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Endometrial Cancer: Recent Developments in Evaluation and Treatment

Endometrial Cancer: Recent Developments in Evaluation and Treatment

Endometrial cancer is the fifth leading cause of cancer in women worldwide, with approximately 150,000 cases diagnosed each year, and is the most common malignancy of the female genital tract in the United States. Dr. Chen and colleagues provide an excellent review of current clinical investigations focusing on the evaluation and treatment of this carcinoma.

Hereditary Endometrial Cancers

Most cases of endometrial carcinoma are thought to be sporadic. However, some clearly have a hereditary origin. Daughters and sisters of women with endometrial carcinoma have a 2.7 relative risk of developing endometrial carcinoma when compared to women without such a family history.[1]

The vast majority of endometrial carcinomas recognized as inherited occur in women affected with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome. This autosomal-dominant inherited disease is associated with an increased risk of developing a number of different types of cancer, especially colorectal cancer, with endometrial carcinoma being the most common extracolonic cancer.[2] Women who are HNPCC carriers have a 10-fold increased risk of developing endometrial carcinoma, compared to the general population. However, the percentage of endometrial cancers due to HNPCC is not well defined.

A small body of literature suggests the possibility of a site-specific form of inherited endometrial carcinoma. However, at present, there are insufficient data to conclusively prove its existence as a clinical genetic entity.

Evolution of Treatment

Many patients with endometrial cancer present with early-stage disease, which has a high rate of cure. However, a significant number of patients present with more advanced disease or unfavorable histologies, which result in significant morbidity and death.

The evolution of therapy for patients with adenocarcinoma of the endometrium has been based on the elucidation of the pattern of spread of the disease, resulting in treatment regimens (adjuvant radiation and/or chemotherapy) tailored to surgicopathologic findings. Such regimens are associated with improved survival and decreased recurrence rates in patients whose disease is confined to the pelvis even in the face of known adverse factors.

It remains unanswered whether patients with intermediate risk factors for recurrence should receive adjuvant therapy. Nevertheless, patients who demonstrate extrauterine disease, especially to the para-aortic lymph nodes, continue to face a dismal prognosis.

Clinical Behavior and Histology

There appear to be two types of endometrial cancer (referred to as type I and type II). The two types differ in epidemiology, presentation, and behavior.

The majority of patients with endometrial carcinoma—about two-thirds of the total—have a history of exposure to estrogen, and their the mean age (59 years) is slightly lower than the overall mean age for patients with the disease. These tumors usually behave in a relatively indolent manner. This group of tumors have been designated “type I endometrial carcinoma” and are often referred to as “estrogen related.” They are generally low grade and low stage, and have a good prognosis.

Both epidemiologic and light microscopic studies have suggested that this type of carcinoma develops from normal epithelium, under the influence of estrogen stimulation, through a continuum of histopathologically recognizable lesions known as hyperplasias. Histologically, the majority of type I tumors tend to have architectural features that resemble the appearance of normal endometrial glands; these tumors are called “endometrioid carcinomas” to denote this resemblance. The overall survival rate for patients with type I endometrial cancer exceeds 80%.

Type II carcinomas, in contrast, are unrelated to estrogenic stimulation, occur in older women (mean age, 68 years), and have an aggressive behavior. Such lesions are characterized by deep myometrial invasion, frequent nodal and extrauterine metastasis, and poor outcome (up to 50% of patients develop recurrences).

Many type II carcinomas are composed of cuboidal cells showing marked cytologic atypia and nuclear pleomorphism that grow in either a glandular or papillary architecture.[3] These features are strikingly similar to those of the serous carcinoma of the ovary, giving rise to the name “uterine serous carcinoma” to distinguish these endometrial tumors from primary serous ovarian tumors.

By definition, serous carcinomas of the endometrium are all high grade, frequently have extrauterine spread by the time of diagnosis, carry a poor prognosis, and behave much like ovarian serous carcinomas.[4] Serous tumors of the endometrium generally arise in the setting of an atrophic, not a hyperplastic, endometrium.

A putative precursor of uterine serous carcinoma has been described and is termed “endometrial intraepithelial carcinoma.”[5] Endometrial intraepithelial carcinoma, even in the absence of definitive invasion in the uterus, can be associated with intraabdominal carcinoma, illustrating the aggressive nature of this neoplastic process.

There are several other minor histologic variants of endometrial carcinoma (eg, mucinous, villoglandular, and clear cell). The appropriate category in which these histologic variants belong is not well established. These histologic variants are rare and poorly understood.

Adjuvant Therapy for Endometrial Cancer

Patients at high risk for developing recurrent endometrial cancer are candidates for adjuvant treatment following primary surgery. Definitions for intermediate-risk patients vary among studies, but generally include stage IA, grade 3 tumors and stages IB or IC cancers of any grade. The benefit of adjuvant treatment following surgery in this group of patients remains unsettled.

The only prospective, randomized trial in endometrial cancer patients with intermediate-risk factors after surgical staging is the Gynecologic Oncology Group study (GOG 99), which randomized intermediate-risk patients to surgery only or surgery plus adjuvant pelvic radiation.[6] Total abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic and para-aortic node sampling were required in all patients. Patients with stage Ib, Ic, IIa, and IIb adenocarcinoma, but not papillary serous or clear cell carcinoma, were eligible. Of 448 women entered into this study, 390 met all of the eligibility requirements. The investigators of this study are currently analyzing the results. Median follow-up is 56 months, with only 9% of patients followed for less than 2 years. To date, there have been 39 recurrences and 52 deaths among these women; 56% of these deaths were the result of the disease or its treatment. The estimated 2-year progression-free survival rate is 88% in patients treated with surgery onlyand 96% in those given pelvic radiation (P = .004).

Thus far, this study shows that use of adjunctive radiation therapy in patients with intermediate-risk endometrial cancer decreases the risk of recurrences but has an unappreciable effect on overall survival. The overall recurrence rate in this study was lower than expected based on prior staging and prognosis studies. One possibility is that this was the result of a trend to perform more complete (therapeutic) rather than incomplete (sampling) lymphadenectomy procedures.

Treatment of Advanced Disease

Although localized endometrial cancer can be effectively treated with surgery and radiation therapy, treatment of advanced endometrial cancer remains controversial. Adjuvant therapy for stage IIIC tumors, particularly pelvic node-positive disease, has primarily consisted of pelvic radiation. Systemic failures occur frequently, suggesting that systemic adjuvant treatment may have a role in patients with stage IIIC or IV disease.[7]

The optimal adjuvant therapy after surgical staging and maximum cytoreduction is unknown. The ongoing protocol GOG 122, which is randomizing patients with advanced endometrial carcinoma to whole-abdominal radiotherapy vs combined doxorubicin-cisplatin (Platinol) chemotherapy, may answer the question of which adjuvant regimen is most effective and least toxic in patients with metastatic endometrial carcinoma.

References

1. Schildkraut JM, Risch N, Thompson WD: Evaluating genetic association among ovarian, breast, and endometrial cancer: Evidence for a breast/ovarian cancer relationship. Am J Hum Genet 45:521-529, 1989.

2. Watson P, Lynch HT: Extracolonic cancer in hereditary nonpolyposis colorectal cancer.Cancer 71:679-685, 1993.

3. Sherman ME, Bitterman P, Rosenheim NB, et al: Uterine serous carcinoma: A morphologically diverse neoplasm with unifying clinicopathologic features. Am J Surg Pathol 16:600, 1992.

4. Nicklin JM, Copeland LJ: Endometrial papillary serous carcinoma: Patterns of spread and treatment. Clin Obstet Gynecol 39:686-695, 1996.

5. Ambros RA, Sherman ME, Zahn CM, et al: Endometrial intraepithelial carcinoma: A distinctive lesion specifically associated with tumors displaying serous differentiation. Hum Pathol 26:1260, 1995.

6. Roberts JA, Brunetto VL, Keys HM, et al: A phase III randomized study of surgery vs surgery plus adjunctive radiation therapy in intermediate-risk endometrial adenocarcinoma (GOG no. 99). Gynecol Oncol 68:135, 1998.

7. Selman AE, Fowler JM, Martinez-Monge R, et al: Doxorubicin and/or cisplatin-based chemotherapy for the treatment of endometrial carcinoma with retroperitoneal lymph node metastases. Int J Gynecol Cancer 8:423-429, 1998.

 
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