposis → colorectal cancer ▪ Sporadic colorectal cancer

Rb (13q14.2 ) Gene Products: ▪ Retinoblastoma protein (Rb protein): ▪ causes cell cycle arrest at the G1 phase by inhibiting E2F transcription factor Associated Malignancies: ▪ Retinoblastoma ▪ An intraocular malignancy that typically manifests during childhood with leukocoria (white fundal reflex instead of the usual red) and strabismus. Associated with loss of heterozygosity of the retinoblastoma tumor suppressor gene (RB1). ▪ Osteosarcoma ▪ A malignant bone-forming tumor that arises from bone mesenchymal tissue and typically occurs in the metaphysis of long bones. Characterized by rapid growth and cortical destruction as well as a florid periosteal reaction with a sunburst pattern on x-ray. Usually arises in individuals before the age of 30 years, but a small subset of cases occurs in elderly patients.

BRCA1 (17q21.31) & BRCA2 (13q13.1) Gene Products: ▪ DNA repair protein Associated Malignancies: ▪ Breast cancer ▪ Ovarian cancer ▪ Pancreatic cancer

CDKN2A (9p21.3) Gene Products: ▪ p16 protein ▪ which normally causes cell cycle arrest at the G1 phase Associated Malignancies: ▪ Melanoma ▪ A highly malignant tumor arising from melanocytes. Risk factors include extensive sun exposure, light skin, and a family history of melanoma. Metastasis is common; risk of metastasis correlates with tumor depth. ▪ Pancreatic cancer APC gene (5q22.2) Gene Products: ▪ A protein that prevents unregulated cell proliferation by inhibiting β-catenin synthesis

MMR gene family: Varies depending on the mutated protein Gene Products: ▪ DNA repair proteins Associated Malignancies: ...