Author
# Complex atypical hyperplasia
# Endometrial carcinoma
Agents used
Response rate (%)
Median follow-up months (range)
Ferenczy (1989)
20
0
MPA
50
5.5 years (2–7 years)
Randall (1997)
17
12
MA, MPA
86
41 (9–79)
Jobo (2001)
20
0
MPA
75
66 (8–281)
Kaku (2001)
10
29
MPA
80
31.5 (10–133)
Minaguchi (2007)
12
19
MPA
91
40.7 (2–109)
Ushijima (2007)
17
28
MPA
67
47.9 (25–73)
Wheeler (2007)
18
26
Oral progestin, LNG-IUD
52
11 (not stated)
Wildemeersch (2007)
8
0
LNG-IUD
87
32 (14–90)
Yu (2009)
17
8
MPA
82
34.6 (7–114)
Signorelli (2009)
10
11
Natural progesterone
57
98 (35–176)
Gunderson (2014)
17
29
MA, LNG-IUD, MPA, misc
65
35 (2–162)
Marra (2014)
89
0
Natural progesterone (3 doses)
89
Not stated
Simpson (2014)
19
25
MPA, MA
55
39 (5–128)
Kudesia (2014)
13
10
Oral prog, LNG-IUD, oral prog+levo IUD
61
13 (3–74)
Total
287
197
71
Consensus on conservative management of complex hyperplasia with atypia consists of serial endometrial sampling every 3–6 months for up to 2 years. Conception should be attempted once the hyperplasia has regressed. Often, these patients require assisted reproductive technologies as the risk factors for their endometrial pathology are also common causes of infertility, namely, components of metabolic syndrome such as obesity, PCOS, and insulin resistance. It is therefore crucial that patients receive evaluation and treatment planning with an infertility specialist in parallel with the treatment for their endometrial hyperplasia.
Reproductive outcomes in women with endometrial hyperplasia and low-grade endometrial carcinoma treated conservatively are mixed and not particularly encouraging. In a small series of 12 women with endometrial carcinoma treated with high-dose medroxyprogesterone acetate (MPA 400–600 mg/day), 70 % of patients attempting to conceive did, and 50 % had full-term deliveries [2]. However, the majority of patients recurred during follow-up and half went on to have subsequent hysterectomy. Yu and colleagues reported four pregnancies among 25 patients treated conservatively with MPA 100–500 mg/day [3]. A total of 14 patients attempted conception, and 13 required assisted reproductive techniques. All four pregnancies were in patients with initial diagnosis of atypical hyperplasia, and three term deliveries were reported with the fourth patient being lost to follow-up.
Nonetheless, medical management is never definitive, and hysterectomy should be performed upon completion of childbearing. For those patients who have completed childbearing, hysterectomy is the standard treatment. In patients undergoing definitive surgical treatment, frozen section should be obtained to evaluate for the possibility of a carcinoma. In younger premenopausal women, the question of ovarian preservation vs. complete staging with bilateral salpingo-oophorectomy is raised. The incidence of ovarian metastasis from an endometrial cancer in a patient with a preop diagnosis of complex hyperplasia is exceedingly low. It is likely in the range of 1–3 % [4]. A multi-institutional review from the 1990s to 2000s revealed an alarming 25 % rate of synchronous ovarian malignancies in young women with a preoperative diagnosis of endometrial cancer [5]. However, 50 % of patients in this series had at least one first- or second-degree relative with malignancy, and 35 % had a first-degree relative with malignancy. This raises the question of whether this cohort accurately represents the risk of ovarian metastasis or synchronous malignancy in the typical population of young women with endometrial hyperplasia as a result of obesity and metabolic syndrome. Another series including 37 patients with endometrial cancer under the age of 45 found an 11 % rate of synchronous ovarian malignancy [6]. A Korean Gynecologic Oncology Group study specifically evaluated ovarian preservation (both intentional and incidental) at the time of hysterectomy with a diagnosis of endometrial malignancy on final pathology [7]. Mean age was 38 years. 175 patients had preservation of at least one ovary, and 31 of whom had a preoperative diagnosis of endometrial hyperplasia. Follow-up was robust with a median of 55 months. Two of the seven recurrences had adnexal metastasis (1.1 %). Both had high risk for recurrence, including one with endometrioid histology who rejected adjuvant treatment and the other with serous histology. Another series reported 13 patients with preservation of at least one ovary at the time of surgery for known endometrial malignancy [8]. There was not a statistically significant difference in overall survival in patients with and without ovarian preservation. However, for stage I patients, there was an improved disease-free survival in women without ovarian preservation, but no improvement in overall survival. Extrapolating from limited data, women with preoperative diagnosis of endometrial hyperplasia should have a lower incidence of ovarian metastasis or synchronous malignancy compared to those with a known endometrial carcinoma. It would be reasonable to retain at least one ovary in young premenopausal women undergoing hysterectomy for endometrial hyperplasia.
Serous Endometrial Intraepithelial Carcinoma
Serous endometrial intraepithelial carcinoma (EIC) is an early form of conventional endometrial serous carcinoma (uterine papillary serous carcinoma) that displays noninvasive patterns of growth in the endometrium but which paradoxically retains the ability for extrauterine spread, presumably through the fallopian tube lumens [9–13]. Accordingly, although EIC is generally conceptualized as an early step in the evolution of endometrial serous carcinoma, it is a fully malignant precursor lesion, rather than potentially malignant precancerous lesion. EIC and conventional endometrial serous carcinoma are largely identical at the molecular and immunophenotypic levels, and as previously noted, both can metastasize and are thus fully malignant [9–13]. Furthermore, there is no difference in patient outcomes between patients with advanced stage EIC and patients with advanced stage conventional serous carcinomas [11]. Therefore, clinical management for EIC is identical to the management for patients with conventional serous carcinomas [9]. There is a significant body of evidence that the lesion endometrial glandular dysplasia is the true precancer for endometrial serous carcinoma [14–16]. However, at present, there is insufficient data to definitively recommend management approaches when one encounters this diagnosis in a sampling specimen.
Serous lesions of the uterus are treated surgically, unless the patient’s comorbidities prohibit surgery. Surgical staging consists of hysterectomy, bilateral salpingo-oophorectomy , pelvic and para-aortic lymphadenectomy , and omentectomy . Though serous lesions of the uterus are frequently compared to serous ovarian carcinomas, unlike serous ovarian carcinomas, minimally invasive surgery is acceptable for serous lesions of the uterus. Parenthetically, in cases of endometrioid adenocarcinoma, there is some evidence that the use of a uterine manipulator in minimally invasive surgery leads to an increase in the incidence of positive cytology. A series from Korea as well as another from Memorial Sloan Kettering both showed a small increase in positive cytology [17, 18]. However, another series of 42 patients from the University of Vermont compared to cytology obtained before and after placement of uterine manipulators. None of the 42 patients had positive cytology either before or after placement [19]. The clinical significance of this in endometrioid histology is questionable. However, there is the concern among gynecologic oncologists that positive cytology for serous lesions of the uterus may be more significant. Some gynecologic oncologists advocate laparoscopic occlusion of the fallopian tubes prior to placement of the uterine manipulator at the time of surgery. There is insufficient data to support or refute this practice. However, laparoscopic tubal occlusion adds minimal operative time and risk to the overall procedure and should be considered in cases of known serous histology.
Serous Tubal Intraepithelial Carcinoma
Serous Tubal Intraepithelial Carcinoma, or STIC , is usually diagnosed as an incidental finding at the time of risk-reducing bilateral salpingo-oophorectomy. There is no current consensus on the management of incidentally diagnosed STIC. Whether or not surgical staging is warranted has been examined by a few retrospective series. Surgical staging for tubal carcinoma is the same as for ovarian carcinoma: bilateral salpingo-oophorectomy, total hysterectomy, omentectomy, peritoneal biopsies, and pelvic and para-aortic lymphadenectomy. Some controversies exist in the use of minimally invasive techniques in staging. Proponents point to the rapid recovery and similar lymph node count achieved through minimally invasive staging. Opponents argue that the mesentery and bowel cannot be adequately assessed via laparoscopy. The details are beyond the scope of this chapter.
A series by Olivier et al. showed three occult tubal carcinomas and two occult ovarian carcinomas in 58 patients with BRCA1 mutations [20]. All five patients underwent subsequent staging, two patients were upstaged, and both developed recurrent disease. The single patient who remained stage 1A was disease-free at 46 months of follow-up. A series by Wethington et al. of 593 risk-reducing surgeries, mostly in BRCA-mutated patients, found an incidence of 2 % (12 cases) [21]. Of these 12 cases, seven went on to have some subsequent surgical intervention. Only one patient had positive cytology. None had any omental, lymph node, or peritoneal involvement on biopsy. None of the patients received any chemotherapy, and no recurrences were noted at follow-up (median 28 months, range 16–44 months). The author concluded that given the low yield of finding metastatic disease, staging is not recommended for incidentally diagnosed STIC.
Another series by Powell et al. of BRCA 1- and BRCA 2-mutated patients followed 17 patients with high-grade noninvasive neoplasia of the fallopian tube, including one patient that also had an occult ovarian noninvasive lesion [22]. All but two had a recorded preop CA-125 level, and all were in the normal range. Of these 17 patients, 2 had positive cytology, and 10 went on to have some additional staging surgery. Four patients received chemotherapy with carboplatin and paclitaxel. Two of these four patients had positive cytology and had undergone additional staging surgery. The other two had negative cytology and did not undergo additional surgery. Only one patient recurred 43 months after risk-reducing surgery and was disease-free at 16 months following completion of debulking followed by chemotherapy. All 17 patients were alive at last follow-up.
Gilks et al. examined the incidental finding of STIC in 21 patients without BRCA mutation (though one patient had Li-Fraumeni syndrome) [23]. Six patients were reported to have undergone staging, and two were upstaged. One recurrence was seen in a patient who remained stage IA after full staging and received no adjuvant chemotherapy. Clinical outcome for the remaining 15 patients was not reported. Table 4.2 provides a summary of above case series.
Table 4.2
Incidentally diagnosed STIC
Author | # Patients with STIC | # Patients surgically staged | # Upstaged | Follow-up months (range) | # With recurrent cancer |
|---|---|---|---|---|---|
Olivier (2004) | 5/58 (8.6 %) | 5 (100 %)
 Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
Get Clinical Tree app for offline access
|