The Story of EmGD

Endometrial serous carcinoma (ESC), previously called as uterine papillary serous carcinoma (UPSC), arises from resting endometrium and is independent of estrogen stimulation. It has been notorious for its aggressive behavior and dismal prognosis with the outcome of a disproportionate number of endometrial cancer deaths although it comprises only about 10-15% of all endometrial cancer. Since its etiology is virtually unknown, it is difficult to manage the patients with ESC. However, identifying precancerous lesion(s) of such disease may provide a good opportunity for early diagnosis and better management.

Serous endometrial intraepithelial carcinoma (EIC) was first proposed as a putative precancer of ESC in 1992 [1] and formalized in 1995 [2], which was defined morphologically as the replacement of endometrial glandular epithelia by frankly malignant cells identical to that of ESC cells without myometrial or stromal invasion. Serous EIC and ESC were assumed to arise in benign atrophic endometrium (AE). How AE “suddenly” becomes serous EIC? This phenomenon was interpreted by many gynecologic pathologists as “De Novo” process. Based on

Dr. Zheng’s understanding, “De Novo” is usually the term people use to explain some observations without in depth understanding. Apparently, there is something missing between benign AE and serous EIC. In 2000, Wenxin Zheng and his colleagues at Yale Pathology made a hypothesis that there must be an entity linking AE and serous EIC. Morphologically, the endometrial glandular cells of this entity should present the degree of nuclear atypia falls short of serous EIC but apparently more than AE and its related reactive changes.

Based on this assumption, Sharon Liang, Dr. Zheng’s gynecologic pathology fellow at Yale and Dr. Zheng started to carefully look for those lesions from ESC uteri. They soon found that there was indeed such entity present in ESC uteri. This was defined as endometrial glandular dysplasia (EmGD). The first 2 articles, one morphologic study and the other molecular study, were published in 2004 in International Journal of Surgical Pathology[Zheng and Liang].

There were several side points worth to mention. One was regarding the terminology EmGD. Zheng’s group originally would like to use endometrial intraepithelial neoplasia (EIN), but the EIN term has been used by Mutter et al for type I endometrial precancers. Therefore, the term EmGD was chosen to describe the new entity. It seems that they may have a chance to unify all endometrial neoplastic process into a single classification system [Click here]. The other was the entity recognition in the gynecologic pathology field. There is a group of pathologists who still consider EmGD is part of the spectrum of serous EIC.

Dr. Zheng once had a conversation with a representative of that group when he presented EmGD story in USCAP meeting in 2003. That representative admitted that they saw “EmGD” lesions back to early 1990s but failed to define it when they described EIC at that time. This was mainly because they did not know how to put all the pieces together to resolve this puzzle.

If EmGD is the precancer of ESC, then what is serous EIC and what is the relationship among EmGD, serous EIC and ESC. Based on clinical findings that serous EIC is commonly associated with extrauterine disease ranging from 33% to 67% and morphologic findings that serous EIC cells are identical to those ESC cells, Zheng’s group further proposed that serous EIC is an early serous carcinoma rather than a precancer of ESC [Zheng and Schwartz]. It is likely that serous EIC develops from EmGD then to ESC. Interestingly, we found that serous EIC or ESC and EmGD are frequently associated with resting endometrium (RE) rather than with AE only. RE includes AE, weakly proliferative endometrium and proliferative endometrium. Not infrequently,women in postmenopausal age are taking hormones as a replacement, which correspond to the proliferative status of the endometrium.

One clinical impact for this finding is that a pathologist should not be afraid of making the diagnosis of ESC when he/she sees the background endometrium is proliferative. Since type II endometrial cancer consists of serous as well as clear cell carcinomas and many ESC uteri having areas of clear cell component or vice versa, Zheng’s group studied uteri with clear cell carcinoma. Luckily, lesions ofclear cell EmGD and clear cell EIC were identified and they are commonly associated with clear cell carcinoma [Fadare]. More recently, Zheng’s group found that lesions of EmGD have frequent p53 gene mutations [Jia]. Furthermore, latent precancer of ESC, a step earlier than EmGD has been just described [Zhang].

Endometrial serous carcinoma (ESC)
Endometrial serous carcinoma (ESC)