Endometrial cancer Grade 1 generalities and histopathology

Endometrial cancer (EC) is the most common cancer of the female reproductive system. In Europe, 1 to 2 in every 100 women will develop EC at some point in their life (based on the ESMO Clinical Practice Guidelines). In the European Union, over 88,000 women are diagnosed with an EA each year. This number is increasing in the majority of European countries. EC usually occurs in women over the age of 50 and thus after menopause, but up to 25% of cases may occur before the menopause [42]. The incidence of EC and the numbers of young women suffering from this disease are increasing globally [43]. It is estimated to increase by 50% to 100% in the next 20 years [44, 45].

Most of EAs are adenocarcinomas. The term “adenocarcinoma” designs a glandular origin as it is composed of “adeno” for glands and “carcinoma” for epithelial cancer. It results of the abnormal growth of epithelial cells from endometrial glands that have the ability to invade or spread firstly the endometrial compartment, then the myometrium and later other parts of the body. Staging is a way of describing where the cancer is located, if or where it has spread, and whether it is affecting other parts of the body in order to adapt treatments.

Doctors assign the stage of EC using the International Federation of Obstetrics and Gynecology (FIGO) system. In stage I, 80% of total EC, the cancer is found only in the uterus compartment, and it has not spread to the cervical stroma or beyond the pelvic area. In this first stage, two distinct sub categories are described: Stage IA and IB. In stage IA, the cancer is found only in the endometrium or less than one-half of the myometrium while in stage IB, the tumor has spread to one-half or more of the myometrium. Doctors also describe EA by its grade to evaluate how much EC cells resemble healthy cells. It is a three-tiered system for histologically classifying ECs, ranging from cancers with well-differentiated cells (grade I), to very poorly-differentiated cells (grade III) [46]. If tumor cells appear similar to healthy tissue and has different cell groupings, it is called "differentiated" or a "low-grade tumor." If the cancerous tissue looks very different from healthy tissue, it is called "poorly differentiated" or a "high-grade tumor." The cancer’s grade may help the doctor predict how quickly the cancer will spread and is used as prognosis.

In this thesis work, only EC Grade 1 Stage 1A and 1B with myometrial invasion was analyzed as our subject of interest is the evaluation of pathological tissue remodeling (invasion and angiogenesis) occurring in early stage EA. Grade I cancers are the least aggressive and have the best prognosis.

The histopathology of ECs is highly diverse but not less essential as it is the principal method for diagnosis. EC is composed of numerous, small, crowded glands with varying degrees of stratification and slight atypia (Figure 7). Nuclear polymorphism is variable but is usually only mild to moderate. We commonly observe large round nuclei with variable prominent nucleoli and a coarse clumped chromatin visible at high magnification, signs of an increase of the mitotic activity. A visible inflammation is often visible.

These glands invade the myometrium in different manners. Five patterns of invasion were recorded in EC grade 1: Infiltrating Glands (IG), Microcystic Elongated and Fragmented Glands (MELF) which is a distinctive histologic variant of the infiltrative gland pattern, broad front (BF), Adenomyosis Like (AL), and Adenoma Malignum (AM). Since all this patterns was present in my cohort study, a description of their histological characteristics will be done on the introduction in order to have a better comprehension and overview (Figure 8).

The IG pattern is the most common pattern of myometrial invasion in EC. This pattern is characterized by individual glands to small cluster of glands with irregular contour that infiltrate the myometrium with and without stromal response. The infiltrative gland pattern was also found in higher stage, (Stage IB and Stage II), and was associated with lymphovascular invasion and recurrence, suggesting that this growth pattern may be associated with tumors having other histologic features typically associated with more aggressive behavior [47]. The second most common pattern is the BF pattern. As indicated by his name, it is characterized by cluster of tight glands without stroma or myometrium space between glands that infiltrate

Figure 7. Histopathology of EC Grade 1.

A. In stage 1A, tumor is confined to the uterus with less than half myometrial invasion while in stage 1B,tumor involves more than half of the myometrium. B. In physiological circumstances, we observe a single columnar glandular epithelium inside the stroma (S). C. Tumor gland of EC grade 1 is characterized by an epithelial proliferation leading to a stratified epitheliumand generates a stromal reaction (SR) in the myometrium.

However, tumor epithelial cells are still well differentiated with a slight pleomorphism. In cancer, lymphocytes (arrow) are visible inside the epithelium and are called tumor-infiltrating lymphocytes (arrow head). H&E stain.

the myometrium with a pushing and undulated border, indicative of an irregular endometrial interface. When the myometrial invasion is superficial, the stromal response is often absent.

The MELF pattern is composed of small, fragmented clusters of tumor cells set (or microcystic glands) in a fibromyxoid, desmoplastic stroma. Accompanying inflammatory cells, notably neutrophils, are typically seen. This pattern is believed to be the result of a stromal response to the IG pattern due to the fact that numerous IG glands are still observable between MELF areas.

However, the microcystic glands could also result from an epithelial to mesenchymal transition (EMT) [48] where the tumor cells detach from the original tumor gland in order to metastasize.

This hypothesis is supported by an immunohistological study in which MELF pattern shows an altered immunophenotype compared with conventional glandular tumor areas. MELF pattern was characterized by reduced E-cadherin expression. Another epithelial marker, cytokeratin CK7, was shown to be partially expressed as some glands gave strong expression while in contrast adjacent unstained tumor glands was observable [49]. This phenomenon can be explained by the fact that MELF pattern in broadly heterogeneous with a mix of MELF glands and IG glands suggesting an intermediate phenotype between epithelial and mesenchymal with a progressive loss of epithelial markers. MELF pattern have been correlated with lymph node metastasis or extra uterine Disease [50, 51]. Nevertheless, pathologists today consider IG and MELF as similar patterns. In the adenomyosis-like pattern, there are too many groups of closely packed neoplastic glands to represent the normal distribution of adenomyosis.

This pattern is characterized by a nest of malignant glands that infiltrate the myometrium in irregular islands and connected lumens. And finally AM, a rare pattern of myometrial invasion comprised of histologically unremarkable glands that infiltrate the myometrium with no surrounding tissue response. Glands are described as little regular and round glands often widely spaced and deeply colonizing the myometrium.