Review Article CURRENT STATUS OF ENDOMETRIAL ( RISK TO RECURRENCE ) CHHABRA

S*,

TEMBHARE

CARCINOMA

A ** ABSTRACT

In some parts of world endometrial cancer (En Ca) accounts for 4-8% of all Ca, fourth position aftger breast, colon lung cancers, in others is less common, lowest rates in India, Southeast Asia. Morbidity, mortality is low because most patients present at early stage for abnormal bleeding though pain also could be there. It was believed that En Ca represents a continuum from benign cystic hyperplasia to complex atypical hyperplasia (CAH), but recent concepts are En hyperplasia & Ca may be two different entities. Screening for En Ca is not cost effective; therefore assessing risk is essential. It needs to be clinically staged for appropriate management. In 94% and 75% cases of atypical hyperplasia and well differentiated En Ca in younger women who wish to preserve their fertility progestins result in complete regression of disease respectively. Studies have shown that patients of hyperplasia without atypia respond well (>80%) to progestin, are not at increased risk of Ca but with atypia 50% respond. Treatment is mainly surgical, based on stage. Radiotherapy, Chemotherapy (hormones and cytotoxic drugs) are needed in advanced cases.

differences in the distribution of known risk factors among different races6. Creaseman et al4 have reported that 75% women are postmenopausal, only 3-10% less than 40 years. Overall morbidity and mortality of En Ca is low because most patients present at early stage because of abnormal bleeding7, but it is associated with an approximately fourfold increase in mortality with ovarian cancer and twofold increase in mortality with breast cancer.

Introduction In some parts of the world endometrial cancer (En Ca) accounts for 4-8% of all Ca, fourth position after breast, colon and lung cancers and approximately 7400 die form the disease1,2, in other parts it is the second most common malignancy in female hereditary non-polyposis colorectal cancers (HNPCC)3 or the most common gynaecological cancer (Gyn ca)4 and the fourth leading Ca in comen with 35000 new cases and 3000 deaths each year in the United States5. However in some parts En Ca is less common, lowest rates are from India, Southeast Asia as a whole4. Some studies have examined differences in En Ca risk among ethnic groups in the United States which do not seem to be explained by

Risk /Protective Factors Increased or prolonged estrogen exposure, either because of early menarche or late menopause, obesity, nulliparity, anovulation, estrogen producing neoplasms or unopposed exogenous estrogen including tamoxifen therapy place a woman at increased risk of En Ca, though 35% patients

* Director Prof. ** Resident, Deptt. of Obs & Gyne, MGIMS

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growth factor I, retinaldehyde dehydrogenase type II, secreted frizzled-related protein 4 and anti-LeY monoclonal antibodies (diagnosed by immunocytochemical cytology) whose expression is altered in cases of endometrial hyperplsia or cancer may be promising early stage tumor markers17. Polycystic ovary disease and subfertility have been found significantly more in cases with cytological atypia; however, they not significant in cases with carcinoma.

with En Ca show no signs of obesity or hyperestrogenism. Hormone replacement therapy (HRT) with estrogen is associated with an eightfold increased incidence but the addition of progestin decreases this risk dramatically8. Epidemiological studies indicate that estrogens, endogenous and exogenous, have a major role in En Ca9. Diabetes has also been associated with increased risk of En Ca in some epidemiological studies. The high diabetes prevalence and mortality among women with En Ca suggests that weight control and regular physical activity are important10. Women with En Ca show higher mean BMI and Waist Hip Ratio (WHR) than who do not have11. With family history of En Ca or breast Ca, risk is more. Radiation, hypertension are also predisposing factors12,13. Given the observed association between obesity and En Ca, it is important to understand how weight loss among obese women may affect their risk of developing En Ca13.

Screening, Symptoms, Signs and Diagnosis Population screening for En Ca is not cost effective; therefore assessing the risk is essential. If there are symptoms, but an adequate pelvic examination is not possible or the woman has risk factors, transvaginal ultrasonography (TVS) is advocated. Perimenopausal women with abnormal uterine bleding(AUB), Postmenopausal Bleeding (PMB), low abdominal pain with a enlarged uterus need to be evaluated. En Ca, precancerous conditions typically result in endometrium greater than 10-12mm. The risk of ca is around 5% in women who have endometrial fluid on ultrasound. Sonohysterography can distinguish endometrium from small polyps & leiomyomas which are sometimes missed during endometrial biopsy18, however because of possibilities of peritoneal dissemintion of malignant cells, sonohysterography and hysteroscopy are not advocated. A patient who has AUB and a thickened endometrium should be rebiopsied if initial biopsy is negative or nondiagnostic. Gull et al19 have evaluated 394 women with PMB and reported relative risk for En Ca 63.9% compared with 22.7% in the age-matched general population. Thegold standard continues to be histopathology of En and the final histopathology of the hysterectomy specimen. Endometrial/endocervical

Low parity, lactation, use of combined oral contraceptives (COC), a diet low in fat and high in plant foods, and physical activity decrease the risk13, OCP use for 5 yers or more reduces the risk by 50%14. Weiderpass et al14 have reported 10% decreased risk per year of COC utilization for atypical hyperplasia as well as for all grades of invasive cancers. The risk is slightly less in cigarette smokers15. Pathogenesis Earlier it was hypothesized that En Ca represents a continuum from benign cystic hyperplasia to complex atypical hyperplasia (CAH), however Berek et al16 have suggested that En hyperplasia & Ca may be two different entities, the distinguishing feature being the presence or absence of cytologic atypia. Recent studies suggest that biomarkers progesterone receptor, insulin-like 19

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Current Status of Endometrial carcinoma (Risk to Recurrence)

curettage is also warranted in asymptomatic postmenopausal women who have endometrial cells on Pap’s smear. Some opine that D and C is a blind technique that often samples less than half the endometrium. MRI has an overall accuracy for deep myometrial invasion with sensitivity of 88-90%, especially contrast enhanced MRI20. Elevated CA 125 levels correlate well with the clinincal course and help in diagnosis of recurrent tumor but may be normal in small recurrences22. Leeuw et al21 have reported that the Micro satellite instability (MSI) analysis and immunohistochemical examinations using hMLH1, hMSH2, and hMSH6 are highly effective. MSI has been found in approximately 30% cases.

cases of atypical hyperplasia and well differentiated En Ca in younger women who wish to preserve their fertility respectively24. However, medical therapy may not be justified if fertility is not an issue, especially if risk factors are present. The cytostatic agents most frequently used are medroxyprogesterone acetate, megestrol & 17 hydroxyl progesterone. Recent studies reveal that progestin alone is as effective as either tamoxifen or gonadotropin- releasing hormone (GnRH) analogues plus progestins25. The duration of therapy varies from three months to one year or longer medroxyprogesterone acetate, in a dosage of 10mg daily, or norethindrone acetate, in a dosage of 2.5mg daily for a minimum of 12 to 14 days per month.

Types

Studies have shown that patients of hyperplasia without atypia respond well (more than 80%) to progestin and are not at increased risk of Ca but with atypia only 50% show response and Ca develops in 25%, in 50% with adenomatous hyperplasia and atypia. Actually 30 to 50% women could have simultaneous invasive ca26. However, some reports reveal that complex atypical hyperplasia (CAH) also regresses and only 10-12% ultimately progress to Ca27.

Most patients with En Ca are adenocarcinoma (61-71%), some adenosqamous Ca; adenoacanthoma (14-24%) and rest are papillary serous tumour & clear cell carcinoma22. STAGING En Ca need to be clinically staged for appropriate management. FIGO advocates surgical staging also in addition to clinical. Surgical staging is by laparotomy with details of possible invsion and thorough bilateral pelvic and paraaortic lymph-node sampling23. Patients with superficial invasion) of uterus and grade I pathology have a very low risk of pelvic or para-aortic metastasis, those with intermediate risk (one-half invasion and grade 2 histology intermediate) have 3 to 6% of pelvic nodal involvement and 2% risk of para-aortic metastasis.

THERAPY Surgery Treatment is mainly surgical, the extent based on the stage of disease. Pelvic and para-aortic lymphadenectomy need to be performed in the intermediate and high risk cases. Some recommend para-aortic node dissection, if there are suspiciously enlarged pelvic nodes, gross adnexal metastasis or when there is outer one third myometrial invasion28. While lymph nodes that are suspicious on palpation or grossly enlarged

Prevention Treatment with progestins results in complete regression of disease in 94% and 75% 20

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Laparoscopic management Laparoscopic surgical staging is believed to be as safe as an open procedure. The five year survival rate of 93-95% is also comparable to the traditional staging laparotomy & hysterectomy30 however significant complications can occur and careful selection is essential. Gynaecology oncology group(GOG) has initiated a study for the feasibility and efficacy of laparoscopic surgical staging and therapy of E Ca31.

are important, fewer than 10% of patients with lymphnode involvement have grossly enlarged nodes. Therefore, it is important to determine the need for lymphadenectomy based on clinical and histologic factors. Some believe that the high risk factors for pelvic lymph node metastasis include deddifferentiation, deep myometrium invasion, cervical involvement, positive peritoneal cytology, adnexal metastasis and distant spread. There are reports that pelvic lymphadenectomy does not improve the prognosis22.

Chemotherapy Because tumor response to cytotoxic chemotherapy has been poor, chemotherapy is used only as adjuvant or palliation. Progestins have been used to treat recurrent disease, but the response rates have been poor32. Systemic chemotherapy is reserved in case of disseminated primary disease or extrapelvic recurrence and although the combination of cisplatin and doxorubicin is commonly used. carboplatin and paclitaxel combination represent an efficacious, low-toxicity regimen30.

Radiotherapy Pelvic radiotherapy (RT) is advocated but increases treatment related morbidity. Servere complications have been reported in 3% and 20% in mild. Extended-field radiation should be considered only for patients with histologically positive lymph nodes. Papillary and clear cell types need to be treated like ovarian carcinoma. In stage II disease with preoperative brachytherapy followed by appropriate surgery, five years disease free survival (DFS) is 80-90% in most studies. Some believe that post operative radiation should be considered in high risk histologic types either simple vaginal vault irradiation or external pelvic irradiation with or without extended abdominal irradiation (based on the extent of disease).17 The addition of vginal cuff brachytherapy boost to pelvic radiation for pelvic control or disease free survival is not recommended29.

Prognosis and Recurrence Factors which affect prognosis are age, medical conditions, tumour size, stage, and abnormalities on pelvic examination, tumour grade, and histologic subtype. Some studies have revealed that there is no association between recurrence and the clinicopathologic variables such as age at diagnosis, body mass index (BMI), histologic grade of tumor, histologic type, stage, depth of myometrial invasion, or whether the patient received adjuvant radiotherapy33. Cervical involvement carries worse prognosis, with 5 year DFS ranging from 45-60%24. In adenocarcinoma and adenocanthoma with appropriate management. 5 years Disease Free Survival (DFS) is 88-91%, with adenosquamous tumours, 62% and 45%

Stage III & IV cases are usually treated with individualized multimodal approach, with post operative pelvic radiotherapy, or using initial cytotoxic or hormonal therapy with or without radiation with local control of pain or bleeding. 21

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5. Walsh C, Holschneider C, Hoang Y et al. Co-existing ovarian malgnancy in young women with endometrial cancer. Obstetrics and Gynaecology 2005; 106: 693-9.

with papillary serous tumours, clear-cell carcinoma respectively. Patients with locally advanced disease have aq 5 year survival of 4-44%. In most patients with recurrence, the disease recurs at a distant site and is thus incurable. Total pelvic exenteration is an option for patients who have a vaginal cuff recurrence after radiation therapy. Offering HRT to survivors is controversial. Additionally 75% of En Ca present with localized disease with potential for significant survival. So the balance of potential and theoretical risk of disease recurrence with HRT against the believed benefits is crucial37. Further it is currently believed that the recurrence ca may not be neocarcinogenesis, but is the clinical manifestation of micrometastasis that were either not detected or not treated successfully at the time of initial therapy2. En Ca is less common in developing countries including India, however longetivity is increasing, so the number of elderly women is going to be more with possibilities of more cases of En Ca. Suspicion helps in timely diagnosis and therapy with better survival. However there are grey areas, so research needs to be continued.

6. Setiawan, Veronica wendy 1: Pike, Malcolm C. 1: Kolonel, Laurence N, 2: Nomura, Abraham M. 2: Goodman, Marc T. 2: Henderson, Brian E, 1: Racial/Ethnic Differences in Endometrial Cancer Risk: The Multiethnic Cohort Study. Am J. of Epidemiology 165(3), 2007, 262-27. 7.

David S, Miller “Should we ofer HRT to ovarian and endometrial cancer survivors? Curr Opin Obstet Gynaecol, 2001; 10(1): 9-14.

8. Bergan L. Beilen M.L.R. Galee M.P.W, YHollera H. Benraade JK. Van leeuwen E. Risk & Prognosis of endometrial carcinoma after - for breast carcinoma. The Lancet; 2000, 356-881. 9. Wild SH, Finalyson AR, Bryden JR, Lee RJ, Bishop JL, Byrne CD and Brewster DH. Cancer, cardiovascular disease and diabetes mortality among women with a history of endometrial cancer. Br J Cancer (2007), 96, 1747-1749. 10. Kristin E, Anderson, Elizabeth Anderson, Pamela J. Mink, Ching Pong Hong, Lawerence H. Kushi Thomas A, Sellers, DeAnn Lazovich, and Aaron R, Folsom. Diabetes and Endometrial Cancer in the lowa women’s Health Study. Cancer Epidemiology, Biomarkers and Prevention 10, 611-616, 2001.

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