ACP 1-11 Pathology of Tumors (tutorial)

Fundamental Terminology and Concepts in Neoplasia

  • Tumor (Historical and Modern Context):

    • Originally, the term referred strictly to "swelling" caused by inflammation.

    • Literally translates to "Abnormal Mass."

    • In modern clinical practice, it is often used synonymously with "Neoplasm."

  • Neoplasia:

    • Literally means "New Growth."

    • Definition: An abnormal, uncoordinated, and excessive growth of tissue.

    • Results in the formation of a new tissue mass consisting of tumor cells and stromal cells.

    • Characteristics: Becomes autonomous, meaning it is independent of physiological stimuli or normal bodies regulation. These growths are usually clonal.

  • Oncology: Derived from the Greek word oncos (meaning tumor), it is the study of tumors.

  • Stroma:

    • These are the supportive tissues located between or under the epithelium in most organs.

    • Components include adipocytes (fatty tissue), blood vessels, and fibroblasts.

    • Can also include specialized connective tissues like bone and cartilage.

  • Components of a Tumor:

    • Parenchyma: The neoplastic cells themselves.

    • Stroma: Supporting host-derived, non-neoplastic connective tissue, inflammatory cells, and blood vessels.

Nomenclature of Neoplasia

  • General Naming Rules: The naming of a tumor depends on whether it is benign or malignant, the cell type it is derived from (epithelial, mesenchymal, blood, or germ cell), and sometimes its specific morphology.

  • Benign Neoplasms: Typically end with the suffix "-oma."

    • Mesenchymal Origin:

      • Fibroblast/Fibrocyte: Fibroma.

      • Adipocyte: Lipoma.

      • Blood Vessel: Hemangioma.

      • Cartilage: Chondroma.

      • Bone: Osteoma.

      • Smooth Muscle: Leiomyoma.

      • Striated Muscle: Rhabdomyoma.

    • Epithelial Origin:

      • Adenoma: Forms gland-like structures (e.g., Thyroid adenoma, Renal cell adenoma, Liver cell adenoma).

      • Papilloma: Produces finger-like projections macroscopically and microscopically (e.g., Squamous cell papilloma).

      • Cystadenoma: Refers to a hollow cystic mass, common in the ovary.

      • Polyp: A mass that projects above a mucosal surface to form a macroscopically visible structure.

  • Malignant Neoplasms: Often referred to as "Cancer" (Latin for crab).

    • Mesenchymal Origin (Sarcomas):

      • Fibroblast: Fibrosarcoma.

      • Adipocyte: Liposarcoma.

      • Blood Vessel: Angiosarcoma.

      • Cartilage: Chondrosarcoma.

      • Bone: Osteosarcoma.

      • Smooth Muscle: Leiomyosarcoma.

      • Striated Muscle: Rhabdomyosarcoma.

    • Epithelial Origin (Carcinomas):

      • Glandular tissue: Adenocarcinoma.

      • Squamous cells: Squamous cell carcinoma.

      • Specific examples include Renal cell carcinoma and Hepatocellular carcinoma (HCC).

  • Exceptions (The "-oma" is Malignant):

    • Lymphoid/Hematoid: Lymphoma, Multiple Myeloma.

    • Skin/Mesothelium: Melanoma, Mesothelioma.

    • Central Nervous System: Glioma.

    • Germ Cell: Seminoma (males), Dysgerminoma (females).

  • Special Categories:

    • Blastoma: Primitive neoplasms that resemble embryonic counterparts; often occur in pediatric populations and are usually malignant (e.g., Retinoblastoma, Hepatoblastoma, Nephroblastoma/Wilms Tumor, Neuroblastoma).

    • Germ Cell Tumors:

      • Teratoma: A special mixed tumor containing recognizable mature or immature cells from more than one germ cell layer (ectoderm, mesoderm, endoderm).

      • Mature teratoma: General benign form.

      • Immature teratoma: Malignant potential.

    • Mixed Tumors: Clonal tumors where the progenitor cell differentiates along more than one lineage (e.g., Pleomorphic adenoma of the salivary gland).

Reporting and Diagnostic Criteria of Tumors

  • Aims of Tumor Reporting:

    • Diagnosis (Benign vs. Malignant).

    • Classification and Grading.

    • Staging.

    • Margin status (whether the tumor was fully removed).

    • Potential for target therapy.

  • Four Pillars of Diagnosis:

    1. Differentiation:

      • Benign tumors are typically well-differentiated (resemble the normal cytology and architecture of the parent tissue).

      • Malignant tumors have variable differentiation.

      • Anaplasia: A total lack of differentiation; considered a hallmark of malignancy and usually indicates a poor prognosis.

      • Features of Anaplastic Cells: Cellular and nuclear pleomorphism, tumor giant cells, atypical mitosis, and loss of polarity.

    2. Growth Rate:

      • Normal < Benign < Malignant.

      • High mitotic rate and specifically atypical mitosis usually signify malignancy.

      • Necrosis: Often central necrosis occurs because the tumor outgrows its blood supply. Necrosis appears eosinophilic with a loss of cell architecture and nuclei.

      • Nuclear Atypia: Features include nucleomegaly, high nuclear-to-cytoplasmic (N/C) ratio, hyperchromasia (dark staining), coarse chromatin, pleomorphism (variation in size/shape), and irregular nuclear membranes.

    3. Presence of Invasion:

      • Invasion is a definitive sign of malignancy.

      • Gross findings: Infiltrative borders, adhesion to neighboring tissue planes, or involvement of other tissue layers.

      • Microscopic findings:

        • Invasion into stroma resulting in a desmoplastic reaction (fibrosis).

        • Lymphatic invasion.

        • Vascular (venous or arterial) invasion.

        • Perineural invasion (around nerves).

    4. Presence of Metastasis:

      • Defined as tumor spreads or implants discontinuous from the primary tumor site.

      • Pathways:

        • Lymphatics: Most common for carcinomas; spreads to regional then distant nodes.

        • Hematogenous (Bloodstream): Typical for sarcomas; spreads via veins/arteries to distant organs (e.g., liver, lungs).

        • Seeding: Through body cavities like the peritoneal, pleural, or pericardial spaces (e.g., "omental cake" in peritoneal metastasis).

      • Sentinel Lymph Node: The first regional lymph node receiving drainage from a primary tumor; used for biopsy to plan treatment.

Staging and Grading Systems

  • Grading:

    • Assesses how aggressive the disease is based on cellular features.

    • Generally uses a 3 or 4-tier system.

    • Higher grade corresponds to a lesser degree of differentiation and more aggressive behavior.

  • Staging:

    • Assess the extent or spread of the malignant neoplasm within the patient.

    • TNM System:

      • T: Size and/or physical extent of the primary tumor.

      • N: Lymph node involvement.

      • M: Presence (M1M_1) or absence (M0M_0) of distant metastasis.

    • Types of Staging: Pathological (pTNM) and Clinical (cTNM).

    • T, N, and M values combine to determine the final Stage (I to IV).

Clinical Effects of Tumors

  • Local Effects (Mass Effect):

    • Compression or impingement on adjacent structures.

    • Brain: Midline shift or herniation.

    • Bowel: Intestinal obstruction (lumen blocking).

    • Stomach: Malignant ulcers leading to GI bleeding.

    • Lung: Involvement of ribs or adjacent structures.

    • Liver: Rupture (specifically in HCC) or secondary biliary sepsis.

  • Systemic Effects:

    • Cachexia: Also known as "Wasting Syndrome."

      • Symptoms: Progressive loss of body fat and muscle, profound weakness, anorexia, and anemia.

      • Mechanism: Generalized increase in metabolism and inflammation involving cytokines like TNF−αTNF-\alpha and IL−1IL-1.

      • Impact: Decreased fitness for surgery and poor recovery.

    • Paraneoplastic Syndromes: Remote effects of cancer not caused by direct metastasis.

      • Endocrine: Ectopic hormone production (e.g., Cushing syndrome, Hypercalcemia).

      • Hypertrophic Osteoarthropathy: Includes finger clubbing and periosteal new bone formation; characteristic of lung cancer.

      • Neurological: Peripheral neuropathy, cortical cerebellar degeneration, myasthenic syndrome.

      • Vascular: Migratory thrombophlebitis (Trousseau sign).

    • Anemia of Chronic Disease.

Pre-invasive Processes and Other Masses

  • Dysplasia:

    • Disordered growth and maturation of an epithelium.

    • It is a pre-invasive neoplastic process that has not yet penetrated the basement membrane.

    • It is potentially reversible.

    • Grading ranges from Low-grade to High-grade (Carcinoma in-situ).

  • Adenoma-Carcinoma Sequence (Example in Colonic Cancer):

    • Normal mucosa →\rightarrow APC 5q215q21 1st hit (Germline/somatic) →\rightarrow Risky mucosa →\rightarrow APC 2nd hit →\rightarrow Adenoma →\rightarrow KRAS proto-oncogene mutation or p53 tumor suppressor gene mutation →\rightarrow Adenocarcinoma.

  • Non-Neoplastic Masses:

    • Hamartoma: An overgrowth of tissues indigenous to a particular site, but they are disorganized and erroneously arranged (e.g., Lung hamartoma).

    • Heterotopia (Heterotopic Rest): Mature tissue occurring in an abnormal site (e.g., pancreatic tissue in the stomach wall).

    • Choristoma: A heterotopia that is clinically significant.

Epidemiology and Environmental Factors

  • Global Cancer Statistics (GLOBOCAN 2022):

    • Incidence: Highest in Asia (49.2%49.2\%), followed by Europe (22.4%22.4\%).

    • Mortality: Asia accounts for 56.1%56.1\% of cancer deaths.

    • Top Cancers by Incidence: Lung, Breast, Colorectum, Prostate, Stomach.

    • Top Cancers by Mortality: Lung, Colorectum, Liver, Breast, Stomach.

  • Hong Kong Cancer Statistics (2022):

    • Top 10 (Both Sexes): Lung, Breast, Colorectum, Prostate, Liver, Stomach, Corpus uteri, Non-Hodgkin lymphoma, Thyroid, Pancreas.

    • Male Specific: Lung is #1, followed by Colorectum and Prostate.

    • Female Specific: Breast is #1, followed by Lung and Colorectum.

  • Risk Factors:

    • Age: Frequency increases generally between the ages of 5555 and 7575, declining after 7575. Rising incidence is due to the accumulation of somatic mutations.

    • Smoking: Linked to 90%90\% of lung cancer deaths; also mouth, pharynx, larynx, pancreas, and bladder cancer.

    • Alcohol: Risk factor for oropharynx, larynx, esophagus, and liver (via cirrhosis) cancers.

    • Obesity: Attributed to 14%14\% of cancer deaths in men and 20%20\% in women.

    • Diet: Red meat is classified by WHO as "probably carcinogenic" (Group 2A), linked to colorectal, pancreatic, and prostate cancer.

    • Radiation: UV rays and ionizing radiation can inactivate tumor suppressor genes like TP53TP53.

  • Occupational Hazards:

    • Arsenic: Lung and skin carcinoma.

    • Asbestos: Lung carcinoma, mesothelioma.

    • Benzene: Acute myeloid leukemia.

    • Vinyl Chloride: Hepatic angiosarcoma.

    • Radon: Lung carcinoma.

  • Infectious Agents (15%15\% of global cancers):

    • Hepatitis B/C: Liver cancer.

    • HPV: Cervical, head, and neck cancers.

    • H. pylori: Stomach cancer and MALT lymphoma.

    • Schistosoma: Bladder cancer (Squamous cell carcinoma).

    • EBV: Hodgkin and Non-Hodgkin lymphoma, Nasopharyngeal cancer.

Case Study Insights

  • Case 1 (Colonic Adenocarcinoma): 80-year-old male with constipation. Grossly shows a fungating mass with an infiltrative border causing intraluminal narrowing. Microscopically shows complex glandular architecture penetrating the muscularis propria into subserosal fat with a desmoplastic reaction.

  • Case 2 (Colonic Adenoma): 40-year-old male, positive fecal occult blood. Shows a 1.8 cm1.8\,cm pedunculated polyp. Tubular adenomas have an increased risk of progressing to adenocarcinoma, specifically correlated with size and high-grade dysplasia.

  • Case 4 (Breast):

    • Malignant: Breast carcinoma shows irregular, infiltrative borders, stony-hard palpation, and nests/cords of cells invading stroma/fat; no capsule.

    • Benign: Fibroadenoma is oval, circumscribed, and encapsulated with a homogenous tan cut surface.

  • Case 5 (Liver Primary vs. Secondary):

    • Primary (HCC): Usually occurs in a cirrhotic background (nodules of variable sizes), common in Hepatitis B carriers; often presents with a green cut surface due to bile production.

    • Secondary (Metastatic): Often presents as multiple whitish nodules within lymphovascular channels; context of a prior primary (e.g., colectomy for colon cancer).