L-12 Pathology Neoplasms and Cancer Metastasis

• Neoplasia is when cells of common origin escape normal proliferation restraints, showing relatively autonomous growth.
• Neoplasia means tumor formation.
• Tumors are solid masses of tissue, but not all are cancerous.

Benign vs. Malignant Neoplasms

• Benign neoplasms grow as compact masses remaining at their origin site.
• Malignant neoplasms penetrate surrounding tissue (invade) and may spread to distant tissues (metastasize).

Solid Neoplasms

• Tumors have neoplastic parenchyma cells and a non-neoplastic stroma, including connective tissue, blood vessels, inflammatory cells, and extracellular matrix (ECM).
• Stroma is also known as the tumor microenvironment.

Features Distinguishing Benign and Malignant Tumors

• Differentiation is the degree to which parenchymal cells resemble original normal cells.
• Invasion is direct extension and penetration by tumor cells into neighboring tissues.
• Metastasis is the spread of tumor cells from their primary location to noncontiguous body tissues.

Differentiation

• Benign neoplasms have well-differentiated parenchymal cells that resemble normal tissue.
• Malignant neoplasms range in parenchymal cell differentiation, lacking differentiation, also known as anaplasia ("cellular atypia").

Anaplasia

• Anaplasia is an irreversible loss of cell differentiation and a malignancy hallmark.
• Cytologic signs of anaplasia include pleomorphism (cell size and shape variation), nuclear abnormalities (increased size, hyperchromatism, nuclei), atypical mitoses, and loss of cellular polarity.

Invasion

• Benign neoplasms are not invasive, remain circumscribed, surrounded by fibroblasts and ECM.
• Malignant neoplasms are invasive, breaching the basement membrane (BM) or ECM once in stroma.

Carcinoma in Situ

• These lesion display malignancy characteristics without basement membrane (BM) invasion.
• Carcinoma in situ classification as cancer is controversial because transformed cells do not cross the BM and spread to adjacent tissues.
• Considered pre-malignant conditions, which may or may not progress.

Metastasis

• Benign neoplasms never metastasize.
• Malignant neoplasms can metastasize to other sites and refer to cancers named after their origin site.
• Metastases development results in 90% of cancer deaths.

Metastatic Dissemination Routes

Lymphatic dissemination occurs through the lymphatic system, typically for carcinomas.

• Hematogenous dissemination occurs through the bloodstream, typically for sarcomas.
• Transcoelomic dissemination is direct seeding in body cavities like peritoneal and pleural cavities, common in ovarian and some lung cancers.

Lymphatic Dissemination

• Breast carcinoma can spread via lymph nodes.

Hematogenous Dissemination

• Malignant tumors invading adipose tissue can penetrate small veins and spread hematogenously.

Transcoelomic Dissemination

• Peritoneal carcinomatosis-metastatic ovarian carcinoma can result from transcoelomic dissemination.
• Malignant neoplasms in organs adjacent to body cavities spread into natural "open fields."

Non-Cancerous Tissue Changes

• Hyperplasia is increased parenchymal cell number, with tissue organized and normal-looking, like breast hyperplasia during puberty, pregnancy, or lactation.
• Dysplasia involves disordered cell growth that looks abnormal under the microscope, mainly affecting tissue organization, and occurring only in epithelial cells.
• Hyperplasia and mild dysplasia are often reversible when the stimulus or offending factor ceases.

Tissue Changes

• Metaplasia is when one cell type replaces another.

Tumor Classification

• Classification of tumors is based on biologic behavior and tissue of origin (Nomenclature), malignancy (Tumor grade), and size/spread (Tumor stage).

Tumors and Cancers

• Cancers can start in almost any body tissue, with distinct growth, spread characteristics, and prognoses.

How Neoplasms are Named

• Tumors are named according to the neoplastic component but also contain nonneoplastic supportive stroma (connective tissue and blood vessels).
• Tumor names include cell type, a modifier indicating benign/malignant, and site of origin.

Benign Neoplasms from Mesoderm

• Tissue origin names end in "oma"

Benign Neoplasms from Epithelium

• Tumors are names based on the characteristics of epithelium

Malignant Neoplasms from Mesoderm

• Tissue origin names end in "sarcoma"

Malignant Neoplasms from Epithelium

• Organ related names end in "carcinoma"

Exceptions to Tumor Nomenclature Rules

• Malignant tumors that end with 'oma' are: melanoma, seminoma, mesothelioma, and lymphoma.
• Tumors are named after the person who discovered them and do not provide any hint about their histogenesis.

Pleomorphic Tumors

• Tumors contain different cell subpopulations.
• Contains Epithelial components and Myxoid stroma that forms cartilage and bone.

Teratomas and Teratocarcinomas

• Teratomas (benign) and teratocarcinomas (malignant) are mixed tumors with cells from more than one germ layer (endoderm, ectoderm, mesoderm).

Blastomas

• Most occur in patients below 5 years old.
• They are Histologically similar to the embryonic form of the organ in which they arise.

Tumor Grade

• Based on Histologic malignancy estimate.
• Considers differentiation (well-differentiated/low grade to poorly differentiated/anaplastic/high grade) and growth rate (Mitosis number).

Tumor Stage

• Based on Clinical estimate of size and extent of tumor spread.
• The TNM Staging System is based on primary Tumor (T) size and invasiveness, spread to regional lymph Nodes (N), and presence of distant Metastasis (M).

Cancer Etiology

• Cancer is caused by chemical carcinogens, physical carcinogens, and oncogenic viruses/microbes.

Chemical Carinogens Direct Damage

• Chemical carcinogens directly damage DNA, leading to mutations that transform normal cells into cancerous cells.

Direct-Acting Carcinogens

• These carcinogens dont require metabolic conversion (e.g., alkylating agents, such as cyclophosphamide).

Indirect-Acting Carcinogens

• Only active when converted by endogenous metabolic systems (such as cytochrome P-450 [CYP] monooxygenases).

Chemical Carcinogens and Cancer

• Polycyclic Aromatic Hydrocarbons (PAH) found in smoke of burned coal, oil, gas, wood, garbage, and tobacco lead to lung cancer.
• Chemotherapeutic drugs can lead to solid and hematological cancers much later.
• Nitrosamines can be formed in the stomach from nitrites found in cured sandwich meats, bacon, salami, and sausages and lead to gastric adenocarcinomas.
• Aflatoxin B₁produced by the fungus Aspergillus flavus in improperly stored grains and nuts can cause Hepatocellular carcinoma.

Carinogen Multistep Progress

• Consists of intiation wich irreversibly alters gene change (= mutation) and Promotion to further expand the clone.
• Promotion is clonal expansion of the mutated cell through proliferation ("fixation" of mutation); which is reversible.
• Ionizing radiation from radioactive elements and atomic bombs can cause thyroid, lung, and breast cancers.
• Non-ionizing radiation (UV) from the sun/tanning beds can cause non-melanoma skin cancers (basal/squamous cell carcinomas) and melanomas

Physical Carcinogens

• Almost all radiations act as carcinogens in high doses, causing double-strand DNA and chromosomal aberrations breaks.
• Ionizing Radiations in miners and survivors showed increases increase thyroid, lung, breast cancers
• Non-ionizing Radiations such as tanning beds and the sun can cause non-melanoma skin cancers (basal cell carcinomas and squamous cell carcinomas) and melanomas.

Physical Carcinogens: Pyrimidine

• Pyrimidine Dimers in DNA by UV light defected cells.
• Patients with xeroderma pigmentosum have a defect in the nucleotide excision repair system, resulting in increased skin cancer predisposition.

Viruses and Microbes

• 15-20% of human cancers are caused by viruses
• Seven are identified to contribute to specific human cancers.

Oncogenic DNA Viruses

• These viruses include Human Papilloma Virus (HPV), Epstein-Barr Virus (EBV), Hepatitis B Virus (HBV), Kaposi Sarcoma-associated Herpesvirus (KSHV), and Merkel Cell Polyomavirus.
• Oncogenic RNA viruses include Human T-cell lymphotropic Virus (HTLV-1) & Hepatitis C Virus (HCV).

Viral Infections and Gene Insertion

• DNA Viruses insert their viral oncogene (v-onc) directly into the host genome (DNA). Retroviruses also carry a viral RNA promoter which is reverse transcribed into DNA and inserted to a proto-oncogene to be activated

Human Papilloma Virus (HPV)

• HPV infects epithelial cells and its subtypes are associated with genital tract lesions.
• HPV 16 & 18 are strongly involved with cancer of cervix.
• Spread via sexual intercourse/skin contact through skin/mucosa tears
• Some are preventable by vaccine

Major HPV Oncoproteins

• E6 inhibits p53, and E7 inhibits Rb, resulting in • Immortalization, •↑ Cell proliferation and genomic instability etc

Epstein Barr Virus (EBV)

• 95% of the population have antibodies against EBV and spread through saliva.
• It is found with Burkitt lymphomas and also high levels of nasopharyngeal carcinomas.

Helicobacter Pylori

• H. pylori is with adenocarcinoma and gastric lymphoma spread through saliva.

Explore the characteristics of neoplasms, focusing on differentiating between benign and malignant types. Understand cancer metastasis, routes of dissemination, and clinical significance. Also, learn about carcinoma in situ and squamous intraepithelial lesion.