The Uterine Cavity Is Lined by Endometrium, Which Is Made of Columnar Cells

Endometrium

นายแพทย์อนันต์ โทนุสิน

Anatomy

The uterus, a hollow muscular organ in the middle of the pelvis, is divided into the corpus, body, and cervix. The most superior portion of the corpus is the fundus.
The uterine cavity is lined by endometrium, which is made of columnar cells.
The muscular layer (myometrium) is composed of smooth muscle fibers.
The peritoneum covers the uterus and forms the broad ligaments laterally.

Epidemiology

Carcinoma of the endometrium is the most common gynecologic malignancy (1).
The incidence peaks in the 50- to 70-year age group; 75% of all cases occur in postmenopausal women (3).
Risk factors for development of endometrial cancer include unopposed estrogen exposure (polycystic ovary or Stein-Leventhal syndrome, obesity, nulliparity, exogenous estrogen, estrogen-secreting tumors of the ovaries), late menopause (>52 years of age), tamoxifen use, previous pelvic irradiation, edematous hyperplasia, low parity, diabetes mellitus, and hypertension.

Natural History

Most endometrial carcinomas are confined to the uterus at the time of diagnosis.
Tumors arising from the endometrium commonly spread into the myometrium and to contiguous areas. Carcinoma of the endometrium may extend directly to the cervix, vagina, parametrial tissue, bladder, or rectum.
Tumor grade and depth of invasion into the myometrium are important prognostic indicators. Deep myometrial invasion is more common with higher-grade tumors.
As depth of myometrial invasion and tumor grade increase, the risk of pelvic and paraaortic lymph node metastases also increases (Table 1).
Peritoneal seeding is common with endometrial cancer because an endometrial lesion may penetrate the uterine wall or seed transtubally. This is most common with papillary serous or clear cell histologies.
Hematogenous metastases are infrequent at presentation but are seen in end-stage patients.

Clinical Presentation

The most common presenting symptom is vaginal bleeding, which is reported by 70% to 80% of patients.
Back pain and pressure symptoms caused by the enlarged uterus on bowel and bladder may occur.
Physical findings are usually minimal; blood in the vagina emanating from the cervical os is the most common finding.

Table 1. Grade, depth of invasion, and metastases in endometrial carcinoma

Depth of invasion / Grade I (n=180) / Grade II (n=288) / Grade III (n=153)
Aortic
node / Pelvic
node / Aortic
node / Pelvic
node / Aortic
node / Pelvic
Node
Endometrium only (n=86)
Superficial (n=281)
Middle (n=115)
Deep (n=139) / 0 (0%)
1 (1%)
1 (5%)
1 (6%) / 0 (0%)
3 (3%)
0 (0%)
2 (11%) / 10 (3%)
5 (4%)
0 (0%)
8 (14%) / 1 (3%)
7 (5%)
6 (9%)
11(19%) / 0 (0%)
2 (4%)
0 (0%)
15(23%) / 0 (0%)
5 (9%)
1 (4%)
22(34%)

(From Creasman WT, Morrow CP, Bundy BN, et al. Surgical pathologic spread patterns of endometrial cancer. Cancer 60:2035, 1987; with paermission).

Diagnostic Workup

No satisfactory screening method is available for detecting endometrial carcinoma is symptomatic patients.
The Papanicolaou smear detects only about 40% of endometrial tumors.
Endometrial biopsy or aspiration curettage is indicated in postmenopausal women with vaginal bleeding or perimenopausal women with menstrual abnormalities, and obviates in most cases the need for dilation and curettage (D&C).
Fractional D&C and cervical biopsy are indicated when there is a high degree of suspicion of cancer, which cannot be diagnosed by endometrial biopsy or aspiration currettage.
Diagnostic studies routinely used in the clinical staging of patients with endometrial cancer vary with stage (Table 2).
Computed tomography of the pelvis and abdomen is recommended for all patients with high-grade tumors or with stage II or higher disease to detect possible nodal or extrauterine spread of cancer.
Magnetic resonance imaging is not helpful in detecting nodal or peritoneal spread, but it is useful in demonstrating the depth of myometrial invasion with an accuracy of approximately 80% (3).
CA 125, a tumor marker, is elevated in 59% patients with advanced or recurrent endometrial carcinoma, but it is no specific (11).

Table 2.Diagnostic workup for endometrial cancer

All stages
History
Physical examination including pelvic examination
Endometrial biopsy or aspiration curettage
Fractional dilatation and curettage (if biopsy or aspiration dose not reveal cancer)
Chest radiograph
Cervical biopsy
Urinary imaging study in all patients before surgery (IVP, ultrasound, or CT)
Complete blood cell count, urinalysis, blood chemistry
Advanced disease or if symptoms warrant
Cystoscopy
Sigmoidoscopy
CT scan or MR imaging
IVP
Barium enema

CT, computed tomography; IVP, intravenous pyelogram; MR, magnetic resonance.

Table 3.Pathologic FIGO corpus cancer staging

Stage IA
Stage IB
Stage IC
Stage IIA
Stage IIB
Stage IIIA
Stage IIIB
Stage IIIC
Stage IVA
Stage IVB / G123
G123
G123
G123
G123
G123
G123
G123
G123 / Tumor limited to endometrium
Invasion to <1/2 myometrium
Invasion>1/2 myometrium
Endocervical glandular involvement only
Cervical stromal invasion
Tumor invasion of serosa or adnexa or positive peritional cytology.
Vaginal metastases
Metastases to pelvic or periaortic lymph nodes
Tumor invasion of bladder or bowel mucosa
Distant metastases including intraabdominal or inguinal lymph nodes

(From International Federation of Gynecology and Obstetrics. Classification and staging of malignant tumors in the female pelvis: annual report on the results of treatment in gynecological cancer. Int J Gynaecol Obstet 28:189-193, 1989; with permission.)

Staging System

Endometrial carcinoma is most widely surgically staged according to guidelines of the International Federation of Gynecology and Obstetrics. (FIGO) (Table 3.)
For inoperable patients, the FIGO clinical staging system, which is based on bimanual pelvic examination under anesthesia and on the diagnostic procedures previously discussed, is recommended.

Pathologic Classification

Endometrioid adenocarcinoma is the most common form of carcinoma of the endometrium, accounting for 75% to 80% of cases.
Endometrioid adenocarcinoma is divided into four subtypes: papillary, secretory, ciliated cells, and adenocarcinoma with squamous differentiation.
Various pathologic classifications of endometrial cancer are known in Table 4.
Serous; clear cell, and pure squamous cell carcinomas are the most aggressive cancers arising from the endometrium.

Table 4.Pathologic classification of endometrial cancer

Endometrioid adenocarcinoma
Papillary
Secretory
Ciliated cell
Adenocarcinoma with squamous differentiation
Mucinous carcinoma
Serous carcinoma
Clear cell carcinoma
Squamous carcinoma
Undifferentiated
Mixed types
Miscellaneous carcinoma
Metastatic

Prognostic Factors

The most significant prognostic factor is clinical or pathologic stage.
The histologic grade of the tumor and depth of myometrial invasion by the tumor have an impact on the incidence of lymph node involvement and on prognosis (5,7) (See Table 1).
The presence of lymphovascular involvement significantly increases the risk of tumor recurrence after surgery.
Age at the time of diagnosis is a prognostic factor. Older patients have a higher chance of myometrial involvement and advanced stage and a lower 5-year survival rate.

Operable Stage I Endometrial Carcinoma

Total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH/BSO) is the basic treatment for all patients with stage I endometrial carcinoma.
In all but grade I lesions, it is recommended that pelvic and periaortic lymph node sampling be performed at the time of surgical exploration. The incidence of nodal involvement in stage I patients with grade I histology is too low to make routine sampling of lymph nodes worthwhile.
Peritoneal washings are recommended for all patients at the time of surgery.
The trend in the United States is to primarily operate on all patients with stage I disease, regardless of tumor grade, to a adequately assess the extent of disease and allow radiation therapy to be tailored to the pathologic findings.
In stage I patients with grade I tumors and less than 50% myometrial invasion only, no further therapy is recommended because the prognosis is very good.
In patients with stage I, grade II disease and less than 50% but more than 25% myometrial invasion, it is debatable whether vaginal cuff irradiation is indicated. This adjuvant therapy is also debated, but may be more justifiable, in patients with stage I, grade III disease and 25% to less than 50% myometrial invasion (6).
In patients with stage I, grade I or II disease with more than 50% myometrial involvement and patients with grade III disease regardless of depth of myometrial involvement, postoperative irradiation is recommended.
Vaginal cuff irradiation is delivered with colpostats or vaginal cylinders. The dose with low dose-rate (LDR) brachytherapy is 60 to 70 Gy to the vaginal mucosa in one or two insertions. With high-dose-rate brachytherapy, the usual prescription is 6 to 7 Gy per fraction at 0.5 cm depth; three fractions are delivered 1 or 2 weeks apart.
At some institutions, high-risk patients are treated with a combination of external beam irradiation and vaginal cuff insertion.

Inoperable Stage I Endometrial Carcinoma

In medically inoperable patients, two brachytherapy insertions for 7000 to 8000 mgRaEq-h (LDR) and external-beam irradiation to the pelvis to a total dose of 50.4 Gy with a midline block at 20 Gy are recommended (3).

Stage II Endometrial Carcinoma

Patients with stage II endometrial carcinoma are subdivided into those with endocervical glandular involvement only and those with cervical stromal invasion.
The gynecologic oncologic community favors surgery followed by postoperative irradiation based on histologic finding.
The incidence of pelvic lymph node involvement varies from 20% to 50% in patients with stromal involvement. This necessitates adequate treatment of nodal areas and parametrial tissues with external pelvic irradiation.
Survival for patients with stage II disease ranges from 50% to 85%. Patients with endocervical glandular involvement only (stage IIA) have a much better 5-year survival rate than those with cervical stromal invasion (stage IIB).

Stage III Endometrial Carcinoma

Treatment for stage III disease must be individualized.
The trend at some institutions in the United States has been to first operate on patients without extensive parametrial or vaginal extension to assess the extent of the disease and debulk the tumor.
All stage III patients are candidates for postoperative irradiation after surgical staging and debulking of the tumor.
Irradiation fields are defined by the histologic extent of the tumor.
Patients with positive peritoneal cytology only may be treated with phosphorus-32 (32P) instillation (15 mCi) or whole-abdomen irradiation. In general, irradiation doses of 30 Gy to the entire abdomen with a pelvic boost to a total dose of 50.4 Gy are recommended.
Patients with periaortic nodal involvement should be treated with extended-field irradiation encompassing the periaortic lymph nodes (2).
The recommended radiation dose to the periaortic lymph nodes is approximately 45 Gy, and the pelvic dose should be taken to 50.4 Gy.
For inoperable patients, whole-pelvis irradiation (20 to 40 Gy) and additional boost to the lateral pelvic wall to 50 to 60 Gy after placement of a midline block (depending on clinical evidence of parametrial invasion), combined with two LDR intracavitary implantations for a total of 5000 to 8000 mgRaEq-h, is the treatment of choice.
Patients with pathologic stage III disease have significantly higher survival (40% to 64%) than patients with clinical stage III disease (20% to 30%). Greven et al. (4) reported a 5-year disease-free survival rate of 57% in 74 patients with pathologic stage III endometrial carcinoma who received postoperative external-beam irradiation to the pelvis or to the pelvis and periaortic lymph nodes, if the nodes were pathologically positive.

Stage IV Endometrial Carcinoma

Patients with bladder or rectal wall involvement without pelvic wall fixation, who are medically operable, may be considered for pelvic exenteration.
Patients with stage IVB disease may be treated with whole pelvic irradiation for control of local symptoms of bleeding, discharge, and pelvic pain.

Radioactive Phosphorus

Intraperitoneal 32P is effective in decreasing recurrences in selected patients with subclinical intraperitoneal disease. The usual dose is 15 mci.
Bowel complications requiring surgical resection in a minority of patients are the only reported adverse effects of intraperitoneal 32P treatment.
It is strongly recommended not to combine 32P treatment and external-beam irradiation to the pelvis because of excessive bowel toxicity.
The optimal treatment for patients with positive cytology remains to be defined.

Hormonal Therapy

Many reports have documented that progestational agents are effective in a selected group of patients with endometrial cancer with overall response rates varying from 9% to 40% (3).
There are no significant differences in responses among the various types of progestational agents (9).
Responses to progesterone therapy are more likely to occur in patients with well differentiated and receptor-positive tumors (10).

Chemotherapy

Doxorubicin (Adriamycin) is the principal therapeutic agent used to treat patients with metastatic endometrial cancer.
Some investigators have shown better median survival time in patients who showed a complete response to doxorubicin (14 months) compared with those who showed no response (3.5 months) (12).

Recurrent Endometrial Carcinoma

Early diagnosis is crucial for success in the treatment of recurrent endometrial carcinoma (8).
Approximately 70% of all relapses occur within the first 2 years after completion of initial therapy; frequent follow-up examinations are highly recommended.
Optimal treatment for recurrent endometrial cancer depends on the size of the recurrent tumor, spread of tumor beyond the confines of the true pelvis, and type of therapy delivered after initial diagnosis.
Isolated vaginal recurrences are rare, particularly in patients who have received adequate initial radiation therapy. Vaginal recurrences usually coexist with more extensive pelvic disease.
For patients with recurrent cancer in the pelvis who have not received previous irradiation, external-beam irradiation to the whole pelvis (45 to 50 Gy in 5 to 6 weeks) is recommended.
An additional boost of 10 to 15 Gy to the tumor bulk can be delivered with external-beam irradiation when the tumor involves the central pelvis or the pelvic side wall.
Vaginal recurrences can receive boost irradiation with intracavitary or interstitial radiation therapy to bring the total tumor dose to 80 Gy.
Treatment for patients with disseminated tumor includes progestational agents, either alone or combined with chemotherapy, depending on the status of estrogen or progesterone receptors.
Radiation therapy is indicated for palliation.

Sequelae of Treatment

The mortality rate of patients who undergo a TAH/BSO is less than 1%; however, concomitant medical problems (obesity, hypertension, heart disease) increase the risk for complications such as infection, wound dehiscence, fistula formation, and bleeding.
Acute complications resulting from pelvic irradiation include fatigue, diarrhea, and cystitis.
Desquamation of vulvar skin from irradiation of the vagina is not uncommon.
Anorexia and vomiting may occur if the periaortic region is irradiated.
Late complications such as chronic cystitis, bowel obstruction, and fistula formation are generally seen in fewer than 10% of patients.
Vaginal stenosis occurs and can be successfully managed with routine use of a vaginal dilator and vaginal estrogen applications.

References

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