10.1 Genetic Disorders & Neoplasia: Mendelian, Chromosomal, Non-Classic Inheritance, Tumor Biology & Markers

Why this area matters

The TOS lists "Mendelian disorders; chromosomal disorders; single gene disorders with non-classic inheritance; benign and malignant neoplasms; grading and staging of tumors; tumor markers". The genetics part supports Pediatrics and Biochemistry. The neoplasia part supports every organ-system pathology item and the oncology parts of Surgery and Medicine.

Mendelian disorders

Marfan syndrome shows tall stature with long limbs, ectopia lentis (upward lens dislocation), mitral valve prolapse, and cystic medial degeneration of the aorta, which leads to dissection. Familial hypercholesterolemia causes xanthomas and premature coronary disease.

Chromosomal disorders

Single-gene disorders with non-classic inheritance

• Trinucleotide-repeat expansion shows anticipation: earlier onset and greater severity in later generations.
  • Fragile X syndrome: CGG repeats in FMR1. Intellectual disability, macro-orchidism, long face.
  • Huntington disease: CAG repeats, autosomal dominant.
  • Myotonic dystrophy: CTG repeats.
  • Friedreich ataxia: GAA repeats.
• Mitochondrial inheritance: passed only through the mother to all her children. Severity varies because of heteroplasmy. Examples are Leber hereditary optic neuropathy and the MELAS and MERRF syndromes.
• Genomic imprinting: the same deletion at 15q11-13 gives:
  • Prader-Willi syndrome when the paternal copy is lost: hyperphagia, obesity, hypotonia, hypogonadism;
  • Angelman syndrome when the maternal copy is lost: seizures, ataxia, inappropriate laughter. Uniparental disomy can produce the same results.
• Gonadal mosaicism explains recurrence of an autosomal dominant disorder when both parents appear normal.

Neoplasia Biology: Benign vs. Malignant Characteristics

A neoplasm is an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of normal tissues, persisting in the same excessive manner after cessation of the stimuli which evoked the change.

• Differentiation & Anaplasia: Differentiation refers to the extent to which parenchymal cells resemble corresponding normal cells morphologically and functionally. Benign neoplasms are well-differentiated. Malignant neoplasms show a range from well to poorly differentiated. Anaplasia (complete lack of differentiation) is a definitive hallmark of high-grade malignancy, featuring cellular and nuclear pleomorphism, hyperchromasia, high nuclear-to-cytoplasmic ratio ($1:1$ rather than normal $1:4$ to $1:6$), atypical bizarre multipolar mitoses, and loss of normal architectural polarity.
• Local Invasion: Benign tumors remain localized, growing as cohesive expansive masses often surrounded by a fibrous pseudocapsule. Malignant tumors invade, infiltrate, and breach tissue boundaries. Breach of the epithelial basement membrane is the fundamental criterion distinguishing invasive carcinoma from carcinoma in situ.
• Metastasis: The spread of tumor cells to physical sites discontinuous with the primary tumor; the absolute hallmark of malignancy (unequivocally identifies a tumor as malignant). Note: Basal cell carcinoma of the skin and primary central nervous system gliomas are locally destructive but virtually never metastasize.
• Routes of Dissemination:
  • Lymphatic Spread: Typical of carcinomas (cancers of epithelial origin), tracking to regional draining sentinel lymph nodes. Exceptions: Follicular thyroid carcinoma, choriocarcinoma, hepatocellular carcinoma, and renal cell carcinoma spread hematogenously.
  • Hematogenous Spread: Typical of sarcomas (cancers of mesenchymal origin), invading thin-walled veins and seeding downstream capillary beds in the liver (portal flow) and lungs (caval flow).
  • Seeding of Body Cavities: Direct invasion across serosal spaces; prototypic in ovarian carcinoma studding peritoneal surfaces, and Krukenberg tumors (gastric signet ring adenocarcinoma metastasizing bilaterally to ovaries).

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Molecular Genetics of Cancer: Oncogenes & Tumor Suppressors

Malignant transformation results from non-lethal genetic damage acquired across eight hallmarks of cancer: self-sufficiency in growth signals, insensitivity to growth-inhibitory signals, evading apoptosis, limitless replicative potential (telomerase reactivation), sustained angiogenesis, tissue invasion and metastasis, altered cellular metabolism (Warburg effect: preference for aerobic glycolysis), and evading immune surveillance.

Proto-oncogenes vs. Tumor Suppressor Genes

• Proto-oncogenes: Normal genes promoting cell growth. Mutation of a single allele (gain-of-function mutation, dominant action) creates an oncogene leading to unregulated proliferation.
• Tumor Suppressor Genes: Normal genes inhibiting cell proliferation or repairing DNA. Inactivation of both alleles (loss-of-function mutation, recessive action at the cellular level) is required for transformation, fulfilling Knudson's Two-Hit Hypothesis.

Staging vs. Grading of Neoplasms

• Histologic Grading: Microscopic determination of differentiation, cellular pleomorphism, and mitotic activity. Ranges from Grade 1 (well-differentiated, low grade) to Grade 4 (undifferentiated/anaplastic, high grade).
• Clinical/Pathologic Staging: Evaluation of tumor size and anatomical extent of anatomical spread in the patient's body, standardized by the AJCC/UICC TNM System:
  • T (Primary Tumor): $T_0$ (no primary), $T_{is}$ (carcinoma in situ), $T_1-T_4$ (increasing size or local invasion depth).
  • N (Regional Lymph Nodes): $N_0$ (no nodal spread), $N_1-N_3$ (increasing number or anatomical nodal chains involved).
  • M (Distant Metastasis): $M_0$ (no distant metastasis), $M_1$ (presence of distant organ metastasis).
• Golden Board Principle: Clinical stage possesses far greater prognostic value and therapeutic influence than histologic grade.

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Paraneoplastic Syndromes & Clinical Tumor Markers

Paraneoplastic Syndromes

Symptom complexes occurring in cancer patients that cannot be explained by local tumor spread, metastasis, or indigenous tissue hormones:

• Hypercalcemia of Malignancy: Production of Parathyroid Hormone-related Protein (PTHrP) by Squamous Cell Carcinoma of the Lung, head and neck tumors, or renal cell carcinoma (distinct from hypercalcemia caused by extensive osteolytic bone metastases).
• Cushing Syndrome: Ectopic production of ACTH by Small Cell Lung Carcinoma (SCLC) or bronchial carcinoids.
• SIADH: Ectopic production of antidiuretic hormone (ADH) by SCLC, leading to euvolemic hyponatremia.
• Lambert-Eaton Myasthenic Syndrome: Autoantibodies directed against presynaptic voltage-gated calcium channels, associated with SCLC (causes proximal muscle weakness that improves with repetitive contraction).
• Trousseau Syndrome (Migratory Thrombophlebitis): Hypercoagulability mediated by circulating tissue factor-like procoagulants, associated with pancreatic adenocarcinoma.

Clinically Important Tumor Markers

Tumor markers are biochemical indicators of malignancy used primarily for monitoring response to therapy, detecting disease recurrence, and disease surveillance, rather than initial primary screening (owing to imperfect sensitivity and specificity):

• Alpha-Fetoprotein (AFP): Hepatocellular Carcinoma (HCC) and non-seminomatous testicular germ cell tumors (specifically Yolk Sac / Endodermal Sinus Tumors).
• Prostate-Specific Antigen (PSA): Prostate adenocarcinoma (also elevated in benign prostatic hyperplasia and acute prostatitis).
• Carcinoembryonic Antigen (CEA): Colorectal adenocarcinoma, pancreatic, and gastric cancers; used to monitor surgical resection and surveillance.
• CA-125: Epithelial ovarian carcinoma; monitored for response to chemotherapy and recurrence.
• Beta-hCG: Gestational trophoblastic disease (Choriocarcinoma, Hydatidiform mole) and testicular choriocarcinomas.
• CA 19-9: Pancreatic adenocarcinoma and cholangiocarcinoma.
• Calcitonin: Medullary Thyroid Carcinoma (arising from parafollicular C cells).

Naming tumors and carcinogenic agents

• Benign tumors end in "-oma": adenoma, papilloma, leiomyoma, lipoma.
• Carcinoma is a malignant epithelial tumor; sarcoma is a malignant mesenchymal tumor.
• Misleading names: lymphoma, melanoma, seminoma and mesothelioma are malignant.
• A hamartoma is a disorganized mass of tissue native to the site. A choristoma is normal tissue in the wrong place.

Chemical carcinogens:

• tobacco (lung, oral, laryngeal, bladder and pancreatic cancer);
• aflatoxin B1 from Aspergillus-contaminated peanuts and corn, which causes TP53 mutation and hepatocellular carcinoma, especially with hepatitis B;
• asbestos (mesothelioma, lung cancer);
• benzene (leukemia);
• vinyl chloride (hepatic angiosarcoma);
• nitrosamines (gastric cancer);
• alkylating agents.

Radiation: ultraviolet light causes skin cancer, and ionizing radiation causes leukemia and thyroid cancer.

Oncogenic microbes:

• HPV 16 and 18 (cervical, anal and oropharyngeal cancer; E6 inactivates p53 and E7 inactivates RB);
• EBV (Burkitt lymphoma, nasopharyngeal carcinoma, Hodgkin lymphoma);
• hepatitis B and C (hepatocellular carcinoma);
• HTLV-1 (adult T-cell leukemia);
• KSHV/HHV-8 (Kaposi sarcoma);
• H. pylori (gastric adenocarcinoma, MALT lymphoma);
• Schistosoma haematobium (bladder squamous carcinoma);
• liver flukes (cholangiocarcinoma).