Uterine Cancer |
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INTRODUCTION | ¡@ |
Invasive neoplasms of the female pelvic organs account for almost 15% of all cancers in women. It was predicted that approximately 77,500 women in the US would be diagnosed with pelvic gynecologic malignancy in 2000.
The most common of these malignancies is uterine cancer, specifically, endometrial cancer. Endometrial cancer is the fourth most common cancer in women, following breast, lung, and colorectal cancer, in that order. However, it is only the eighth most common cause of cancer deaths because it is usually detected in early stages.
Of the 36,100 cases predicted for 2000, only 6,500 cancer deaths were predicted for that year. Ovarian cancer accounts for the largest number of cancer deaths from pelvic gynecologic malignancies with 23,100 new cases and 14,000 deaths predicted for 2000.
History of the Procedure: Cancer of the uterine corpus is
the most common pelvic gynecologic malignancy in the US and most developed
countries with access to sufficient health care. Approximately 95% of these
malignancies are carcinomas of the endometrium. The most common symptom in up to
90% of women is postmenopausal (PMP) bleeding. Most women recognize the need for
prompt evaluation, although only 10-20% of women with PMP vaginal bleeding have
a gynecologic malignancy. Because of this prompt evaluation, 70-75% of women are
diagnosed with surgical stage I disease. Currently, there are no screening tests
for cancer of the uterus that are recommended for asymptomatic women. In women
who take tamoxifen following breast cancer, some studies have suggested that
routine endometrial sampling or transvaginal sonography to evaluate the
endometrial stripe may have a role in early detection of uterine cancer. None of
these studies have been definitive. The early detection, presenting symptoms,
and higher survival rate make it unlikely
that screening will have a successful impact on earlier detection and increased
survival.
Sixty percent of endometrial carcinomas are adenocarcinomas. Other histologic subtypes include adenosquamous, clear cell, and papillary serous carcinomas. Sarcomas make up about 4% of uterine corpus malignancies, including carcinosarcomas or mixed homologous müllerian tumors (48-50%), leiomyosarcomas (38-40%), and endometrial stromal sarcomas (8-10%). The remaining sarcomas are made up of heterologous tumors - tumors that contain histologic components foreign to the uterus, such as rhabdomyosarcomas, osteosarcomas, and chondrosarcomas. This chapter will focus on endometrial cancer but will briefly address uterine sarcomas.
Problem: Uterine cancer is defined as any invasive neoplasm of the uterine corpus.
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Frequency: Approximately 37,400 women were predicted to develop this form of malignancy in 1999 in the US. This incidence increased from the 36,000 cases diagnosed in 1998 in the US. After doubling in the early 1970s, the incidence has remained fairly constant. There were 6,400 predicted deaths in 1999.
Endometrial cancer is primarily a disease of postmenopausal women. The average age at diagnosis is approximately 60 years. Women diagnosed with endometrial cancer before the age of 40 make up only 4-5% of the total cases. These women invariably have specific risk factors such as morbid obesity, chronic anovulation, and hereditary syndromes. Endometrial cancer is more common in white women when compared to black women.
Uterine sarcomas, regardless of the histologic subtype, are more common in black women. Leiomyosarcomas tend to occur more often between the ages of 30-50, as compared to carcinosarcomas and endometrial stromal sarcomas, which have much higher incidence after age 50.
Etiology:
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Pathophysiology: Endometrial cancer may originate in a small area (eg, within an endometrial polyp) or a diffuse multifocal pattern. Early tumor growth is characterized by an exophytic and spreading pattern. As noted in the next section, this growth is characterized by friability and spontaneous bleeding, even at early stages. Later tumor growth is characterized by myometrial invasion and growth toward the cervix. There are 4 routes of spread beyond the uterus:
Adenocarcinoma of the endometrium, the most common histology, is usually preceded by adenomatous hyperplasia with atypia. Simple and complex endometrial hyperplasia with atypia progress to adenocarcinoma in 8-29% of cases, respectively. Without atypia, simple and complex hyperplasia progress to cancer in only 1 and 3% of cases, respectively.
Endometrial adenocarcinoma is histologically characterized by cribriform glands (or glandular crowding) with little, if any, stromal tissue between the glands. Nuclear atypia, variation in gland size, and increased mitoses are common in adenocarcinoma. Well-differentiated tumors may be confused with complex hyperplasia with atypia histologically. Likewise, poorly differentiated tumors might be confused with sarcomas histologically. The differentiation of endometrial cancers is one of the most important prognostic factors. Grade 1, 2, and 3 tumors make up approximately 45, 35, and 20%, respectively, of adenocarcinomas of the endometrium. The 5-year survival of clinical stage I cancers is 94, 88, and 79% for grade 1, 2, and 3 tumors, respectively. The degree of histologic differentiation of adenocarcinoma of the endometrium is defined as follows:
Less histologic differentiation is associated with higher incidence of deep (>one half) myometrial invasion and lymph node metastases. Subsequently, the depth of myometrial invasion and presence of tumor in the lymph nodes is directly related to recurrence rates and 5-year survival.
Histological variants:
As described in the introduction, there are other histologic variants of endometrial carcinoma. Some tumors have more than one histologic variant. There is an element of malignant squamous differentiation in 5-6% of endometrial cancers. These tumors are adenosquamous carcinomas. When corrected for grade, however, the presence of squamous components has not demonstrated a significant difference in prognosis when compared to pure adenocarcinomas.
Uterine papillary serous carcinoma (UPSC) is an aggressive variant of endometrial cancer found in 5% of cases. It is characterized by a higher incidence of deep myometrial invasion, lymph-vascular space involvement, lymph node metastases, extrauterine disease, and positive peritoneal cytology and implants. Even with surgical stage I, 5-year survival is 60%. UPSC resembles papillary serous carcinoma of the ovary histologically. Unfortunately, UPSC does not share the same response to cytotoxic agents as does its ovarian counterpart. In fact, neither radiation therapy nor chemotherapy has proven to be highly successful forms of adjuvant therapy for this histologic variant of endometrial carcinoma. There are often elements of clear cell carcinoma associated with UPSC.
Clear cell carcinoma is another variant of endometrial carcinoma characterized by its aggressive behavior. It makes up about 3-6% of all endometrial carcinomas. Five-year survival for these tumors is 45-60%. Nuclear grade adds no prognostic information in terms of survival.
In regards to uterine sarcomas, specifically leiomyosarcomas (LMS), the histopathologic diagnosis can be unclear until the time of definitive surgery. Diagnosis of LMS is felt to depend on the number of mitoses (or mitotic count) and the degree of cellular atypia. The diagnosis of LMS vs. leiomyoma and leiomyoma with high mitotic activity or uncertain malignant potential is based on the metastatic potential of the tumor. The mitotic count and cellular atypia correlates to this metastatic potential.
Although there is still controversy in the diagnosis of LMS, several studies support the theory that if the mitotic count is less than 5 per 10 high-powered fields (HPF), the tumor is a leiomyoma with negligible metastatic potential regardless of the presence of any cellular atypia. Likewise, the tumor has a high metastatic potential and is considered a LMS, regardless of the degree of cellular atypia if the mitotic count is greater than 10 per 10 HPF. There are some who believe mitotic count alone is not a good indicator of metastatic potential.
Carcinosarcomas or homologous mixed müllerian tumors (MMT) typically have an endometrioid carcinoma, usually a higher grade, and an undifferentiated spindle cell sarcoma. The sarcomatous portion of the tumor may exhibit an ESS pattern, if differentiated. MMTs are termed heterologous only if identifiable extrauterine histology is demonstrated. MMTs are characterized by early extrauterine spread and lymph node metastases. Extrauterine disease and lymph node metastases are directly related to depth of myometrial invasion and presence of cervical disease. Presence of heterologous elements does not seem to affect prognosis in terms of initial extent of disease.
Endometrial stromal sarcomas (ESS) can be divided into 2 categories: low-grade (LGESS) and high-grade (HGESS) ESS. LGESS is characterized by fewer than 5-10 mitoses per 10 HPF and minimal cellular atypia. These tumors can have a recurrence rate of up to 50% but demonstrate indolent growth and late recurrences. HGESS have a greater mitotic count and degree of cellular atypia. Risk of recurrence in both LGESS and HGESS is determined not only by histological characteristics, but also by surgical stage and extent of disease. It is interesting to note that some authors believe there is no true HGESS.
Clinical: As stated earlier, the most common symptom is post-menopausal (PMP) bleeding. Only 10-20% of women with PMP vaginal bleeding have a gynecologic malignancy. Endometrial cancer is diagnosed in 12-16% of women with PMP bleeding. The differential diagnosis must include breakthrough bleeding with estrogen replacement therapy, atrophic endometrium, atrophic vaginitis, endometrial/cervical polyps, and submucosal leiomyomas. In Third World countries, the most common cause of post-menopausal bleeding is cervical cancer. As the patient's age and number of risk factors (listed above) increase, the etiology of the PMP bleeding is more likely endometrial cancer. Women with premenopausal bleeding due to endometrial cancer are usually older than 40 years. However, the diagnosis of endometrial cancer needs to be considered in younger women with a history of anovulatory bleeding and obesity.
Other presenting symptoms may include purulent genital discharge, pain, weight loss, and a change in bladder or bowel habits. These are symptoms of advanced disease. Fortunately, the majority of endometrial cancer is diagnosed prior to this clinical presentation because of the recognition of PMP bleeding as a possible early symptom of cancer. Less than 5% of endometrial cancer is diagnosed incidentally when the patient is asymptomatic. The finding of atypical glandular cells on PAP smear in a postmenopausal woman is strongly suggestive of uterine malignancy.
Uterine sarcomas can present in a similar fashion to endometrial carcinomas. Leiomyosarcomas may present in the early 50s with irregular menses or PMP bleeding. Other symptoms include pain, pelvic pressure, and rapidly enlarging pelvic mass. Unfortunately, the diagnosis is rarely made prior to definitive surgery. Endometrial stromal sarcomas usually present with PMP bleeding, pelvic pain, and an enlarging mass. Like mixed müllerian tumors, ESS typically presents in the seventh decade of life. Like the other 2 sarcomas, irregular and PMP bleeding are the most common symptoms of mixed müllerian tumors. Weight loss, anorexia, and change in bowel or bladder habits are all signs of advanced disease in each case.
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INDICATIONS | ¡@ |
The 2 mainstays of primary treatment in endometrial cancer and uterine sarcomas are surgery and radiotherapy. Chemotherapy plays a role in adjuvant therapy for uterine sarcomas, in addition to recurrent or metastatic endometrial cancer. Hormonal therapy also has a role in adjuvant therapy in receptor-positive endometrial cancers. Details regarding all of these therapies will be discussed later in this chapter.
Knowledge of the surgicopathologic as well as clinical staging of cancer of the uterine corpus (FIGO 1988) is crucial in developing an appropriate management plan for endometrial cancer and uterine sarcomas. The staging classification is as follows (grading classification in pathophysiology section):
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| Stage I, Grade 1, 2, or 3 Tumor confined to the uterine corpus |
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| IA | Limited to the endometrium |
| IB | Invasion of less than one-half the myometrium |
| IC | Invasion to or more than one-half the myometrium |
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| Stage II, Grade 1, 2, or 3 | |
| IIA | Endocervical glandular involvement only |
| IIB | Cervical stromal invasion |
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| Stage III, Grade 1, 2, or 3 | |
| IIIA | Invades serosa and/or adnexa, and/or positive peritoneal cytology |
| IIIB | Vaginal metastases |
| IIIC | Metastases to pelvic and/or para-aortic lymph nodes |
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| Stage IV, Grade 1, 2, or 3 | |
| IVA | Invasion of bladder and/or bowel mucosa |
| IVB | Distant metastases including intra-abdominal and/or inguinal lymph nodes |
Most endometrial cancers will be diagnosed as stage I tumors. In fact, most endometrial cancer can be cured with surgery alone and relatively few patients need adjuvant radiotherapy. In the past, surgery and radiation therapy were both used as primary therapy. However, it is now known that survival with surgery is 15-20% better than with primary radiation therapy. Thus, primary radiation therapy is reserved for those patients who are poor surgical candidates or for those with unresectable disease.
Like endometrial cancer, primary surgical therapy is the first step in treatment of uterine sarcomas. In fact, a number of these tumors is found at the time of surgery for benign indications such as uterine leiomyomata and dysfunctional uterine bleeding, or postoperatively. Approximately 1% of women over 40 years of age undergoing a hysterectomy for uterine leiomyomata have LMS by pathologic diagnosis.
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RELEVANT ANATOMY AND CONTRAINDICATIONS | ¡@ |
Relevant Anatomy: Please refer to the following for relevant surgical anatomy.
Figure 3, Sagittal view of the female pelvis
Figure 4, Laparoscopic view of normal pelvis
Figure 5, Pelvic vessels and branches of the internal iliac artery
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WORKUP | ¡@ |
Lab Studies:
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Imaging Studies:
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Other Tests:
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Diagnostic Procedures:
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The technique of dilatation & curettage (D&C) is still the gold standard for the diagnosis of endometrial cancer. If the office biopsy is negative or inadequate, if the endometrial thickness by ultrasound is greater than 5 mm, or if there is a high degree of suspicion, the patient will need curettage under anesthesia to exclude malignancy.
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TREATMENT | ¡@ |
Medical therapy: Although surgical therapy and surgicopathologic staging is the mainstay of treatment for the majority of endometrial cancers and uterine sarcomas, non-surgical therapies, such as radiation therapy, chemotherapy, and hormonal therapy, play a role in the treatment of uterine cancers. Most of these therapies, however, are utilized as adjuvant/adjunctive therapy or in the treatment of recurrences or metastatic disease.
Of these therapies, only radiotherapy has any place in primary therapy for endometrial cancer and uterine sarcomas. Primary radiotherapy (total dose to tumor of up to 80 Gy) is the treatment of choice for those patients who are poor surgical candidates. Although the survival rate with primary radiation alone is 15-20% less than with surgery, the morbidity and mortality from surgical therapy in some patients may outweigh the benefits gained in terms of survival and recurrence.
The other instance where primary radiation is recommended is with stage III disease based on vaginal and/or parametrial extension, where complete resection of the tumor with primary surgery is unlikely. Even in this case, adjuvant hysterectomy, adnexectomy, and pelvic lymphadenectomy 6 weeks after radiation is completed, when feasible. Treatment of clinical stage IV disease is individualized based on the disease sites. In addition to surgical therapy, radiation therapy is usually administered for bone and CNS metastases, as well as for local tumor control if there is extension to the bladder or rectum. This will be discussed in more detail later, in addition to the other forms of adjuvant therapy that are helpful in advanced disease. Primary radiation for uterine sarcomas is usually limited to those patients who are medically inoperable.
Surgical therapy: Exploratory surgery with staging is the
treatment of choice in stage I and early stage II disease. The type of surgery
performed is dependent on the preoperative exam, as well as the intraoperative
findings. Well-differentiated endometrioid adenocarcinomas of the endometrium
without adverse risk factors are treated by simple total abdominal hysterectomy
and bilateral salpingo-oophorectomy (TAH/BSO). The caveat is that one must be
aware of those patients who are at risk for deep myometrial invasion, lymph node
or extrapelvic metastases, or local extension to the cervix. These patients need
a gynecologic oncologist, trained to perform extensive staging procedures. Risk
factors include clinical cervical extension, atypical histology (eg, papillary
serous, clear cell), FIGO grade 2 or 3 tumors,
elevated CA-125, and the thin elderly patient.
Staging:
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The majority of patients with endometrial cancer fall in this category. Preoperative work-up and risk assessment is completed. The patient then undergoes a TAH/BSO, and pelvic washings through a vertical midline incision. Removing a vaginal cuff margin does not decrease incidence of local recurrences. If the patient had preoperative risk factors for more advanced disease, such as clear cell or papillary serous histology, grade 2 or 3 endometrioid adenocarcinoma, or elevated CA-125, the surgeon should proceed with bilateral pelvic and selective para-aortic lymphadenectomy (BPPLND), omental and peritoneal biopsies. Otherwise, the hysterectomy specimen is sent immediately for gross pathologic and frozen section histologic analysis.
If there is evidence of a grade 2 or 3 tumor, greater than 50% invasion of the myometrium, adnexal metastases, cervical extension, elements of papillary serous or clear cell histology, lymph-vascular space involvement, or more than half of the endometrial cavity is involved, the surgeon should then proceed with the extended staging noted above. Of course, extended staging should be performed if there is suspicious lymphadenopathy or extrapelvic disease even in absence of the aforementioned adverse risk factors. Less than one-quarter of patients with endometrial cancer have an indication for selective para-aortic lymph node sampling.
Morbidity with extended staging when performed by surgeons trained in these techniques is not dramatically increased. However, some patients specifically the elderly are better served by extrafascial hysterectomy and bilateral adnexectomy alone, even in light of adverse risk factors.
Adjuvant hysterectomy and bilateral adnexectomy following preoperative radiotherapy with external beam with 1 brachytherapy application (total dose of 65-75 Gy) is occasionally performed. However, most surgeons will opt for primary surgical therapy followed by postoperative radiation, given that postoperative radiotherapy is no different from preoperative radiotherapy in terms of decreasing the incidence of local recurrences.
Vaginal hysterectomy may be used in the morbidly obese or medically infirm patient who may tolerate the vaginal approach better than the abdominal approach. Recent studies demonstrate similar survival rates for clinical stage I disease. Tumor differentiation, depth of myometrial invasion, and age are significantly associated with recurrence rates and survival. Laparoscopic techniques are discussed later.
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Endometrial cancer with overt clinical involvement of the cervix can be treated by several approaches. There are patients whose tumors lend themselves to complete surgical resection. However, the traditional procedure of choice is a Wertheim radical hysterectomy with BPPLND, followed by postoperative radiation based on pathologic results. It has been suggested that TAH/BSO and BPPLND followed by postoperative radiation based on pathologic results is adequate for clinical stage II disease. Another option is whole-pelvic radiotherapy (40-50 Gy), usually with 1 application of brachytherapy (total dose 65-75 Gy) followed by adjuvant TAH/BSO six weeks after completion of radiation.
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Surgical treatment of stage III endometrial cancer depends upon the specific clinical findings. As discussed above, vaginal extension (stage IIIB) or involvement of the parametria by local extension, though technically not part of the FIGO staging, are indications for primary radiation therapy. This may be followed with TAH/BSO if residual tumor is resectable. Clinical stage III disease based on the presence of an adnexal mass should be treated with laparotomy, TAH/BSO, pelvic washings, and BPPLND. This approach offers the advantage of surgicopathologic staging and definitive diagnosis of the adnexal mass. This is important as the differential of the adnexal mass includes metastatic endometrial cancer, malignant ovarian/tubal neoplasm, benign ovarian/tubal pathology, or metastatic disease from another primary tumor site.
The prognosis differs greatly for a benign ovarian neoplasm as compared to metastatic endometrial cancer to the adnexa. Stage III disease based solely upon positive peritoneal cytology, where the disease is otherwise limited to the uterus, is only diagnosed postoperatively. This will be discussed later.
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Treatment of clinical stage IV disease is determined by whether there is local extension into the bladder or rectum (stage IVA) or distant/extrapelvic metastases (IVB). Primary radiation for stage IVA disease is discussed in the medical therapy section. The role of surgery in stage IVB disease may involve one of tumor-reduction or palliative chemotherapy or radiation. Tumor-reductive surgery is typically followed with adjuvant/adjunctive chemotherapy, hormonal therapy, and/or radiation therapy. This is discussed later.
Surgery with staging is also the primary treatment of choice for uterine sarcomas. Patients with a LMS, MMT, or HGESS benefit from total abdominal hysterectomy and bilateral salpingo-oophorectomy through a vertical midline incision, with pelvic washings, omental biopsy, and selective pelvic and para-aortic lymphadenectomy. Lymphadenectomy for LGESSs is of limited value since the incidence of lymph node metastases is low. The difficulty with LMS and LGESS is that the diagnosis is usually made intra- or postoperatively. HGESSs and MMTs are typically diagnosed preoperatively. Subsequently, surgical therapy for patients with LMS and LGESS is often incomplete unless surgeons comfortable with extensive staging are available. The management dilemma is dealt with in the postoperative period.
Preoperative details: After diagnosis of endometrial cancer or uterine sarcoma is made, preoperative work-up should include complete blood count, electrolytes, CA-125 (if atypical presentation or histology), chest radiogram, and any of the above-noted tests, as indicated. Also, the patient should be in compliance with routine health maintenance screening (ie, mammography, Pap smear, and sigmoidoscopy/colonoscopy as indicated by age or symptoms).
If the patient has specific symptoms such as neurologic abnormalities, bone pain, or respiratory complaints, a directed metastatic work-up should be done preoperatively (eg, head CT/MRI or bone scan).
Other tests that are occasionally utilized are barium enemas, intravenous pyelogram, proctosigmoidoscopy, and cystoscopy. These are more important in the patient who is medically inoperable. Nonsurgical treatment can then be individualized for these patients. Again, the adverse risk factors discovered preoperatively should prompt a referral to the gynecologic oncologist because the probability that extensive staging will be required is increased.
Postoperative details: In order to determine the need for postoperative adjuvant therapy, patients are stratified according to risk. Pathologic features, such as depth of myometrial invasion, lymph-vascular space involvement, atypical histology, cervical extension, and nuclear grade, are important in determining risk for recurrence and, subsequently, the need for adjuvant therapy. With endometrial cancer that is clinically confined to the uterus, there are typically 3 separate categories for recurrence risk:
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There is no proven benefit in adjuvant chemotherapy and/or hormonal therapy in early stage endometrial cancer.
After tumor reductive surgery for extrapelvic/advanced disease at the time of laparotomy, adjuvant/adjunctive therapy is individualized. Localized radiation therapy is given for CNS and bone metastases. Adjuvant whole-abdominal radiation therapy is reserved for those that have no macroscopic extrapelvic disease secondary to its high morbidity; however, this is controversial. Otherwise, these patients are treated with chemotherapy and/or progestin or anti-estrogen therapy. Medroxyprogesterone acetate and Megestrol therapy is efficacious for those low-grade tumors that are estrogen- and/or progesterone-receptor positive.
Tamoxifen is an effective alternative in the face of contraindications to progestin therapy (eg, coronary artery disease and breast cancer). There is a 75-80% objective response with ER/PR positive tumors compared to less than 5% in the absence of ER/PR. Unfortunately, the tumors that tend to have intra-abdominal metastases are high grade and are less likely to be ER/PR positive (15-41%). It is useful in cases of advanced disease to send tissue, specifically from metastatic sites, for receptor analysis. Metastases are receptor positive in 25% of metastatic tumors compared to 60% of primary tumors.
If advanced disease is not amenable to localized/whole-abdominal radiotherapy or hormonal therapy, chemotherapy is initiated. Doxorubicin and cisplatin are the most effective agents used. Combination of the 2 agents increases the progression-free interval, with a complete remission in about 10-15% of cases and a partial response in 25%.
Whole-pelvic radiotherapy, sometimes systemic chemotherapy, is recommended for clear cell carcinoma and papillary serous carcinoma with negative surgical staging, negative LVSI, and minimal myometrial invasion. IF UPSC is more advanced, patients may receive chemotherapy with cisplatin, cyclophosphamide, and doxorubicin. Studies have not demonstrated a consistent response to chemotherapy. UPSC does not respond as well to platinum-based chemotherapy as does its ovarian epithelial counterpart.
The major curative treatment of uterine sarcomas is TAH/BSO with surgical staging. However, a significant number of these tumors are diagnosed intraoperatively and postoperatively. Subsequently, there is typically a need for postoperative therapy, although there is generally disagreement about its efficacy in terms of survival. At times, it may be necessary to re-operate for removal of remaining gynecologic organs with surgical staging. In terms of adjuvant therapy, whole-pelvic radiation or progestin therapy is recommended for LGESS only with extrauterine disease or LVSI. Whole-pelvic radiation improves local control for HGESS, especially stage I disease.
However, if advanced disease is present, progestin therapy and doxorubicin-based chemotherapy have a role. Because of the increased tendency for LMS to hematogenously spread and recur at distant/extrapelvic sites, whole-pelvic radiotherapy is relatively ineffective. Chemotherapy with doxorubicin, ifosfamide, etoposide, and/or cisplatin can be utilized with LMSs. MMTs that are limited to the pelvis benefit from whole-pelvic radiation in regards to local control. Those patients with evidence of extrapelvic disease may respond to additional postoperative therapy with doxorubicin, cisplatin, and/or ifosfamide. These cytotoxic therapies have demonstrated up to a 20% complete response rate in patients with advanced or recurrent disease.
In conclusion, radiation therapy provides local tumor control but no consistent improvement in survival. Chemotherapy and hormonal therapy are better suited for evidence of extrapelvic spread but yield somewhat inconsistent results. For these reasons, postoperative therapy for uterine sarcomas is quite variable.
Follow-up care: Routine surveillance intervals are typically every 3 months for the first year, every 4 months for the second year, every 6 months for the third and fourth year, and annually thereafter. Each visit should include pelvic exam, PAP smears of the vagina, and lymph node survey. Chest radiograms are typically done annually. CA-125 determinations are especially helpful if it was elevated preoperatively. Approximately 75-95% of recurrences are diagnosed within 3 years of treatment. The majority of these are discovered during evaluation of the symptomatic patient. The majority of recurrences in early stage disease are at the vaginal cuff and pelvis.
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OUTCOME AND PROGNOSIS | ¡@ |
As stated earlier, because of the typical early clinical presentation, the majority of endometrial cancer is endometrioid adenocarcinoma, well-differentiated and stage I disease. Overall 5-year survival for all grades and histological subtypes is 87, 72, 51, and 9% for surgical stage I, II, III, IV disease, respectively. Overall 5-year survival for all grades and histological subtypes is 69, 48, 31, and 13% for clinical stage I, II, III, IV disease, respectively. The nuclear grade is an important determinant of prognosis. For surgical stage I disease, 5-year survival for grade 1, 2, and 3 endometrial carcinoma is 92, 87, and 74%, respectively.
In terms of histologic subtype, clear cell and papillary serous carcinomas have the lowest overall 5-year survival. When looking at all stages together, the 5-year survival for clear cell and papillary serous carcinomas is 51 and 46%, respectively. Endometrioid adenocarcinoma has an overall 5-year survival of approximately 76%. Adenosquamous carcinoma has an overall 5-year survival of approximately 68%.
Increasing nuclear grade is associated with deeper myometrial invasion. Deeper myometrial invasion is, in turn, associated with pelvic and para-aortic lymph node metastases. These are all adverse prognostic factors. Recurrence rates up to 46% are seen with deep myometrial invasion (greater than one-half) as compared to 8-13% with superficial or no invasion.
As stated in the last section, the majority of recurrences of endometrial cancer are diagnosed within 3 years. Recurrences in patients treated with surgery alone tend to be more localized to the pelvis, particularly at the vaginal cuff. These recurrences are usually amenable to radiation therapy, surgical excision, occasionally pelvic exenteration, or a combination of surgical excision and radiation. The prognosis for these patients is better if the original diagnosis was more than 2 years before the recurrence.
Endometrial cancer treated with surgery and radiation that do recur are less often localized, and as such, are less amenable to localized therapy such as surgical excision and radiation. The most common extrapelvic sites for recurrences include lung, abdomen, para-aortic lymph nodes, brain, bone, and liver. Distant recurrences also present in the anterior scalene, supraclavicular, and inguinal lymph nodes. If the tumor is hormone-receptor rich, it may be amenable to progestin or anti-estrogen therapy. Otherwise, the same chemotherapy that is used for advanced endometrial cancer has been studied for recurrent disease, with the same results that are discussed earlier in this chapter.
Recurrence is the rule for uterine sarcomas. Stage I uterine sarcomas recur in up to 50% of cases. The overall 5-year survival for LMSs is 15-25%. Stage I LMSs have a 58 and 70% 5-year survival with surgery without and with radiation therapy, respectively.
Recurrences are rarely localized, and tend to reappear in the lungs most often. Stage I LGESSs and HGESSs have 5-year survivals of 80 and 50%, respectively.
As expected, advanced disease has a much worse prognosis, with a 5-year survival of 0-33% for stages II-IV. Early stage MMT have a 5-year survival of approximately 50%, while stage II-IV 5-year survival is 5-15%.
Localized disease, pelvic or extrapelvic, may be responsive to surgical excision or radiation therapy. Although doxorubicin, ifosfamide, and cisplatin have been studied and utilized in treatment of distant multifocal recurrent disease, no definitive choice of chemotherapeutic has been recommended for the treatment of recurrent uterine sarcomas.
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FUTURE AND CONTROVERSIES | ¡@ |
Laparoscopy
Laparoscopic-assisted vaginal hysterectomy or laparoscopic hysterectomy are 2 more recent surgical options. With the advances in laparoscopic equipment, surgeons are able to perform more radical surgeries laparoscopically, with the benefit of reduced recovery time.
As this technique develops, more information will be available regarding survival rates in comparison to approach by laparotomy. A recent study from Memorial Sloan-Kettering Cancer Center with 18 months of follow-up that demonstrated no significant difference in recurrence rates for stage I disease between LAVH and TAH.
It also may prove to be useful in staging for incompletely staged patients. In patients that require adjuvant radiation, LAVH offers the theoretical benefit of decreased adhesions and morbidity secondary to radiation effects in the postoperative pelvis.
Malignant cytology
There is still debate regarding management of surgical stage III endometrial cancer by positive peritoneal cytology with disease otherwise limited to the uterine corpus. Several multivariate studies have demonstrated that positive peritoneal cytology is an adverse risk factor for recurrence. Therapy still has not been refined.
Options include intraperitoneal P32, progestin therapy, chemotherapy, or whole-abdominal radiation. However, one must review the cytopathology carefully before initiating any of these treatments. Some studies have suggested isolated positive cytology in clinical stage I disease has no adverse effects on outcome.
Estrogen replacement therapy
The use of estrogen replacement therapy (ERT) in women with a history of endometrial cancer is controversial in stage I, grade 1 endometrioid adenocarcinoma. Although data is limited, patients who are in complete remission or who have surgical stage 1 and have undergone optimal treatment may be candidates for ERT.
Therapy should be individualized and extensive counseling regarding risks, benefits, and alternatives must be completed prior to initiating ERT. An alternative for relief of vasomotor symptoms is clonidine. Raloxifene is selective estrogen receptor modulator, has bone protective benefits without increased risk of endometrial or breast cancer, and may be also be used as an alternative. However, vasomotor symptoms may worsen with raloxifene.
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PICTURES | ¡@ |
| Caption: Picture 1. Figure 1. Typical histologic pattern, specifically cribriform glandular appearance of endometrioid adenocarcinoma of the endometrium. There is increased nuclear atypia and mitotic figures. |
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| Caption: Picture 2. Figure 2. Papillary serous adenocarcinoma of the endometrium |
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| Caption: Picture 6. Figure 6. Uterine leiomyosarcoma |
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| Caption: Picture 7. Figure 7. High grade endometrial stromal sarcoma |
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| Caption: Picture 8. Figure 8. Transvaginal ultrasound demonstrating a enlarged endometrial stripe (EMS=2.4cm) |
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| Caption: Picture 9. Figure 9. Angiographic view of the pelvic vessels. This patient had pelvic recurrence of a renal cell carcinoma (seen on the right side of the image). |
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BIBLIOGRAPHY | ¡@ |
