The endometrium, which is the lining of the uterus, is a dynamic tissue that undergoes constant change throughout the reproductive years. Its role is to prepare a receptive environment for a fertilized egg and, if pregnancy does not occur, to shed during menstruation. Understanding the normal physiological states of this tissue is the first step in differentiating health from disease.
The Role of the Normal Secretory Phase
The secretory phase is a normal, predictable period within the menstrual cycle, occurring after ovulation. It begins when the ovary releases an egg, and the resulting structure, the corpus luteum, produces high levels of the hormone progesterone. Progesterone acts directly on the uterine lining, transforming it from a proliferative state into one primed for potential implantation.
This hormonal influence triggers distinct structural changes that are easily identifiable under a microscope. The endometrial glands, which were previously straight, become highly coiled and tortuous, sometimes described as having a “sawtooth” appearance in cross-section. The epithelial cells lining these glands begin to produce and store glycogen and mucus, forming temporary vacuoles that shift from the base of the cell to the top as they secrete their contents.
The stroma, the connective tissue supporting the glands, also changes, becoming edematous or swollen with fluid in the mid-secretory phase. Later in the phase, the stromal cells near the surface begin to enlarge and take on an epithelial-like appearance, a process called predecidual change.
How Endometrial Cancer Differs from Normal Tissue
The normal secretory endometrium is definitively not a sign of cancer, but rather an indication of a functioning menstrual cycle. Endometrial cancer, specifically Endometrioid Carcinoma, is characterized by the uncontrolled, abnormal growth of cells that have the capacity to invade surrounding tissue. This fundamental difference between a temporary, organized physiological state and a destructive, permanent disease is evident at the cellular level.
Under the microscope, normal secretory tissue maintains an organized structure with a clear balance between glands and the surrounding stroma. In contrast, cancerous tissue exhibits a profound loss of organization, often showing glands that are packed tightly together, a phenomenon known as a “back-to-back” arrangement, with little or no intervening stroma. The cells within the cancerous glands display cellular atypia, meaning they look significantly abnormal compared to their healthy counterparts.
In normal secretory cells, the nuclei are uniform and polarized, typically positioned at the base of the cell due to the presence of secretory vacuoles. Cancer cells, however, show nuclear changes such as variation in size and shape (pleomorphism), prominent nucleoli, and stratification, where nuclei are no longer aligned in a single row. Furthermore, neoplastic cells have a dramatically higher rate of cell division, which can be measured by markers like the Ki67 index.
Understanding Pre-Cancerous Conditions
While the normal secretory phase is healthy, some conditions that cause the endometrium to thicken can be confused with or precede cancer. Endometrial hyperplasia is an overgrowth of the endometrial lining that is not cancer, but represents a spectrum of risk. This condition typically results from prolonged, unopposed exposure to estrogen, which encourages the lining to proliferate without the balancing effect of progesterone.
Hyperplasia is categorized based on the architectural complexity of the glands and the presence of cellular abnormalities, known as atypia. Non-atypical hyperplasia involves glandular crowding but lacks significant cellular changes and carries a low risk of progressing to malignancy. However, when cellular atypia is present, the condition is now often referred to as Endometrial Intraepithelial Neoplasia (EIN).
This atypical form is considered a true pre-cancerous condition because the cells already possess some of the abnormal features seen in carcinoma, significantly increasing the likelihood of progression to cancer. Diagnosis of these conditions is usually made following a biopsy or a dilation and curettage (D&C) procedure, where a pathologist examines the tissue for glandular crowding, architectural disorder, and nuclear atypia.