INTRODUCTION

Corpus cancer is the most frequently occurring female genital cancer.

 In developed countries, adenocarcinoma of the endometrium is the most common gynecological cancer; however, in developing countries, it is much less frequent than carcinoma of the cervix. In the United States in the early part of the 20th century, cancer of the cervix killed more women than any other cancer, but in the ensuing decades, the incidence for that malignancy decreased precipitously. The impact of screening with the Papanicolaou (Pap) smear has been credited with decreased incidence. In less-developed countries, screening for cervical cancer is performed very infrequently, and therefore, cancer of the cervix is quite prevalent.

Age:

  • Endometrial adenocarcinoma occurs during the reproductive and menopausal years.
  • The median age of persons with this malignancy is early in the seventh decade of life, although the largest number of patients are aged 50-59 years. Approximately 5% of women younger than 40 years have adenocarcinoma, and 20-25% of women are diagnosed before menopause. 

CLINICAL FEATURES

History:

  • Because approximately 75% of women with endometrial cancer are postmenopausal, the most common symptom is postmenopausal bleeding.
    • Investigate all bleeding during menopause unless the patient is on cyclic replacement therapy with normally anticipated withdrawal bleeding. The duration or amount (staining vs gross) of bleeding does not make any difference.
    • The fact that only approximately 20% of postmenopausal bleeding is due to cancer is appreciated, but obviously, the diagnosis must be eliminated in these patients.
  • Because 25% of endometrial cancers are in patients who are perimenopausal or premenopausal, symptoms suggestive of cancer may be more subtle. The idea that any type of bleeding during the perimenopausal period probably is due to menopause is a common misconception. This irregular bleeding often is ignored by the patient and even health care providers. Remember that the normal bleeding pattern during this time should become lighter and lighter and further and further apart. Heavy frequent menstrual periods or intermenstrual bleeding needs to be evaluated.

Physical:

  • Bleeding leads to evaluation of the endometrium.
    • In the vast majority of cases, no gross evidence of disease is noted.
    • The uterus may be of normal size upon pelvic examination.
    • Cancer can be present upon cervical evaluation and, less frequently, in the upper vagina or periurethrally.

Causes:Multiple epidemiological risk factors have been identified in patients who have adenocarcinoma of the endometrium.

  • Endogenous factors
    • Obesity increases the risk for developing endometrial cancer, and some data suggest that a 10-fold increase in risk occurs if an individual is more than 50 lb heavier than the ideal weight for that person.
    • Nulliparity also increases risk 2- to 3-fold compared to parity.

o        An individual who has had a late menopause (when aged >52 y) also appears to have an increased risk.

·         Unopposed estrogen

o        Unopposed estrogen, either as replacement therapy or endogenously produced (eg, granulosa cell tumor, polycystic ovarian disease), increases the risk of endometrial cancer several times.

o        Obesity is known to increase endogenous estrogen because the presence of fat appears to be responsible for conversion of androstenedione to estrogen compounds at a much higher rate than if fat is not present.

o        Anovulation, which may be secondary to unopposed estrogen, also appears to contribute to this situation.

·         Tamoxifen

o        The most widely used anticancer drug is tamoxifen, and this drug has been suggested by some studies to cause an increased incidence of adenocarcinoma of the endometrium. These data were derived from retrospective analyses in which adenocarcinoma of the endometrium was not an endpoint in multiple prospective randomized studies evaluating the role of tamoxifen in patients with breast cancer.

o        A recent case control study using the SEER database indicates that when confounding factors have been corrected, an increased risk of endometrial cancer in patients on tamoxifen does not appear to exist. This study is very reassuring because the potential for an increased number of women taking tamoxifen is becoming apparent, particularly as the prophylactic role of tamoxifen is being explored.

·         Combination oral contraceptives

o        In contrast to tamoxifen, increasing data exist noting that the use of combination oral contraceptives (OCs) decreases the risk of developing endometrial cancer.

o        Several studies have noted that women who use OCs at some time have a 0.5 relative risk of developing endometrial cancer compared to women who have never used OCs.

o        This protection occurs in women who have used OCs for at least 12 months, and the protection continues for at least 10 years after OC use. Protection is most notable for nulliparous women.

·         Cigarette smoking

o        Smoking apparently decreases the risk of developing endometrial cancer.

o        The effects of smoking are related to body weight. Heavier women who smoke have the greatest reduction in risk.

o        Women who smoke are known to undergo menopause 1-2 years earlier than women who do not smoke.

o        Although smoking apparently reduces the risk of developing early stages of endometrial cancer, this advantage is strongly outweighed by the increased risk of lung cancer and other major health problems associated with smoking.

·         Associated medical conditions

o        Some associated medical conditions have been found to increase the incidence of endometrial cancer.

o        Breast, colon, and ovarian cancers frequently are seen in women with endometrial cancer.

o        Data suggest that women who have had breast cancer have a 2- to 3-fold increased risk of subsequently developing endometrial cancer.

·         Family history: Individuals with a family history of endometrial cancer appear to be at increased risk.

·         Phenotype characteristics

o        At one time, a classic phenotypic characteristic was thought to exist for a woman who would develop endometrial cancer. This phenotype included patients who were obese, nulliparous, and anovulatory in many instances. More recently, the existence of 2 pathogenic types of endometrial cancer was appreciated.

o        The first type occurs in women who fall into the classic category. These women are obese; have hyperlipidemia; have signs of hyperestrogenism, such as anovulatory uterine bleeding, infertility, and late onset of menopause; and may have hyperplasia of the ovarian and endometrial stromas. These patients tend to be white; obese; nulliparous; and have a well-differentiated, superficially invasive cancer that is highly sensitive to progestin. These patients have a very favorable prognosis with removal of the uterus. Extrauterine disease is unusual in this group of patients.

o        In contrast, the second pathogenic type occurs in women who have none of the disease states present in the classic presentation. These individuals tend to have a poorly differentiated tumor, deep myometrial invasion, a high degree of metastasis in the lymph nodes, decreased sensitivity to progestin, and a very poor prognosis. These latter patients tend to be thin and multiparous, and, more frequently, they are black. Most patients with endometrial cancer fall into this latter category.

 

DIFFERENTIAL DIAGNOSIS

Bleeding from the lower genital tract can occur from the cervix, vulva, or vagina. If the bleeding is due to neoplasms, gross inspection usually helps identify these lesions. If cervical cytology findings are abnormal and no gross lesions are identified, further evaluation needs to be performed. Atrophic changes in the vagina may lead to bleeding, particularly postcoital. Bleeding from the uterus may be due to many benign lesions (eg, polyps, endometritis) or hormone replacement therapy.

 

 

LABORATORY STUDIES

 

Imaging Studies:
  • Vaginal ultrasound
    • During the recent past, the increased use of the vaginal ultrasound to evaluate the endometrial stripe has been reported.
    • Some investigators feel that this should be the first diagnostic procedure because vaginal ultrasound is less invasive than endometrial biopsy.
    • One of the difficulties with using the endometrial stripe as a criterion for further diagnostic tests (eg, endometrial biopsy) is that several conditions may be present that give a false reading on the endometrial stripe. This is particularly true in a patient who might have an endometrial polyp or who has been taking tamoxifen.
  • Hydroultrasound
    • If a thickened endometrium is present, perform a hydroultrasound to make sure a false-positive result is not present. This is accomplished by placing a small volume of saline into the endometrial cavity and then repeating the vaginal ultrasound.
    • In many instances in which the original vaginal ultrasound shows significant endometrial thickness, a sonoultrasound can differentiate other pathology from true endometrial thickness.
    • Another problem that arises is that the thickness of the endometrium can vary considerably depending on different factors. The thickness of the endometrium depends on whether or not the patient is perimenopausal or postmenopausal (and for how long), whether she is on hormone replacement therapy, and whether the therapy includes estrogen alone or estrogen plus progesterone. Currently, no generally accepted guidelines exist for each of these different clinical scenarios.

Procedures:

  • Endometrial biopsy
    • Although fractional dilatation and curettage (D&C) historically was the definitive diagnostic procedure to help rule out endometrial cancer, today the endometrial biopsy as an office procedure is quick, well tolerated, and quite sensitive for making the diagnosis.
    • If endometrial pathology is not present on biopsy specimens and the patient has no further bleeding, no additional diagnostic tests need to be performed.
    • If the patient continues to be symptomatic, then further evaluate the endometrial cavity.
  • Hysteroscopic-directed biopsy: Another diagnostic procedure that has been advocated by some as an even more accurate way of determining the status of the endometrium is hysteroscopic-directed biopsy; however, studies have shown that when results are compared to the histopathology, both false-positive results and false-negatives results may be noted using this technique.
  • Dilatation and curettage: The role today of the formal D&C probably is very limited because the diagnosis usually can be made in the office.
  • An examination under anesthesia may be necessary in a patient who is bleeding and has a cervical os that is very stenotic. Anesthesia may be required to carry out adequate dilatation for endometrial sampling.

 

Histologic Findings:

 

Pathological diagnosis obviously is the criterion standard for evaluation of the endometrial cavity. A high index of suspicion must be maintained if a diagnosis of endometrial cancer is considered.

Endometrioid adenocarcinoma is the most frequent histopathologic subtype. A squamous component, either benign (adenocanthoma) or malignant (adenosquamous), does not affect prognosis, but the grade of the adeno component does affect prognosis. Papillary serous and clear cell histotypes confer a poor prognosis but, fortunately, are infrequent compared to adenocarcinoma. Secretory carcinomas are the least frequently occurring cancers and have a good prognosis.

Staging:

  • The International Federation of Gynecology and Obstetrics (FIGO) staging system for carcinoma of corpus uteri is as follows:
    • Stage IA - Tumor limited to endometrium
    • Stage IB - Invasion to less than one half the myometrium
    • Stage IC - Invasion to more than one half the myometrium
    • Stage IIA - Endocervical glandular involvement only

o        Stage IIB - Cervical stromal invasion  

o        Stage IIIA - Tumor invades serosa and/or adnexa and/or positive peritoneal cytology

o        Stage IIIB - Vaginal metastasis

o        Stage IIIC - Metastases to pelvic and/or paraaortic lymph nodes

o        Stage IVA - Tumor invasion of bladder and/or bowel mucosa

o        Stage IVB - Distant metastases including intraabdominal and/or inguinal lymph nodes

 

·         Cases of carcinoma of the corpus should be classified (or graded) according to the degree of histologic differentiation. The histopathology and degree of differentiation is as follows:

o        Class G1 - Nonsquamous or nonmorular solid growth pattern of 5% or less

o        Class G2 - Nonsquamous or nonmorular solid growth pattern of 6-50%

o        Class G3 - Nonsquamous or nonmorular solid growth pattern of more than 50%

 

TREATMENT 

Surgical Care: Since 1988, the FIGO, whose Gynecologic Oncology Committee was responsible for the staging of gynecological cancer, recommended that corpus cancer be staged surgically. Previously, clinical evaluation was used for staging, and multiple studies noted the inaccuracy of clinical staging when compared to surgical pathological findings. Therefore, once the diagnosis of endometrial cancer has been made, routine presurgical evaluation to assess operability is performed.

  • Special studies, such as CT scans of the abdomen and pelvis or MRIs, are not performed routinely.
  • Once preoperative evaluation, which may include chest radiograph, ECG, and appropriate blood studies, has been performed and the results are found to be normal, the patient is deemed a surgical candidate. Then, an exploratory laparotomy, total abdominal hysterectomy, bilateral salpingo-oophorectomy, peritoneal cytology, and pelvic and paraaortic lymphadenectomy are performed.
  • Obviously, if intraperitoneal disease is identified at the time of surgery, attempts are made at surgical removal.
  • Staging then is determined based on surgical pathologic findings . Subsequent therapy, if needed, then is determined, depending on the surgical pathological findings of the operative procedure.


MEDICATION

The goals of pharmacotherapy are to eradicate the carcinoma, reduce morbidity, and prevent complications.

Drug Category: Chemotherapeutic agents -- Used in the treatment of endometrial cancer. Inhibit cell growth and proliferation.

CISPLATIN:

50-100 mg/m2 IV q3-4wk  

 

FOLLOW-UP

 

Complications:

  • Complications that may occur from therapy include complications that normally are expected from the surgical procedure itself. Because a lymphadenectomy is performed, increased bleeding could develop; however, unique complications from the procedure usually do not occur.
  • Postoperative complications can be expected, depending on the preoperative clinical condition of the patient. As noted previously many of these patients have comorbidities such as hypertension, obesity, diabetes, and increasing age.
  • One postoperative complication that may be somewhat more common is thromboembolism because this is increased in patients who have cancer, are obese, and are older. Most physicians today use some type of prophylaxis, either external pneumatic compression or low-dose heparin.

Prognosis:

  • Multiple prognostic factors exist for endometrial cancer. These prognostic factors generally are related to surgical pathological findings. As in all cancers, the stage of the disease is the most important prognostic factor. Obviously, the surgical procedure helps determine the stage. Listed below are prognostic factors that may relate specifically to the stage of the disease and, thereby, may affect overall survival.
    • Pathology
      • The majority of endometrial carcinomas are endometrioid adenocarcinomas. Adenoacanthomas (benign squamous components) and adenosquamous carcinoma (malignant squamous components) make up the next largest category.

§         Clear cell and papillary serous adenocarcinomas represent approximately 10% of all endometrial cancers and are considered to be poor histopathological subtypes. These latter subtypes tend to have deeply invasive myometrial involvement, and they have a propensity for extrauterine spread, even though the myometrium may be superficially involved.

§         Previously, a patient with an adenosquamous carcinoma was thought to have a poor prognostic histotype because of the malignant squamous component.

§         Contemporary data suggest that irrespective of whether a squamous component is present (either benign or malignant), prognosis is related directly to the grade of the adeno component and not the fact that a squamous malignancy is present. If a malignant squamous component is present, a greater tendency exists for a more poorly differentiated adeno component to be present.

o        Histological differentiation

      • The degree of histological differentiation of endometrial cancer has long been accepted as a sensitive indicator of prognosis.

§         Patients with well-differentiated adenocarcinomas tend to have involvement of the endometrium or superficial myometrium, and extrauterine disease is unusual.

§         On the other hand, if a poorly differentiated lesion is present, these cancers tend to be much more aggressive, involving significant myometrial invasion, and often have extrauterine metastasis, either with positive peritoneal cytology, retroperitoneal spread, or involvement of the pelvic and/or paraaortic lymph nodes.

§         Because papillary and clear cell carcinomas carry a relatively poor prognosis, these subtypes usually are not graded but are considered in the same category as a poorly differentiated cancer.

o        Myometrial invasion

      • The degree of myometrial invasion continues to be a consistent indication of tumor virulence.

§         As the depth of myometrial invasion increases, a greater chance of having extrauterine disease exists.

§         As noted above, grade and depth of invasion, as a generalization, are interrelated. As the grade of the tumor increases, an increase usually occurs in the depth of myometrial invasion; however, exceptions exist in that a grade 1 lesion can have deep myometrial invasion and a grade 3 lesion can be limited to the endometrium.

§         When grade and depth of invasion are evaluated separately, the depth of invasion appears to be a more important prognostic factor than the grade of the tumor.

o        Peritoneal cytology

      • Cytological evaluation of the peritoneum appears to be an important prognostic factor.

§         Although a universal agreement about the significance of cytological evaluation does not exist, the vast majority of data in the literature suggest that it is an independent prognostic factor.

§         Cytological evaluation also appears to correlate with other prognostic factors, such as depth of myometrial invasion and lymph node metastasis.

§         The FIGO staging system takes the status of peritoneal cytology into consideration in that if malignant cells are present in the peritoneal cytology without any other evidence of extrauterine disease, the patient is classified as having stage IIIA disease. If ascitic fluid is not present at the time of the exploratory laparotomy, a saline lavage of the pelvis and lower abdomen is performed and the specimen is submitted for cytological evaluation.

o        Lymph node metastasis

      • A considerable number of patients who were thought to have clinical stage I endometrial cancer were, in fact, found to have lymph node metastasis when histopathological evaluation was performed on the lymph nodes.

§         Again, a correlation among multiple prognostic factors has been shown to be present. Patients with poorly differentiated cancers, papillary serous and clear cell carcinomas, deep myometrial invasion, positive peritoneal cytology, or adnexal metastasis tend to have an increased risk of having lymph node metastasis.

§         Subsequent therapy after primary surgery depends on prognostic factors and spread of the disease. If the disease is limited to the uterus, surgery appears to be adequate treatment, with the possible exception of patients who have poorly differentiated deeply invasive myometrium. In these patients, data suggest that, possibly, postoperative irradiation may be of benefit. In patients who have disease outside of the uterus, radiation therapy may be effective; however, this has not been evaluated in a prospective randomized study. Most investigators irradiate the appropriate area if lymph node metastasis is present.

§         In patients with advanced disease (ie, intraperitoneal disease, disease outside of the peritoneal cavity), systemic chemotherapy may be of benefit. Studies suggest that cisplatin and doxorubicin probably are the drugs of choice when systemic chemotherapy is needed. As previously noted, staging is the most important prognostic factor.

 

Using the FIGO surgical staging classification from the recent annual report (worldwide data evaluation), 5-year survival rates of 87%, 76%, 63%, and 37% were noted for stages I, II, III, and IV of the disease, respectively. Because substages exist that take into consideration prognostic factors, 4 of the substages within stage I actually have better than 90% 5-year survival rates.

MISCELLANEOUS

 

  • Multiple new prognostic factors of endometrial cancer are being evaluated and are brought about by newer technology, which allows for molecular biological evaluation. Because these evaluations are new, no general agreement has been reached about their importance.
    • Flow cytometry has been used in ploidy analysis (cellular nuclear DNA content) and to measure the proliferative fraction of tumor cells (S phase).
    • The prognostic factors of the endometrial cancer precursor 1 score (ie, myometrial invasion, DNA ploidy, and mean shortest nuclear axis) have been evaluated, and in at least one study, multivariant analysis was noted to be important prognostically.
    • Several other molecular biological characteristics have been noted to be important prognostically, including HER2/NEU and TP53 gene overexpression.
    • Newer characteristics are being identified almost daily. Obviously, the necessity for standardization is needed before applicability is available and conclusions can be reached. As experience is gained with these factors, they may be the new prognostic factors for endometrial cancer.
  • Controversies exist with using pelvic and paraaortic lymphadenectomy in the management of adenocarcinoma of the endometrium, as follows:
    • When proposed, the FIGO surgical staging classification was questioned as being efficacious by many investigators. However, data suggest that the gynecologic oncology community worldwide has accepted the surgical staging classification. In fact, lymphadenectomies are being performed routinely by these investigators.