Differentiation and Cellular Atypia
Benign neoplasms retain a high degree of differentiation, whereas malignant ones exhibit a wide spectrum—from well-differentiated to entirely undifferentiated. The complete loss of resemblance to mature tissue is called anaplasia. According to current concepts, carcinomas do not develop as a result of dedifferentiation of mature elements, but are initially formed from undifferentiated cells possessing stem cell properties.
Cellular atypia affects all cell components, but is most prominent in the nucleus. Nuclei enlarge drastically (due to polyploidy, endomitosis, and impaired DNA endoreduplication), and their contours become irregular and notched. Chromatin is distributed chaotically, condensing into clumps beneath the nuclear membrane (karyolemma). The proportion of inactive DNA (heterochromatin) increases, reflecting functional primitivism. Viral particles, tubular structures, and nuclear membrane pockets may be found inside the nucleus.
Ultrastructural Changes and Mitoses
Electron microscopy reveals profound organelle rearrangements that constitute *ultrastructural atypia:
- Nucleoli and membrane: Nucleoli become more numerous, enlarge, and do not disappear during division (they persist). The number of pores in the nuclear membrane decreases, impairing nucleocytoplasmic transport.
- Mitochondria: Due to the shift to anaerobic glycolysis, their number generally decreases (with exceptions such as oncocytomas and granular cell renal cell carcinomas). Giant forms with disrupted cristae orientation appear.
- Cytoskeleton: Microtubules and microfilaments are arranged haphazardly. This disrupts the function of adhesion molecules (integrins, cadherins), which drives invasive growth and metastasis.
- Surface: The cell membrane forms folds and microvilli where carcinogen receptors concentrate.
Mitotic activity is of particular diagnostic significance. It is extremely high in undifferentiated tumors. However, mitosis by itself does not imply malignancy. The true criteria are atypical mitotic figures: tripolar, tetrapolar, and multipolar mitotic spindles.
Biochemical and Antigenic Atypia
Tumor cells alter their metabolism to survive under hypoxic conditions. This biochemical (histochemical) atypia is manifested by the enhanced synthesis of oncoproteins, growth factors, and embryonic receptors. Simultaneously, the levels of histones and cyclic adenosine monophosphate (cAMP) drop.
Antigenic atypia involves restructuring the immune profile. The tumor loses normal tissue-specific antigens and histocompatibility antigens, which helps it establish host tolerance and evade the immune response. In return, tumor-specific and oncofetal antigens appear.
Evidence for their existence comes from transplant rejection experiments in inbred mice and the detection of cytotoxic T lymphocytes in tumor infiltrates (e.g., in human melanomas). Specific antigens have been identified in neuroblastoma, Burkitt lymphoma, and osteogenic sarcoma. Their identification by immunohistochemical methods is critical for accurate diagnosis.
Functional Atypia and Stroma Changes
Changes in cellular specialization lead to functional atypia. The cell loses its original functions and may acquire entirely new ones. A striking example: in poorly differentiated scirrhous gastric carcinoma, cells stop producing mucin and actively synthesize collagen for the tumor stroma.
In rapidly growing anaplastic tumors, the stroma is often sparse and fails to keep pace with parenchymal growth. Due to insufficient blood supply, extensive areas of ischemic necrosis form in the center of such neoplasms. Additionally, tumor giant cells with multiple hyperchromatic nuclei may be found in the tissue, which must be distinguished during differential diagnosis from foreign-body macrophage giant cells and Langhans giant cells.