Basics of morphogenesis and theories of carcinogenesis
When studying morphogenesis, pathomorphology answers four key questions: what is the source of the cells (does the tumor arise de novo or in stages), what is the essence of the developmental stages, what is the clonality (monoclonal or polyclonal origin), and how the neoplasm interacts with the organism.
There are two main theories of cell transformation:
- Theory of saltatory transformation. Assumes tumor development without preceding tissue changes (single-stage model). Supported by data from experimental viral carcinogenesis.
- Theory of staged transformation. Developed by L.M. Shabad and supported by most experimental models. Based on the accumulation of mutations in somatic cells.
An important role in initiation is played by cancer stem (initiating) cells. They sustain the growth of the node. Their proportion in the population is extremely small (e.g., 0.1–1.0% in acute myeloid leukemia), yet their survival after treatment leads to relapses. Note: the presence of such cells has not been proven for all tumor types.
Stages of tumor development
Historically, L.M. Shabad distinguished four stages: focal hyperplasia, diffuse hyperplasia, benign tumor, and malignant tumor (the first three referred to preneoplastic processes). Currently, the classification of morphogenesis stages has been refined:
- Preneoplasia stage. Includes hyperplasia and preneoplastic dysplasia. Pathological processes affect both the stroma and the parenchyma. The main morphological criterion is the appearance of signs of cellular atypia.
- Non-invasive tumor stage (carcinoma in situ).
- Invasive growth stage.
- Metastasis stage.
Features of non-invasive cancer (Carcinoma in situ)
Progression of dysplasia under the influence of additional factors leads to genetic rearrangements and malignant transformation. A malignant cell arises, forming a clone.
At the carcinoma in situ stage (intraepithelial neoplasia), the tumor grows "within itself". The basement membrane is intact, and its own blood vessels and stroma are absent. Nutrition is carried out exclusively through the diffusion of substances from the tissue fluid of adjacent normal tissues.
Why is there no angiogenesis at this stage? There are two hypotheses. The first attributes this to the small mass of the tumor (lack of stimulating factors). The second, more likely hypothesis explains this by the absence of specific genetic rearrangements necessary to trigger invasive growth.
Invasion and genetic model of progression
Upon transition to the invasive tumor stage, infiltrative growth begins. The neoplasm acquires a developed vascular network, forms a stroma, and clear boundaries with healthy tissue disappear due to cell proliferation. The pathogenesis of invasion proceeds in 3 phases and is strictly controlled by genetics.
The classic model of staged mutation accumulation is colorectal precancer:
| Morphological stage | Genetic alterations | Localization |
|---|---|---|
| Hyperplastic epithelium | Mutations or loss of APC, MCC | Chromosome 5q |
| Early adenoma | Impaired DNA methylation | — |
| Late adenoma | Mutation of K-ras, loss of DCC | Chromosomes 12q, 18q |
| Carcinoma | Mutation and loss of p53 | Chromosome 17q |
| Metastatic carcinoma | Accumulation of mutations | Deletion of 17q |
Briefly: answers to topical questions
What three phases are distinguished in the pathogenesis of tumor invasive growth?
Three consecutive phases are distinguished in the pathogenesis of tumor invasive growth.
- First phase (Epithelial-mesenchymal transition) — weakening of intercellular bonds, increased expression of molecules for mobility and integrins.
- Second phase (Matrix degradation) — secretion of proteolytic enzymes by the tumor cell and destruction of the extracellular matrix to clear the pathway for invasion.
- Third phase (Migration) — accumulation of fibronectin and laminin breakdown products, which act as chemoattractants, drawing tumor cells into the zone of degradation.
Which morphological changes of nuclei and cells are classified as signs of cellular atypia?
Signs of cellular atypia include marked changes in the structure of cells and their nuclei.
- Cellular changes (polymorphism) — pronounced variability in shape and size, presence of giant, small primitive, and multinucleated cells.
- Nuclear changes — polyploidy, hyperchromasia (marked dark staining), increased nuclear-cytoplasmic ratio, polymorphism, irregular contours, and the appearance of large nucleoli.
Cellular atypia also includes altered mitotic activity with the appearance of atypical mitotic figures.
What are the main differences between a benign and a malignant tumor?
The main differences between a benign and a malignant tumor lie in the nature of atypia, the degree of cell differentiation, and the type of growth.
| Sign | Benign tumor | Malignant tumor |
|---|---|---|
| Atypia | Only tissue atypia is characteristic | Both types of atypia are present: cellular and tissue |
| Cells | Built from mature, differentiated elements | Cells and nuclei exhibit significant polymorphism |
| Mitoses | Extremely rare | Presence of atypical mitotic figures |
| Growth pattern | Expansive (displaces tissues, forms a capsule) | Infiltrative (invades and destroys surrounding structures) |
What are the main pathways of malignant tumor metastasis?
There are four main mechanisms of tumor cell dissemination from the primary site to other organs and tissues.
- Lymphatic — spread via lymphatic vessels (retrograde metastasis against the lymph flow is possible).
- Hematogenous — spread via blood vessels.
- Perineural — spread along nerve trunks.
- Implantation — contact spread along serous membranes.
Which growth factors stimulate angiogenesis during the transition of a tumor to the invasive stage?
Tumor angiogenesis is associated with angiogenic growth factors and the composition of the extracellular matrix. Angiogenesis factors include:
- Fibroblast growth factors; these include Folkman factor, produced by malignant tumor cells, which stimulates the proliferation of vascular wall elements and vessel growth.
- Angiogenin.
- Angiopoietins.
Components of the extracellular matrix are also important, including laminin, fibronectin, and type IV collagen. The growth of the neoplasm directly depends on the development of the vascular network; tumor vessels are often defective, predominantly of the capillary type.
To memorize the modern stages of morphogenesis, use the phrase "Imagine Invisible Invasion of Metastases": Pre-tumor, Non-invasive stage (in situ), Invasive growth, Metastasis.
Class and exam questions
Why can a tumor recur after successful treatment?
If therapy destroys the bulk of the cells but preserves tumor stem (initiating) cells, they survive and restart the growth of the neoplasm.
What does cancer feed on at the carcinoma in situ stage if it has no blood vessels?
At this stage, the tumor nodule receives nutrients via diffusion from the tissue fluid of neighboring healthy structures.
What is the main morphological sign of pre-tumor dysplasia?
The key criterion is the appearance of signs of cellular atypia in the parenchymal elements of the tissue.
What else to study on this topic
- Mechanisms and three phases of tumor invasive growth
- The role of epigenetic changes (disrupted DNA methylation) in the development of early adenomas
- Interaction between the developing neoplasm and the tumor-bearing organism
- Evidence base for viral carcinogenesis (single-step model)
- Monoclonal and polyclonal origin of tumors
Master the entire topic in the "Pathological Anatomy" course
This is a summary. The course covers everything tested in classes and exams.
- Complete study guide on "Tumor Morphogenesis and Progression" and 4,414 more pages of the subject
- Assignments and quizzes after every topic — just like in a colloquium
- AI tutor answers questions on the topic anytime
- 153 video lessons on the subject
Other topics in the section "Tumor Growth"
Free video lessons: pathological anatomyShort lessons with study notes — no registration required.
Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.