Proliferation

Regulation and mechanisms of pathological proliferation

The process of cell division is under strict control. For instance, in the endometrium, regulation involves not only estrogens but also growth factors, cytokines, arachidonic acid metabolites, as well as the cellular and humoral immune system. Pathological tissue transformation is a complex process affecting all links of the neuroendocrine system.

A key mechanism in the pathogenesis of hyperplasias and tumors is an imbalance between cell proliferation and apoptosis. When cells acquire resistance to apoptosis, an accumulation of altered and excessively proliferating elements occurs. This very process leads to neoplastic changes. Furthermore, pathological proliferation can develop even with normal hormonal ratios. Thus, glandular-fibrous polyps arise against a normal hormonal background in 75% of cases, yet the vast majority of such patients (95.3%) show signs of infection or chronic inflammation.

Cellular sources of proliferation

Various cell types can proliferate, which determines the histogenesis of neoplasms:

• Keratinocytes: cells of the epidermis and mucous membranes. Their malignant proliferation with squamous differentiation leads to the development of squamous cell carcinoma. Meanwhile, the cells retain intercellular bridges and can form foci of hyperkeratosis—"epithelial pearls".
• Melanocytes: dendritic cells of neuroectodermal origin located among the cells of the basal layer of the epidermis. Normally, their ratio to keratinocytes ranges from 1:4 to 1:9. They synthesize the pigment melanin from the amino acid tyrosine. Excessive proliferation of melanocytes is observed in the formation of nevi, whereas malignant proliferation of atypical forms occurs in melanoma.

Proliferation in benign and dysplastic processes

Excessive cell multiplication without signs of malignancy is characteristic of hyperplasias and dysplasias.

• Endometrial hyperplasia: histologically manifested by excessive growth and structural changes in the glands. An increase in the number of glands, their dilation, disruption of their regular distribution in the stroma, and the absence of separation of the mucosa into compact and spongy layers are observed. An important criterion is the absence of cytologic atypia. The risk of progression to carcinoma depends on the severity of the process: 1% for simple hyperplasia and about 3% for complex hyperplasia.
• Dysplastic nevi: characterized by enhanced cell proliferation and lentiginous melanocytic hyperplasia (uneven distribution of melanocyte nests along the dermoepidermal junction). Melanocyte nests may coalesce, forming bridges between epidermal rete ridges. Mild cellular atypia is present, and the epidermal component of proliferation extends beyond the dermal component ("shoulder" phenomenon).

Proliferation in malignant growth

During malignant transformation, cells lose contact inhibition and the capacity for orderly differentiation.

• Melanoma: carcinogenesis is based on mutations in genes of cell proliferation signaling pathways (specifically, the BRAF gene). Atypical melanocytes begin to multiply uncontrollably. Initially, the tumor undergoes a horizontal (radial) growth phase—intraepidermal proliferation of cells along the dermoepidermal junction. This is followed by the vertical growth phase, when proliferating complexes grow asymmetrically deep into the dermis.
• Squamous cell carcinoma: distinguished by high mitotic activity. Microscopically, an abundance of mitoses is detected, including atypical ones. The tumor consists of haphazardly arranged complexes of large cells with anaplastic nuclei.
• Basal cell carcinoma: the growth of certain variants of this tumor may be accompanied by concomitant melanocyte proliferation, leading to enhanced pigmentation of tumor cells and the appearance of melanophages in the stroma.

Class and exam questions

What else to study on this topic

• Histological criteria and classification of endometrial hyperplasia.
• Morphological picture and architecture of dysplastic nevi ("shoulder" phenomenon).
• Growth phases of malignant melanoma and the molecular basis of its carcinogenesis.
• Specific differentiation features of squamous cell carcinoma ("epithelial pearls").
• Additional morphological features of basal cell carcinoma (stromal amyloidosis, cyst formation).

Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.