سرطان الرحم: والنهج الحديث لإدارة الجراحية

[وهك] ممارسة نشرة وسريرية إدارة لمقدمي الرعاية الصحية. قدمت منحة للتربية وصحة المرأة وتربية مركز ([وهك]).

Uterine or endometrial cancer is the most commonly diagnosed gynecologic malignancy; almost every gynecologist will encounter it. Adenocarcinoma of the endometrium (also known as endometrial cancer, or more broadly as uterine cancer or carcinoma of the uterus corpus) is the most common malignancy of the female genital tract in the United States. Most patients with endometrial cancer will present with early-stage disease. In approximately 75% of patients with adenocarcinoma of the endometrium, the invasive neoplasm is confined to the uterus at diagnosis (1). Endometrioid adenocarcinomas tend to have an excellent prognosis, because the early symptoms of irregular vaginal bleeding (in this predominately postmenopausal patient population) often prompt patients to seek care when the disease is at an early and curable stage. Thus, endometrial cancer is often localized, yielding a generally high survival rate. Although the rate of metastasis in these patients is low, proffering excellent prognoses, the standard of treatment in many practices still include a complete or selective pelvic and para-aortic lymphadenectomy for staging; and accurate surgical staging is the most important prognostic factor. Many patients will undergo a comprehensive lymphadenectomy despite having disease confined to the uterus, resulting in prolonged operating time, additional cost, and potential side effects, such as lower extremity lymphedema. However, recent studies show that a complete lymphadenectomy may have no therapeutic benefit in patients with early-stage endometrial cancer. Sentinel lymph node (SLN) mapping, which has been used in other cancer types, may be an acceptable surgical strategy between a complete lymphadenectomy and no nodal evaluation in patients with endometrial cancer.

The purpose of this document is to review the current understanding of endometrial cancer and to provide guidelines for management that have been validated by appropriately conducted outcome-based research when available. Additional guidelines on the basis of consensus and expert opinion also are presented. A thorough understanding of the epidemiology, pathophysiology, and diagnostic and management strategies for this type of cancer allows the gynecologists to identify women at increased risk, contribute toward risk reduction, and facilitate early diagnosis. Sentinel lymph node (SLN) mapping is based on the concept that lymph node metastasis is the result of an orderly process; that is, lymph drains in a specific pattern away from the tumor, and therefore, if the SLN, or first node, is negative for metastasis, then the nodes after the SLN, should be negative. This approach can help patients avoid the side effects associated with a complete lymphadenectomy, although disease must be thoroughly staged for accurate prognosis and determination of appropriate treatment approach.


Background

In the United States, endometrial cancer will be diagnosed in an estimated 54,870 women in 2015, with 10,170 succumbing to the disease (2). The mean age of diagnosis in the United States is 63 years (3). Caucasian women have a 2.81% lifetime risk of developing uterine cancer compared with a 2.48% lifetime risk for African American women (3). African American women are more likely to have non-endometrioid, high-grade tumors (known as type II), which are associated with a more advanced stage of disease (stage III and stage IV) at the time of diagnosis, compared with Caucasian women who have similar demographic characteristics (4).

Risk factors for uterine neoplasms include increased levels of estrogen (caused by obesity, diabetes, high-fat diet), early age at menarche, nulliparity, late age at menopause, Lynch syndrome, older age (>55 years), and tamoxifen use. Thus, the incidence of uterine cancer is increasing because of increased life expectancy and obesity.

Surgical lymphadenectomy and radiation are common components of therapy for women with endometrial cancer and are thought to increase the risk of developing lower extremity lymphedema. These patients may also have comorbid conditions such as obesity that further increases their risk. Once present, the symptoms and local effects of lymphedema can only be managed, not cured. The resulting disability may lead to severe lifelong morbidity including pain, skin breakdown, impaired mobility, difficulty with self-care, psychological morbidity, and impaired quality of life (5).


Classification and Histopathology

Endometrial cancer can be categorized broadly into two types that differ in epidemiology, genetics, prognosis, and even treatment:

  1. Type I, or endometrioid adenocarcinoma, is the most common histologic type of endometrial cancer and accounts for more than three fourths of all cases. Most cases of type I cancer are low grade and confined to the uterus when diagnosed; and
  2. Type II is characterized by clear cell and papillary serous tumor histologies; and type II cancer is considered to be high grade and to have significant risk of extrauterine disease and a poorer prognosis than type I cancer.

The precursor lesion of type I endometrioid adenocarcinoma is endometrial hyperplasia (also known as atypical endometrial hyperplasia). There are currently two systems of endometrial precancer nomenclature in common usage:

  1. The World Health Organization (WHO) 1994 schema, which includes the "atypical endometrial hyperplasia" designation, and
  2. The endometrial intraepithelial neoplasia diagnostic schema developed by the International Endometrial Collaborative Group (6).

The endometrial intraepithelial neoplasia schema is increasingly viewed as preferable because it more clearly distinguishes between clinic-pathologic entities that are managed differently. When endometrial intraepithelial neoplasia is absent, the risk of progression to endometrioid carcinoma ranges from 1% to 8%, depending on the degree of architectural complexity (7). Endometrial intraepithelial neoplasia however, is much more likely to progress to cancer and may be found coexisting with an undiagnosed endometrioid carcinoma in 30%-50% of cases (7). Uterine papillary serous carcinoma accounts for only approximately 10% of all cases of uterine cancer, but it is responsible for the deaths of almost 40% of patients with endometrial cancer (8). The precursor lesion is thought to be endometrial intraepithelial carcinoma. Serous endometrial intraepithelial carcinoma may be associated with an extrauterine tumor at the time of diagnosis and with risk of occurrence, spread, and eventual death from tumor. Clear cell histology also is rare but is associated with a similar poor prognosis. Carcinosarcoma, also known as malignant mixed mullerian tumor of uterus, is another histologic cell type with a poor prognosis and may represent a subset of adenocarcinoma.


The Pelvic and Para-Aortic Lymph Nodes

There is no substitute for a detailed knowledge of the anatomy of the pelvis and abdomen. The physician who pursues gynecologic oncology as a career must be completely familiar with the pelvis, abdomen, retroperitoneum, and the lymphatic drainage of the female genital tract. No amount of surgical skill or knowledge of cancer therapy can compensate for the lack of this knowledge.

Lymphatic drainage from the cervix follows the uterine arteries and cardinal ligaments to the pelvic lymph nodes, which include the external iliac, internal iliac (hypogastric), and obturator groups. From these pelvic nodes, the drainage proceeds superiorly through the common iliac lymph nodes and then up to the para-aortic nodes. The lymphatic drainage from both the uterine corpus and the ovaries follows one of the three routes (see figure below):

  1. 1. Along the uterine arteries in the broad ligaments to the pelvic nodes;
  2. T2. In channels following the round ligaments to the inguinal lymph nodes;
  3. 3. Along the ovarian lymphatics in the infundibulopelvic ligaments directly up to the para-aortic nodes.

The para-aortic lymph nodes are part of the lumbar lymph node group. There are three sub-groups: preaortic, retroaortic and lateral aortic (right and left). The preaortic group drains the abdominal part of the gastrointestinal tract down to the mid-rectum, whereas the retroaortic group has no special area of drainage. The lateral group receives lymphatic drainage from the iliac lymph nodes, ovaries, and other pelvic viscera (apart from the alimentary tract), and therefore it is this group of nodes that is sampled in the surgical staging of gynecologic malignancies.


Histology of Ovarian Cancer

Figure 1. The pelvic and para-aortic lymph nodes and their relationship to the major retroperitoneal vessels; IVC: Inferior Vena Cava

There are typically 15 to 20 lateral aortic nodes per side. They are located adjacent to the aorta, anterior to the lumbar spine, extending bilaterally to the medial margins of the psoas major muscles, and up to the diaphragmatic crura. The lateral nodes usually dissected in gynecologic oncology span the region from the aortic bifurcation up to either the inferior mesenteric artery or the renal veins. The first major blood vessel encountered during a caudad-to-cephalad para-aortic node dissection is the inferior mesenteric artery. The inferior mesenteric artery originates from the anterior surface of the aorta approximately 3 to 4 cm above the aortic bifurcation. Next, the right and left ovarian arteries arise from their respective sides of aorta about 5 to 6 cm above the bifurcation. The right ovarian vein inserts into the right side of the inferior vena cava approximately 1 cm below the right renal vein. The left ovarian vein does not insert directly into the inferior vena cava, but rather follows a path close to the left ureter, inserting into left renal vein lateral to the left border of the aorta. Three or four pairs of lumbar arteries and veins arise from the posterior surfaces of the aorta and inferior vena cava.


International Federation of Gynecology and Obstetrics' (FIGO's) Surgical Staging System for Endometrial Cancer

The advantages of comprehensive surgical staging lie in diagnosis, prognosis, and proper triage of patients for adjuvant therapy. Comprehensive surgical staging of endometrial cancer involves removing the uterus, cervix, adnexa, and pelvic and para-aortic lymph node tissues as well as obtaining pelvic washings. Pelvic lymphadenectomy typically is defined as removal of the nodal tissue from the distal half of the common iliac arteries, the anterior and medial aspect of the external iliac artery and vein down to the point at which the deep circumflex iliac vein down to the point at which the deep circumflex iliac vein crosses the external iliac artery, and the obturator fat pad anterior to the obturator nerve. Para-aortic lymph node dissection is defined as removal of nodal tissue over the distal inferior vena cava from the level of the inferior mesenteric artery to the mid-right common iliac artery and removal of the nodal tissue between the aorta and left ureter from the inferior mesenteric artery to the mid-left common iliac artery. Adequate nodal dissection requires that lymphatic tissue be demonstrated pathologically from each side (right and left), but no minimum nodal counts have been established. Thus, some practitioners may choose selective lymph node sampling rather than full dissection. Retrospective data suggest that patients who undergo multiple site sampling have improved survival rates over those who have limited sampling or no sampling performed (9).

The International Federation of Gynecology and Obstetrics' (FIGO's) surgical staging system for endometrial cancer is based on surgical pathology, and comprehensive staging allows for accurate definition of disease extent (10). When comprehensive surgical staging has identified stage I disease, pathologic findings of the hysterectomy specimen and patient factors can identify patients who might benefit from further treatment.


 
    Stage I*
    IA*
    IB*
 
Tumor confined to the corpus uteri;
No or less than half myometrial invasion;
Invasion equal to or more than half of the myometrium.
 Uterine Cancer Diagram Stage I
 
    Stage II*
 
Tumor invades cervical stroma, but does not extend beyond the uterus †
 Uterine Cancer Diagram Stage II
 
    Stage III*
    Stage IIIA*
    Stage IIIB*
    Stage IIIC*
    Stage IIIC1*
    Stage IIIC*
 
Local and/or regional spread of tumor;
Tumor invades the serosa of the corpus uteri and/or adnexae ‡
Vaginal and/or parametrial involvement ‡
Metastases to pelvic and/or para-aortic lymph nodes‡
Positive pelvic nodes;
Positive para-aortic lymph nodes with or without positive pelvic lymph nodes.
 Uterine Cancer Diagram Stage II
 
    Stage IV*
    Stage IVA*
    Stage IVB*
 
Tumor invades bladder and/or bowel mucosa, and/or distant metastases;
Tumor invasion of bladder and/or bowel mucosa;
Distant metastases, including intra-abdominal metastases and/or inguinal lymph nodes.
 Uterine Cancer Diagram Stage II

 *Either grade 1, grade 2, grade 3.
 †Endocervical glandular involvement only should be considered as stage I and no longer stage II
 ‡Positive cytology has to be reported separately without changing the stage

 Figure 2. Carcinoma of the corpus uteri; staging uterine cancer. Primary tumor and metastases (International Federation of Gynecology and obstetrics)


Comprehensive surgical staging is associated with inherent risks. Potential complications include injury to major blood vessels or nerves, lymphedema, and associated cellulitis. Lymphedema can have an adverse effect on quality of life (11). The exact incidence of lymphedema is unknown, but a recent study reported its occurrence in 47% of patients who underwent lymphadenectomy (11),(12). The Gynecologic Oncology Group (GOG) currently is undertaking a prospective evaluation of the true incidence of lymphedema. Negative effects can be avoided by limiting the pelvic lymphadenectomy to the region cephalad to the deep circumflex iliac vein, avoiding removal of the circumflex iliac nodes distal to the external iliac nodes (12). Lymphadenectomy may alter or eliminate the need for adjuvant therapy and its associated morbidity.


Selection Criteria for Candidates for Conservative Treatment of Endometrial Cancer

Up to 30% of patients in whom endometrial cancer is diagnosed are younger than 54 years, and approximately 9% of women in whom the disease is diagnosed are younger than 44 years (13). Patients considering fertility-sparing options for the treatment of endometrial cancer should be counseled that data on cancer-related and pregnancy-related outcomes are limited. Although the common assumption is that premenopausal women would have early-stage, low-grade malignancies, this may not be the case. In a population-based registry (Geneva Cancer Registry), 3.2% of women with endometrial cancer were 45 years or younger, and only 18% of these women had stage IA, grade 1 endometrial cancer at the time of final surgical pathology (14). Therefore, it is imperative to select carefully those women who may be candidates for fertility-sparing approaches to the management of endometrial cancer.

Patients who are considering fertility-sparing treatment should be evaluated with diagnostic modalities aimed at detecting advanced or high-risk disease. For women who wish to pursue fertility-sparing options, dilation and curettage (D&C) may be better at evaluating the tumor grade than office endometrial biopsy. On study showed that only 10% of cases diagnosed by D&C were upgraded at the time of hysterectomy compared with 26% of those diagnosed by endometrial biopsy (12). In addition to higher tumor grade, greater depth of myometrial invasion is associated with an elevated risk of extrauterine or nodal metastases. Compared with ultrasonography and computed tomography (CT), magnetic resonance imaging (MRI) may be the preferred modality to evaluate the presence or absence of myometrial invasion (15). Other potentially useful interventions include laparoscopic staging and determination of hormone receptor status (15).

Summary of selection criteria for conservative treatment (15):

  • A well-differentiated, grade 1, endometrioid endometrial carcinoma;
  • No myometrial invasion;
  • No extrauterine involvement (no synchronous ovarian tumor or metastases, no suspicious retroperitoneal nodes);
  • Strong desire for fertility sparing;
  • No contraindications for medical management;
  • Patient understands and accepts that data on cancer-related and pregnancy-related outcomes are limited (informed consent).

Importance of Lymph Node Assessment

Most of the women with endometrial cancer will present with early-stage disease (90%), without metastasis (16). Because most of these tumors will be confined to the uterus (FIGO stage I), the 5-year overall survival rate in this patient population is 80% to 90% (16),(17). Approximately 10% to 15% of these will, in fact, have metastatic nodal disease, and nearly 15% will be deemed to have grade 1 tumors preoperatively on office biopsy or dilatation and curettage will actually have higher-grade disease on final pathologic review after hysterectomy; therefore, it is of utmost importance to stage and treat these patients properly and avoid missing undetected metastatic disease that may upstage the patient (18). Most patients with endometrial cancer will undergo initial surgical treatment that will include a total hysterectomy, bilateral salpingo-oophorectomy, and pelvic washings. Although the rate of metastasis in this patient population is low, the standard of treatment also includes a complete or selective pelvic and para-aortic lymphadenectomy for staging disease. Proper surgical staging, the most important prognostic factor, provides information on the actual extent of disease rather than on perceived risks based on uterine factors, such as grade, histology, and depth of myometrial invasion, which helps tailor adjuvant therapy (19). Unfortunately, many patients with early-stage endometrial cancer will undergo surgery with sufficient nodal evaluation, with their nodes being palpated, biopsied only if enlarged, or completely ignored (19).

Studies have shown rates of nodal assessment as low as 30%, although that percentage has increased as the importance of nodal assessment has been realized (18),(19). When surgical staging is inadequately performed, patients can be subjected to unnecessary adjuvant therapy, such as pelvic radiation therapy and its associated side effects. Based on the current standard of treatment, surgeons are faced with the dilemma of "understanding" versus "over-treating". Traditionally, it has been suggested that the more nodes removed, the better the chance of detecting metastasis, but also the more likely the patient will develop side effects. The use of SLN mapping in patients with endometrial cancer may be as acceptable solution, providing a middle ground between the polarized schools of thought: complete lymphadenectomy and no nodal evaluation. The logic of the SLN approach lies in targeting the "correct" nodes, or those most likely to harbor disease based on lymphatic flow, rather than removing a greater number of nodes to perform thorough staging. Ultimately, the end goal of both approaches is adequate staging. A potential pitfall to SLN mapping is that some, but possibly not all, positive lymph nodes may be removed, leaving the question: does every microscopically positive node need to be removed to stage patients? And is there a potential therapeutic role of removing normal-appearing lymph node?


Lymphedema after Surgery for Endometrial Cancer

Surgical lymphadenectomy and radiation are common components of therapy for women with endometrial cancer and are thought in combination to increase the risk of developing lower extremity lymphedema. These patients may also have comorbid conditions such as obesity that further increase their risk. Once present, the symptoms and local effects of lymphedema can only be managed, not cured. The resulting disability may lead to severe lifelong morbidity including pain, skin breakdown, impaired mobility, difficulty with self-care, psychosocial morbidity, and impaired quality of life (20). Current estimates of the prevalence and burden of lower extremity lymphedema in patients with endometrial cancer are unreliable as a result of a requirement for extended prospective follow-up. Signs and symptoms are often ignored or unrecognized, and the diagnosis may be challenging because the condition is frequently bilateral, prohibiting comparison with an uninvolved contralateral limb (in contrast to upper extremity lymphedema in the context of axillary lymphadenectomy for breast cancer). Furthermore, it may be difficult to distinguish adiposity from lymphedema, particularly in obese patients.

In a Mayo Clinic study 1,048 consecutive patients who were operated on between 1999 and 2008 for endometrial cancer were mailed a survey, which included validated 13-item lymphedema screening questionnaire and two validated quality-of-life measures. Logistic regression models were fit to identify factors associated with prevalent lymphedema; a multivariable model was obtained using stepwise and backward variable selection methods. The relationship between lymphedema and obesity with each quality-of-life score was evaluated separate multivariable linear models. The conclusion of the study was; the attributable risk of developing lower extremity lymphedema was 23% for patients with endometrial cancer who underwent lymphadenectomy compared with hysterectomy alone with an overall prevalence of 47%. Lymphedema was associated with reductions in multiple quality-of-life domains (21).

Consensus opinion suggests that lower extremity lymphedema is present in nearly half of surveyed endometrial cancer survivors and is associated with clinically significantly reductions in nearly every quality-of-life domain tested irrespective of body mass index (BMI). In addition to radiation therapy, obesity, and congestive heart failure, lymphadenectomy is independently associated with lower extremity lymphedema in multivariable analysis with an attributable risk of 23%. These findings are important, recognizing that patients with endometrial cancer frequently live long enough to develop delayed side effects of lymphadenectomy with high rates of lymphedema and associated reductions in quality of life. The reported higher cost of care, higher short-term morbidity, and lack of survival benefit for low-risk patients cast further doubt on the value of complete lymphadenectomy for the majority of patients (22). Risks of lymphedema in this patient population signal a need to improve preoperative counseling and therapeutic interventions for the treatment of lymphedema.

Strategies to reduce lymphedema include omission of lymphadenectomy in low-risk patients. SLN mapping has also been used, but preliminary data suggest it may be unacceptably high for patients at high risk, and according to the most accepted algorithm, 35% to 50% of patients who undergo SLN dissection with nevertheless require unilateral or even bilateral lymphadenectomy. Long-term assessments are therefore necessary to demonstrate reductions in lymphedema for patients who undergo SLN mapping. Finally, several investigations have shown that preservation of the distal-most external iliac lymph node at the circumflex vein may reduce lymphedema (23).


Road to Sentinel Lymph Node (SLN) Mapping

Most patients with endometrial cancer will present with early-stage disease. Although the rate of metastasis in these patients is low, proffering excellent prognoses, the standard of care in many practices still includes a complete or selective pelvic and para-aortic lymphadenectomy for staging, and accurate surgical staging is the most important prognostic factor. Many patients will undergo a comprehensive lymphadenectomy despite having disease confined to the uterus, resulting in prolonged operating time, additional cost, and potential side effects, such as lower extremity lymphedema. However, recent studies show that a complete lymphadenectomy may have no therapeutic benefit to in patients with early-stage endometrial cancer. SLN mapping, which has been used in other cancer types, may be an acceptable surgical strategy between a complete lymphadenectomy and no nodal evaluation in patients with endometrial cancer. SLN mapping is based on the concept that lymph node metastasis is the result of an orderly process; that is, lymph drains in a specific pattern away from the tumor, and therefore, if the SLN or first node is negative for metastasis, then the nodes after the SLN should also be negative. This approach can help patients avoid the side effects associated with a complete lymphadenectomy, although disease must be thoroughly staged for accurate prognosis and determination of appropriate treatment approach. Surgeon experience, adherence to an SLN algorithm, and the use of pathologic "ultra-staging" are key factors for successful SLN mapping.

In current practice, the importance of lymph node assessment for proper surgical staging in this patient population cannot be stressed enough, although lymph node removal may increase operative time and blood loss, and is associated with vascular injury, lower extremity lymphedema, and lymphocyst formation. A Study in the Treatment of Endometrial Cancer (ASTEC) was a randomized multicenter study of more than 1,400 patients, which showed no therapeutic benefit to lymphadenectomy in early-stage endometrial cancer (24); however, almost half of the patients randomized to the lymph node dissection arm had 9 or fewer nodes removed (i.e. possible inadequate staging via a non-SLN approach). The ASTEC trial was also criticized because many patients were treated with postoperative radiation regardless of the status of their lymph nodes. Recently, the retrospective study on Survival Effect of Para-Aortic Lymphadenectomy (SEPAL) in endometrial cancer showed that overall survival was significantly improved in select intermediate- and high-risk patients undergoing pelvic and para-aortic lymph node dissection (25). However, the median number of nodes removed was much larger than in most studies, and it was also difficult to determine whether the improvement in overall survival was a result of the removal of the para-aortic nodes or the adjuvant chemotherapy (25).

In a pilot study of 42 patients with grade 1 endometrioid endometrial cancer, the most common were the internal iliac, 52 (36%); external iliac, 43 (30%); obturator, 34 (23%); and common iliac regions, 11 (8%); these are the areas involved in a pelvic nodal dissection. Only 5 cases (3%) had para-aortic SLN involvement (18). The para-aortic nodal dissection may be an area of possible over-staging, which would be limited with successful negative bilateral pelvic SLN mapping. In other words, what seems to be important as far as staging is the proper determination of uterine fundus-contained disease versus disease outside the uterine fundus, and the pathologist determining the grade of tumor as low- versus high-grade (grade 1-2 endometrioid is considered low-grade, and grade 3 endometrioid or serous, clear cell, or carcinosarcoma is considered high-grade). Even pelvic lymph nodes, which are more likely to contain metastatic disease, may sometimes be unnecessarily removed (over-staged). For example, the "circumflex iliac" lymph nodes are often removed during a routine bilateral pelvic lymphadenectomy, and these nodes are often benign, especially when other nodal areas are also negative (26). Removing these nodes may cause lymphatic obstructions to the lower extremity, lower abdominal wall, and pubic region, increasing the risk of lymphedema (26).


Sentinel Lymph Nodes Diagram Pelvic Area

Figure 3:
A. The most common drainage routes, usually when the lymphatic trunks cross over the obliterated umbilical ligament; the most common locations of sentinel lymph nodes after a cervical injection are medial to the external iliac, ventral to the hypogastric, or in the superior part of the obturator space.
B. The less common location of sentinel lymph nodes, usually seen when lymphatic trunks do not cross over the umbilical ligament but follow the mesoureter cephalad to the common iliac and presacral sentinel lymph nodes.


Sentinel Lymph Node (SLN) Mapping Techniques

A radioactive tracer and colored dye (often blue or green) are used to locate "hot" nodes or visualize colored nodes. SLNs are considered positive if they contain macrometastasis (tumor clusters >2 mm), micrometastasis (tumor clusters 0.2 - 2.0 mm), or isolated tumor cells (single tumor cells or tumor clusters ≤ 0.2 mm). The treatment of women with only isolated tumor cells in SLNs is still a subject of much current research. SLNs containing only isolated cytokeratin-positive "cells" should be considered negative for metastasis (27). Three different types of SLN mapping techniques exist based on site of injection: 1) uterine subserosal, 2) cervical (see figure 4 below), and 3) endometrial via hysteroscopy (28). Most of the groups prefer a cervical injection, although others have argued that a peritumoral injection, either hysteroscopic or fundal, is more appropriate. Their rationale for using a cervical injection includes the following: 1) the main lymphatic drainage to the uterus is from the parametria; therefore, a combined superficial (1-3 mm) and deep (1-2 cm) cervical injection is adequate; 2) the cervix is easily accessible; 3) the cervix in women with endometrial cancer is rarely distorted by anatomic variations, such as myomas, which sometimes make uterine serosal mapping impossible; 4) the cervix in women with endometrial cancer is rarely scarred from prior procedures, such as conization or bulky tumor infiltration; and 5) a uterine fundal serosa mapping does not reflect the parametrial lymphatic drainage of the uterus (the main route of drainage), and most early-stage endometrial cancers do not have disease infiltrating and ulcerating the uterine fundal serosa. The main argument against the cervical injection is that it has lower para-aortic detection rate, as opposed to the hysteroscopic approach and when the pelvic lymph nodes are negative for metastasis, disease is unlikely to be found in the para-aortic nodes, and to date, no definitive well-documented association exists between para-aortic nodal assessment and improved overall survival.


Diagram Direct Cervical Injection Sites

Figure 4: Three different options for direct cervical injection:
A. 2-sided option.
B and C. 4-quadrant options.


In a recent large meta-analysis, it is reported a decrease in detection rates when the cervical method was not used, although without significance (29). These investigators also recommended that the "subserosal injection-only" technique be avoided because of decreased sensitivity. For these reasons and based on the authors' experience and that of other investigators, they prefer the cervical-only approach and describe the procedure herein.


Lymphoscintigraphy

A radio-labeled colloid, usually technetium-99 (99mTc), is injected into cervix the day of or the day before surgery. The 99mTc is then carried via lymph through the lymphatic capillaries to the SLNs. In the "short" protocol (day of surgery), 0.2 to 1.0 mCi of the 99mTc is injected. In the "long" protocol (20-24 hours before surgery), an additional 2.0 to 4.0 mCi of colloid is used. A preoperative planner lymphoscintigram is taken 20 to 30 minutes after injection for a short protocol, and immediate "dynamic" images and subsequent "static" images are taken to locate the nodes. Gamma probes, such as a laparoscopic SLN probe or a handheld open-procedure SLN probe, are used to detect the hot nodes. Single-photon emission computed tomography (SPECT), which uses 3-dimensional localization of hot nodes also detected through a gamma probe, can be used (29).

Colored Dye Injection: The colored dye (isosulfan blue 1, methylene blue 1%, or patent blue 2.5% sodium) is injected while the patient is under anesthesia in the operating room. The dye is injected the same way as the radiotracer. A spinal needle or Potocky-type needle is used to inject 4 mL of dye into the cervical submucosal and stroma. The 4 mL can be divided into 4 separate injections, 1 into each quadrant of the cervix (1 mL each). The injections also can be given at 3 and 9 o'clock positions (as shown above), which correspond to the parametria and will keep the bladder flap from being stained, which is seen with the 12 o'clock injection. The dye should be injected slowly, at a rate of 5 to 10 seconds per quadrant. Complications with blue dye are rare, consisting mostly of allergic reactions, including swelling and pruritis of hands, feet, abdomen, and neck. Severe reactions include edema of the face and glottis, respiratory distress, and shock. Blue dye will also turn the urine blue-green for up to 24 hours.

Fluorescent SLN Imaging with Indocyanine Green: Indocyanine green (ICG), using near-infrared fluorescence imaging, has recently emerged as an excellent dye for SLN mapping. The 25 mg dry powder bottle is mixed with 20 mL of sterile water in the operating room, and 2 to 4 mL is injected directly into the cervix in similar fashion to that of blue dye. The main contraindication is iodine allergy, which the current available product contains. The SLN detection rates with ICG and the bilateral SLN detection rates appear comparable or better than those of blue dye only or radio-colloid (30). Fluorescent SLN localization with ICG is currently the preferred mapping approach at our institution.


Pathology

A key component of the added value of SLN procedures in endometrial cancer is enhanced pathology, also known as ultrastaging. The protocol used at our institution is described herein. The initial examination is performed using hematoxylin and eosin (H&E) staining. If the H&E assessment is negative, 2 adjacent 5-micrometers sections are cut from each paraffin block at each of 2 levels, 50 mcg apart. At each level, one side is stained with H&E and the other with immunohistochemistry using the anticytokeratin AE1:AE3 (Ventana Medical Systems, Inc., Tucson, AZ) for a total of 4 slides per block. With immunohistochemistry ultrastaging, and additional 3% to 4% of micrometastasis to SLNs, which may have been otherwise missed by routine H&E staining, can be detected (31).

SLN Mapping Algorithm

Maintaining a low false-negative rate is a major priority in any SLN program. In this study of 498 patients with endometrial cancer the authors showed that incorporating SLN mapping algorithm significantly reduced the false-negative rate of the procedure (32). An SLN was identified in 401 (81%) of the 498 patients and correctly diagnosed metastatic nodal disease in 40 of 47 patients who had at least 1 SLN mapped (14.9% false-negative rate). Applying the algorithm decreased the false-negative rate to 1.9%, because the algorithm takes into account grossly enlarged suspicious nodes and includes a side-specific lymphadenectomy for the non-mapping hemi-pelvis. Only 1 patient with and isolated positive right para-aortic lymph node was not detected by the algorithm. Sensitivity increased from 85.1% to 98.1%, and the negative predictive value increased from 98.1% to 99.8% (32).

The SLN algorithm includes: 1) peritoneal and serosal evaluation and washings; 2) retroperitoneal evaluation, including the removal of all SLNs and any suspicious nodes; and 3) a side-specific pelvic, common iliac, and interiliac lymph node dissection if there is no mapping on a hemi-pelvis. Since incorporating SLN mapping algorithm in 2008, the rate of full lymphadenectomy decreased from 65% to 23% at most of the institutions, with a parallel decrease in median operating room and operative times (≈ 1 hour and ≈ 40 minutes, respectively). The median number of nodes removed also decreased (from 20 to 7). The point of SLN mapping is reduce the number of nodes that need to be removed for staging by targeting those likely to contain metastasis in the hopes of avoiding more extensive dissections and maintaining the ability to find microscopic nodal disease. This decreased rate of comprehensive lymphadenectomy and number of nodes removed has not compromised the rate of detection of metastatic nodal involvement, even in stage IIIC disease (33).


diagram showing Sentinel lymph node (SLN) mapping algorithm

Abbreviation: LND, lymph node dissection
Figure 5: Sentinel lymph node (SLN) mapping algorithm


Moving Forward with Sentinel Lymph Node (SLN) Mapping

The current apprehension with SLN mapping is the associated detection and false-negative rates, a circumstance in which and SLN is found to be negative even though the lymph nodes are found to have metastasis during lymphadenectomy. A failed mapping, on the other hand, is a situation in which SLN is not identified, which is the opposite of the detection rate, and a failed mapping requires a side-specific lymphadenectomy to exclude disease. In the 2009 study of 42 patients with a diagnosis of grade 1 endometrial carcinoma; all positive cases were detected by the SLN, with no false-negatives. The sensitivity of the SLN procedure in the 36 patients (86%) who had and SLN identified was 100% (34). An acceptable SLN detection rate varies among practices, but a detection rate of 80% to 90% or greater are preferred.

The frequency of lymphadenectomy in the surgical treatment of endometrioid endometrial cancer increased by 4.2% annually from 1998 to 2007 and decreased by 1.6% annually from 2007 to 2012 (35). Some recent studies have cast doubt on the necessity of lymphadenectomy in patients at low risk for lymph node metastasis. In 2014, the Society of Gynecologic Oncology issued guidelines stating that lymphadenectomy may not be necessary in patients with endometrial cancer meeting the following criteria: tumor smaller than 2 cm, no tumor invasion beyond 50% of myometrial thickness, and low- to moderate-grade endometrioid histology (35).

To examine the treatment and survival of elderly women diagnosed with advanced-stage, high-grade endometrial cancer; this study (36) performed a retrospective cohort study of women diagnosed between 2003 and 2011 with advanced-stage, high-grade endometrial cancers (grade 3 adenocarcinoma, carcinosarcoma, clear-cell carcinoma, and uterine serous carcinoma) using the National Cancer Database. Women were stratified by age: younger than 55, 55-64, 65-74, 75-84, and 85 years old or older. Multivariate logistic regression models and Cox proportional hazards survival methods for all-cause mortality were used for analyses. Conclusion was elderly women with high-grade endometrial cancer are less likely to be treated with surgery, chemotherapy, or radiation (36).

With increasing surgeon experience and a corresponding increase in detection rates of 90% or greater, combined with a decrease in false-negative rates, SLN mapping can play a more prominent role in lymph node assessment and staging in early-stage endometrial cancer. For now, the standard in many practices continues to include a comprehensive lymphadenectomy versus no nodal assessment, but as its therapeutic benefit comes into question (ASTEC and other studies) and its associated side effects continue to be reported, this may change. However, prospective studies to validate the use of SLN mapping in this patient population are needed and ongoing.


Summary

Routine preoperative assessment of patients with endometrial cancer with imaging tests that evaluate for metastasis is not necessary. The initial management of endometrial cancer should include comprehensive surgical staging (total hysterectomy, bilateral salpingo-oophorectomy (BSO), and pelvic and para-aortic lymphadenectomy and the collection of peritoneal cytology (pelvic washing). Exception to this approach should be made only after consultation with a practitioner specializing in the treatment of endometrial cancer, such as a gynecologic oncologist. Minimally invasive surgery should be embraced as the standard surgical approach for comprehensive surgical staging in women with endometrial cancer. Lymph node dissection identifies patients requiring treatment with radiation therapy and/or chemotherapy. A subset of patients may not benefit from lymphadenectomy; however, these patients are difficult to identify preoperatively because of the uncontrollable variables of change in grade and depth of invasion on final pathology.

On the national level, increasing use of lymphadenectomy in the treatment of endometrioid endometrial cancer, without consideration of risk factors for nodal metastasis, resulted in modest gains in staging accuracy at the cost of many additional procedures. Such an approach was likely to have caused significant additional morbidity, because lymphadenectomy increases the risk of postoperative complications, lymphedema, and lymphocyst formation. The adoption of a more selective approach to lymphadenectomy, as seen after 2007, was associated with a reduction in the frequency of negative lymphadenectomy without concomitant loss in staging accuracy. Further research is required to determine how much the frequency of lymphadenectomy can be reduced through a selective approach without decrement to the identification of patients with nodal metastasis. SLN mapping and biopsy is an appealing solution to the tradeoff between improvement in detection of nodal metastasis and additional surgical morbidity posed by complete lymphadenectomy and is currently undergoing prospective evaluation.


Suggested Reading:

  1. Uterine Cancer: Early Detection
    http://www.womenshealthsection.com/content/gyno/gyno007.php3

  2. Uterine Cancer: Staging & Management
    http://www.womenshealthsection.com/content/gyno/gyno008.php3

  3. Uterine Cancer: Pathologic Features
    http://www.womenshealthsection.com/content/gynpc/gynpc005.php3

Funding: Special thanks to, WHEC Global Health Initiative, for providing the funding and support for the research and development for this series of articles. We invite our partners to join our efforts in early diagnosis and eliminating female genital cancers, worldwide.

Acknowledgement: Special thanks to Tashanna K.N. Myers, MD, FACOG; Assistant Professor of Obstetrics and Gynecology; Tufts University School of Medicine; Gynecologist Oncologist at Baystate Health, Springfield, MA (USA) for serving as reviewer and helpful suggestions in compiling this review.


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