Prognostic Factors for Early-Stage Endometrial Cancer Management in Fertile Patients

Research Article

Austin J Obstet Gynecol. 2023; 10(2): 1218.

Prognostic Factors for Early-Stage Endometrial Cancer Management in Fertile Patients

Vasilios Tanos¹; Zoe Zervides²; Panayiotis Tanos³*

Professor Obstetrics and Gynaecology, University of Nicosia, Medical School and Aretaeio Hospital, Cyprus MBBS Student, University of Nicosia, Class of 2025, Cyprus Foundation Year Doctor, Antrim Area Hospital, Antrim, Northern Ireland

*Corresponding author: Panayiotis Tanos Foundation Year Doctor, Antrim Area Hospital, Antrim, Northern Ireland. Email: p.tanos@outlook.com

Received: May 23, 2023 Accepted: June 16, 2023 Published: June 23, 2023

Abstract

Introduction: Early-Stage Endometrial Cancer (ES-EC) presents a treatment challenge for women who would like to preserve their genital organs and complete their family planning. Delayed first pregnancy and aging of women in combination with high-definition sonography and cancer awareness is expected to increase the incidence of young women with ES-EC demanding Fertility Sparring Surgery (FSS).

Methods: A thorough literature search was conducted using Medline (OVID), Embase, and Cochrane Library electronic databases in order to identify eligible studies published up to November 2021.

Results: Age is an imperative determinator for FSS in ES-EC, since fertility potential is compromised with age and oocytes carrying higher risk of fragmented DNA. Favourable prognostic factors to FSS include, age younger than 35 years old, absent genetic predisposition to EC, fertile females with normospermic partners, negative histology for cancer cells after hysteroscopic biopsies and progesterone treatment, normal adnexal findings in Trans Vaginal Ultrasound (TVU), absent myometrial carcinomatous invasion in Magnetic Resonance Imaging (MRI) and absence of lympho-vascular involvement in Computerised Tomography Scan. Careful selection of patients based on favourable prognostic factors diminishes the risk of recurrence and allows for the opportunity of reproductive organs preservation until family planning is achieved in a reasonable time frame. Additionally, our review points out the need of hysteroscopic guidance in endometrial sampling for primary EC diagnosis as well as for the endometrial surveillance every 3-6 months follow-ups until pregnancy.

Conclusion: After FSS decision, a strict time frame of one year to achieve pregnancy is essential in order to secure patient’s safety and to reduce the risk of early recurrency in EC.For both endometrial and ovarian cancer, prevention Hysterectomy and Bilateral Salpingo-oophorectomy should preferably be performed by the completion of child bearing age and before the age of 40 years. It is vital that the advantages and risks of FSS must be discussed openly, including the risk of undetectable by imaging occult gynecological cancer which can compromise life expectancy.

Keywords: Endometrial adenocarcinoma; Early-stage endometrial cancer; Conservative treatment; Atypical endometrial hyperplasia; GnRH agonist; Fertility-sparing-surgery

Introduction

According to the World Health Organization, Endometrial Carcinoma (EC) is the most common gynaecological cancer in Europe, with a 5-year prevalence of 34.7% out of 445 805 cases [1]. The incidence of EC is approximately 15,000 newly diagnosed women each year, of which 1600 (10.7%) young women will die of the disease [2]. Four percent of EC occurs in women of reproductive age. In low-risk disease, total hysterectomy and bilateral salpingo-oophorectomy, provide patients up to 93% chance of cure [3]. However, temporal preservation of the uterus in Early-Stage Endometrial Cancer (ES-EC) for reproductive reasons raises primarily medical but also ethical and social dilemmas.

Usually, young age, nulliparity, previous pregnancy loss, infertility, early stage of the disease and the strong wish of the patient for motherhood, oblige the Gynaecologist to review and compromise the standard surgical management for ES-EC. The preservation of the uterus for an uncertain time, even at early stage of EC increases the risk of disease progression and has a bad prognosis for life expectancy. When a young woman with EC has no partner then the decision to preserve the uterus for an unknown time interval is becoming a complex health matter and a big challenge for the treating physicians.

Family planning and the decision to preserve or excise the uterus depends on personal but also societal and cultural beliefs and is of extraordinary importance. A young woman with EC who does not have children nor a uterus, is endangered to social and family isolation. Therefore, patient-specific characteristics are important when considering fertility sparring treatment. Every woman has unique social interests, beliefs, and preferences which should be considered in the shared decision-making process. However, decisions on fertility are equally difficult for both the patient and the treating gynaecologist and therefore, management should involve an experienced, expert, multidisciplinary team.

Preliminary evidence in disease progression and life expectancy in patients following temporal uterine preservation for ES-EC, are encouraging and appears to be in general an accepted management option. In a recent systematic review by Schuurman et al. 62.6% of patients with complete remission on hormonal therapy were reported to have a pregnancy wish. Among these patients with complete remission, 36.9% became pregnant [4].

Women with histologically well described type of EC (G1 or G2) and with stage 1 confined to the endometrium, are candidates for progestin therapy. Fertility Sparring Surgery (FSS) could also be considered as a valid option for reproductively aged patients with stage IA type I and G2 EC. Nevertheless, the long-term outcome, survival rate and quality of life in these patients is not yet prospectively investigated.

Four different groups of young patients seem to be involved in ES-EC diagnosis; a) Patients with family history, with 1st degree relatives or multiple 2nd and 3rd degree relatives with EC and/or colon cancer b) Patients with genetic predisposition and inherited risk after testing for Mismatched Repair (MMR) mutated genes c) Women with EC risk factors (PCOD, obese with BMI >30 and >40, endometrial thickness over 20mm) d) Women diagnosed during examination for abnormal uterine bleeding and EC has been reported in endometrial biopsy; Despite FSS availability and preference by many, the lack of evidence-based consensus and guidelines for selected patients, treatment methods and follow-up, complicates the decision-making process [5]. Identification of favourable prognostic factors indicating low risk patients with EC recurrency will select the best candidates with ES-EC for FSS [101-103].

The purpose of this review is to identify the clinical symptomatology, imaging indices, biological, chemical, genetic, and epidemiological factors that can support conservative management of patients with ES-EC (Stage IA Type I and G2); offering a chance for motherhood, prior to hysterectomy. Projected prognostic markers could assist in selecting patients with better prognosis and further guide to a strategy which can minimise the risk of recurrency. Furthermore, results can be used to improve pre-treatment counseling and management decisions for reproductive-age patients at ES-EC.

Methods

Search Strategy

A literature search was conducted using the electronic bibliographic databases Medline (OVID), Embase, and the Cochrane Library to identify eligible studies published in English language. We searched for keywords and equivalent words in the title/abstract and translated the search terms according to the standards of each database. Keywords for endometrial adenocarcinoma, Endometrial Neoplasms, Endometrial Carcinoma, Endometrial Hyperplasia, Conservative Treatment, Gonadotropin-Releasing Hormone, Fertility, Fertility Preservation, and Infertility were combined with terms for fertility-sparing treatments in general and surgery specifically. Reference lists of the included studies and retrieved review articles were searched to identify relevant articles not found in the initial search.

Study Selection

The articles retrieved during the searches were screened for relevance on title/abstract and subsequently full text by the two authors independently. Discrepancies were resolved by consensus after discussion and assessment by both authors. Included articles needed to specify oncological and/or reproductive outcomes after FSS, i.e., endometrial resection, endometrial sampling, absence of myometrial and lymphoglandular invasion, response to progesterone treatment and uterine preservation combined with hormonal therapy in early-stage endometrial cancer.

Data

Published articles on invasive endometrial cancer and absent FSS treatment were excluded from our analysis. The following studies were also excluded: (1) review articles without any new patient data, (2) case reports or small case series with less than 20 patients, (3) letters to editors, commentaries, or (conference) abstracts. Of the articles with duplicate patient information and articles updating prior published series, we included the articles with the most recent and complete data.

Results

The best evidence currently available on oncological and reproductive risk and prognosis after FSS for early-stage endometrial cancer are reported and summarized.

Prognostic Factors

Family History: Patients with first- or second-degree relatives diagnosed with EC and/or colon cancer below the age of 50 have increased cumulative risk of EC by 3.8% and 3% respectively [6,7]. Counselling of family members and investigation of familial pedigree and genetic predisposition is recommended. Furthermore, genetic analysis is offered in all high-risk women and surveillance for carriers of MSH2, MLH1 and MSH6 mutations has been recommended from age 30, 35 and 40 years respectively [8]. These women are counselled to be investigated with frequent annual colonoscopies and TVU scanning measuring endometrial thickness, adnexal morphology and Ca 125 and CEA serum levels [6-8].

Surveillance for EC in Human Non-Polyposis Colorectal Cancer (HNPCC) (Lynch syndrome) mutation carriers should start at the age of 35 years. However, individual factors need to be taken into consideration and patient tailored screening programs are encouraged to be followed. The decision on the starting age of surveillance should integrate knowledge on the specific mutation, history of family events as well as individual treatment and preferable preventative measures. Screening of the endometrium by annual transvaginal ultrasound as well as annual or biennial biopsy until hysterectomy should be considered in all MMR and HNPCC mutation carriers. Unfortunately, the risk of any occult malignancy during prophylactic surgery for women with HNPCC has been reported to be up to 17% [9]. Therefore, standardization of the order in which protein evaluation, genetic sampling and hysteroscopy are done is pertinent.

Patients with Genetic Predisposition: EC is characterized by various genetic alterations. The most frequent is located at chromosome 10q23 (PTEN gene alteration). PTEN loss is profound in both HNPCC and sporadic EC cases. PTEN gene behaves as a tumour suppressor gene and encodes for a lipid and a protein phosphatase, inducing cell cycle arrest at the G1/S checkpoint and inhibiting growth-factor-stimulated MAPK signaling and focal adhesion formation as well as cell spread and migration, respectively [10].

Approximately 3% of all EC and about 10% of Mismatch Repair Deficient (MMRd) or microsatellite unstable EC are related to germline mutations of one of the MMR genes; MLH1, PMS2, MSH2 and MSH6 [11]. The International Society of Gynecological Pathology recommended using MMR-Immunohistochemistry (IHC) testing for both MMR status and Microsatellite Instability (MSI) in all EC samples, irrespective of patients age [12]. Using IHC the expression of four MMR proteins MLH1, PMS2, MSH6, and MSH2 are assessed and in addition, PMS2 and MSH6 antibodies can be also assessed [13].

The inactivation of MMR genes and MMR protein dysfunction may be the results of germline mutations or spontaneous hypermutation alterations, which may induce MSI. The diagnostic sites of MSI include more than a hundred thousand areas of short tandem repetitive DNA sequences. As recommended by the National Cancer Institute, BAT25 and BAT26 mononucleotide repeats and D5S346, D2S123, and D17S250 dinucleotide repeats are the standard panel sites for MSI testing [14]. MSI-H or dMMR has been specifically detected in HNPCC-associated tumors, including EC [15].

Even though currently there is limited evidence on the benefits of HNPCC-associated EC screening, it requires specialized attention. HNPCC-associated EC has been linked to pre-invasive hyperplasia and particularly concurrent complex atypical hyperplasia. HNPCC-associated EC cases lack additional mutations, suggesting that in the mismatch repair defect context, few additional molecular changes lead from pre-invasive lesions to carcinoma. Therefore, EC patients identified as having an increased risk of HNPCC should be offered genetic counseling and surveillance [16]. For these patients, hysterectomy and bilateral salpingo-oophorectomy should be performed as a preventative measure for endometrial and ovarian cancer. This should preferably be before the age of 40 years, at the completion of childbearing age. Prior to this all advantages and disadvantages of prophylactic surgery must be discussed, including the risk of occult gynecological cancer detection at prophylactic surgery [17].

Lastly, Bokhman et.al. 1983 have characterised EC into 70-80% Estrogen-dependent ENDOMETRIOID EC (EECs) which are linked to unopposed estrogen stimulation in young postmenopausal women. The other 10-20%, are characterised as Non-Endometrioid EC (NEECs) and are associated with a history of atrophic endometrium in older postmenopausal women. NEECs patients usually present with a higher-grade EC and have less favourable outcomes [18-20]. EECs and NEECs are not only differentiated according to clinical and histopathological variables but also according to activation and inactivation of certain genes. EECs have K-ras, Her2/neu and b-Catenin gain-of function as well as microsatellite and PTEN loss-of function. Whereas P53 loss-of function is presented more on NEECs. However, the effect of the aforementioned genes and the benefits of this classification in premenopausal women is unclear [21].

Hence, in patients with evidenced genetic predisposition to EC, FSS is contraindicated.

Clinical Symptoms

Age of EC onset: Even though younger women may not be symptomatic as quickly as older women they tend to have better prognosis than post-menopausal women in EC. Younger women often appear to have lower grade tumors which do not grow deep into the myometrium and which are clinically detected at earlier stages. In contrast, older women often appear to present with more aggressive tumour types and disease advancement and as a result, have a less favorable prognosis.

In a sample of young patients with EC and a median age of 46 years old, Parc et al., 2000 verified 34% women with microsatellite instability. The microsatellite positive group showed an absence of hMLH1, hMLH2 expression for 57% and 19% respectively as well as 23.8% normal protein expression [22].

Obesity: The risk of EC is increased 5 times when BMI is over 30 and 20 times when BMI is over 40 as compared to general female population with normal BMI. Additionally, in metabolic syndrome when obesity is combined with diabetes and high blood pressure, has been linked with a less favourable prognosis [23]. Factors increasing the obstetrical risks might also be added and considered prior to FSS.

Diabetes Mellitus: A recent meta-analysis showed diabetic women at a 72% increased risk of EC compared to those without diabetes [24]. Currently the most advocated mechanisms are hyper-glycemia, -lipidemia, -insulinemia, disorders of leptin and adiponectin and abnormal fat metabolism. T-cells and macrophages attack these adipose cells and cause chronic inflammation, leading to an increase in Inflammatory cytokines (IL6, TNF-a/b), adipokines (visfatin, leptin) and inflammatory mediators C-reactive protein as well as protease inhibitor (plasminogen activator inhibitor-1) which can all lead to proliferation, invasion and even metastasis of the primary tumour. Most of these inflammatory mediators further increase aromatase which accelerates estrogen synthesis by inhibiting the synthesis of Sex Hormone Binding Globulins (SHBG) [25].

Blood Pressure: High blood pressure, increasing levels of diastolic blood pressure and in particular, systolic blood pressure as well as a history of hypertension have been associated with increased risk of EC in several studies, but the results have not been consistent. However, a meta-analysis of 19 case-control and 6 cohort studies suggested that women with hypertension may have a 61% increase in the relative risk of developing EC [26]. The associations remained positive, statistically significant and had heterogeneity in almost all subgroup analyses. Confounding factors adjusted for were smoking (p=0.02), BMI (p=0.003), the use of oral contraceptives (p=0.02), hormone replacement therapy (p=0.08), parity (p=0.03), and menopausal age (p=0.07) [27].

Polycystic Ovarian Disease: Patients with Polycystic Ovarian Syndrome (PCOS) who have period irregularities, unopposed estrogens and do not receive any treatment, are reported to have a 2.7-fold increased risk for developing EC. A major contributing factor for this increased risk of malignancy is prolonged exposure of the endometrium to unopposed estrogen that results from anovulation. Ding et al. 2018 reported a statistically significant increased risk of EC for women with PCOS, but no association risk between PCOS and ovarian or breast cancer. The incidence of EC was reported to be 226 in women with PCOS in comparison to 15 per 100,000 person-years in the control groups [28].

Other than unopposed estrogen exposure to the endometrium, there more molecular mechanisms linked to increase risk of EC in women with PCOS; insulin resistance as well as endometrial overexpression of insulin like growth factor-1, insulin like growth factor binding protein-1, PTEN genes, sterol regulatory binding protein-1 and lastly endometrial overexpression of adiponectin [29]. Nair et al. 2013 explain that derangements in adipocyte, lipid and fatty acid metabolism, increased EC risk, either through inflammation promotion or through fatty acids release from cancer-associated adipocytes which are used in cancer cells for intracellular energy production [30].

Shafiee et.al. 2020, demonstrated that although lipid compounds mechanisms have been linked to EC, plasma concentrations of LDL low density lipoproteins and high density lipoproteis HLD do not directly correlate to EC and therefore cannot currently be used as biomarkers for EC in PCOS. However, women with PCOS and monoacylglycerol 24:0 and capric acid metabolites showed comparable changes in tissue to women with ES-EC and lower BMI, which If validated and correlated with plasma results in future studies, it could be used as possible biomarkers for ES-EC in women with PCOS [31].

Imaging

Ultrasound scanning, Computed Tomography (CT), and Magnetic Resonance Imaging (MRI) are extensively used to rule out endometrial thickening, myometrial involvement and extrauterine disease and in order to eliminate the need of definitive surgery, enabling the option of FSS.

Transvaginal Ultrasound (TVU): TVU is considered the first line screening modality to follow up high risk women for ES-EC in peri- and post- menopausal women as well as women in reproductive age. The maximum Endometrial Thickness (ET) measured by TVU provides a reliable index of EC risk. More specifically, ET measurements over 15mm has a fivefold increase in EC risk. When ET is over 20mm, this risk increases by 20 times more than the risk in general population [32]. In premenopausal patients who undergo selective estrogen receptor modulators therapy when endometrial thickness <15mm endometrial hyperplasia is less likely to occur [33].

TVU with a "power" angio-Doppler technique can be a valuable diagnostic method in hyperplasia and cancer of the endometrium, and especially useful in the early stages of these pathologies. Szpurek et al. 2000 report irregular vascularity of the endometrium, in 12.2% and 81.2% in patients with hyperplasia and EC respectively [34]. However, Angio Doppler technique as a prognostic factor in EC has not been implemented in the daily practice for young women.

Magnetic Resonance Imaging (MRI): Contrast-enhanced MRI (fused T2- and diffusion-weighted) is the preferred modality in ruling out invasive cancer and myometrial involvement and has an accuracy of 88% [35,36]. Bathen et al., 2000 reported an accuracy of 83% in differentiating between cancer and normal samples by analysing lipid metabolic profiles using nuclear magnetic resonance [37]. Recent studies report that MRI has a sensitivity of 90% and specificity of 98% for the staging of early IB1 tumors. The addition of DWI and DCE imaging enables the detection of tumors smaller than 1cm [38,39]. Bourgioti et al. [40] described a highly accurate tumor origin prediction MRI scoring system that discriminates between EC and cervical cancer, with sensitivity up to 96.6% and specificity up to 100%. However, for the detection of metastatic lymph nodes, moderate sensitivity (43%) and specificity (73%) has been demonstrated [41].

Computed Tomography (CT): CT is the preferable modality in assessing the extrauterine encroachment of EC although CT sensitivity in the detection of adnexal involvement of EC has been reported to be only 60% [42, 43]. Hence, it has been argued that diagnostic laparoscopy is probably essential to be performed to rule out the presence of extrauterine disease before initiating fertility-sparing treatments [44].

Positron Emission Tomography-CT is mainly used for detecting the enlargement of retroperitoneal nodes suspicious for metastatic disease with 100% sensitivity and 94% specificity at assessing nodal disease [45]. Eighty-seven percent of tumor recurrence occurs within 3 years after surgery and it has a 46% chance of it recurring at regional lymph nodes [46].

Hysteroscopic Findings

Hysteroscopy has a determinant role in providing FSS for cases with ES-EC. Primarily hysteroscopy can diagnose the anatomical location, extension and depth of the carcinomatous lesion and consequently can provide together with sonography and MRI the appropriate management options and follow-up plan. Timing and frequency of these examinations is of pivotal importance and will determine the time interval for uterine preservation to achieve a pregnancy. The current hysteroscopy procedure as an outpatient setting provides extra comfort and safety to frequent endometrial examinations even every 3-4 months until the patient gets pregnant. The examination performed by an experienced hysteroscopist should include a structured surveillance and should be meticulous and informative. History and previous hysteroscopies text, images records and video recordings should be reviewed prior to every new hysteroscopic examination. The intrauterine pressure used at the initial stage of hysteroscopy should be kept low as possible because this a) reduces the risk of malignant cell spreading, b) decreases the risk of pain and discomfort of the patient, c) overdistention deforms the normal appearance of the endometrium since in physiological condition the anterior wall is lying over the posterior wall. In addition, the vaginoscopic approach using no speculum, tenaculum or sound provides painless hysteroscopy in an office setting.

The option to use a double flow hysteroscope with a working channel with biopsy forceps seems to be the most acceptable approach allowing multiple direct biopsies. Once a lesion is identified a wide excision biopsy should be followed, trying to include the whole lesion in surface and depth. In case atypical cells are reported by histopathology a revision of the anatomical location should be performed in the following hysteroscopy.

Currently cervical Dilatation and Curettage (D&C) usually follows hysteroscopy, providing an extra safety and reassurance of a healthy endometrium. However, the D&C is done mainly for medical legal reasons, and it is common knowledge that blind curettage as well as Pipelle-blind endometrial sampling have low sensitivity and are insufficient in ruling out EC in high-risk women [47]. Tissue Removal Systems (TRS) can provide an excellent view and fast endometrial curettage by adjusting the depth of endometrial sampling. Hence, TRSs might be proposed and encouraged for high-risk patients with EC after FSS. Lastly, directed wide excision biopsies provide additional safety as any suspected lesion can be accompanied by an adjacent biopsy to verify the clear margins of a cancerous sample [47].

In case of uncertain biopsy results and the need to confirm histopathological results, an additional hysteroscopy and lesion wide excision might be advised to reassure the depth, extend and grade of the endometrial carcinoma. It should also be noted that the staging of EC is by surgical approach and the standard treatment is total hysterectomy, bilateral salpingo-oophorectomy, pelvic washing, and/or lymphadenectomy as portrayed in Figure 1 [48]. Hence, the effort to demarcate and classify the ES-EC cannot replace the standard of surgical staging care but to support the temporal FSS to conception and delivery.

Citation: Tanos V, Zervides Z, Tanos P. Prognostic Factors for Early-Stage Endometrial Cancer Management in Fertile Patients. Austin J Obstet Gynecol. 2023; 10(2): 1218.