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Uterine Cancer Pathophysiology

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General Information About Endometrial Cancer

Cancer of the endometrium is the most common gynecologic malignancy in the United States and accounts for 6% of all cancers in women. The majority of cases are diagnosed at an early stage and are amenable to treatment with surgery alone. However, patients with pathologic features predictive of a high rate of relapse and patients with extrauterine spread at diagnosis have a high rate of relapse despite adjuvant therapy.

Incidence and Mortality

Estimated new cases and deaths from cancer of the uterine corpus, which includes the endometrium, in the United States in 2017:[1]

  • New cases: 61,380.
  • Deaths: 10,920.

Endometrial cancer is usually diagnosed and treated at an early stage. Cardiovascular disease is the most common cause of death in patients with endometrial cancer because of the related metabolic risk factors.[2]

Anatomy

The endometrium is the inner lining of the uterus and has both functional and basal layers. The functional layer is hormonally sensitive and is shed in a cyclical pattern during menstruation in reproductive-age women. Both estrogen and progesterone are necessary to maintain a normal endometrial lining. However, factors that lead to an excess of estrogen, including obesity and anovulation, lead to an increase in the deposition of the endometrial lining. These changes may lead to endometrial hyperplasia, and, in some cases, endometrial cancer. Whatever the cause, a thickened lining will lead to sloughing of the endometrial tissue through the endometrial canal and into the vagina. As a result, heavy menstrual bleeding or bleeding after menopause are often the initial signs of endometrial cancer. This symptom tends to happen early in the disease course, allowing for identification of the disease at an early stage for most women.

 

Risk Factors

Risk factors for endometrial cancer include the following:

  • Endometrial hyperplasia.
  • Hormone therapy.[3,4]
  • Tamoxifen therapy.[5,6]
  • Obesity.
  • Reproductive factors (nulliparity, early menarche/late menopause, or polycystic ovarian syndrome).
  • Family history/genetic predisposition.[7,8]
  • Hyperinsulinemia.[9]

Prolonged, unopposed estrogen exposure has been associated with an increased risk of endometrial cancer.[3,4] However, combined estrogen and progesterone therapy prevents the increase in risk of endometrial cancer associated with unopposed estrogen use.[10,11]

Tamoxifen, which is used for both the treatment and prevention of breast cancer (NSABP-B-14), is associated with an increased risk of endometrial cancer related to the estrogenic effect of tamoxifen on the endometrium.[5,6] It is important that patients who are receiving tamoxifen and experiencing abnormal uterine bleeding have follow-up examinations and biopsy of the endometrial lining. The U.S. Food and Drug Administration released a black box warning that includes data about the increase in uterine malignancies associated with tamoxifen use. (Refer to the Lynch Syndrome (LS) section in the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information about risk factors for LS-associated endometrial cancer.)

Clinical Features

Irregular vaginal bleeding is the most common presenting sign of endometrial cancer. It generally occurs early in the disease process, and is the reason why most patients are diagnosed with highly curable stage I endometrial cancer.

Diagnostic Evaluation

The following procedures may be used to detect endometrial cancer:

  • Transvaginal ultrasound.
  • Endometrial biopsy.
  • Pelvic exam.
  • Dilatation and curettage (D&C).
  • Hysteroscopy.

To definitively diagnose endometrial cancer, a procedure that directly samples the endometrial tissue is necessary.

The Pap smear is not a reliable screening procedure for the detection of endometrial cancer, even though a retrospective study found a strong correlation between positive cervical cytology and high-risk endometrial disease (i.e., high-grade tumor and deep myometrial invasion).[12] A prospective study found a statistically significant association between malignant cytology and increased risk of nodal disease.[13]

Prognostic Factors

Prognostic factors for endometrial cancer include the following:

  • Tumor stage and grade (including extrauterine nodal spread).
  • Hormone receptor status.

Tumor stage and grade (including extrauterine nodal spread)

The following table highlights the risk of nodal metastasis based on findings at the time of staging surgery:[14]

 

Table 1. Risk of Nodal Metastasis in Clinical Stage I Endometrial Cancer

Prognostic GroupPatient CharacteristicsRisk of Nodal Involvement
AGrade 1 tumors involving only endometrium<5%
No evidence of intraperitoneal spread
BGrade 2–3 tumors5%–9% pelvic nodes
Invasion of <50% of myometrium
No intraperitoneal spread4% periaortic nodes
CDeep muscle invasion20%–60% pelvic nodes
High-grade tumors10%–30% periaortic nodes
Intraperitoneal spread

A Gynecologic Oncology Group study related surgical-pathologic parameters and postoperative treatment to recurrence-free interval and recurrence site. Grade 3 histology and deep myometrial invasion in patients without extrauterine spread were the greatest determinants of recurrence. In this study, the frequency of recurrence was greatly increased with the following:[15,16]

  • Positive pelvic nodes.
  • Adnexal metastasis.
  • Positive peritoneal cytology.
  • Capillary space involvement.
  • Involvement of the isthmus or cervix.
  • Positive periaortic nodes (includes all grades and depth of invasion). Of the cases with aortic node metastases, 98% were in patients with positive pelvic nodes, intra-abdominal metastases, or tumor invasion of the outer 33% of the myometrium.

When the only evidence of extrauterine spread is positive peritoneal cytology, the influence on outcome is unclear. The value of therapy directed at this cytologic finding is not well founded,[17-22] and some data are contradictory.[23] Although the collection of cytology specimens is still suggested, a positive result does not upstage the cancer. Other extrauterine disease must be present before additional postoperative therapy is considered.

Involvement of the capillary-lymphatic space on histopathologic examination correlates with extrauterine and nodal spread of tumor.[24]

Hormone receptor status

Progesterone and estrogen receptors, assessed either by biochemical or immunohistochemical methods, are included, when possible, in the evaluation of patients with stage I and stage II cancer.[25-27]

One report found progesterone receptor levels to be the single most important prognostic indicator of 3-year survival in clinical stages I and II disease. Patients with progesterone receptor levels above 100 had a 3-year disease-free survival (DFS) of 93%, compared with a 36% DFS for a level below 100. After adjusting for progesterone receptor levels, only cervical involvement and peritoneal cytology were significant prognostic variables.[28]

Other reports confirm the importance of hormone receptor status as an independent prognostic factor.[29] Additionally, immunohistochemical staining of paraffin-embedded tissue for both estrogen and progesterone receptors has been shown to correlate with Féderation Internationale de Gynécologie et d’Obstétrique (FIGO) grade and survival.[25-27]

Other prognostic factors

Other factors predictive of poor prognosis include the following:[27,30,31]

  • A high S-phase fraction.
  • Aneuploidy.
  • Absence of PTEN.
  • PIK3CA mutation status.
  • p53 mutation status.
  • Her-2/neu overexpression.
  • Oncogene expression (e.g., overexpression of the Her-2/neu oncogene has been associated with a poor overall prognosis).

A general review of prognostic factors has been published.[32]

 

References

  1. American Cancer Society: Cancer Facts and Figures 2017. Atlanta, Ga: American Cancer Society, 2017. Available onlineExit Disclaimer. Last accessed October 13, 2017.
  2. Ward KK, Shah NR, Saenz CC, et al.: Cardiovascular disease is the leading cause of death among endometrial cancer patients. Gynecol Oncol 126 (2): 176-9, 2012. [PUBMED Abstract]
  3. Ziel HK, Finkle WD: Increased risk of endometrial carcinoma among users of conjugated estrogens. N Engl J Med 293 (23): 1167-70, 1975. [PUBMED Abstract]
  4. Jick SS, Walker AM, Jick H: Estrogens, progesterone, and endometrial cancer. Epidemiology 4 (1): 20-4, 1993. [PUBMED Abstract]
  5. van Leeuwen FE, Benraadt J, Coebergh JW, et al.: Risk of endometrial cancer after tamoxifen treatment of breast cancer. Lancet 343 (8895): 448-52, 1994. [PUBMED Abstract]
  6. Fisher B, Costantino JP, Redmond CK, et al.: Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst 86 (7): 527-37, 1994. [PUBMED Abstract]
  7. Lynch HT, Lynch J, Conway T, et al.: Familial aggregation of carcinoma of the endometrium. Am J Obstet Gynecol 171 (1): 24-7, 1994. [PUBMED Abstract]
  8. Lu KH, Schorge JO, Rodabaugh KJ, et al.: Prospective determination of prevalence of lynch syndrome in young women with endometrial cancer. J Clin Oncol 25 (33): 5158-64, 2007. [PUBMED Abstract]
  9. Nead KT, Sharp SJ, Thompson DJ, et al.: Evidence of a Causal Association Between Insulinemia and Endometrial Cancer: A Mendelian Randomization Analysis. J Natl Cancer Inst 107 (9): , 2015. [PUBMED Abstract]
  10. Jick SS: Combined estrogen and progesterone use and endometrial cancer. Epidemiology 4 (4): 384, 1993. [PUBMED Abstract]
  11. Bilezikian JP: Major issues regarding estrogen replacement therapy in postmenopausal women. J Womens Health 3 (4): 273-82, 1994.
  12. DuBeshter B, Warshal DP, Angel C, et al.: Endometrial carcinoma: the relevance of cervical cytology. Obstet Gynecol 77 (3): 458-62, 1991. [PUBMED Abstract]
  13. Larson DM, Johnson KK, Reyes CN Jr, et al.: Prognostic significance of malignant cervical cytology in patients with endometrial cancer. Obstet Gynecol 84 (3): 399-403, 1994. [PUBMED Abstract]
  14. Takeshima N, Hirai Y, Tanaka N, et al.: Pelvic lymph node metastasis in endometrial cancer with no myometrial invasion. Obstet Gynecol 88 (2): 280-2, 1996. [PUBMED Abstract]
  15. Morrow CP, Bundy BN, Kurman RJ, et al.: Relationship between surgical-pathological risk factors and outcome in clinical stage I and II carcinoma of the endometrium: a Gynecologic Oncology Group study. Gynecol Oncol 40 (1): 55-65, 1991. [PUBMED Abstract]
  16. Lanciano RM, Corn BW, Schultz DJ, et al.: The justification for a surgical staging system in endometrial carcinoma. Radiother Oncol 28 (3): 189-96, 1993. [PUBMED Abstract]
  17. Ambros RA, Kurman RJ: Combined assessment of vascular and myometrial invasion as a model to predict prognosis in stage I endometrioid adenocarcinoma of the uterine corpus. Cancer 69 (6): 1424-31, 1992. [PUBMED Abstract]
  18. Turner DA, Gershenson DM, Atkinson N, et al.: The prognostic significance of peritoneal cytology for stage I endometrial cancer. Obstet Gynecol 74 (5): 775-80, 1989. [PUBMED Abstract]
  19. Piver MS, Recio FO, Baker TR, et al.: A prospective trial of progesterone therapy for malignant peritoneal cytology in patients with endometrial carcinoma. Gynecol Oncol 47 (3): 373-6, 1992. [PUBMED Abstract]
  20. Kadar N, Homesley HD, Malfetano JH: Positive peritoneal cytology is an adverse factor in endometrial carcinoma only if there is other evidence of extrauterine disease. Gynecol Oncol 46 (2): 145-9, 1992. [PUBMED Abstract]
  21. Lurain JR: The significance of positive peritoneal cytology in endometrial cancer. Gynecol Oncol 46 (2): 143-4, 1992. [PUBMED Abstract]
  22. Lurain JR, Rice BL, Rademaker AW, et al.: Prognostic factors associated with recurrence in clinical stage I adenocarcinoma of the endometrium. Obstet Gynecol 78 (1): 63-9, 1991. [PUBMED Abstract]
  23. Garg G, Gao F, Wright JD, et al.: Positive peritoneal cytology is an independent risk-factor in early stage endometrial cancer. Gynecol Oncol 128 (1): 77-82, 2013. [PUBMED Abstract]
  24. Hanson MB, van Nagell JR Jr, Powell DE, et al.: The prognostic significance of lymph-vascular space invasion in stage I endometrial cancer. Cancer 55 (8): 1753-7, 1985. [PUBMED Abstract]
  25. Carcangiu ML, Chambers JT, Voynick IM, et al.: Immunohistochemical evaluation of estrogen and progesterone receptor content in 183 patients with endometrial carcinoma. Part I: Clinical and histologic correlations. Am J Clin Pathol 94 (3): 247-54, 1990. [PUBMED Abstract]
  26. Chambers JT, Carcangiu ML, Voynick IM, et al.: Immunohistochemical evaluation of estrogen and progesterone receptor content in 183 patients with endometrial carcinoma. Part II: Correlation between biochemical and immunohistochemical methods and survival. Am J Clin Pathol 94 (3): 255-60, 1990. [PUBMED Abstract]
  27. Gurpide E: Endometrial cancer: biochemical and clinical correlates. J Natl Cancer Inst 83 (6): 405-16, 1991. [PUBMED Abstract]
  28. Ingram SS, Rosenman J, Heath R, et al.: The predictive value of progesterone receptor levels in endometrial cancer. Int J Radiat Oncol Biol Phys 17 (1): 21-7, 1989. [PUBMED Abstract]
  29. Creasman WT: Prognostic significance of hormone receptors in endometrial cancer. Cancer 71 (4 Suppl): 1467-70, 1993. [PUBMED Abstract]
  30. Friberg LG, Norén H, Delle U: Prognostic value of DNA ploidy and S-phase fraction in endometrial cancer stage I and II: a prospective 5-year survival study. Gynecol Oncol 53 (1): 64-9, 1994. [PUBMED Abstract]
  31. Hetzel DJ, Wilson TO, Keeney GL, et al.: HER-2/neu expression: a major prognostic factor in endometrial cancer. Gynecol Oncol 47 (2): 179-85, 1992. [PUBMED Abstract]
  32. Binder PS, Mutch DG: Update on prognostic markers for endometrial cancer. Womens Health (Lond Engl) 10 (3): 277-88, 2014. [PUBMED Abstract]

 

Source:

https://www.cancer.gov/types/uterine/hp/endometrial-treatment-pdq

Hyperlink:
https://www.cancer.gov/types/uterine/hp/endometrial-treatment-pdq