**1. Introduction**

Endometrial cancer represents over 96% of uterine cancer and is the most common gynecologic cancer in the developed countries with an estimated prevalence of 142,200 women diagnosed in 2011 worldwide1.

This cancer affects mainly postmenopausal women, 95% of cases occurring in patients over 40 years of age; nonetheless up to 14% of patients are premenopausal, and 5% of cases occurs under the age of 40 years.

The 26th Annual Report of the International Federation of Gynecology and Obstetrics (FIGO) states that 83% of endometrial cancer patients are diagnosed and treated at early stage (FIGO I and II) with 5 year actuarial survival rates ranging from 85% to 91%2.

Different treatments plans can be proposed for cancer of uterine corpus, but the standard treatment for this disease has been and remains hysterectomy.

The FIGO (Fédération Internationale de Gynécologie Obstétrique) staging system for this pathology has been recently reviewed and approved at the TNM UICC Core Group meeting in Geneva at the beginning of May 20083 and subsequently adopted by the American Joint Committee on Cancer (AJCC).

The proposed changes to the staging for endometrial cancer are linked to the data provided by the FIGO Annual Report and confirmed by other publications (Table 1).

The surgical treatment for most patients affected by endometrial cancer includes the thorough a surgical exploration of the abdominal cavity with collection of free peritoneal fluid/ peritoneal washing for cytologic evaluation, total extrafascial hysterectomy with bilateral salpingoophorectomy. The traditional abdominal access is laparotomic with vertical midline incision. The removal of pelvic/paraortic lymph nodes is also required to perform an adequate staging according to FIGO guidelines.

Usually this cancer belongs to perimenopausal age, a small percentage of cases affecting younger women.

Most premenopausal patients have a favorable disease-free survival rate (93%) compared to older patients (86%), with a higher rate of low-grade and low-stage disease.

The overall good prognosis in young women affected by early stage endometrial cancer makes fertility-sparing management an attractive option to this group of patients.


\* Either G1, G2, or G3

\*\* Endocervical glandular involvement only should be considered as Stage I and no longer as Stage II \*\*\* Positive cytology has to be reported separately without changing the stage.

Table 1. Endometrial Cancer: New FIGO Staging.

The progressive increasing incidence of endometrial cancer in the last few decades combined with the increase of absolute number of under forty's with childbearing desire have forced clinicians to consider fertility-sparing options in treatment of this pathology.

These strategies include endocrine treatment and surgical ovarian preservation.

Fertility-sparing endocrine treatment is founded on the use progestational agents. The clinical staging system proposed by the FIGO in 1971 is still applicable for patients who attempt for a medical fertility sparing option (table 2).


Table 2. Corpus Cancer Clinical Staging, FIGO 1971.

The use of progestational agents is still a subject of investigation in young patients with early stage disease 4,5,6 and it has been shown to have reasonable success particularly in women with low-grade disease 7. A recent multicenter phase II study of treatment with medroxyprogesterone acetate for endometrial carcinoma and for atypical hyperplasia in young women by Ushijima and colleagues found a complete response in 55% and 82% of cases respectively, with a 47% recurrence rate observed during the 2-year follow up period.

IIIC2 Positive para-aortic lymph nodes with or without positive pelvic lymph nodes

IVB Distant metastases, including intraabdominal metastases and/or inguinal

Stage II\* Tumor invades cervical stroma, but does not extend beyond the uterus\*\*

Stage IV\* Tumor invades bladder and/or bowel mucosa, and/or distant metastases

\*\* Endocervical glandular involvement only should be considered as Stage I and no longer as Stage II

The progressive increasing incidence of endometrial cancer in the last few decades combined with the increase of absolute number of under forty's with childbearing desire have forced clinicians to consider fertility-sparing options in treatment of this pathology.

Fertility-sparing endocrine treatment is founded on the use progestational agents. The clinical staging system proposed by the FIGO in 1971 is still applicable for patients who

These strategies include endocrine treatment and surgical ovarian preservation.

G2 Differentiated adenomatous carcinoma with partly solid areas G3 Predominantly solid or entirely undifferentiated carcinoma

III Carcinoma extends outside the uterus but not outside the true pelvis

IV Carcinoma extends outside the true pelvis or involves the bladder or rectum

The use of progestational agents is still a subject of investigation in young patients with early stage disease 4,5,6 and it has been shown to have reasonable success particularly in women with low-grade disease 7. A recent multicenter phase II study of treatment with medroxyprogesterone acetate for endometrial carcinoma and for atypical hyperplasia in young women by Ushijima and colleagues found a complete response in 55% and 82% of cases respectively, with a 47% recurrence rate observed during the 2-year follow up period.

Stage I\* Tumor confined to the corpus uteri

IIIC1 Positive pelvic nodes

lymph nodes

Table 1. Endometrial Cancer: New FIGO Staging.

attempt for a medical fertility sparing option (table 2).

G1 Highly differentiated adenomatous carcinoma

II Carcinoma involves the corpus and cervix

Table 2. Corpus Cancer Clinical Staging, FIGO 1971.

I Carcinoma is confined to the corpus IA Length of the uterine cavity is 8 cm or less IB Length of the uterine cavity is more than 8 cm

Histologic subtypes of adenocarcinoma

\* Either G1, G2, or G3

Stage characteristics

IA No or less than half myometrial invasion

IIIA Tumor invades the serosa and/or adnexae\*\*\* IIIB Vaginal and/or parametrial involvement

IVA Tumor invasion of bladder and/or bowel mucosa

\*\*\* Positive cytology has to be reported separately without changing the stage.

Stage III\* Local and/or regional spread of the tumor

IB Invasion to or more than half of the myometrium

IIIC Metastases to the pelvic and/or para-aortic lymph nodes

Progestational uterine-preserving treatment is a reasonable option in women affected by early stage, low-grade endometrial cancer, but these patients should be widely counseled about the high recurrence risk observed in cases responding to progestins (about 50% of cases), and thus recommended to close follow-up because of the substantial rate of recurrence.4

MRI, with its high soft tissue contrast resolution and multiplanar capability, has been evaluated in several series. Most of them reported data on the prediction of deep myometrial invasion. In these series the sensitivity of the radiological procedure ranges between 71% to 83%, the specificity between 74% to 96% with Negative and Positive Predictice Values between 86%-97% and 80%-91% respectively.<sup>8</sup> <sup>9</sup> <sup>10</sup>

If the requirement for conservative treatment is no myometrial invasion, then MRI is a poor screening test with an NPV of only 46%11.

Ovarian preservation in young patients, preferably in early stage, low grade cases, may be considered taking into account the potential risk of missing occult ovarian metastases or coexisting synchronous ovarian primary tumors 12,5 and the potential risk of endocrine stimulation of residual microscopic endometrial cancer foci 13,14,15,16

Twenty-three coexisting synchronous epithelial ovarian tumors and 3 metastatic disease were reported in a cohort of 102 women younger than 45 years with endometrial cancer, thus ovarian cancer accounting for 25% of the study cohort. In this report, 4 patients (15%) had normal preoperative imaging of the adnexa, and 4 (15%) had benign appearing ovaries at the time of intraoperative assessment. Recent results of a Surveillance, Epidemiology, and End Results Database (SEER) analysis on ovarian preservation applied to 402 out of 3269 evaluable premenopausal women with stage I endometrial cancer (12%) showed that ovarian preservation may be safe and had no effect on either cancer-specific survival or overall survival. However, it must be considered that young patients could harbor a genetic predisposition to multiple site primary cancer 17.

The Lynch syndrome is an autosomal-dominant cancer susceptibility syndrome associated with early-onset colon, rectal, ovary, small bowel, ureter/renal pelvis, and endometrial cancer. This syndrome occurs in nearly 10% of endometrial cancer patients less than 50 years of age, compared to the 2% to 5% of all endometrial cancer cases, and the risk of ovarian cancer in patients affected by HNPCC is 10% to 12%.

The omission of a bilateral salpingo-oophorectomy should be carefully counseled in these young high-risk patients, and all the known devices should be used to best define their effective risk of ovarian cancer, such as genetic evaluation of mismatch repair defects or BRCA1 and BRCA2 germ line gene mutations.

However in the preoperative counseling the clinician has to make the patient clearly understanding that a negative genetic evaluation does not eliminate the risk of synchronous or metachronous ovarian cancers.

Usually, overall surgical cure rates for endometrial cancer are high but, unfortunately, up to 25% of affected patients have a poor prognosis when the disease is widely spread at diagnosis or characterized by poor clinical-pathological risk factors such as high grade of histological differentiation, deep myometrial invasion or unfavorable histology (clear cells / serous papillary pattern). Treatment planning must be tailored depending on tumor grade, depth of myometrial invasion, and extension to cervical stroma: these factors are directly related to the risk of regional lymph node and distant metastasis, influencing overall prognosis.

Laparotomic surgery has been considered the standard surgical approach in patients affected by endometrial cancer. This surgery must include an initial exploration of the abdominal and pelvic cavities, peritoneal free fluid or washing collection for cytology, biopsy of any suspicious extra uterine lesion, total extrafascial hysterectomy with bilateral salpingo-oophorectomy. In order to complete the surgical staging, the dissection of pelvic and para-aortic lymph nodes are recommended by FIGO.

Vaginal hysterectomy has often been defined as the simplest and least morbid approach and different studies found similar treatment outcomes in stage I endometrial cancer patients treated with vaginal or laparotomic hysterectomy 18,19,20. Still, limitations to vaginal approach are the lack of exploration and of cytological evaluation of the abdominal cavity, difficulty in performing salpingo-oophorectomy and the inability to perform a thorough evaluation of lymph nodes 19. This surgical approach should be considered a valid alternative for high-risk patients with co-morbidities that can contraindicate abdominal procedures.21,22

In the latest years, hysterectomy and bilateral salpingo-oophorectomy performed by a laparoscopic-assisted-vaginal (LAVH) or total laparoscopic (TLH) approach have increasingly been integrated in the standard practice of endometrial cancer patients. These techniques are able to overcome some of the limitations of the vaginal approach.

Initial case reports and small single-institution retrospective series described laparoscopic technique and demonstrated its feasibility during the early '90s 23,24,25; subsequently larger series, randomized small size trial, and finally a multi-institutional randomized controlled trial, evaluated the feasibility and survival outcomes of laparoscopy in endometrial cancer patients 26,27,28,29. A small prospective trial 26 randomized 70 patients with FIGO stage I-III endometrial carcinoma to radical vaginal or laparoscopy-assisted simple hysterectomy or simple or radical abdominal hysterectomy with or without lymph node resection. The laparoscopic group showed significantly lower blood loss and transfusion rates, while the number of pelvic and para-aortic lymph nodes, duration of surgery, and incidence of postoperative complications were similar for both groups. A significantly shorter hospital stay was found in the laparoscopic group, in accordance with other Authors 35,36. No significant differences were observed between the laparoscopic and laparotomy groups in terms of disease recurrence rate and long-term survival (97.3% vs. 93.3% and 83.9% vs. 90.9%, respectively).

The conclusion of this study was that laparoscopic staging combined with laparoscopically assisted vaginal hysterectomy can be recommended for the treatment of women with endometrial cancer, offering a less invasive approach that is associated with less intraoperative and postoperative morbidity.

Results of a large randomized trial (LAP II trial) from the Gynecologic Oncology Group (GOG) comparing laparoscopic hysterectomy with comprehensive surgical staging to the traditional laparotomy technique were recently published 29,30.

The study enrolled 2616 patients with clinical stage I to IIA uterine cancer and randomized 920 patients to the open arm, and 1,696 to laparoscopy. The conversion rate from laparoscopy to open procedure was 26%; it increased with increasing patient obesity. Median number of removed pelvic nodes was similar between each technique, while a statistically significant higher para-aortic node dissection rate was observed in the laparotomy group (97% versus 94%). Most importantly, the frequencies of patients found to have positive lymph nodes were the same in both groups (9%). The rate of postoperative complications, median blood loss, and median length of hospital stay were significantly lower in the laparoscopy group, despite the relatively high conversion rate.

Laparotomic surgery has been considered the standard surgical approach in patients affected by endometrial cancer. This surgery must include an initial exploration of the abdominal and pelvic cavities, peritoneal free fluid or washing collection for cytology, biopsy of any suspicious extra uterine lesion, total extrafascial hysterectomy with bilateral salpingo-oophorectomy. In order to complete the surgical staging, the dissection of pelvic

Vaginal hysterectomy has often been defined as the simplest and least morbid approach and different studies found similar treatment outcomes in stage I endometrial cancer patients treated with vaginal or laparotomic hysterectomy 18,19,20. Still, limitations to vaginal approach are the lack of exploration and of cytological evaluation of the abdominal cavity, difficulty in performing salpingo-oophorectomy and the inability to perform a thorough evaluation of lymph nodes 19. This surgical approach should be considered a valid alternative for high-risk

In the latest years, hysterectomy and bilateral salpingo-oophorectomy performed by a laparoscopic-assisted-vaginal (LAVH) or total laparoscopic (TLH) approach have increasingly been integrated in the standard practice of endometrial cancer patients. These

Initial case reports and small single-institution retrospective series described laparoscopic technique and demonstrated its feasibility during the early '90s 23,24,25; subsequently larger series, randomized small size trial, and finally a multi-institutional randomized controlled trial, evaluated the feasibility and survival outcomes of laparoscopy in endometrial cancer patients 26,27,28,29. A small prospective trial 26 randomized 70 patients with FIGO stage I-III endometrial carcinoma to radical vaginal or laparoscopy-assisted simple hysterectomy or simple or radical abdominal hysterectomy with or without lymph node resection. The laparoscopic group showed significantly lower blood loss and transfusion rates, while the number of pelvic and para-aortic lymph nodes, duration of surgery, and incidence of postoperative complications were similar for both groups. A significantly shorter hospital stay was found in the laparoscopic group, in accordance with other Authors 35,36. No significant differences were observed between the laparoscopic and laparotomy groups in terms of disease recurrence rate and long-term survival (97.3% vs. 93.3% and 83.9% vs.

The conclusion of this study was that laparoscopic staging combined with laparoscopically assisted vaginal hysterectomy can be recommended for the treatment of women with endometrial cancer, offering a less invasive approach that is associated with less

Results of a large randomized trial (LAP II trial) from the Gynecologic Oncology Group (GOG) comparing laparoscopic hysterectomy with comprehensive surgical staging to the

The study enrolled 2616 patients with clinical stage I to IIA uterine cancer and randomized 920 patients to the open arm, and 1,696 to laparoscopy. The conversion rate from laparoscopy to open procedure was 26%; it increased with increasing patient obesity. Median number of removed pelvic nodes was similar between each technique, while a statistically significant higher para-aortic node dissection rate was observed in the laparotomy group (97% versus 94%). Most importantly, the frequencies of patients found to have positive lymph nodes were the same in both groups (9%). The rate of postoperative complications, median blood loss, and median length of hospital stay were significantly

patients with co-morbidities that can contraindicate abdominal procedures.21,22

techniques are able to overcome some of the limitations of the vaginal approach.

and para-aortic lymph nodes are recommended by FIGO.

90.9%, respectively).

intraoperative and postoperative morbidity.

traditional laparotomy technique were recently published 29,30.

lower in the laparoscopy group, despite the relatively high conversion rate.

The authors concluded that laparoscopic surgical staging is an acceptable and possibly a better option, particularly when the surgery can be successfully completed laparoscopically, even if the results specific to long-term oncologic outcomes are not known.

Age and obesity have been suggested as relative contraindications to laparoscopic surgery. Similar conclusions where reached by Scribner et al. 31

The authors concluded that, with the growth of an aging patient population, the laparoscopic management of endometrial cancer is a viable option.

Obese patients have also been suggested to be poor laparoscopic candidates due to difficulties in establishing pneumoperitoneum, poorer visualization, inability to tolerate steep Trendelenburg positioning needed to facilitate the surgery, and difficulties with ventilation. It is important to mention that complete surgical staging is more difficult in obese patients regardless of the surgical approach.

In a study of Eltabbakh et al. comparing LAVH and abdominal approach in women with BMI between 28 and 60 32 laparoscopic conversion was required only in 8% of patients: laparoscopic surgery was associated with a longer operative time (195

minutes vs. 138 minutes), more pelvic nodes (mean 11 vs. 5), less pain medicine requirement, and shorter hospital stay (2.5 vs. 5.6 days) were recorded.

Total laparoscopic hysterectomy has also been shown to be feasible in heavier patients 33. In the prospective GOG series, there was ≥80% success rate with patients with a BMI of 27 or less, but even at a BMI of 35, 65% could have successful laparoscopic surgery. 34

In conclusion, the surgical approach and the technique used to remove the uterus with the ovaries does not represent a source of controversy since the comprehensive surgical pathological evaluation should be accomplished with different approaches. 25

Minimal access surgery is being applied increasingly in gynecological oncology and is now a commonplace in the surgical treatment of endometrial cancer.

The widespread adoption of laparoscopy has been slow due to the prolonged learning curve needed to become proficient in such a technique. The development of robotic surgery has facilitated the use of laparoscopy due to the faster and easier learning curve.

In robotic surgery, the main surgeon sits at the surgeon console located away from the patient, places his index fingers and thumbs in the master rings and along with foot pedals is able to control all the robotic instruments held by the patient-side cart through a computer-based technology. Endometrial cancer is particularly suited for robotic surgery for several reasons. The majority of women with endometrial cancers are obese and at greater risk for postoperative wound complications, and would benefit from a minimally invasive procedure with smaller incisions, resulting in less risk for wound problems. However, at the same time obesity increases the degree of difficulty of management via laparoscopy: the level of difficulty of operating in an obese patient via robotic surgery is minimal. In a retrospective comparison of obese women and morbidly obese women undergoing traditional laparoscopic approach vs. robotic-assisted approach, better surgical outcomes were observed in the group undergoing robotic-assisted laparoscopy. 35

Actually there are no published data of survival in endometrial cancer patients treated with robotic system that has been introduced in clinical practice short time ago. However, early case series thus far reported suggests that robotic surgery for endometrial cancer is feasible and safe. The use of robotic-assisted laparoscopy for the management of endometrial cancer is expected to be rapid, paralleling the growth that has been observed with radical prostatectomy.

Another important issue in the management of endometrial cancer is the tailoring of "radicality" according to the "clinical stage" of the disease.

Radical hysterectomy is the standard of care of early stage cervical cancer (IA2–IB1), but its role in endometrial cancer remains unclear 36. A radical surgical approach to endometrial cancer requires the uterus to be removed with parametria, paracolpos, and an adequate vaginal cuff, and ensures wider tumor-free resection margins than those obtained with total abdominal hysterectomy. The main goals of the radical surgical approach for stage I endometrial cancer are a better local control of the disease and a reduction in the use of adjuvant radiation with its possible related complications.

A multicenter randomized Italian trial 37 aimed to determine whether a modified radical (Piver– Rutledge class II) hysterectomy can improve survival and loco regional control compared to the standard extrafascial (Piver–Rutledge class I) hysterectomy. The Authors randomized 520 early stage endometrial cancer patients and evaluated the difference between Class I vs. Class II group in terms of loco regional control, disease-free and overall survival, and treatment-related morbidity.

Intraoperative and postoperative complications rates were similar in the two arms, but there were slight imbalances with respect to urinary complications. Although class II hysterectomy turned out to be feasible in most patients enrolled onto our study (only 19 of the 279assigned to class II underwent class I hysterectomy), it was far longer (20 min) and was associated with greater blood loss (50 ml) than class I.

The univariate and multivariate estimates of the HRs of recurrence confirm that class II hysterectomy offers no benefit.

The identification of spread to draining lymph node basins is considered of outmost importance since it can change the prognosis and modify the use of postoperative therapies. However no consensus exists regarding the role and the extension of lymphadenectomy in the primary surgical setting and more controversial is the therapeutical role of this procedure.

In women submitted to systematic lymphadenectomy without clinical suspect of nodal metastasis, pelvic lymph node involvement may be assessed in 8 to 28% of patients. 38, 39.

The risk of pelvic and/or paraortic nodal metastases 2 depends on hystotype, myometrial invasion and hystological grade of differentiation, ranging from 0% up to 20% in M0G1 and M3G3 patients (see Table 3).


P-, P+: negative, positive pelvic nodes; A-, A+: negative, positive aortic nodes; M0: no myometrial invasion M≤50%: myometrial invasion ≤50% M>50%: myometrial invasion >50 %.

Table 3. Carcinoma of the corpus uteri. Patients treated in 1999-2001. Lymhnodal status (a).

Even if there is no evidence that risk/benefit balance is in favor of lymphadenectomy however this procedure can cause potentially significant morbidity in approximately 11% of cases 40. The relevance of lymph node status is of outmost importance for the prognosis of this disease. For this reason this procedure represents a fundamental step in staging the disease 3. The main risks attributable to nodal dissections include increased operative time, potential for blood loss associated with vascular injuries eventually requiring blood transfusion, genitofemoral

Radical hysterectomy is the standard of care of early stage cervical cancer (IA2–IB1), but its role in endometrial cancer remains unclear 36. A radical surgical approach to endometrial cancer requires the uterus to be removed with parametria, paracolpos, and an adequate vaginal cuff, and ensures wider tumor-free resection margins than those obtained with total abdominal hysterectomy. The main goals of the radical surgical approach for stage I endometrial cancer are a better local control of the disease and a reduction in the use of

A multicenter randomized Italian trial 37 aimed to determine whether a modified radical (Piver– Rutledge class II) hysterectomy can improve survival and loco regional control compared to the standard extrafascial (Piver–Rutledge class I) hysterectomy. The Authors randomized 520 early stage endometrial cancer patients and evaluated the difference between Class I vs. Class II group in terms of loco regional control, disease-free and overall

Intraoperative and postoperative complications rates were similar in the two arms, but there were slight imbalances with respect to urinary complications. Although class II hysterectomy turned out to be feasible in most patients enrolled onto our study (only 19 of the 279assigned to class II underwent class I hysterectomy), it was far longer (20 min) and

The univariate and multivariate estimates of the HRs of recurrence confirm that class II

The identification of spread to draining lymph node basins is considered of outmost importance since it can change the prognosis and modify the use of postoperative therapies. However no consensus exists regarding the role and the extension of lymphadenectomy in the primary surgical setting and more controversial is the therapeutical role of this procedure. In women submitted to systematic lymphadenectomy without clinical suspect of nodal metastasis, pelvic lymph node involvement may be assessed in 8 to 28% of patients. 38, 39. The risk of pelvic and/or paraortic nodal metastases 2 depends on hystotype, myometrial invasion and hystological grade of differentiation, ranging from 0% up to 20% in M0G1 and

Myometrial invasion P-A-(%) P+A-(%) P-A+(%) P+A+(%) Unknown 97.42 1.81 0.17 0.60 M0 94.20 3.40 0.60 1.80 M≤50% 93.88 4.56 0.62 0.94 M>50% 73.90 18.41 1.56 6.14

Table 3. Carcinoma of the corpus uteri. Patients treated in 1999-2001. Lymhnodal status (a). Even if there is no evidence that risk/benefit balance is in favor of lymphadenectomy however this procedure can cause potentially significant morbidity in approximately 11% of cases 40. The relevance of lymph node status is of outmost importance for the prognosis of this disease. For this reason this procedure represents a fundamental step in staging the disease 3. The main risks attributable to nodal dissections include increased operative time, potential for blood loss associated with vascular injuries eventually requiring blood transfusion, genitofemoral

adjuvant radiation with its possible related complications.

was associated with greater blood loss (50 ml) than class I.

survival, and treatment-related morbidity.

hysterectomy offers no benefit.

M3G3 patients (see Table 3).

P-, P+: negative, positive pelvic nodes; A-, A+: negative, positive aortic nodes;

M0: no myometrial invasion M≤50%: myometrial invasion ≤50% M>50%: myometrial invasion >50 %. nerve injury with resulting numbness and paresthesias over medial thighs, lymphocysts formation, and lymphedema.

Many believe that nodal dissection should be reserved for those with sufficient risk of nodal disease. Most important factors related to incidence of nodal metastases are tumor grade and depth of myometrial invasion as we can see analyzing data of GOG 33 study 38. Patients with grade 1 lesion with inner part of myometrium involved showed a 3% risk of nodal metastasis defined by the Authors "negligible". Patients with grade 3 lesions with deep myometrial invasion showed a 34% risk of nodal localizations.

Clear cell tumors and serous papillary tumors are more often affected by nodal metastasis (30-50% of risk independently by prognostic factors on surgical specimen) 41.

Usually the risks related to nodal resection are acceptable, if this procedure is managed by skilled and well trained physicians, and this procedure deeply influences the use of postoperative treatment: less indications for radiation therapy or use of vaginal cuff brachytherapy instead of whole pelvic external irradiation 42 43. Without nodal information, physicians must rely on uterine factors to estimate the probability for nodal disease and pelvic failure to determine the need for postoperative radiation. This estimation can result in a substantial increase in the use of radiation.

The advantages of systematic lymphadenectomy are evidenced in some retrospective studies. Other observational studies, however, have not shown any such benefit. Until 2011 no class I evidence paper had been published.

MRC ASTEC trial 44 enrolled 1408 women with proven endometrial carcinoma from 85 centers in four countries.

This randomized trial did not showed any evidence of benefit with systematic lymphadenectomy for endometrial cancer in terms of overall, disease-specific, and recurrence-free survival. Overall morbidity was low, but there was a substantial increase in the incidence of lymphedema in the lymphadenectomy group compared with standard surgery. The Authors concluded that the balance of risks and benefits for systematic iliac and obturator lymphadenectomy does not favor this intervention, with no clear evidence of benefit in terms of overall or recurrence-free survival and increased risk of lymphedema. These results suggest that lymphadenectomy in patients affected by endometrial cancer, whose neoplasm is preoperatively diagnosed as confined to the corpus, has no therapeutic effect and is therefore not justified as a therapeutic procedure. Nevertheless this surgical procedure is required for surgical staging in order to identify those patients who will have benefit from adjuvant treatment.

It must be noted that this trial received a number of criticisms concerning the inclusion of a large number of women at low risk of nodal metastases and variable extent of nodal dissection between recruiting centers.

An Italian randomized prospective study 45 recruited 514 patients with preoperative FIGO stage I endometrial carcinoma (Stage IB with grade 1 lesions were excluded from randomization), randomly assigned to undergo pelvic systematic lymphadenectomy or no lymphadenectomy whose anatomical and numerical extent was clearly defined in the study design. No lack of consistency between the centers and uniformly high nodal counts were detected.

According to the Authors, pelvic systematic lymphadenectomy did not change the natural history of the disease since the pattern of disease recurrence, was similar between the two groups. However, pelvic lymphadenectomy did allow for a more accurate prognosis on the basis of the pathological lymph node assessment and, in this trial, provided for approximately 10% of the upstaging to surgical stage IIIC (P < .001).

The role of para-aortic lymphadenectomy is another field of debate: the anatomic extent and level of dissection remain ill defined for patients undergoing para-aortic node sampling or systematic dissection. 46,47,48,49

Reports that address the routes of lymphatic dissemination in endometrial cancer have suggested that the principal connections are between the uterine corpus and the external iliac and obturator basins 50,51,52. A direct route may exist from the corpus to the paraaortic node-bearing basins by the lymphatic channels adjacent to the gonadal vessels within the infundibulopelvic ligament 51,52. Other reports have also suggested a potential direct lymphatic communication between the external iliac and obturator basins and the paraaortic node-bearing tissue 48,53. Therefore, an a priori assertion exists that the paraaortic nodebearing tissue in the region of the origin and insertion of the gonadal arteries and veins, respectively, would be favored sites for nodal involvement.

In absence of metastatic pelvic nodes, isolated positive para-aortic nodes are identified in a small number of patients. The historical data from GOG 33 showed that isolated para-aortic nodal metastases occurred in 2% of patients. These data also suggest that when positive, outcomes are improved in patients who have complete surgical resection of para-aortic nodes. This effect may be simply be a consequence of better staging rather than a true therapeutic effect. Another explanation may be that extensive lymphadenectomy reflects overall better care. The use of Radiation therapy responding to positivity of para-aortic nodes may be another explanation of better survival in patients submitted to this procedure 54.

The risks of paraortic nodal involvement are essentially the same that predicts the pelvic nodal spread (depth of myometrial invasion, nuclear grading, and the presence of lymph-vascular space involvement) 46,55. Mariani et al. showed that patients at high risk for para-aortic nodal disease (based on invasion >50%, palpable positive pelvic nodes, positive adnexa) who did not have para-aortic dissection or who had biopsy only and who were managed as though paraaortic nodes were positive had 5-year survival of 71% compared to 85% for those patients with positive para-aortic nodes who did undergo complete resection 56.

At the present time, the superior extent of para-aortic dissection should be at least to the level of the inferior mesenteric artery (IMA). The Mayo Clinic group retrospectively in their series observed that the routinely performed lymphadenectomies only up to the IMA potentially miss 38% to 46% of patients with positive para-aortic nodes because of the high rate of isolated involvement above the IMA. Furthermore, 63% of patients in Mayo's series with positive lymph nodes below the IMA also had positive nodes above the IMA that would have escaped detection if the dissection had been limited to the lower node basins. Thus, the node-bearing tissue between the IMA and the renal vessels appears in their experience of outmost importance for the assessment of the extent of disease and thus for determination of overall treatment dispositions. 56 This extended para-aortic dissection is feasible laparoscopically as well laparotomically 57. Prospective data describing the frequency of high para-aortic/renal nodes are awaited.

More recently a large prospective trial compared the outcomes after complete pelvic lymphadenectomy or combined pelvic and para-aortic lymphadenectomy. The trial was non-randomized and was conducted at two sites, one in which pelvic lymphadenectomy was standard and a second where combined pelvic and para-aortic dissection was standard. More than 600 women were included. The authors report significantly increased overall survival in women undergoing para-aortic dissection and argue that women at intermediate or high risk of disease recurrence should have both pelvic and para-aortic lymphadenectomy 58. No benefit was seen in low risk patients. Although the groups were

The role of para-aortic lymphadenectomy is another field of debate: the anatomic extent and level of dissection remain ill defined for patients undergoing para-aortic node sampling or

Reports that address the routes of lymphatic dissemination in endometrial cancer have suggested that the principal connections are between the uterine corpus and the external iliac and obturator basins 50,51,52. A direct route may exist from the corpus to the paraaortic node-bearing basins by the lymphatic channels adjacent to the gonadal vessels within the infundibulopelvic ligament 51,52. Other reports have also suggested a potential direct lymphatic communication between the external iliac and obturator basins and the paraaortic node-bearing tissue 48,53. Therefore, an a priori assertion exists that the paraaortic nodebearing tissue in the region of the origin and insertion of the gonadal arteries and veins,

In absence of metastatic pelvic nodes, isolated positive para-aortic nodes are identified in a small number of patients. The historical data from GOG 33 showed that isolated para-aortic nodal metastases occurred in 2% of patients. These data also suggest that when positive, outcomes are improved in patients who have complete surgical resection of para-aortic nodes. This effect may be simply be a consequence of better staging rather than a true therapeutic effect. Another explanation may be that extensive lymphadenectomy reflects overall better care. The use of Radiation therapy responding to positivity of para-aortic nodes may be

The risks of paraortic nodal involvement are essentially the same that predicts the pelvic nodal spread (depth of myometrial invasion, nuclear grading, and the presence of lymph-vascular space involvement) 46,55. Mariani et al. showed that patients at high risk for para-aortic nodal disease (based on invasion >50%, palpable positive pelvic nodes, positive adnexa) who did not have para-aortic dissection or who had biopsy only and who were managed as though paraaortic nodes were positive had 5-year survival of 71% compared to 85% for those patients with

At the present time, the superior extent of para-aortic dissection should be at least to the level of the inferior mesenteric artery (IMA). The Mayo Clinic group retrospectively in their series observed that the routinely performed lymphadenectomies only up to the IMA potentially miss 38% to 46% of patients with positive para-aortic nodes because of the high rate of isolated involvement above the IMA. Furthermore, 63% of patients in Mayo's series with positive lymph nodes below the IMA also had positive nodes above the IMA that would have escaped detection if the dissection had been limited to the lower node basins. Thus, the node-bearing tissue between the IMA and the renal vessels appears in their experience of outmost importance for the assessment of the extent of disease and thus for determination of overall treatment dispositions. 56 This extended para-aortic dissection is feasible laparoscopically as well laparotomically 57. Prospective data describing the

More recently a large prospective trial compared the outcomes after complete pelvic lymphadenectomy or combined pelvic and para-aortic lymphadenectomy. The trial was non-randomized and was conducted at two sites, one in which pelvic lymphadenectomy was standard and a second where combined pelvic and para-aortic dissection was standard. More than 600 women were included. The authors report significantly increased overall survival in women undergoing para-aortic dissection and argue that women at intermediate or high risk of disease recurrence should have both pelvic and para-aortic lymphadenectomy 58. No benefit was seen in low risk patients. Although the groups were

another explanation of better survival in patients submitted to this procedure 54.

positive para-aortic nodes who did undergo complete resection 56.

frequency of high para-aortic/renal nodes are awaited.

systematic dissection. 46,47,48,49

respectively, would be favored sites for nodal involvement.

comparable in most respects with a similar proportion of non-endometrioid carcinomas, 77% of women in the pelvic/para-aortic group received systemic chemotherapy compared with only 45% of women in the pelvic node group. These results do not argue convincingly for para-aortic lymphadenectomy in women at higher risk of disease recurrence or distant metastasis but do suggest that this is an area that should be addressed by a properly constructed clinical trial.

A recent Cochrane Review 59 assessed that published data do not support the routine use of pelvic lymphadenectomy in the treatment of endometrial cancer thought to be confined to the uterus at presentation. There was no statistically significant difference in survival between the groups. Meta-analysis indicated no significant difference in overall and recurrence-free survival between women who received lymphadenectomy and those who received no lymphadenectomy (pooled HR = 1.07, 95% CI: 0.81 to 1.43 and HR = 1.23, 95% CI: 0.96 to 1.58 for overall and recurrence-free survival respectively) and, in terms of harmful effects of treatment, women who did not receive lymphadenectomy showed a clear benefit. No good quality data were found which assessed the role of para-aortic lymphadenectomy, or removal of grossly enlarged lymph nodes. Further research is needed to allow more individualized treatment strategies, ensuring that women with more aggressive cancers receive appropriate treatment, whilst not exposing women with a better prognosis to potentially serious side effects. In addition, it is imperative to assess the impact of any intervention on quality of life in any future study, particularly for a cancer with good survival rates.

Although lymphadenectomy continues to be controversial for some, over the last 30 years our knowledge of the lymph node involvement in endometrial cancer has increased and how that information can be used to benefit our patients. Lymphadenectomy in endometrial cancer is certainly diagnostic and it may be also therapeutic if systematic pelvic and paraaortic procedures are performed. At the present time low risk patients can avoid this surgical assessment but there is no general agreement in the definition of the "low risk category". Recent data, and a new molecular staging system could improve our knowledge and would probably lead to a consensus in the near future.

#### **2. Debulking**

Endometrial cancer is often diagnosed at a stage I disease (71%) 60. A low percentage of cases present at an advanced stage, defined by FIGO stage III and IV. Nonetheless, rare histopathologic types of endometrial cancer, such as papillary-serous (4% of cases) and clear cell carcinomas (2% of cases) frequently present at an advanced stage, both accounting for 14% of advanced stage (FIGO III and IV) compared with 4% of early stage (FIGO I and II) endometrial cancer patients 61,62.

The management of endometrial cancer is reviewed in several papers; still, limited evidence is available how to manage patients with advanced stage disease. The treatment of this relatively rare group of patients is frequently individualised and it depends on the surgical ability to resect disease.

In patients with macroscopic intraperitoneal disease it is debated if optimal surgical cytoreduction is indicated, and in these cases options include the resection of the easily removable disease such as uterus, adnexa, and omentum, versus performing a wider cytoreductive effort. Different retrospective studies evaluated the impact of surgical cytoreduction on the outcome of advanced endometrial cancer patients, suggesting that survival correlates with the volume of residual disease.

Goff et al 63 analysed 47 cases of stage IV endometrial cancer, observing a statistically significant improvement of median survival in the cases of no bulky disease at the end of surgery compared to patients not completely cytoreducted (18 vs. 8 months respectively).

Chi et al 64 also found a significatively longer median survival in the subgroup of patients treated with optimal cytoreduction (residual tumor < 2 cm) among 55 cases of stage IV endometrial cancer, compared to patients with residual tumor > 2 cm (31 months vs. 12 months).

Bristow et al 65 defines optimal cytoreduction as largest residual tumor < 1 cm and showed that median survival was 34 months after optimal cytoreduction compared to 11 months when suboptimal cytoreduction was performed, with a residual tumor > 1 cm, and again the difference were statistically significative.

In conclusion, it can be assessed that in all cases with no firm contraindication for surgery, primary treatment should include surgery, with an exception for patients with distant metastases: for these cases there may be a limited role of surgery such as to provide control of vaginal bleeding.

Still, the warranty for an optimal cytoreduction in cases with disease outside the uterus is only based on some retrospective studies made on relative small number of patients, different stage of disease are often included and different definitions of surgical cytoreduction are employed. Thus, these studies are difficult to compare, and no randomized trial has been carried out to confirm the advantage of optimal cytoreduction on survival.

Nonetheless, available data suggest that an optimal cytoreduction in advanced stage endometrial cancer is associated with improved survival of these patients.

#### **3. Refferences**


Goff et al 63 analysed 47 cases of stage IV endometrial cancer, observing a statistically significant improvement of median survival in the cases of no bulky disease at the end of surgery compared to patients not completely cytoreducted (18 vs. 8 months respectively). Chi et al 64 also found a significatively longer median survival in the subgroup of patients treated with optimal cytoreduction (residual tumor < 2 cm) among 55 cases of stage IV endometrial cancer, compared to patients with residual tumor > 2 cm (31 months vs. 12

Bristow et al 65 defines optimal cytoreduction as largest residual tumor < 1 cm and showed that median survival was 34 months after optimal cytoreduction compared to 11 months when suboptimal cytoreduction was performed, with a residual tumor > 1 cm, and again the

In conclusion, it can be assessed that in all cases with no firm contraindication for surgery, primary treatment should include surgery, with an exception for patients with distant metastases: for these cases there may be a limited role of surgery such as to provide control

Still, the warranty for an optimal cytoreduction in cases with disease outside the uterus is only based on some retrospective studies made on relative small number of patients, different stage of disease are often included and different definitions of surgical cytoreduction are employed. Thus, these studies are difficult to compare, and no randomized trial has been carried out to

Nonetheless, available data suggest that an optimal cytoreduction in advanced stage

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