For information about the treatments listed below, see Treatment Option Overview. To learn about the cancer stages, see Stages of Soft Tissue Sarcoma.

Treatment of stage I soft tissue sarcoma may include the following:

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

For information about the treatments listed below, see Treatment Option Overview. To learn about the cancer stages, see Stages of Soft Tissue Sarcoma.

Treatment of stage II soft tissue sarcoma and stage III soft tissue sarcoma that has not spread to lymph nodes may include the following:

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

For information about the treatments listed below, see Treatment Option Overview. To learn about the cancer stages, see Stages of Soft Tissue Sarcoma.

Treatment of stage III soft tissue sarcoma that has spread to lymph nodes (advanced) may include the following:

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

For information about the treatments listed below, see Treatment Option Overview. To learn about the cancer stages, see Stages of Soft Tissue Sarcoma.

Treatment of stage IV soft tissue sarcoma may include the following:

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

For information about the treatments listed below, see Treatment Option Overview. To learn about the cancer stages, see Stages of Soft Tissue Sarcoma.

Treatment of recurrent soft tissue sarcoma may include the following:

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

For more information from the National Cancer Institute about soft tissue sarcomas, see the following:

For general cancer information and other resources from the National Cancer Institute, visit:

Uterine sarcoma accounts for less than 1% of gynecologic malignancies and 2% to 5% of all uterine malignancies.[1] The following tumors arise primarily from three distinct tissues:

These three distinct entities are often grouped together as uterine sarcomas; however, each type of tumor is being studied in separate clinical trials.

Carcinosarcoma (the preferred designation by the World Health Organization [WHO]) is also referred to as mixed mesodermal sarcoma or mullerian tumor. Controversy exists about the following issues:

The stromal components of carcinosarcoma are further characterized by homologous elements, such as malignant mesenchymal tissue considered possibly native to the uterus, or heterologous elements, such as striated muscle, cartilage, or bone, which are foreign to the uterus. Carcinosarcoma parallels endometrial cancer in its postmenopausal predominance and in other epidemiological features. Increasingly, the treatment of carcinosarcoma is becoming similar to combined modality approaches for endometrial adenocarcinoma.

Other rare forms of uterine sarcoma also fall under the WHO classification for mesenchymal and mixed tumors of the uterus. These sarcomas include the following:[2,3]

For more information, see Childhood Rhabdomyosarcoma Treatment.

Surgery alone can be curative if the malignancy is contained within the uterus. The value of pelvic radiation therapy is not established. Current studies consist primarily of phase II chemotherapy trials for patients with advanced disease. Adjuvant chemotherapy following complete resection for patients with stage I or II disease was not found to be effective in a randomized trial.[10] Yet, nonrandomized trials have reported improved survival following adjuvant chemotherapy with or without radiation therapy.[11–13]

References

1. Forney JP, Buschbaum HJ: Classifying, staging, and treating uterine sarcomas. Contemp Ob Gyn 18(3):47, 50, 55-56, 61-62, 64, 69, 1981.
2. Gershenson D, McGuire W, Gore Martin, et al.: Gynecologic Cancer: Controversies in Management. 3rd ed. Churchill Livingstone, 2004.
3. Tavassoéli F, Devilee P, et al.: Pathology and Genetics of Tumours of the Breast and Female Genital Organs. International Agency for Research on Cancer, 2004.
4. Bergman L, Beelen ML, Gallee MP, et al.: Risk and prognosis of endometrial cancer after tamoxifen for breast cancer. Comprehensive Cancer Centres’ ALERT Group. Assessment of Liver and Endometrial cancer Risk following Tamoxifen. Lancet 356 (9233): 881-7, 2000. [PUBMED Abstract]
5. Cohen I: Endometrial pathologies associated with postmenopausal tamoxifen treatment. Gynecol Oncol 94 (2): 256-66, 2004. [PUBMED Abstract]
6. Wickerham DL, Fisher B, Wolmark N, et al.: Association of tamoxifen and uterine sarcoma. J Clin Oncol 20 (11): 2758-60, 2002. [PUBMED Abstract]
7. Major FJ, Blessing JA, Silverberg SG, et al.: Prognostic factors in early-stage uterine sarcoma. A Gynecologic Oncology Group study. Cancer 71 (4 Suppl): 1702-9, 1993. [PUBMED Abstract]
8. Evans HL, Chawla SP, Simpson C, et al.: Smooth muscle neoplasms of the uterus other than ordinary leiomyoma. A study of 46 cases, with emphasis on diagnostic criteria and prognostic factors. Cancer 62 (10): 2239-47, 1988. [PUBMED Abstract]
9. Oláh KS, Dunn JA, Gee H: Leiomyosarcomas have a poorer prognosis than mixed mesodermal tumours when adjusting for known prognostic factors: the result of a retrospective study of 423 cases of uterine sarcoma. Br J Obstet Gynaecol 99 (7): 590-4, 1992. [PUBMED Abstract]
10. Omura GA, Blessing JA, Major F, et al.: A randomized clinical trial of adjuvant adriamycin in uterine sarcomas: a Gynecologic Oncology Group Study. J Clin Oncol 3 (9): 1240-5, 1985. [PUBMED Abstract]
11. Piver MS, Lele SB, Marchetti DL, et al.: Effect of adjuvant chemotherapy on time to recurrence and survival of stage I uterine sarcomas. J Surg Oncol 38 (4): 233-9, 1988. [PUBMED Abstract]
12. van Nagell JR, Hanson MB, Donaldson ES, et al.: Adjuvant vincristine, dactinomycin, and cyclophosphamide therapy in stage I uterine sarcomas. A pilot study. Cancer 57 (8): 1451-4, 1986. [PUBMED Abstract]
13. Peters WA, Rivkin SE, Smith MR, et al.: Cisplatin and adriamycin combination chemotherapy for uterine stromal sarcomas and mixed mesodermal tumors. Gynecol Oncol 34 (3): 323-7, 1989. [PUBMED Abstract]

The most common histological types of uterine sarcomas include:

The uterine neoplasm classification of the International Society of Gynecologic Pathologists and the World Health Organization uses the term carcinosarcoma for all primary uterine neoplasms containing malignant elements of both epithelial and stromal light microscopic appearances, regardless of whether malignant heterologous elements are present.[1]

References

1. Silverberg SG, Major FJ, Blessing JA, et al.: Carcinosarcoma (malignant mixed mesodermal tumor) of the uterus. A Gynecologic Oncology Group pathologic study of 203 cases. Int J Gynecol Pathol 9 (1): 1-19, 1990. [PUBMED Abstract]

References

1. Mbatani N, Olawaiye AB, Prat J: Uterine sarcomas. Int J Gynaecol Obstet 143 (Suppl 2): 51-58, 2018. [PUBMED Abstract]
2. Corpus uteri – sarcoma. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp 671-80.

Surgery is often the principal means of diagnosis and is the primary treatment for all patients with uterine sarcoma. If the diagnosis is known, the extent of surgery is planned according to the stage of the tumor. Hysterectomy is usually performed when a uterine malignancy is suspected, except for rare instances when preservation of the uterus in a young patient is deemed safe for the type of cancer (e.g., a totally confined low-grade leiomyosarcoma in a woman who desires to retain childbearing potential). Medically suitable patients with the preoperative diagnosis of uterine sarcoma are considered candidates for abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic and periaortic selective lymphadenectomy. Cytologic washings are obtained from the pelvis and abdomen. Thorough examination of the diaphragm, omentum, and upper abdomen is performed.

There is no firm evidence from a prospective study that adjuvant chemotherapy or radiation therapy is of benefit for patients with uterine sarcoma.[1] In one Gynecologic Oncology Group (GOG) study, the use of adjuvant doxorubicin did not alter the survival rate of patients with resected stage I or stage II uterine sarcomas; however, interpretation of these results is difficult because this study included some patients who received radiation and three types of uterine sarcomas that have variable responses to doxorubicin.[1][Level of evidence A1] Because the risk of disease recurrence is high, even with localized presentations, many physicians have considered the use of adjuvant chemotherapy or radiation therapy.[2] Another GOG study (GOG-0150 [NCT00002546]) addressed radiation therapy versus adjuvant chemotherapy.[3]

References

1. Omura GA, Blessing JA, Major F, et al.: A randomized clinical trial of adjuvant adriamycin in uterine sarcomas: a Gynecologic Oncology Group Study. J Clin Oncol 3 (9): 1240-5, 1985. [PUBMED Abstract]
2. Kohorn EI, Schwartz PE, Chambers JT, et al.: Adjuvant therapy in mixed mullerian tumors of the uterus. Gynecol Oncol 23 (2): 212-21, 1986. [PUBMED Abstract]
3. Wolfson AH, Brady MF, Rocereto T, et al.: A gynecologic oncology group randomized phase III trial of whole abdominal irradiation (WAI) vs. cisplatin-ifosfamide and mesna (CIM) as post-surgical therapy in stage I-IV carcinosarcoma (CS) of the uterus. Gynecol Oncol 107 (2): 177-85, 2007. [PUBMED Abstract]

References

1. Hornback NB, Omura G, Major FJ: Observations on the use of adjuvant radiation therapy in patients with stage I and II uterine sarcoma. Int J Radiat Oncol Biol Phys 12 (12): 2127-30, 1986. [PUBMED Abstract]
2. Larson B, Silfverswärd C, Nilsson B, et al.: Mixed müllerian tumours of the uterus–prognostic factors: a clinical and histopathologic study of 147 cases. Radiother Oncol 17 (2): 123-32, 1990. [PUBMED Abstract]
3. Peters WA, Rivkin SE, Smith MR, et al.: Cisplatin and adriamycin combination chemotherapy for uterine stromal sarcomas and mixed mesodermal tumors. Gynecol Oncol 34 (3): 323-7, 1989. [PUBMED Abstract]

References

1. Hornback NB, Omura G, Major FJ: Observations on the use of adjuvant radiation therapy in patients with stage I and II uterine sarcoma. Int J Radiat Oncol Biol Phys 12 (12): 2127-30, 1986. [PUBMED Abstract]
2. Peters WA, Rivkin SE, Smith MR, et al.: Cisplatin and adriamycin combination chemotherapy for uterine stromal sarcomas and mixed mesodermal tumors. Gynecol Oncol 34 (3): 323-7, 1989. [PUBMED Abstract]

Phase II chemotherapy studies by the Gynecologic Oncology Group have documented some antitumor activity for cisplatin, doxorubicin, and ifosfamide.[1,2] These studies have also documented differences in response leading to separate trials for patients with carcinosarcomas and leiomyosarcomas. In patients previously untreated with chemotherapy, ifosfamide had a 32.2% response rate in patients with carcinosarcomas [3] and a 17.2% partial response rate in patients with leiomyosarcomas.[2]

GOG-108 was a randomized trial that examined the use of ifosfamide with or without cisplatin as first-line therapy for patients with measurable advanced or recurrent carcinosarcomas. Patients in the combination arm had a higher response rate (54% vs. 34%) and longer progression-free survival (PFS) (6 months vs. 4 months). However, patients did not have a significant improvement in survival (9 months vs. 8 months).[4][Level of evidence A1] The follow-up GOG-0161 study [NCT00003128] used 3-day ifosfamide regimens (instead of the more toxic 5-day regimen in the preceding study) given alone or in combination with paclitaxel (with filgrastim starting on day 4).[5] The combination was superior in response rates (45% vs. 29%), PFS (8.4 months vs. 5.8 months), and overall survival (13.5 months vs. 8.4 months). The hazard ratio for death favored the combination (0.69; 95% confidence interval, 0.49–0.97).[5][Level of evidence A1] In this study, 52% of 179 evaluable patients had recurrent disease, 18% had stage III disease, and 30% had stage IV disease. In addition, imbalances were present in the sites of disease and in the use of prior radiation therapy, and 30 patients were excluded for wrong pathology.

A role for chemotherapy as an adjuvant to surgery has not been established.

References

1. Thigpen JT, Blessing JA, Beecham J, et al.: Phase II trial of cisplatin as first-line chemotherapy in patients with advanced or recurrent uterine sarcomas: a Gynecologic Oncology Group study. J Clin Oncol 9 (11): 1962-6, 1991. [PUBMED Abstract]
2. Sutton GP, Blessing JA, Barrett RJ, et al.: Phase II trial of ifosfamide and mesna in leiomyosarcoma of the uterus: a Gynecologic Oncology Group study. Am J Obstet Gynecol 166 (2): 556-9, 1992. [PUBMED Abstract]
3. Sutton GP, Blessing JA, Rosenshein N, et al.: Phase II trial of ifosfamide and mesna in mixed mesodermal tumors of the uterus (a Gynecologic Oncology Group study). Am J Obstet Gynecol 161 (2): 309-12, 1989. [PUBMED Abstract]
4. Sutton G, Brunetto VL, Kilgore L, et al.: A phase III trial of ifosfamide with or without cisplatin in carcinosarcoma of the uterus: A Gynecologic Oncology Group Study. Gynecol Oncol 79 (2): 147-53, 2000. [PUBMED Abstract]
5. Homesley HD, Filiaci V, Markman M, et al.: Phase III trial of ifosfamide with or without paclitaxel in advanced uterine carcinosarcoma: a Gynecologic Oncology Group Study. J Clin Oncol 25 (5): 526-31, 2007. [PUBMED Abstract]

There is currently no standard therapy for patients with stage IV disease. These patients should enroll in an ongoing clinical trial.

Phase II chemotherapy studies by the Gynecologic Oncology Group have documented some antitumor activity for cisplatin, doxorubicin, and ifosfamide.[1,2] These studies have also documented differences in response leading to separate trials for patients with carcinosarcomas and leiomyosarcomas. In patients previously untreated with chemotherapy, ifosfamide had a 32.2% response rate in patients with carcinosarcomas,[2] a 33% response rate in patients with endometrial stromal cell sarcomas,[3], and a 17.2% partial response rate in patients with leiomyosarcomas.[4] Doxorubicin in combination with dacarbazine or cyclophosphamide is no more active than doxorubicin alone for advanced disease.[5,6] Cisplatin has activity as first-line therapy and minimal activity as second-line therapy for patients with carcinosarcomas, but cisplatin is inactive as first- or second-line therapy for patients with leiomyosarcomas.[1,7]

GOG-108 was a randomized trial that examined the use of ifosfamide with or without cisplatin as first-line therapy for patients with measurable advanced or recurrent carcinosarcomas. Patients in the combination arm had a higher response rate (54% vs. 34%) and longer progression-free survival (PFS) (6 months vs. 4 months). However, patients did not have a significant improvement in survival (9 months vs. 8 months).[8][Level of evidence A1] The follow-up GOG-0161 study [NCT00003128] used 3-day ifosfamide regimens (instead of the more toxic 5-day regimen in the preceding study) given alone or in combination with paclitaxel (with filgrastim starting on day 4).[9] The combination was superior in response rates (45% vs. 29%), PFS (8.4 months vs. 5.8 months), and overall survival (13.5 months vs. 8.4 months). The hazard ratio for death favored the combination (0.69; 95% confidence interval, 0.49–0.97).[9][Level of evidence A1] In this study, 52% of 179 evaluable patients had recurrent disease, 18% had stage III disease, and 30% had stage IV disease. In addition, imbalances were present in the sites of disease and in the use of prior radiation therapy, and 30 patients were excluded for wrong pathology.

References

1. Thigpen JT, Blessing JA, Beecham J, et al.: Phase II trial of cisplatin as first-line chemotherapy in patients with advanced or recurrent uterine sarcomas: a Gynecologic Oncology Group study. J Clin Oncol 9 (11): 1962-6, 1991. [PUBMED Abstract]
2. Sutton GP, Blessing JA, Rosenshein N, et al.: Phase II trial of ifosfamide and mesna in mixed mesodermal tumors of the uterus (a Gynecologic Oncology Group study). Am J Obstet Gynecol 161 (2): 309-12, 1989. [PUBMED Abstract]
3. Sutton G, Blessing JA, Park R, et al.: Ifosfamide treatment of recurrent or metastatic endometrial stromal sarcomas previously unexposed to chemotherapy: a study of the Gynecologic Oncology Group. Obstet Gynecol 87 (5 Pt 1): 747-50, 1996. [PUBMED Abstract]
4. Sutton GP, Blessing JA, Barrett RJ, et al.: Phase II trial of ifosfamide and mesna in leiomyosarcoma of the uterus: a Gynecologic Oncology Group study. Am J Obstet Gynecol 166 (2): 556-9, 1992. [PUBMED Abstract]
5. Omura GA, Major FJ, Blessing JA, et al.: A randomized study of adriamycin with and without dimethyl triazenoimidazole carboxamide in advanced uterine sarcomas. Cancer 52 (4): 626-32, 1983. [PUBMED Abstract]
6. Muss HB, Bundy B, DiSaia PJ, et al.: Treatment of recurrent or advanced uterine sarcoma. A randomized trial of doxorubicin versus doxorubicin and cyclophosphamide (a phase III trial of the Gynecologic Oncology Group). Cancer 55 (8): 1648-53, 1985. [PUBMED Abstract]
7. Thigpen JT, Blessing JA, Wilbanks GD: Cisplatin as second-line chemotherapy in the treatment of advanced or recurrent leiomyosarcoma of the uterus. A phase II trial of the Gynecologic Oncology Group. Am J Clin Oncol 9 (1): 18-20, 1986. [PUBMED Abstract]
8. Sutton G, Brunetto VL, Kilgore L, et al.: A phase III trial of ifosfamide with or without cisplatin in carcinosarcoma of the uterus: A Gynecologic Oncology Group Study. Gynecol Oncol 79 (2): 147-53, 2000. [PUBMED Abstract]
9. Homesley HD, Filiaci V, Markman M, et al.: Phase III trial of ifosfamide with or without paclitaxel in advanced uterine carcinosarcoma: a Gynecologic Oncology Group Study. J Clin Oncol 25 (5): 526-31, 2007. [PUBMED Abstract]

References

1. Thigpen JT, Blessing JA, Beecham J, et al.: Phase II trial of cisplatin as first-line chemotherapy in patients with advanced or recurrent uterine sarcomas: a Gynecologic Oncology Group study. J Clin Oncol 9 (11): 1962-6, 1991. [PUBMED Abstract]
2. Sutton GP, Blessing JA, Rosenshein N, et al.: Phase II trial of ifosfamide and mesna in mixed mesodermal tumors of the uterus (a Gynecologic Oncology Group study). Am J Obstet Gynecol 161 (2): 309-12, 1989. [PUBMED Abstract]
3. Sutton G, Blessing JA, Park R, et al.: Ifosfamide treatment of recurrent or metastatic endometrial stromal sarcomas previously unexposed to chemotherapy: a study of the Gynecologic Oncology Group. Obstet Gynecol 87 (5 Pt 1): 747-50, 1996. [PUBMED Abstract]
4. Sutton GP, Blessing JA, Barrett RJ, et al.: Phase II trial of ifosfamide and mesna in leiomyosarcoma of the uterus: a Gynecologic Oncology Group study. Am J Obstet Gynecol 166 (2): 556-9, 1992. [PUBMED Abstract]
5. Omura GA, Major FJ, Blessing JA, et al.: A randomized study of adriamycin with and without dimethyl triazenoimidazole carboxamide in advanced uterine sarcomas. Cancer 52 (4): 626-32, 1983. [PUBMED Abstract]
6. Muss HB, Bundy B, DiSaia PJ, et al.: Treatment of recurrent or advanced uterine sarcoma. A randomized trial of doxorubicin versus doxorubicin and cyclophosphamide (a phase III trial of the Gynecologic Oncology Group). Cancer 55 (8): 1648-53, 1985. [PUBMED Abstract]
7. Thigpen JT, Blessing JA, Wilbanks GD: Cisplatin as second-line chemotherapy in the treatment of advanced or recurrent leiomyosarcoma of the uterus. A phase II trial of the Gynecologic Oncology Group. Am J Clin Oncol 9 (1): 18-20, 1986. [PUBMED Abstract]
8. Hensley ML, Maki R, Venkatraman E, et al.: Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase II trial. J Clin Oncol 20 (12): 2824-31, 2002. [PUBMED Abstract]
9. Sutton G, Brunetto VL, Kilgore L, et al.: A phase III trial of ifosfamide with or without cisplatin in carcinosarcoma of the uterus: A Gynecologic Oncology Group Study. Gynecol Oncol 79 (2): 147-53, 2000. [PUBMED Abstract]
10. Homesley HD, Filiaci V, Markman M, et al.: Phase III trial of ifosfamide with or without paclitaxel in advanced uterine carcinosarcoma: a Gynecologic Oncology Group Study. J Clin Oncol 25 (5): 526-31, 2007. [PUBMED Abstract]
11. Katz L, Merino MJ, Sakamoto H, et al.: Endometrial stromal sarcoma: a clinicopathologic study of 11 cases with determination of estrogen and progestin receptor levels in three tumors. Gynecol Oncol 26 (1): 87-97, 1987. [PUBMED Abstract]

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

Cancer of the endometrium is the most common gynecologic malignancy in the United States and accounts for 7% of all cancers in women. Most cases are diagnosed at an early stage and are amenable to treatment with surgery alone.[1] However, patients with pathological features predictive of a high rate of relapse and patients with extrauterine spread at diagnosis have a high rate of relapse despite adjuvant therapy. The most common cause of death in patients with endometrial cancer is cardiovascular disease because of 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.

Enlarge

References

1. American Cancer Society: Cancer Facts and Figures 2025. American Cancer Society, 2025. Available online. Last accessed January 16, 2025.
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. Beral V, Bull D, Reeves G, et al.: Endometrial cancer and hormone-replacement therapy in the Million Women Study. Lancet 365 (9470): 1543-51, 2005 Apr 30-May 6. [PUBMED Abstract]
4. Anderson GL, Limacher M, Assaf AR, et al.: Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 291 (14): 1701-12, 2004. [PUBMED Abstract]
5. Furness S, Roberts H, Marjoribanks J, et al.: Hormone therapy in postmenopausal women and risk of endometrial hyperplasia. Cochrane Database Syst Rev (2): CD000402, 2009. [PUBMED Abstract]
6. Grady D, Gebretsadik T, Kerlikowske K, et al.: Hormone replacement therapy and endometrial cancer risk: a meta-analysis. Obstet Gynecol 85 (2): 304-13, 1995. [PUBMED Abstract]
7. Smith DC, Prentice R, Thompson DJ, et al.: Association of exogenous estrogen and endometrial carcinoma. N Engl J Med 293 (23): 1164-7, 1975. [PUBMED Abstract]
8. Mack TM, Pike MC, Henderson BE, et al.: Estrogens and endometrial cancer in a retirement community. N Engl J Med 294 (23): 1262-7, 1976. [PUBMED Abstract]
9. 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]
10. Walker AM, Jick H: Cancer of the corpus uteri: increasing incidence in the United States, 1970–1975. Am J Epidemiol 110 (1): 47-51, 1979. [PUBMED Abstract]
11. Gray LA, Christopherson WM, Hoover RN: Estrogens and endometrial carcinoma. Obstet Gynecol 49 (4): 385-9, 1977. [PUBMED Abstract]
12. McDonald TW, Annegers JF, O’Fallon WM, et al.: Exogenous estrogen and endometrial carcinoma: case-control and incidence study. Am J Obstet Gynecol 127 (6): 572-80, 1977. [PUBMED Abstract]
13. Antunes CM, Strolley PD, Rosenshein NB, et al.: Endometrial cancer and estrogen use. Report of a large case-control study. N Engl J Med 300 (1): 9-13, 1979. [PUBMED Abstract]
14. Shapiro S, Kelly JP, Rosenberg L, et al.: Risk of localized and widespread endometrial cancer in relation to recent and discontinued use of conjugated estrogens. N Engl J Med 313 (16): 969-72, 1985. [PUBMED Abstract]
15. 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]
16. Cummings SR, Eckert S, Krueger KA, et al.: The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. JAMA 281 (23): 2189-97, 1999. [PUBMED Abstract]
17. DeMichele A, Troxel AB, Berlin JA, et al.: Impact of raloxifene or tamoxifen use on endometrial cancer risk: a population-based case-control study. J Clin Oncol 26 (25): 4151-9, 2008. [PUBMED Abstract]
18. Bergström A, Pisani P, Tenet V, et al.: Overweight as an avoidable cause of cancer in Europe. Int J Cancer 91 (3): 421-30, 2001. [PUBMED Abstract]
19. Aune D, Navarro Rosenblatt DA, Chan DS, et al.: Anthropometric factors and endometrial cancer risk: a systematic review and dose-response meta-analysis of prospective studies. Ann Oncol 26 (8): 1635-48, 2015. [PUBMED Abstract]
20. Esposito K, Chiodini P, Capuano A, et al.: Metabolic syndrome and endometrial cancer: a meta-analysis. Endocrine 45 (1): 28-36, 2014. [PUBMED Abstract]
21. Troisi R, Potischman N, Hoover RN, et al.: Insulin and endometrial cancer. Am J Epidemiol 146 (6): 476-82, 1997. [PUBMED Abstract]
22. Tsilidis KK, Kasimis JC, Lopez DS, et al.: Type 2 diabetes and cancer: umbrella review of meta-analyses of observational studies. BMJ 350: g7607, 2015. [PUBMED Abstract]
23. Dossus L, Allen N, Kaaks R, et al.: Reproductive risk factors and endometrial cancer: the European Prospective Investigation into Cancer and Nutrition. Int J Cancer 127 (2): 442-51, 2010. [PUBMED Abstract]
24. Brown SB, Hankinson SE: Endogenous estrogens and the risk of breast, endometrial, and ovarian cancers. Steroids 99 (Pt A): 8-10, 2015. [PUBMED Abstract]
25. Barry JA, Azizia MM, Hardiman PJ: Risk of endometrial, ovarian and breast cancer in women with polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update 20 (5): 748-58, 2014 Sep-Oct. [PUBMED Abstract]
26. Win AK, Reece JC, Ryan S: Family history and risk of endometrial cancer: a systematic review and meta-analysis. Obstet Gynecol 125 (1): 89-98, 2015. [PUBMED Abstract]
27. Daniels MS: Genetic testing by cancer site: uterus. Cancer J 18 (4): 338-42, 2012 Jul-Aug. [PUBMED Abstract]
28. Dunlop MG, Farrington SM, Nicholl I, et al.: Population carrier frequency of hMSH2 and hMLH1 mutations. Br J Cancer 83 (12): 1643-5, 2000. [PUBMED Abstract]
29. 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]
30. 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]
31. Widra EA, Dunton CJ, McHugh M, et al.: Endometrial hyperplasia and the risk of carcinoma. Int J Gynecol Cancer 5 (3): 233-235, 1995. [PUBMED Abstract]
32. Jick SS, Walker AM, Jick H: Estrogens, progesterone, and endometrial cancer. Epidemiology 4 (1): 20-4, 1993. [PUBMED Abstract]
33. Jick SS: Combined estrogen and progesterone use and endometrial cancer. Epidemiology 4 (4): 384, 1993. [PUBMED Abstract]
34. Bilezikian JP: Major issues regarding estrogen replacement therapy in postmenopausal women. J Womens Health 3 (4): 273-82, 1994.
35. 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]
36. DuBeshter B, Warshal DP, Angel C, et al.: Endometrial carcinoma: the relevance of cervical cytology. Obstet Gynecol 77 (3): 458-62, 1991. [PUBMED Abstract]
37. Larson DM, Johnson KK, Reyes CN, et al.: Prognostic significance of malignant cervical cytology in patients with endometrial cancer. Obstet Gynecol 84 (3): 399-403, 1994. [PUBMED Abstract]
38. 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]
39. 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]
40. 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]
41. 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]
42. 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]
43. 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]
44. 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]
45. Lurain JR: The significance of positive peritoneal cytology in endometrial cancer. Gynecol Oncol 46 (2): 143-4, 1992. [PUBMED Abstract]
46. 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]
47. 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]
48. Hanson MB, van Nagell 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]
49. 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]
50. 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]
51. Gurpide E: Endometrial cancer: biochemical and clinical correlates. J Natl Cancer Inst 83 (6): 405-16, 1991. [PUBMED Abstract]
52. 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]
53. Creasman WT: Prognostic significance of hormone receptors in endometrial cancer. Cancer 71 (4 Suppl): 1467-70, 1993. [PUBMED Abstract]
54. 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]
55. 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]
56. Binder PS, Mutch DG: Update on prognostic markers for endometrial cancer. Womens Health (Lond Engl) 10 (3): 277-88, 2014. [PUBMED Abstract]

Endometrial cancers are classified as one of the following two types:

The most common type of endometrial cancer is endometrioid adenocarcinoma.

Frequency of endometrial cancer cell types is as follows:

References

1. Gusberg SB: Virulence factors in endometrial cancer. Cancer 71 (4 Suppl): 1464-6, 1993. [PUBMED Abstract]
2. Zaino RJ, Kurman R, Herbold D, et al.: The significance of squamous differentiation in endometrial carcinoma. Data from a Gynecologic Oncology Group study. Cancer 68 (10): 2293-302, 1991. [PUBMED Abstract]
3. Kandoth C, Schultz N, Cherniack AD, et al.: Integrated genomic characterization of endometrial carcinoma. Nature 497 (7447): 67-73, 2013. [PUBMED Abstract]
4. Talhouk A, McConechy MK, Leung S, et al.: A clinically applicable molecular-based classification for endometrial cancers. Br J Cancer 113 (2): 299-310, 2015. [PUBMED Abstract]

FIGO Staging

The Fédération Internationale de Gynécologie et d’Obstétrique (FIGO) and the American Joint Committee on Cancer (AJCC) have both designated staging systems for endometrial cancer. The FIGO system is the most commonly used staging system for endometrial cancer.[3–5] The 2023 FIGO staging update has not been widely adopted because it incorporates molecular-based results, and some physicians do not have access to those data for their patients. Additionally, given the significant changes in the 2023 FIGO staging system, especially in the definition of early stage disease, more outcome data are needed so it might be more prudent to use the 2021 system in a clinical setting while discussing prognosis and treatment with patients. Therefore, both the 2023 and the 2021 FIGO staging systems are presented in this section.

FIGO stages I to IV are further subdivided by the histological grade (G) of the tumor, for example, stage IB G2. Carcinosarcomas, which had previously been designated as sarcomas, are now considered poorly differentiated adenocarcinomas; as such, they are included in this system.[5]

2023 FIGO staging for endometrial cancer

Table 2. 2023 FIGO Definitions for Stage I Cancer of the Endometriuma,b,c

Stage		Description
T = primary tumor; N = regional lymph node; M = distant metastasis; p = pathological; AJCC = American Joint Committee on Cancer; ESGO-ESTRO-ESP = European Society of Gynaecological Oncology, European Society for Radiotherapy and Oncology, European Society of Pathology; FIGO = Fédération Internationale de Gynécologie et d’Obstétrique; ITC = isolated tumor cell; LVSI = lymphovascular space involvement; MMRd = mismatch repair deficiency; NSMP = no specific molecular profile; POLEmut = pathogenic POLE mutation; p53abn = TP53 abnormal; SLN = sentinel lymph node; WHO = World Health Organization.
aAdapted from FIGO Committee on Gynecologic Oncology.[3]
bEndometrial cancer is surgically staged and pathologically examined. In all stages, the grade of the lesion, the histological type and LVSI must be recorded. If available and feasible, molecular classification testing (POLEmut, MMRd, NSMP, p53abn) is encouraged in all patients with endometrial cancer for prognostic risk-group stratification and as factors that might influence adjuvant and systemic treatment decisions (see Table 6).
cIn early endometrial cancer, the standard surgery is a total hysterectomy with bilateral salpingo-oophorectomy via a minimally invasive laparoscopic approach. Staging procedures include infracolic omentectomy in specific histological subtypes, such as serous and undifferentiated endometrial carcinoma, as well as carcinosarcoma, due to the high risk of microscopic omental metastases. Lymph node staging should be performed in patients with intermediate-high/high-risk disease. SLN biopsy is an adequate alternative to systematic lymphadenectomy for staging proposes. SLN biopsy can also be considered in patients with low−/low-intermediate-risk disease to rule out occult lymph node metastases and to identify disease truly confined to the uterus. Thus, the ESGO-ESTRO-ESP guidelines allow an approach of SLN in all patients with endometrial carcinoma, which is endorsed by FIGO. In assumed early endometrial cancer, an SLN biopsy in an adequate alternative to systematic lymphadenectomy in high-intermediate and high-risk cases for the purpose of lymph node staging and can also be considered in low–/intermediate-risk disease to rule out occult lymph node metastases. An SLN biopsy should be done in association with thorough (ultrastaging) staging as it will increase the detection of low-volume disease in lymph nodes.
dLow-grade endometrioid carcinomas involving both the endometrium and the ovary are considered to have a good prognosis, and no adjuvant treatment is recommended if all the below criteria are met. Disease limited to low-grade endometrioid carcinomas involving the endometrium and ovaries (Stage IA3) must be distinguished from extensive spread of the endometrial carcinoma to the ovary (Stage IIIA1), by the following criteria: (1) no more than superficial myometrial invasion is present (<50%); (2) absence of extensive/substantial LVSI; (3) absence of additional metastases; and (4) the ovarian tumor is unilateral, limited to the ovary, without capsule invasion/rupture (equivalent to pT1a).
eLVSI as defined in WHO 2021: extensive/substantial, ≥5 vessels involved.
fGrade and histological type are as follows: (1) Serous adenocarcinomas, clear cell adenocarcinomas, mesonephric-like carcinomas, gastrointestinal-type mucinous endometrial carcinoma, undifferentiated carcinomas, and carcinosarcomas are considered high grade by definition. For endometrioid carcinomas, grade is based on the proportion of solid areas: low grade = grade 1 (≤5%) and grade 2 (6%–50%); and high grade = grade 3 (>50%). Nuclear atypia excessive for the grade raises the grade of a grade 1 or 2 tumor by one. The presence of unusual nuclear atypia in an architecturally low-grade tumor should prompt the evaluation of TP53 and consideration of serous carcinoma. Adenocarcinomas with squamous differentiation are graded according to the microscopic features of the glandular component; (2) Nonaggressive histological types are composed of low-grade (grade 1 and 2) endometrioid carcinomas. Aggressive histological types are composed of high-grade endometrioid carcinomas (grade 3), serous, clear cell, undifferentiated, mixed, mesonephric-like, gastrointestinal mucinous type carcinomas, and carcinosarcomas; and (3) It should be noted that high-grade endometrioid carcinomas (grade 3) are a prognostically, clinically, and molecularly heterogenous disease, and the tumor type that benefits most from applying molecular classification for improved prognostication and for treatment decision-making. Without molecular classification, high-grade endometrioid carcinomas cannot appropriately be allocated to a risk group, and thus, molecular profiling is particularly recommended in these patients. For practical purposes and to avoid undertreatment of patients, if the molecular classification is unknown, high-grade endometrioid carcinomas were grouped together with the aggressive histological types in the actual FIGO classification.
gMicrometastases are considered to be metastatic involvement (pN1 [mi]). The prognostic significance of ITCs is unclear. The presence of ITCs should be documented and is regarded as pN0(I+). According to the AJCC 8th edition staging, macrometastases are >2 mm in size, micrometastases are >0.2–2 mm and/or >200 cells, and ITCs are ≤0.2 mm and ≤200 cells. These definitions are based on staging established by FIGO and the 8th edition of the AJCC Cancer Staging Manual.
I		Confined to the uterine corpus and ovary.d
IA		Disease limited to the endometrium OR nonaggressive histological type, i.e., low-grade endometrioid, with invasion of less than half of myometrium with no or focal LVSI OR good prognosis disease.
	IA1	Nonaggressive histological type limited to an endometrial polyp OR confined to the endometrium.
	IA2	Nonaggressive histological types involving less than half of the myometrium with no or focal LVSI.
	IA3	Low-grade endometrioid carcinomas limited to the uterus and ovary.d
IB		Nonaggressive histological types with invasion of half or more of the myometrium, and with no or focal LVSI.e
IC		Aggressive histological typesf limited to a polyp or confined to the endometrium.

Table 3. 2023 FIGO Definitions for Stage II Cancer of the Endometriuma,b,c

Stage	Description
FIGO = Fédération Internationale de Gynécologie et d’Obstétrique; LVSI = lymphovascular space involvement.
aAdapted from FIGO Committee on Gynecologic Oncology.[3]
For the explanations for footnotes b−f, see Table 2.
II	Invasion of cervical stroma without extrauterine extension OR with substantial LVSI OR aggressive histological types with myometrial invasion.
IIA	Invasion of the cervical stroma of nonaggressive histological types.
IIB	Substantial LVSIe of nonaggressive histological types.
IIC	Aggressive histological typesf with any myometrial involvement.

Table 4. 2023 FIGO Definitions for Stage III Cancer of the Endometriuma,b,c

Stage		Description
FIGO = Fédération Internationale de Gynécologie et d’Obstétrique.
aAdapted from FIGO Committee on Gynecologic Oncology.[3]
For the explanations for footnotes b−d and g, see Table 2.
III		Local and/or regional spread of the tumor of any histological subtype.
IIIA		Invasion of uterine serosa, adnexa, or both by direct extension or metastasis.
	IIIA1	Spread to ovary or fallopian tube (except when meeting stage IA3 criteria).d
	IIIA2	Involvement of uterine subserosa or spread through the uterine serosa.
IIIB		Metastasis or direct spread to the vagina and/or to the parametria or pelvic peritoneum.
	IIIB1	Metastasis or direct spread to the vagina and/or the parametria.
	IIIB2	Metastasis to the pelvic peritoneum.
IIIC		Metastasis to the pelvic or para-aortic lymph nodes or both.g
	IIIC1	Metastasis to the pelvic lymph nodes.
	IIIC1i	Micrometastasis.
	IIIC1ii	Macrometastasis.
	IIIC2	Metastasis to para-aortic lymph nodes up to the renal vessels, with or without metastasis to the pelvic lymph nodes.
	IIIC2i	Micrometastasis.
	IIIC2ii	Macrometastasis.

Table 5. 2023 FIGO Definitions for Stage IV Cancer of the Endometriuma,b,c

Stage	Description
FIGO = Fédération Internationale de Gynécologie et d’Obstétrique.
aAdapted from FIGO Committee on Gynecologic Oncology.[3]
For the explanations for footnotes b−c, see Table 2.
IV	Spread to the bladder mucosa and/or intestinal mucosa and/or distance metastasis.
IVA	Invasion of the bladder mucosa and/or the intestinal/bowel mucosa.
IVB	Abdominal peritoneal metastasis beyond the pelvis.
IVC	Distant metastasis, including metastasis to any extra- or intra-abdominal lymph nodes above the renal vessels, lungs, liver, brain, or bone.

Table 6. 2023 FIGO Definitions for Endometrial Cancer Stage With Molecular Classificationa,b

Stage Designation	Molecular Findings in Patients With Early Endometrial Cancer (Stages I and II After Surgical Staging)
FIGO = Fédération Internationale de Gynécologie et d’Obstétrique; LVSI = lymphovascular space involvement; MMRd = mismatch repair deficiency; MSI = microsatellite instability; NSMP = no specific molecular profile; POLEmut = pathogenic POLE mutation; p53abn = TP53 abnormal.
aAdapted from FIGO Committee on Gynecologic Oncology.[3]
bWhen feasible, the addition of molecular subtype to the staging criteria allows a better prediction of prognosis in a staging/prognosis scheme. The performance of complete molecular classification (POLEmut, MMRd, NSMP, p53abn) is encouraged in all cases of endometrial cancer for prognostic risk-group stratification and as potential influencing factors of adjuvant or systemic treatment decisions. Molecular subtype assignment can be done on a biopsy, in which case it need not be repeated on the hysterectomy specimen. When performed, these molecular classifications should be recorded in all stages. A pathogenic POLE mutation (POLEmut) is associated with a good prognosis. MMRd or MSI and NSMP are associated with an intermediate prognosis. Abnormal TP53 (p53abn) is associated with a poor prognosis. When the molecular classification is known the staging is modified as follows: (1) FIGO Stages I and II are based on surgical/anatomical and histological findings. In case the molecular classification reveals POLEmut or p53abn status, the FIGO stage is modified in the early stage of the disease. This is depicted in the FIGO stage by the addition of “m” for molecular classification, and a subscript is added to denote POLEmut or p53abn status, as shown in the table. MMRd or NSMP status do not modify early FIGO stages; however, these molecular classifications should be recorded for the purpose of data collection. When molecular classification reveals MMRd or NSMP, it should be recorded as Stage ImMMRd or Stage ImNSMP and Stage IImMMRd or Stage IImNSMP; (2) FIGO Stages III and IV are based on surgical/anatomical findings. The stage category is not modified by molecular classification; however, the molecular classification should be recorded if known. When the molecular classification is known, it should be recorded as Stage IIIm or Stage IVm with the appropriate subscript for the purpose of data collection. For example, when molecular classification reveals p53abn, it should be recorded as Stage IIImp53abn or Stage IVmp53abn.
IAmPOLEmut	POLEmut endometrial carcinoma, confined to the uterine corpus or with cervical extension, regardless of the degree of LVSI or histological type.
IICmp53abn	p53abn endometrial carcinoma confined to the uterine corpus with any myometrial invasion, with or without cervical invasion, and regardless of the degree of LVSI or histological type.

2021 FIGO staging for endometrial cancer

Table 7. 2021 FIGO Definitions for Stage I Cancer of the Endometriuma

Stage	Description	Illustration
FIGO = Fédération Internationale de Gynécologie et d’Obstétrique.
aAdapted from FIGO Committee on Gynecologic Oncology.[4]
bG1, G2, or G3 (G = grade).
Ib	Tumor confined to the corpus uteri.	Enlarge
IAb	No or less than half myometrial invasion.
IBb	Invasion equal to or more than half of the myometrium.

Table 8. 2021 FIGO Definitions for Stage II Cancer of the Endometriuma

Stage	Description	Illustration
FIGO = Fédération Internationale de Gynécologie et d’Obstétrique.
aAdapted from FIGO Committee on Gynecologic Oncology.[4]
bG1, G2, or G3 (G = grade).
cEndocervical glandular involvement is considered stage I; it is no longer considered stage II.
IIb	Tumor invades cervical stroma but does not extend beyond the uterus.c	Enlarge

Table 9. 2021 FIGO Definitions for Stage III Cancer of the Endometriuma

Stage	Description	Illustration
FIGO = Fédération Internationale de Gynécologie et d’Obstétrique.
aAdapted from FIGO Committee on Gynecologic Oncology.[4]
bG1, G2, or G3 (G = grade).
cPositive cytology has to be reported separately without changing the stage.
IIIb	Local and/or regional spread of the tumor.
IIIAb	Tumor invades the serosa of the corpus uteri and/or adnexae.c	Enlarge
IIIBb	Vaginal and/or parametrial involvement.c	Enlarge
IIICb	Metastases to pelvic and/or para-aortic lymph nodes.c	Enlarge
IIIC1b	Positive pelvic nodes.
IIIC2b	Positive para-aortic lymph nodes with or without positive pelvic lymph nodes.

Table 10. 2021 FIGO Definitions for Stage IV Cancer of the Endometriuma

Stage	Description	Illustration
FIGO = Fédération Internationale de Gynécologie et d’Obstétrique.
aAdapted from FIGO Committee on Gynecologic Oncology.[4]
bG1, G2, or G3 (G = grade).
IVb	Tumor invades bladder and/or bowel mucosa, and/or distant metastases.
IVAb	Tumor invasion of bladder and/or bowel mucosa.	Enlarge
IVBb	Distant metastases, including intra-abdominal metastases and/or inguinal lymph nodes.	Enlarge

References

1. Hendrickson M, Ross J, Eifel PJ, et al.: Adenocarcinoma of the endometrium: analysis of 256 cases with carcinoma limited to the uterine corpus. Pathology review and analysis of prognostic variables. Gynecol Oncol 13 (3): 373-92, 1982. [PUBMED Abstract]
2. Nori D, Hilaris BS, Tome M, et al.: Combined surgery and radiation in endometrial carcinoma: an analysis of prognostic factors. Int J Radiat Oncol Biol Phys 13 (4): 489-97, 1987. [PUBMED Abstract]
3. Berek JS, Matias-Guiu X, Creutzberg C, et al.: FIGO staging of endometrial cancer: 2023. Int J Gynaecol Obstet 162 (2): 383-394, 2023. [PUBMED Abstract]
4. Koskas M, Amant F, Mirza MR, et al.: Cancer of the corpus uteri: 2021 update. Int J Gynaecol Obstet 155 (Suppl 1): 45-60, 2021. [PUBMED Abstract]
5. Corpus uteri – carcinoma and carcinosarcoma. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp 661-69.

The degree of tumor differentiation has an important effect on the natural history of this disease and on treatment selection.

Patients with endometrial cancer who have localized disease are usually cured. Best results are obtained with one of two standard treatments:

Patients with regional and distant metastases are rarely cured, although they are occasionally responsive to standard hormone therapy.

Progestational agents have been evaluated as adjuvant therapy in several randomized trials. A meta-analysis by the Cochrane group confirms no clinical benefit to adjuvant progestogens in clinical stage I disease.[1][Level of evidence A1]

The treatment options for each stage of endometrial cancer are presented in Table 11.

References

1. Martin-Hirsch PP, Bryant A, Keep SL, et al.: Adjuvant progestagens for endometrial cancer. Cochrane Database Syst Rev (6): CD001040, 2011. [PUBMED Abstract]

References

1. Kiess AP, Damast S, Makker V, et al.: Five-year outcomes of adjuvant carboplatin/paclitaxel chemotherapy and intravaginal radiation for stage I-II papillary serous endometrial cancer. Gynecol Oncol 127 (2): 321-5, 2012. [PUBMED Abstract]
2. Boruta DM, Gehrig PA, Fader AN, et al.: Management of women with uterine papillary serous cancer: a Society of Gynecologic Oncology (SGO) review. Gynecol Oncol 115 (1): 142-53, 2009. [PUBMED Abstract]
3. Huh WK, Powell M, Leath CA, et al.: Uterine papillary serous carcinoma: comparisons of outcomes in surgical Stage I patients with and without adjuvant therapy. Gynecol Oncol 91 (3): 470-5, 2003. [PUBMED Abstract]
4. Fader AN, Drake RD, O’Malley DM, et al.: Platinum/taxane-based chemotherapy with or without radiation therapy favorably impacts survival outcomes in stage I uterine papillary serous carcinoma. Cancer 115 (10): 2119-27, 2009. [PUBMED Abstract]
5. Kelly MG, O’malley DM, Hui P, et al.: Improved survival in surgical stage I patients with uterine papillary serous carcinoma (UPSC) treated with adjuvant platinum-based chemotherapy. Gynecol Oncol 98 (3): 353-9, 2005. [PUBMED Abstract]
6. Havrilesky LJ, Secord AA, Bae-Jump V, et al.: Outcomes in surgical stage I uterine papillary serous carcinoma. Gynecol Oncol 105 (3): 677-82, 2007. [PUBMED Abstract]
7. Dietrich CS, Modesitt SC, DePriest PD, et al.: The efficacy of adjuvant platinum-based chemotherapy in Stage I uterine papillary serous carcinoma (UPSC). Gynecol Oncol 99 (3): 557-63, 2005. [PUBMED Abstract]
8. Townamchai K, Berkowitz R, Bhagwat M, et al.: Vaginal brachytherapy for early stage uterine papillary serous and clear cell endometrial cancer. Gynecol Oncol 129 (1): 18-21, 2013. [PUBMED Abstract]
9. Barney BM, Petersen IA, Mariani A, et al.: The role of vaginal brachytherapy in the treatment of surgical stage I papillary serous or clear cell endometrial cancer. Int J Radiat Oncol Biol Phys 85 (1): 109-15, 2013. [PUBMED Abstract]
10. Hornback NB, Omura G, Major FJ: Observations on the use of adjuvant radiation therapy in patients with stage I and II uterine sarcoma. Int J Radiat Oncol Biol Phys 12 (12): 2127-30, 1986. [PUBMED Abstract]
11. Peters WA, Rivkin SE, Smith MR, et al.: Cisplatin and adriamycin combination chemotherapy for uterine stromal sarcomas and mixed mesodermal tumors. Gynecol Oncol 34 (3): 323-7, 1989. [PUBMED Abstract]
12. Ayhan A, Taskiran C, Celik C, et al.: The long-term survival of women with surgical stage II endometrioid type endometrial cancer. Gynecol Oncol 93 (1): 9-13, 2004. [PUBMED Abstract]
13. Eltabbakh GH, Moore AD: Survival of women with surgical stage II endometrial cancer. Gynecol Oncol 74 (1): 80-5, 1999. [PUBMED Abstract]
14. Orezzoli JP, Sioletic S, Olawaiye A, et al.: Stage II endometrioid adenocarcinoma of the endometrium: clinical implications of cervical stromal invasion. Gynecol Oncol 113 (3): 316-23, 2009. [PUBMED Abstract]
15. Walker JL, Piedmonte MR, Spirtos NM, et al.: Laparoscopy compared with laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group Study LAP2. J Clin Oncol 27 (32): 5331-6, 2009. [PUBMED Abstract]
16. Mariani A, Dowdy SC, Cliby WA, et al.: Prospective assessment of lymphatic dissemination in endometrial cancer: a paradigm shift in surgical staging. Gynecol Oncol 109 (1): 11-8, 2008. [PUBMED Abstract]
17. Mariani A, Webb MJ, Keeney GL, et al.: Low-risk corpus cancer: is lymphadenectomy or radiotherapy necessary? Am J Obstet Gynecol 182 (6): 1506-19, 2000. [PUBMED Abstract]
18. Barlin JN, Khoury-Collado F, Kim CH, et al.: The importance of applying a sentinel lymph node mapping algorithm in endometrial cancer staging: beyond removal of blue nodes. Gynecol Oncol 125 (3): 531-5, 2012. [PUBMED Abstract]
19. Janda M, Gebski V, Brand A, et al.: Quality of life after total laparoscopic hysterectomy versus total abdominal hysterectomy for stage I endometrial cancer (LACE): a randomised trial. Lancet Oncol 11 (8): 772-80, 2010. [PUBMED Abstract]
20. Mourits MJ, Bijen CB, Arts HJ, et al.: Safety of laparoscopy versus laparotomy in early-stage endometrial cancer: a randomised trial. Lancet Oncol 11 (8): 763-71, 2010. [PUBMED Abstract]
21. Kornblith AB, Huang HQ, Walker JL, et al.: Quality of life of patients with endometrial cancer undergoing laparoscopic international federation of gynecology and obstetrics staging compared with laparotomy: a Gynecologic Oncology Group study. J Clin Oncol 27 (32): 5337-42, 2009. [PUBMED Abstract]
22. Walker JL, Piedmonte MR, Spirtos NM, et al.: Recurrence and survival after random assignment to laparoscopy versus laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group LAP2 Study. J Clin Oncol 30 (7): 695-700, 2012. [PUBMED Abstract]
23. Galaal K, Bryant A, Fisher AD, et al.: Laparoscopy versus laparotomy for the management of early stage endometrial cancer. Cochrane Database Syst Rev 9: CD006655, 2012. [PUBMED Abstract]
24. Aalders J, Abeler V, Kolstad P, et al.: Postoperative external irradiation and prognostic parameters in stage I endometrial carcinoma: clinical and histopathologic study of 540 patients. Obstet Gynecol 56 (4): 419-27, 1980. [PUBMED Abstract]
25. 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]
26. Marchetti DL, Caglar H, Driscoll DL, et al.: Pelvic radiation in stage I endometrial adenocarcinoma with high-risk attributes. Gynecol Oncol 37 (1): 51-4, 1990. [PUBMED Abstract]
27. Creutzberg CL, van Putten WL, Koper PC, et al.: Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. PORTEC Study Group. Post Operative Radiation Therapy in Endometrial Carcinoma. Lancet 355 (9213): 1404-11, 2000. [PUBMED Abstract]
28. Kong A, Johnson N, Kitchener HC, et al.: Adjuvant radiotherapy for stage I endometrial cancer: an updated Cochrane systematic review and meta-analysis. J Natl Cancer Inst 104 (21): 1625-34, 2012. [PUBMED Abstract]
29. Nout RA, Smit VT, Putter H, et al.: Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, non-inferiority, randomised trial. Lancet 375 (9717): 816-23, 2010. [PUBMED Abstract]
30. Onsrud M, Cvancarova M, Hellebust TP, et al.: Long-term outcomes after pelvic radiation for early-stage endometrial cancer. J Clin Oncol 31 (31): 3951-6, 2013. [PUBMED Abstract]
31. Keys HM, Roberts JA, Brunetto VL, et al.: A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 92 (3): 744-51, 2004. [PUBMED Abstract]
32. Scholten AN, van Putten WL, Beerman H, et al.: Postoperative radiotherapy for Stage 1 endometrial carcinoma: long-term outcome of the randomized PORTEC trial with central pathology review. Int J Radiat Oncol Biol Phys 63 (3): 834-8, 2005. [PUBMED Abstract]
33. Bertelsen K, Ortoft G, Hansen ES: Survival of Danish patients with endometrial cancer in the intermediate-risk group not given postoperative radiotherapy: the Danish Endometrial Cancer Study (DEMCA). Int J Gynecol Cancer 21 (7): 1191-9, 2011. [PUBMED Abstract]
34. Nout RA, Putter H, Jürgenliemk-Schulz IM, et al.: Five-year quality of life of endometrial cancer patients treated in the randomised Post Operative Radiation Therapy in Endometrial Cancer (PORTEC-2) trial and comparison with norm data. Eur J Cancer 48 (11): 1638-48, 2012. [PUBMED Abstract]
35. Eltabbakh GH, Piver MS, Hempling RE, et al.: Excellent long-term survival and absence of vaginal recurrences in 332 patients with low-risk stage I endometrial adenocarcinoma treated with hysterectomy and vaginal brachytherapy without formal staging lymph node sampling: report of a prospective trial. Int J Radiat Oncol Biol Phys 38 (2): 373-80, 1997. [PUBMED Abstract]
36. Stokes S, Bedwinek J, Kao MS, et al.: Treatment of stage I adenocarcinoma of the endometrium by hysterectomy and adjuvant irradiation: a retrospective analysis of 304 patients. Int J Radiat Oncol Biol Phys 12 (3): 339-44, 1986. [PUBMED Abstract]
37. Grigsby PW, Kuske RR, Perez CA, et al.: Medically inoperable stage I adenocarcinoma of the endometrium treated with radiotherapy alone. Int J Radiat Oncol Biol Phys 13 (4): 483-8, 1987. [PUBMED Abstract]

References

1. Shih KK, Yun E, Gardner GJ, et al.: Surgical cytoreduction in stage IV endometrioid endometrial carcinoma. Gynecol Oncol 122 (3): 608-11, 2011. [PUBMED Abstract]
2. Barlin JN, Puri I, Bristow RE: Cytoreductive surgery for advanced or recurrent endometrial cancer: a meta-analysis. Gynecol Oncol 118 (1): 14-8, 2010. [PUBMED Abstract]
3. Ball HG, Blessing JA, Lentz SS, et al.: A phase II trial of paclitaxel in patients with advanced or recurrent adenocarcinoma of the endometrium: a Gynecologic Oncology Group study. Gynecol Oncol 62 (2): 278-81, 1996. [PUBMED Abstract]
4. Thigpen JT, Brady MF, Homesley HD, et al.: Phase III trial of doxorubicin with or without cisplatin in advanced endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 22 (19): 3902-8, 2004. [PUBMED Abstract]
5. Fleming GF, Brunetto VL, Cella D, et al.: Phase III trial of doxorubicin plus cisplatin with or without paclitaxel plus filgrastim in advanced endometrial carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol 22 (11): 2159-66, 2004. [PUBMED Abstract]
6. Fleming GF, Filiaci VL, Bentley RC, et al.: Phase III randomized trial of doxorubicin + cisplatin versus doxorubicin + 24-h paclitaxel + filgrastim in endometrial carcinoma: a Gynecologic Oncology Group study. Ann Oncol 15 (8): 1173-8, 2004. [PUBMED Abstract]
7. Arimoto T, Nakagawa S, Yasugi T, et al.: Treatment with paclitaxel plus carboplatin, alone or with irradiation, of advanced or recurrent endometrial carcinoma. Gynecol Oncol 104 (1): 32-5, 2007. [PUBMED Abstract]
8. Sovak MA, Hensley ML, Dupont J, et al.: Paclitaxel and carboplatin in the adjuvant treatment of patients with high-risk stage III and IV endometrial cancer: a retrospective study. Gynecol Oncol 103 (2): 451-7, 2006. [PUBMED Abstract]
9. Hoskins PJ, Swenerton KD, Pike JA, et al.: Paclitaxel and carboplatin, alone or with irradiation, in advanced or recurrent endometrial cancer: a phase II study. J Clin Oncol 19 (20): 4048-53, 2001. [PUBMED Abstract]
10. Pectasides D, Xiros N, Papaxoinis G, et al.: Carboplatin and paclitaxel in advanced or metastatic endometrial cancer. Gynecol Oncol 109 (2): 250-4, 2008. [PUBMED Abstract]
11. Nomura H, Aoki D, Takahashi F, et al.: Randomized phase II study comparing docetaxel plus cisplatin, docetaxel plus carboplatin, and paclitaxel plus carboplatin in patients with advanced or recurrent endometrial carcinoma: a Japanese Gynecologic Oncology Group study (JGOG2041). Ann Oncol 22 (3): 636-42, 2011. [PUBMED Abstract]
12. Dimopoulos MA, Papadimitriou CA, Georgoulias V, et al.: Paclitaxel and cisplatin in advanced or recurrent carcinoma of the endometrium: long-term results of a phase II multicenter study. Gynecol Oncol 78 (1): 52-7, 2000. [PUBMED Abstract]
13. Miller DS, Filiaci VL, Mannel RS, et al.: Carboplatin and Paclitaxel for Advanced Endometrial Cancer: Final Overall Survival and Adverse Event Analysis of a Phase III Trial (NRG Oncology/GOG0209). J Clin Oncol 38 (33): 3841-3850, 2020. [PUBMED Abstract]
14. Randall ME, Filiaci VL, Muss H, et al.: Randomized phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol 24 (1): 36-44, 2006. [PUBMED Abstract]
15. Sutton G, Brunetto VL, Kilgore L, et al.: A phase III trial of ifosfamide with or without cisplatin in carcinosarcoma of the uterus: A Gynecologic Oncology Group Study. Gynecol Oncol 79 (2): 147-53, 2000. [PUBMED Abstract]
16. Homesley HD, Filiaci V, Markman M, et al.: Phase III trial of ifosfamide with or without paclitaxel in advanced uterine carcinosarcoma: a Gynecologic Oncology Group Study. J Clin Oncol 25 (5): 526-31, 2007. [PUBMED Abstract]
17. Wegner RE, Beriwal S, Heron DE, et al.: Definitive radiation therapy for endometrial cancer in medically inoperable elderly patients. Brachytherapy 9 (3): 260-5, 2010 Jul-Sep. [PUBMED Abstract]
18. Kupelian PA, Eifel PJ, Tornos C, et al.: Treatment of endometrial carcinoma with radiation therapy alone. Int J Radiat Oncol Biol Phys 27 (4): 817-24, 1993. [PUBMED Abstract]
19. Lentz SS: Advanced and recurrent endometrial carcinoma: hormonal therapy. Semin Oncol 21 (1): 100-6, 1994. [PUBMED Abstract]
20. Kauppila A: Oestrogen and progestin receptors as prognostic indicators in endometrial cancer. A review of the literature. Acta Oncol 28 (4): 561-6, 1989. [PUBMED Abstract]
21. Kauppila A, Friberg LG: Hormonal and cytotoxic chemotherapy for endometrial carcinoma. Steroid receptors in the selection of appropriate therapy. Acta Obstet Gynecol Scand Suppl 101: 59-64, 1981. [PUBMED Abstract]
22. Quinn MA, Campbell JJ: Tamoxifen therapy in advanced/recurrent endometrial carcinoma. Gynecol Oncol 32 (1): 1-3, 1989. [PUBMED Abstract]
23. Lindemann K, Malander S, Christensen RD, et al.: Examestane in advanced or recurrent endometrial carcinoma: a prospective phase II study by the Nordic Society of Gynecologic Oncology (NSGO). BMC Cancer 14: 68, 2014. [PUBMED Abstract]
24. Slomovitz BM, Lu KH, Johnston T, et al.: A phase 2 study of the oral mammalian target of rapamycin inhibitor, everolimus, in patients with recurrent endometrial carcinoma. Cancer 116 (23): 5415-9, 2010. [PUBMED Abstract]
25. Colombo N, McMeekin DS, Schwartz PE, et al.: Ridaforolimus as a single agent in advanced endometrial cancer: results of a single-arm, phase 2 trial. Br J Cancer 108 (5): 1021-6, 2013. [PUBMED Abstract]
26. Tsoref D, Welch S, Lau S, et al.: Phase II study of oral ridaforolimus in women with recurrent or metastatic endometrial cancer. Gynecol Oncol 135 (2): 184-9, 2014. [PUBMED Abstract]
27. Slomovitz BM, Jiang Y, Yates MS, et al.: Phase II study of everolimus and letrozole in patients with recurrent endometrial carcinoma. J Clin Oncol 33 (8): 930-6, 2015. [PUBMED Abstract]
28. Aghajanian C, Sill MW, Darcy KM, et al.: Phase II trial of bevacizumab in recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study. J Clin Oncol 29 (16): 2259-65, 2011. [PUBMED Abstract]
29. Alvarez EA, Brady WE, Walker JL, et al.: Phase II trial of combination bevacizumab and temsirolimus in the treatment of recurrent or persistent endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 129 (1): 22-7, 2013. [PUBMED Abstract]
30. Makker V, Colombo N, Casado Herráez A, et al.: Lenvatinib Plus Pembrolizumab in Previously Treated Advanced Endometrial Cancer: Updated Efficacy and Safety From the Randomized Phase III Study 309/KEYNOTE-775. J Clin Oncol 41 (16): 2904-2910, 2023. [PUBMED Abstract]
31. Eskander RN, Sill MW, Beffa L, et al.: Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer. N Engl J Med 388 (23): 2159-2170, 2023. [PUBMED Abstract]
32. Van Gorp T, Cibula D, Lv W, et al.: ENGOT-en11/GOG-3053/KEYNOTE-B21: a randomised, double-blind, phase III study of pembrolizumab or placebo plus adjuvant chemotherapy with or without radiotherapy in patients with newly diagnosed, high-risk endometrial cancer. Ann Oncol 35 (11): 968-980, 2024. [PUBMED Abstract]
33. Slomovitz BM, Cibula D, Lv W, et al.: Pembrolizumab or Placebo Plus Adjuvant Chemotherapy With or Without Radiotherapy for Newly Diagnosed, High-Risk Endometrial Cancer: Results in Mismatch Repair-Deficient Tumors. J Clin Oncol 43 (3): 251-259, 2025. [PUBMED Abstract]
34. Mirza MR, Chase DM, Slomovitz BM, et al.: Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer. N Engl J Med 388 (23): 2145-2158, 2023. [PUBMED Abstract]
35. Greven KM, Curran WJ, Whittington R, et al.: Analysis of failure patterns in stage III endometrial carcinoma and therapeutic implications. Int J Radiat Oncol Biol Phys 17 (1): 35-9, 1989. [PUBMED Abstract]

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

Screening is looking for cancer before a person has any symptoms. This can help find cancer at an early stage. When abnormal tissue or cancer is found early, it may be easier to treat. By the time symptoms appear, cancer may have begun to spread.

Scientists are trying to better understand which people are more likely to get certain types of cancer. They also study the things we do and the things around us to see if they cause cancer. This information helps doctors recommend who should be screened for cancer, which screening tests should be used, and how often the tests should be done.

It is important to remember that your doctor does not necessarily think you have cancer if he or she suggests a screening test. Screening tests are given when you have no cancer symptoms.

If a screening test result is abnormal, you may need to have more tests done to find out if you have cancer. These are called diagnostic tests.

For information about the treatments listed below, visit the Treatment Option Overview section.

Treatment of stage I leiomyosarcoma of the uterus, stage I endometrial stromal sarcoma, and stage I adenosarcoma of the uterus may include:

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

For information about the treatments listed below, visit the Treatment Option Overview section.

Treatment of stage II leiomyosarcoma of the uterus, stage II endometrial stromal sarcoma, and stage II adenosarcoma of the uterus may include:

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

For information about the treatments listed below, visit the Treatment Option Overview section.

Treatment of stage III leiomyosarcoma of the uterus, stage III endometrial stromal sarcoma, and stage III adenosarcoma of the uterus may include:

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

There is no standard treatment for patients with stage IV leiomyosarcoma of the uterus, stage IV endometrial stromal sarcoma, or stage IV adenosarcoma of the uterus. Treatment may include a clinical trial using chemotherapy.

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

For information about the treatments listed below, visit the Treatment Option Overview section.

There is no standard treatment for recurrent uterine sarcoma. Treatment may include a clinical trial using chemotherapy.

For patients with recurrent carcinosarcoma (a certain type of tumor), treatment may include:

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

For more information from the National Cancer Institute about uterine sarcoma, visit the Uterine Cancer Home Page.

For general cancer information and other resources from the National Cancer Institute, visit:

Note: The Summary of Evidence section summarizes the published evidence on this topic. The rest of the summary describes the evidence in more detail.

Other PDQ summaries on Endometrial Cancer Prevention; Endometrial Cancer Treatment; and Uterine Sarcoma Treatment are also available.

References

1. American Cancer Society: Cancer Facts and Figures 2025. American Cancer Society, 2025. Available online. Last accessed January 16, 2025.
2. American Cancer Society: Detailed Guide: Endometrial Cancer: What are the Risk Factors for Endometrial Cancer? Atlanta, Ga: American Cancer Society, 2005. Available online. Last accessed April 8, 2025.
3. Jick H, Walker AM, Rothman KJ: The epidemic of endometrial cancer: a commentary. Am J Public Health 70 (3): 264-7, 1980. [PUBMED Abstract]
4. Pike MC, Peters RK, Cozen W, et al.: Estrogen-progestin replacement therapy and endometrial cancer. J Natl Cancer Inst 89 (15): 1110-6, 1997. [PUBMED Abstract]
5. Persson I, Weiderpass E, Bergkvist L, et al.: Risks of breast and endometrial cancer after estrogen and estrogen-progestin replacement. Cancer Causes Control 10 (4): 253-60, 1999. [PUBMED Abstract]
6. Heiss G, Wallace R, Anderson GL, et al.: Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin. JAMA 299 (9): 1036-45, 2008. [PUBMED Abstract]
7. Doherty JA, Cushing-Haugen KL, Saltzman BS, et al.: Long-term use of postmenopausal estrogen and progestin hormone therapies and the risk of endometrial cancer. Am J Obstet Gynecol 197 (2): 139.e1-7, 2007. [PUBMED Abstract]
8. Barakat RR, Bundy BN, Spirtos NM, et al.: Randomized double-blind trial of estrogen replacement therapy versus placebo in stage I or II endometrial cancer: a Gynecologic Oncology Group Study. J Clin Oncol 24 (4): 587-92, 2006. [PUBMED Abstract]
9. Cuzick J, Forbes JF, Sestak I, et al.: Long-term results of tamoxifen prophylaxis for breast cancer–96-month follow-up of the randomized IBIS-I trial. J Natl Cancer Inst 99 (4): 272-82, 2007. [PUBMED Abstract]
10. Watson P, Vasen HF, Mecklin JP, et al.: The risk of endometrial cancer in hereditary nonpolyposis colorectal cancer. Am J Med 96 (6): 516-20, 1994. [PUBMED Abstract]
11. Aarnio M, Mecklin JP, Aaltonen LA, et al.: Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Int J Cancer 64 (6): 430-3, 1995. [PUBMED Abstract]
12. Aarnio M, Sankila R, Pukkala E, et al.: Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer 81 (2): 214-8, 1999. [PUBMED Abstract]
13. Berends MJ, Wu Y, Sijmons RH, et al.: Toward new strategies to select young endometrial cancer patients for mismatch repair gene mutation analysis. J Clin Oncol 21 (23): 4364-70, 2003. [PUBMED Abstract]
14. Boks DE, Trujillo AP, Voogd AC, et al.: Survival analysis of endometrial carcinoma associated with hereditary nonpolyposis colorectal cancer. Int J Cancer 102 (2): 198-200, 2002. [PUBMED Abstract]
15. Barrett RJ, Harlan LC, Wesley MN, et al.: Endometrial cancer: stage at diagnosis and associated factors in black and white patients. Am J Obstet Gynecol 173 (2): 414-22; discussion 422-3, 1995. [PUBMED Abstract]
16. Madison T, Schottenfeld D, James SA, et al.: Endometrial cancer: socioeconomic status and racial/ethnic differences in stage at diagnosis, treatment, and survival. Am J Public Health 94 (12): 2104-11, 2004. [PUBMED Abstract]
17. Coates RJ, Click LA, Harlan LC, et al.: Differences between black and white patients with cancer of the uterine corpus in interval from symptom recognition to initial medical consultation (United States). Cancer Causes Control 7 (3): 328-36, 1996. [PUBMED Abstract]

Measuring endometrial thickness (ET) with transvaginal ultrasound (TVU) and endometrial sampling with cytological examination have been proposed as possible screening modalities for endometrial cancer. The Papanicolaou (Pap) test, used successfully for screening for cervical cancer, is too insensitive to be used as a screening technique for the detection of endometrial cancer,[1] although occasionally the Pap test may fortuitously identify endometrial abnormalities, such as endometrial cancer.

Routine screening of asymptomatic women for endometrial cancer has not been evaluated for its impact on endometrial cancer mortality.[2,3] Although high-risk groups can be identified, the benefit of screening in reducing endometrial cancer mortality in these high-risk groups has not been evaluated. Using the same cutoffs to define an abnormal ET in asymptomatic women [4] as used in symptomatic women [5] would result in large numbers of false-positive test results and larger numbers of unnecessary referrals for cytological evaluations. Published recommendations for screening certain groups of women at high risk of endometrial carcinoma are based on opinion regarding presumptive benefit.[6]

References

1. Burk JR, Lehman HF, Wolf FS: Inadequacy of papanicolaou smears in the detection of endometrial cancer. N Engl J Med 291 (4): 191-2, 1974. [PUBMED Abstract]
2. Pritchard KI: Screening for endometrial cancer: is it effective? Ann Intern Med 110 (3): 177-9, 1989. [PUBMED Abstract]
3. Eddy D: ACS report on the cancer-related health checkup. CA Cancer J Clin 30 (4): 193-240, 1980 Jul-Aug. [PUBMED Abstract]
4. Smith-Bindman R, Weiss E, Feldstein V: How thick is too thick? When endometrial thickness should prompt biopsy in postmenopausal women without vaginal bleeding. Ultrasound Obstet Gynecol 24 (5): 558-65, 2004. [PUBMED Abstract]
5. Smith-Bindman R, Kerlikowske K, Feldstein VA, et al.: Endovaginal ultrasound to exclude endometrial cancer and other endometrial abnormalities. JAMA 280 (17): 1510-7, 1998. [PUBMED Abstract]
6. Burke W, Petersen G, Lynch P, et al.: Recommendations for follow-up care of individuals with an inherited predisposition to cancer. I. Hereditary nonpolyposis colon cancer. Cancer Genetics Studies Consortium. JAMA 277 (11): 915-9, 1997. [PUBMED Abstract]
7. Gull B, Karlsson B, Milsom I, et al.: Can ultrasound replace dilation and curettage? A longitudinal evaluation of postmenopausal bleeding and transvaginal sonographic measurement of the endometrium as predictors of endometrial cancer. Am J Obstet Gynecol 188 (2): 401-8, 2003. [PUBMED Abstract]
8. Fleischer AC, Wheeler JE, Lindsay I, et al.: An assessment of the value of ultrasonographic screening for endometrial disease in postmenopausal women without symptoms. Am J Obstet Gynecol 184 (2): 70-5, 2001. [PUBMED Abstract]
9. Langer RD, Pierce JJ, O’Hanlan KA, et al.: Transvaginal ultrasonography compared with endometrial biopsy for the detection of endometrial disease. Postmenopausal Estrogen/Progestin Interventions Trial. N Engl J Med 337 (25): 1792-8, 1997. [PUBMED Abstract]
10. Archer DF, McIntyre-Seltman K, Wilborn WW, et al.: Endometrial morphology in asymptomatic postmenopausal women. Am J Obstet Gynecol 165 (2): 317-20; discussion 320-2, 1991. [PUBMED Abstract]
11. Fung MF, Reid A, Faught W, et al.: Prospective longitudinal study of ultrasound screening for endometrial abnormalities in women with breast cancer receiving tamoxifen. Gynecol Oncol 91 (1): 154-9, 2003. [PUBMED Abstract]
12. Clarke MA, Long BJ, Del Mar Morillo A, et al.: Association of Endometrial Cancer Risk With Postmenopausal Bleeding in Women: A Systematic Review and Meta-analysis. JAMA Intern Med 178 (9): 1210-1222, 2018. [PUBMED Abstract]
13. Duffy S, Jackson TL, Lansdown M, et al.: The ATAC adjuvant breast cancer trial in postmenopausal women: baseline endometrial subprotocol data. BJOG 110 (12): 1099-106, 2003. [PUBMED Abstract]
14. Bradley WH, Boente MP, Brooker D, et al.: Hysteroscopy and cytology in endometrial cancer. Obstet Gynecol 104 (5 Pt 1): 1030-3, 2004. [PUBMED Abstract]
15. Gumus II, Keskin EA, Kiliç E, et al.: Diagnostic value of hysteroscopy and hysterosonography in endometrial abnormalities in asymptomatic postmenopausal women. Arch Gynecol Obstet 278 (3): 241-4, 2008. [PUBMED Abstract]

References

1. ACOG committee opinion. Routine cancer screening. Number 185, September 1997 (replaces no. 128, October 1993). Committee on Gynecologic Practice. American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet 59 (2): 157-61, 1997. [PUBMED Abstract]
2. Korhonen MO, Symons JP, Hyde BM, et al.: Histologic classification and pathologic findings for endometrial biopsy specimens obtained from 2964 perimenopausal and postmenopausal women undergoing screening for continuous hormones as replacement therapy (CHART 2 Study). Am J Obstet Gynecol 176 (2): 377-80, 1997. [PUBMED Abstract]
3. Watson P, Vasen HF, Mecklin JP, et al.: The risk of endometrial cancer in hereditary nonpolyposis colorectal cancer. Am J Med 96 (6): 516-20, 1994. [PUBMED Abstract]
4. Aarnio M, Sankila R, Pukkala E, et al.: Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer 81 (2): 214-8, 1999. [PUBMED Abstract]
5. Vasen HF, Wijnen JT, Menko FH, et al.: Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology 110 (4): 1020-7, 1996. [PUBMED Abstract]
6. Dunlop MG, Farrington SM, Carothers AD, et al.: Cancer risk associated with germline DNA mismatch repair gene mutations. Hum Mol Genet 6 (1): 105-10, 1997. [PUBMED Abstract]
7. Lancaster JM, Powell CB, Kauff ND, et al.: Society of Gynecologic Oncologists Education Committee statement on risk assessment for inherited gynecologic cancer predispositions. Gynecol Oncol 107 (2): 159-62, 2007. [PUBMED Abstract]
8. Boks DE, Trujillo AP, Voogd AC, et al.: Survival analysis of endometrial carcinoma associated with hereditary nonpolyposis colorectal cancer. Int J Cancer 102 (2): 198-200, 2002. [PUBMED Abstract]
9. Burke W, Petersen G, Lynch P, et al.: Recommendations for follow-up care of individuals with an inherited predisposition to cancer. I. Hereditary nonpolyposis colon cancer. Cancer Genetics Studies Consortium. JAMA 277 (11): 915-9, 1997. [PUBMED Abstract]
10. Vasen HF, Mecklin JP, Khan PM, et al.: The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum 34 (5): 424-5, 1991. [PUBMED Abstract]
11. Smith RA, Cokkinides V, Eyre HJ: American Cancer Society Guidelines for the Early Detection of Cancer, 2005. CA Cancer J Clin 55 (1): 31-44; quiz 55-6, 2005 Jan-Feb. [PUBMED Abstract]
12. Barakat RR: Tamoxifen and endometrial neoplasia. Clin Obstet Gynecol 39 (3): 629-40, 1996. [PUBMED Abstract]
13. ACOG committee opinion. Tamoxifen and endometrial cancer. Number 169, February 1996. Committee on Gynecologic Practice. American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet 53 (2): 197-9, 1996. [PUBMED Abstract]
14. Fisher B, Costantino JP, Wickerham DL, et al.: Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90 (18): 1371-88, 1998. [PUBMED Abstract]
15. Barakat RR, Wong G, Curtin JP, et al.: Tamoxifen use in breast cancer patients who subsequently develop corpus cancer is not associated with a higher incidence of adverse histologic features. Gynecol Oncol 55 (2): 164-8, 1994. [PUBMED Abstract]
16. Fornander T, Hellström AC, Moberger B: Descriptive clinicopathologic study of 17 patients with endometrial cancer during or after adjuvant tamoxifen in early breast cancer. J Natl Cancer Inst 85 (22): 1850-5, 1993. [PUBMED Abstract]
17. Barakat RR, Gilewski TA, Almadrones L, et al.: Effect of adjuvant tamoxifen on the endometrium in women with breast cancer: a prospective study using office endometrial biopsy. J Clin Oncol 18 (20): 3459-63, 2000. [PUBMED Abstract]

Abnormal ultrasound typically requires further investigation including endometrial biopsy (sampling). The evidence is solid that endometrial sampling may result in discomfort, bleeding, infection, and rarely uterine perforation. A study designed to evaluate performance, patient acceptance, and cost-effectiveness of blind biopsy, hysteroscopy with biopsy, and ultrasound in 683 women with vaginal bleeding, reported that minor events, including discomfort and distress, occurred in 16% of women who had hysteroscopy with biopsy, and in 10% of the women who had a blind biopsy.[1] A group of researchers studied 13,600 diagnostic and operative hysteroscopic procedures and found a lower complication rate among diagnostic procedures (0.13%) compared with operative procedures (0.28%).[2] Risks associated with false-positive test results include anxiety and additional diagnostic testing and surgery. Endometrial cancers may be missed on endometrial sampling and ultrasound.

References

1. Critchley HO, Warner P, Lee AJ, et al.: Evaluation of abnormal uterine bleeding: comparison of three outpatient procedures within cohorts defined by age and menopausal status. Health Technol Assess 8 (34): iii-iv, 1-139, 2004. [PUBMED Abstract]
2. Jansen FW, Vredevoogd CB, van Ulzen K, et al.: Complications of hysteroscopy: a prospective, multicenter study. Obstet Gynecol 96 (2): 266-70, 2000. [PUBMED Abstract]

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Significance

Updated statistics with estimated new cases and deaths for 2025 (cited American Cancer Society as reference 1). Also revised text to state that between 2013 and 2022, death rates for endometrial cancer increased by 1.5% per year.

This summary is written and maintained by the PDQ Screening and Prevention Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

This executive summary reviews the topics covered in Genetics of Prostate Cancer and provides hyperlinks to detailed sections that describe available evidence on each topic.

Prostate cancer is highly heritable. Up to 60% of prostate cancer risk is caused by inherited factors.[1,2] The inherited risk is comprised of risk from common genetic variants and risk from pathogenic variants in moderate-risk and high-risk genes. As with breast and colon cancers, familial clustering of prostate cancer has been reported frequently.[3]

Prostate cancer clusters with particular intensity in some families. Highly to moderately penetrant genetic variants are thought to be associated with prostate cancer risk in these families. Members of these families may benefit from genetic counseling. Additionally, polygenic risk scores derived from combinations of single nucleotide polymorphisms, in addition to other risk factors like family history, race, and age/stage of prostate cancer diagnosis, have also been developed.[4,5] Recommendations and guidelines for genetic counseling referrals are based on an individual’s age at prostate cancer diagnosis, prostate cancer stage at diagnosis, and specific patterns of cancer in the family history.[6,7] However, uptake of genetic testing based on an individual’s family history of prostate cancer and/or a diagnosis of prostate cancer is variably implemented across practice settings and geographical regions.[8–10] For more information about genetic testing criteria for prostate cancer, see Table 2.

References

1. Houlahan KE, Livingstone J, Fox NS, et al.: A polygenic two-hit hypothesis for prostate cancer. J Natl Cancer Inst 115 (4): 468-472, 2023. [PUBMED Abstract]
2. Mucci LA, Hjelmborg JB, Harris JR, et al.: Familial Risk and Heritability of Cancer Among Twins in Nordic Countries. JAMA 315 (1): 68-76, 2016. [PUBMED Abstract]
3. Seibert TM, Garraway IP, Plym A, et al.: Genetic Risk Prediction for Prostate Cancer: Implications for Early Detection and Prevention. Eur Urol 83 (3): 241-248, 2023. [PUBMED Abstract]
4. Pagadala MS, Lynch J, Karunamuni R, et al.: Polygenic risk of any, metastatic, and fatal prostate cancer in the Million Veteran Program. J Natl Cancer Inst 115 (2): 190-199, 2023. [PUBMED Abstract]
5. Huynh-Le MP, Karunamuni R, Fan CC, et al.: Prostate cancer risk stratification improvement across multiple ancestries with new polygenic hazard score. Prostate Cancer Prostatic Dis 25 (4): 755-761, 2022. [PUBMED Abstract]
6. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Version 2.2024. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2023. Available online with free registration. Last accessed September 18, 2024.
7. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer Early Detection. Version 2.2023. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2023. Available online with free registration. Last accessed November 30, 2023.
8. Clark NM, Flanagan MR: ASO Author Reflections: Low Genetic Testing Utilization Among Patients with Breast, Ovarian, Pancreatic, and Prostate Cancers. Ann Surg Oncol 30 (3): 1327-1328, 2023. [PUBMED Abstract]
9. Giri VN, Morgan TM, Morris DS, et al.: Genetic testing in prostate cancer management: Considerations informing primary care. CA Cancer J Clin 72 (4): 360-371, 2022. [PUBMED Abstract]
10. Russo J, Giri VN: Germline testing and genetic counselling in prostate cancer. Nat Rev Urol 19 (6): 331-343, 2022. [PUBMED Abstract]

References

1. American Cancer Society: Cancer Facts and Figures 2025. American Cancer Society, 2025. Available online. Last accessed January 16, 2025.
2. Salinas CA, Tsodikov A, Ishak-Howard M, et al.: Prostate cancer in young men: an important clinical entity. Nat Rev Urol 11 (6): 317-23, 2014. [PUBMED Abstract]
3. Sung H, Ferlay J, Siegel RL, et al.: Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 71 (3): 209-249, 2021. [PUBMED Abstract]
4. Krimphove MJ, Cole AP, Fletcher SA, et al.: Evaluation of the contribution of demographics, access to health care, treatment, and tumor characteristics to racial differences in survival of advanced prostate cancer. Prostate Cancer Prostatic Dis 22 (1): 125-136, 2019. [PUBMED Abstract]
5. Fletcher SA, Marchese M, Cole AP, et al.: Geographic Distribution of Racial Differences in Prostate Cancer Mortality. JAMA Netw Open 3 (3): e201839, 2020. [PUBMED Abstract]
6. Carter BS, Beaty TH, Steinberg GD, et al.: Mendelian inheritance of familial prostate cancer. Proc Natl Acad Sci U S A 89 (8): 3367-71, 1992. [PUBMED Abstract]
7. Grönberg H, Damber L, Damber JE: Familial prostate cancer in Sweden. A nationwide register cohort study. Cancer 77 (1): 138-43, 1996. [PUBMED Abstract]
8. Cannon L, Bishop DT, Skolnick M, et al.: Genetic epidemiology of prostate cancer in the Utah Mormon genealogy. Cancer Surv 1 (1): 47-69, 1982.
9. Saarimäki L, Tammela TL, Määttänen L, et al.: Family history in the Finnish Prostate Cancer Screening Trial. Int J Cancer 136 (9): 2172-7, 2015. [PUBMED Abstract]
10. Barber L, Gerke T, Markt SC, et al.: Family History of Breast or Prostate Cancer and Prostate Cancer Risk. Clin Cancer Res 24 (23): 5910-5917, 2018. [PUBMED Abstract]
11. Ghadirian P, Howe GR, Hislop TG, et al.: Family history of prostate cancer: a multi-center case-control study in Canada. Int J Cancer 70 (6): 679-81, 1997. [PUBMED Abstract]
12. Stanford JL, Ostrander EA: Familial prostate cancer. Epidemiol Rev 23 (1): 19-23, 2001. [PUBMED Abstract]
13. Matikaine MP, Pukkala E, Schleutker J, et al.: Relatives of prostate cancer patients have an increased risk of prostate and stomach cancers: a population-based, cancer registry study in Finland. Cancer Causes Control 12 (3): 223-30, 2001. [PUBMED Abstract]
14. Kiciński M, Vangronsveld J, Nawrot TS: An epidemiological reappraisal of the familial aggregation of prostate cancer: a meta-analysis. PLoS One 6 (10): e27130, 2011. [PUBMED Abstract]
15. Cerhan JR, Parker AS, Putnam SD, et al.: Family history and prostate cancer risk in a population-based cohort of Iowa men. Cancer Epidemiol Biomarkers Prev 8 (1): 53-60, 1999. [PUBMED Abstract]
16. Kalish LA, McDougal WS, McKinlay JB: Family history and the risk of prostate cancer. Urology 56 (5): 803-6, 2000. [PUBMED Abstract]
17. Damber L, Grönberg H, Damber JE: Familial prostate cancer and possible associated malignancies: nation-wide register cohort study in Sweden. Int J Cancer 78 (3): 293-7, 1998. [PUBMED Abstract]
18. Agalliu I, Karlins E, Kwon EM, et al.: Rare germline mutations in the BRCA2 gene are associated with early-onset prostate cancer. Br J Cancer 97 (6): 826-31, 2007. [PUBMED Abstract]
19. Edwards SM, Kote-Jarai Z, Meitz J, et al.: Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene. Am J Hum Genet 72 (1): 1-12, 2003. [PUBMED Abstract]
20. Ford D, Easton DF, Bishop DT, et al.: Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet 343 (8899): 692-5, 1994. [PUBMED Abstract]
21. Gayther SA, de Foy KA, Harrington P, et al.: The frequency of germ-line mutations in the breast cancer predisposition genes BRCA1 and BRCA2 in familial prostate cancer. The Cancer Research Campaign/British Prostate Group United Kingdom Familial Prostate Cancer Study Collaborators. Cancer Res 60 (16): 4513-8, 2000. [PUBMED Abstract]
22. Beebe-Dimmer JL, Yee C, Cote ML, et al.: Familial clustering of breast and prostate cancer and risk of postmenopausal breast cancer in the Women’s Health Initiative Study. Cancer 121 (8): 1265-72, 2015. [PUBMED Abstract]
23. Sellers TA, Potter JD, Rich SS, et al.: Familial clustering of breast and prostate cancers and risk of postmenopausal breast cancer. J Natl Cancer Inst 86 (24): 1860-5, 1994. [PUBMED Abstract]
24. Dominguez-Valentin M, Sampson JR, Seppälä TT, et al.: Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database. Genet Med 22 (1): 15-25, 2020. [PUBMED Abstract]
25. Samadder NJ, Smith KR, Wong J, et al.: Cancer Risk in Families Fulfilling the Amsterdam Criteria for Lynch Syndrome. JAMA Oncol 3 (12): 1697-1701, 2017. [PUBMED Abstract]
26. Whittemore AS, Wu AH, Kolonel LN, et al.: Family history and prostate cancer risk in black, white, and Asian men in the United States and Canada. Am J Epidemiol 141 (8): 732-40, 1995. [PUBMED Abstract]
27. Clements MB, Vertosick EA, Guerrios-Rivera L, et al.: Defining the Impact of Family History on Detection of High-grade Prostate Cancer in a Large Multi-institutional Cohort. Eur Urol 82 (2): 163-169, 2022. [PUBMED Abstract]
28. Beebe-Dimmer JL, Kapron AL, Fraser AM, et al.: Risk of Prostate Cancer Associated With Familial and Hereditary Cancer Syndromes. J Clin Oncol 38 (16): 1807-1813, 2020. [PUBMED Abstract]
29. Seibert TM, Garraway IP, Plym A, et al.: Genetic Risk Prediction for Prostate Cancer: Implications for Early Detection and Prevention. Eur Urol 83 (3): 241-248, 2023. [PUBMED Abstract]
30. Mucci LA, Hjelmborg JB, Harris JR, et al.: Familial Risk and Heritability of Cancer Among Twins in Nordic Countries. JAMA 315 (1): 68-76, 2016. [PUBMED Abstract]
31. Bree KK, Hensley PJ, Pettaway CA: Germline Predisposition to Prostate Cancer in Diverse Populations. Urol Clin North Am 48 (3): 411-423, 2021. [PUBMED Abstract]

Risk assessment for prostate cancer primarily involves the intake of a patient’s family cancer history. Family history intake includes the following:

*Cancers include, but are not limited to, the following: prostate, breast, pancreas, colorectal, uterine, ovarian, upper gastrointestinal (GI), and skin cancers.

Ancestry is also an important component of the family history. Ashkenazi Jewish ancestry on either side of the family may prompt greater suspicion for founder pathogenic variants in BRCA1 and BRCA2, which could lead to increased cancer risk in a family. Men of African descent (Black men) also have a higher risk for prostate cancer. Within the United States, Black men (191.5 cases/100,000 men) have approximately a 67% higher incidence rate of prostate cancer than White men (114.5 cases/100,000 men).[1] Black men also have more than twice the rate of prostate cancer–specific death (37.2 deaths/100,000 men) than White men (18.1 deaths/100,000 men).[1] This increased prostate cancer risk may be due to challenges, including the following: 1) access to care, 2) limited awareness of prostate cancer screening programs, 3) limited engagement in prostate cancer screening/genetic testing, and 4) the presence of specific genetic markers that can increase prostate cancer risk.[2–6]

These familial risk factors are then incorporated into recommendations for prostate cancer screening. National guidelines recommend discussing prostate cancer screening with prostate-specific antigen (PSA) and digital rectal exam between the ages of 45 and 75 years for individuals at average risk for prostate cancer.

In contrast, prostate cancer screening is recommended to start at age 40 years for individuals in these high-risk groups:

Men of Black/African descent.

Men with germline pathogenic variants that increase prostate cancer risk.

Men who have family histories with features suggestive of hereditary cancer syndromes like the following:

The role of additional markers, such as polygenic risk scores, in prostate cancer risk assessment is evolving. Additional screening strategies, like multiparametric magnetic resonance imaging (mpMRI), are also being studied.

References

1. American Cancer Society: Cancer Facts and Figures 2025. American Cancer Society, 2025. Available online. Last accessed January 16, 2025.
2. Liadi Y, Campbell T, Dike P, et al.: Prostate cancer metastasis and health disparities: a systematic review. Prostate Cancer Prostatic Dis 27 (2): 183-191, 2024. [PUBMED Abstract]
3. Nair SS, Chakravarty D, Dovey ZS, et al.: Why do African-American men face higher risks for lethal prostate cancer? Curr Opin Urol 32 (1): 96-101, 2022. [PUBMED Abstract]
4. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Version 2.2024. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2023. Available online with free registration. Last accessed September 18, 2024.
5. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer Early Detection. Version 2.2023. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2023. Available online with free registration. Last accessed November 30, 2023.
6. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer. Version 4.2023. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2023. Available online with free registration. Last accessed November 30, 2023.

The criteria for consideration of genetic testing for prostate cancer varies depending on the current guidelines and expert opinion consensus, as summarized in Table 2.[1–5] Hereditary prostate cancer genetic testing criteria are based on an individual’s family history, personal/disease characteristics, and tumor sequencing results. The genes recommended for genetic testing vary based on national guidelines and consensus conference recommendations. Precision therapy has emerged as a major driver for germline genetic testing and may be a separate reason to pursue testing beyond the criteria stated in Table 2. The National Comprehensive Cancer Network (NCCN) Prostate Cancer guidelines recommend testing for at least BRCA1, BRCA2, ATM, CHEK2, PALB2, HOXB13, MLH1, MSH2, MSH6, and PMS2 for men meeting specific testing indications.[4] A consensus conference in 2019 addressed the role of genetic testing for inherited prostate cancer.[6] Family history–based indications for genetic testing included testing for BRCA1/BRCA2, HOXB13, DNA mismatch repair (MMR) genes, and ATM. Tumor sequencing that identifies variants that may be germline in origin, like variants in BRCA1/BRCA2, DNA MMR genes, or ATM and other genes, warrants confirmatory germline testing. Somatic findings for which germline testing is considered include the following:

It is recommended that germline genetic testing candidates undergo genetic education and counseling before participating in testing. Genetic counseling provides information about genetic testing and possible testing outcomes (including risks, benefits, limitations, and familial, psychological, and health care–based implications that vary depending on results). Genetic education and counseling help individuals make informed decisions about whether they should undergo germline genetic testing. For more information on genetic education and genetic counseling, see Cancer Genetics Risk Assessment and Counseling.

References

1. Giri VN, Knudsen KE, Kelly WK, et al.: Role of Genetic Testing for Inherited Prostate Cancer Risk: Philadelphia Prostate Cancer Consensus Conference 2017. J Clin Oncol 36 (4): 414-424, 2018. [PUBMED Abstract]
2. Gillessen S, Attard G, Beer TM, et al.: Management of Patients with Advanced Prostate Cancer: The Report of the Advanced Prostate Cancer Consensus Conference APCCC 2017. Eur Urol 73 (2): 178-211, 2018. [PUBMED Abstract]
3. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Version 2.2024. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2023. Available online with free registration. Last accessed September 18, 2024.
4. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer. Version 4.2023. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2023. Available online with free registration. Last accessed November 30, 2023.
5. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer Early Detection. Version 2.2023. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2023. Available online with free registration. Last accessed November 30, 2023.
6. Giri VN, Knudsen KE, Kelly WK, et al.: Implementation of Germline Testing for Prostate Cancer: Philadelphia Prostate Cancer Consensus Conference 2019. J Clin Oncol 38 (24): 2798-2811, 2020. [PUBMED Abstract]
7. Raymond VM, Gray SW, Roychowdhury S, et al.: Germline Findings in Tumor-Only Sequencing: Points to Consider for Clinicians and Laboratories. J Natl Cancer Inst 108 (4): , 2016. [PUBMED Abstract]
8. Gillessen S, Attard G, Beer TM, et al.: Management of Patients with Advanced Prostate Cancer: Report of the Advanced Prostate Cancer Consensus Conference 2019. Eur Urol 77 (4): 508-547, 2020. [PUBMED Abstract]

Since next-generation sequencing (NGS) has become readily available and patent restrictions have been eliminated, several clinical laboratories offer multigene panel testing at a cost that is comparable to that of single-gene testing. Three types of genetic test results can be reported: 1) pathogenic/likely pathogenic variants, 2) variants of uncertain significance (VUS), or 3) negative results. Patients need pretest genetic counseling or informed consent to understand germline genetic testing results. For example, patients should understand that VUS can be reported, that VUS do not immediately impact care/inform cancer risk, and that VUS may be reclassified as either pathogenic/likely pathogenic or benign/likely benign when more data are acquired. For more information on genetic counseling considerations and research associated with multigene testing, see the Multigene (panel) testing section in Cancer Genetics Risk Assessment and Counseling.

Prostate cancer is highly heritable. More than half of an individual’s prostate cancer risk is inherited from one’s parents.[1] Considerable work has been performed to identify and characterize inherited germline variants that contribute to the genetic portion of prostate cancer risk. For most patients, the bulk of inherited risk is conferred by hundreds of genetic polymorphisms, which are common in the general population. Each of these polymorphisms slightly increases prostate cancer risk. For a small subset of patients, prostate cancer risk is generated by rare, deleterious variants located in specific genes. In this section, we will describe the specific genes implicated in inherited prostate cancer risk and the many common polymorphisms (which are typically located in the genomic space between genes) that create a risk profile for most patients.

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References

1. Mucci LA, Hjelmborg JB, Harris JR, et al.: Familial Risk and Heritability of Cancer Among Twins in Nordic Countries. JAMA 315 (1): 68-76, 2016. [PUBMED Abstract]
2. Thompson D, Easton DF; Breast Cancer Linkage Consortium: Cancer Incidence in BRCA1 mutation carriers. J Natl Cancer Inst 94 (18): 1358-65, 2002. [PUBMED Abstract]
3. Nyberg T, Tischkowitz M, Antoniou AC: BRCA1 and BRCA2 pathogenic variants and prostate cancer risk: systematic review and meta-analysis. Br J Cancer 126 (7): 1067-1081, 2022. [PUBMED Abstract]
4. Mersch J, Jackson MA, Park M, et al.: Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarian. Cancer 121 (2): 269-75, 2015. [PUBMED Abstract]
5. Nastiuk KL, Mansukhani M, Terry MB, et al.: Common mutations in BRCA1 and BRCA2 do not contribute to early prostate cancer in Jewish men. Prostate 40 (3): 172-7, 1999. [PUBMED Abstract]
6. Vazina A, Baniel J, Yaacobi Y, et al.: The rate of the founder Jewish mutations in BRCA1 and BRCA2 in prostate cancer patients in Israel. Br J Cancer 83 (4): 463-6, 2000. [PUBMED Abstract]
7. Lehrer S, Fodor F, Stock RG, et al.: Absence of 185delAG mutation of the BRCA1 gene and 6174delT mutation of the BRCA2 gene in Ashkenazi Jewish men with prostate cancer. Br J Cancer 78 (6): 771-3, 1998. [PUBMED Abstract]
8. Struewing JP, Abeliovich D, Peretz T, et al.: The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals. Nat Genet 11 (2): 198-200, 1995. [PUBMED Abstract]
9. Oddoux C, Struewing JP, Clayton CM, et al.: The carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1%. Nat Genet 14 (2): 188-90, 1996. [PUBMED Abstract]
10. Roa BB, Boyd AA, Volcik K, et al.: Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nat Genet 14 (2): 185-7, 1996. [PUBMED Abstract]
11. Struewing JP, Hartge P, Wacholder S, et al.: The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 336 (20): 1401-8, 1997. [PUBMED Abstract]
12. Nyberg T, Frost D, Barrowdale D, et al.: Prostate Cancer Risks for Male BRCA1 and BRCA2 Mutation Carriers: A Prospective Cohort Study. Eur Urol 77 (1): 24-35, 2020. [PUBMED Abstract]
13. Patel VL, Busch EL, Friebel TM, et al.: Association of Genomic Domains in BRCA1 and BRCA2 with Prostate Cancer Risk and Aggressiveness. Cancer Res 80 (3): 624-638, 2020. [PUBMED Abstract]
14. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Version 2.2024. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2023. Available online with free registration. Last accessed September 18, 2024.
15. Taylor RA, Fraser M, Livingstone J, et al.: Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories. Nat Commun 8: 13671, 2017. [PUBMED Abstract]
16. Oh M, Alkhushaym N, Fallatah S, et al.: The association of BRCA1 and BRCA2 mutations with prostate cancer risk, frequency, and mortality: A meta-analysis. Prostate 79 (8): 880-895, 2019. [PUBMED Abstract]
17. Lange EM, Gillanders EM, Davis CC, et al.: Genome-wide scan for prostate cancer susceptibility genes using families from the University of Michigan prostate cancer genetics project finds evidence for linkage on chromosome 17 near BRCA1. Prostate 57 (4): 326-34, 2003. [PUBMED Abstract]
18. Lange EM, Robbins CM, Gillanders EM, et al.: Fine-mapping the putative chromosome 17q21-22 prostate cancer susceptibility gene to a 10 cM region based on linkage analysis. Hum Genet 121 (1): 49-55, 2007. [PUBMED Abstract]
19. Ewing CM, Ray AM, Lange EM, et al.: Germline mutations in HOXB13 and prostate-cancer risk. N Engl J Med 366 (2): 141-9, 2012. [PUBMED Abstract]
20. Schroeck FR, Zuhlke KA, Siddiqui J, et al.: Testing for the recurrent HOXB13 G84E germline mutation in men with clinical indications for prostate biopsy. J Urol 189 (3): 849-53, 2013. [PUBMED Abstract]
21. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer Early Detection. Version 2.2023. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2023. Available online with free registration. Last accessed November 30, 2023.
22. Xu J, Lange EM, Lu L, et al.: HOXB13 is a susceptibility gene for prostate cancer: results from the International Consortium for Prostate Cancer Genetics (ICPCG). Hum Genet 132 (1): 5-14, 2013. [PUBMED Abstract]
23. Chen Z, Greenwood C, Isaacs WB, et al.: The G84E mutation of HOXB13 is associated with increased risk for prostate cancer: results from the REDUCE trial. Carcinogenesis 34 (6): 1260-4, 2013. [PUBMED Abstract]
24. Shang Z, Zhu S, Zhang H, et al.: Germline homeobox B13 (HOXB13) G84E mutation and prostate cancer risk in European descendants: a meta-analysis of 24,213 cases and 73, 631 controls. Eur Urol 64 (1): 173-6, 2013. [PUBMED Abstract]
25. Handorf E, Crumpler N, Gross L, et al.: Prevalence of the HOXB13 G84E mutation among unaffected men with a family history of prostate cancer. J Genet Couns 23 (3): 371-6, 2014. [PUBMED Abstract]
26. Laitinen VH, Wahlfors T, Saaristo L, et al.: HOXB13 G84E mutation in Finland: population-based analysis of prostate, breast, and colorectal cancer risk. Cancer Epidemiol Biomarkers Prev 22 (3): 452-60, 2013. [PUBMED Abstract]
27. Witte JS, Mefford J, Plummer SJ, et al.: HOXB13 mutation and prostate cancer: studies of siblings and aggressive disease. Cancer Epidemiol Biomarkers Prev 22 (4): 675-80, 2013. [PUBMED Abstract]
28. Beebe-Dimmer JL, Hathcock M, Yee C, et al.: The HOXB13 G84E Mutation Is Associated with an Increased Risk for Prostate Cancer and Other Malignancies. Cancer Epidemiol Biomarkers Prev 24 (9): 1366-72, 2015. [PUBMED Abstract]
29. Gudmundsson J, Sulem P, Gudbjartsson DF, et al.: A study based on whole-genome sequencing yields a rare variant at 8q24 associated with prostate cancer. Nat Genet 44 (12): 1326-9, 2012. [PUBMED Abstract]
30. Huang H, Cai B: G84E mutation in HOXB13 is firmly associated with prostate cancer risk: a meta-analysis. Tumour Biol 35 (2): 1177-82, 2014. [PUBMED Abstract]
31. Cai Q, Wang X, Li X, et al.: Germline HOXB13 p.Gly84Glu mutation and cancer susceptibility: a pooled analysis of 25 epidemiological studies with 145,257 participates. Oncotarget 6 (39): 42312-21, 2015. [PUBMED Abstract]
32. Stott-Miller M, Karyadi DM, Smith T, et al.: HOXB13 mutations in a population-based, case-control study of prostate cancer. Prostate 73 (6): 634-41, 2013. [PUBMED Abstract]
33. Alanee S, Shah S, Vijai J, et al.: Prevalence of HOXB13 mutation in a population of Ashkenazi Jewish men treated for prostate cancer. Fam Cancer 12 (4): 597-600, 2013. [PUBMED Abstract]
34. Kote-Jarai Z, Mikropoulos C, Leongamornlert DA, et al.: Prevalence of the HOXB13 G84E germline mutation in British men and correlation with prostate cancer risk, tumour characteristics and clinical outcomes. Ann Oncol 26 (4): 756-61, 2015. [PUBMED Abstract]
35. Sipeky C, Gao P, Zhang Q, et al.: Synergistic Interaction of HOXB13 and CIP2A Predisposes to Aggressive Prostate Cancer. Clin Cancer Res 24 (24): 6265-6276, 2018. [PUBMED Abstract]
36. Lin X, Qu L, Chen Z, et al.: A novel germline mutation in HOXB13 is associated with prostate cancer risk in Chinese men. Prostate 73 (2): 169-75, 2013. [PUBMED Abstract]
37. Momozawa Y, Iwasaki Y, Hirata M, et al.: Germline Pathogenic Variants in 7636 Japanese Patients With Prostate Cancer and 12 366 Controls. J Natl Cancer Inst 112 (4): 369-376, 2020. [PUBMED Abstract]
38. Marlin R, Créoff M, Merle S, et al.: Mutation HOXB13 c.853delT in Martinican prostate cancer patients. Prostate 80 (6): 463-470, 2020. [PUBMED Abstract]
39. Na R, Wei J, Sample CJ, et al.: The HOXB13 variant X285K is associated with clinical significance and early age at diagnosis in African American prostate cancer patients. Br J Cancer 126 (5): 791-796, 2022. [PUBMED Abstract]
40. Darst BF, Hughley R, Pfennig A, et al.: A Rare Germline HOXB13 Variant Contributes to Risk of Prostate Cancer in Men of African Ancestry. Eur Urol 81 (5): 458-462, 2022. [PUBMED Abstract]
41. Karlsson R, Aly M, Clements M, et al.: A population-based assessment of germline HOXB13 G84E mutation and prostate cancer risk. Eur Urol 65 (1): 169-76, 2014. [PUBMED Abstract]
42. MacInnis RJ, Severi G, Baglietto L, et al.: Population-based estimate of prostate cancer risk for carriers of the HOXB13 missense mutation G84E. PLoS One 8 (2): e54727, 2013. [PUBMED Abstract]
43. Nyberg T, Govindasami K, Leslie G, et al.: Homeobox B13 G84E Mutation and Prostate Cancer Risk. Eur Urol 75 (5): 834-845, 2019. [PUBMED Abstract]
44. Soravia C, van der Klift H, Bründler MA, et al.: Prostate cancer is part of the hereditary non-polyposis colorectal cancer (HNPCC) tumor spectrum. Am J Med Genet 121A (2): 159-62, 2003. [PUBMED Abstract]
45. Haraldsdottir S, Hampel H, Wei L, et al.: Prostate cancer incidence in males with Lynch syndrome. Genet Med 16 (7): 553-7, 2014. [PUBMED Abstract]
46. Grindedal EM, Møller P, Eeles R, et al.: Germ-line mutations in mismatch repair genes associated with prostate cancer. Cancer Epidemiol Biomarkers Prev 18 (9): 2460-7, 2009. [PUBMED Abstract]
47. Langeberg WJ, Kwon EM, Koopmeiners JS, et al.: Population-based study of the association of variants in mismatch repair genes with prostate cancer risk and outcomes. Cancer Epidemiol Biomarkers Prev 19 (1): 258-64, 2010. [PUBMED Abstract]
48. Bauer CM, Ray AM, Halstead-Nussloch BA, et al.: Hereditary prostate cancer as a feature of Lynch syndrome. Fam Cancer 10 (1): 37-42, 2011. [PUBMED Abstract]
49. Dominguez-Valentin M, Joost P, Therkildsen C, et al.: Frequent mismatch-repair defects link prostate cancer to Lynch syndrome. BMC Urol 16: 15, 2016. [PUBMED Abstract]
50. Raymond VM, Mukherjee B, Wang F, et al.: Elevated risk of prostate cancer among men with Lynch syndrome. J Clin Oncol 31 (14): 1713-8, 2013. [PUBMED Abstract]
51. Ryan S, Jenkins MA, Win AK: Risk of prostate cancer in Lynch syndrome: a systematic review and meta-analysis. Cancer Epidemiol Biomarkers Prev 23 (3): 437-49, 2014. [PUBMED Abstract]
52. Rosty C, Walsh MD, Lindor NM, et al.: High prevalence of mismatch repair deficiency in prostate cancers diagnosed in mismatch repair gene mutation carriers from the colon cancer family registry. Fam Cancer 13 (4): 573-82, 2014. [PUBMED Abstract]
53. Dominguez-Valentin M, Sampson JR, Seppälä TT, et al.: Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database. Genet Med 22 (1): 15-25, 2020. [PUBMED Abstract]
54. Guedes LB, Antonarakis ES, Schweizer MT, et al.: MSH2 Loss in Primary Prostate Cancer. Clin Cancer Res 23 (22): 6863-6874, 2017. [PUBMED Abstract]
55. Kovacs ME, Papp J, Szentirmay Z, et al.: Deletions removing the last exon of TACSTD1 constitute a distinct class of mutations predisposing to Lynch syndrome. Hum Mutat 30 (2): 197-203, 2009. [PUBMED Abstract]
56. Pritchard CC, Mateo J, Walsh MF, et al.: Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med 375 (5): 443-53, 2016. [PUBMED Abstract]
57. Savitsky K, Bar-Shira A, Gilad S, et al.: A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 268 (5218): 1749-53, 1995. [PUBMED Abstract]
58. Dombernowsky SL, Weischer M, Allin KH, et al.: Risk of cancer by ATM missense mutations in the general population. J Clin Oncol 26 (18): 3057-62, 2008. [PUBMED Abstract]
59. Angèle S, Falconer A, Edwards SM, et al.: ATM polymorphisms as risk factors for prostate cancer development. Br J Cancer 91 (4): 783-7, 2004. [PUBMED Abstract]
60. Meyer A, Wilhelm B, Dörk T, et al.: ATM missense variant P1054R predisposes to prostate cancer. Radiother Oncol 83 (3): 283-8, 2007. [PUBMED Abstract]
61. Schumacher FR, Al Olama AA, Berndt SI, et al.: Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci. Nat Genet 50 (7): 928-936, 2018. [PUBMED Abstract]
62. Karlsson Q, Brook MN, Dadaev T, et al.: Rare Germline Variants in ATM Predispose to Prostate Cancer: A PRACTICAL Consortium Study. Eur Urol Oncol 4 (4): 570-579, 2021. [PUBMED Abstract]
63. Wang Y, Dai B, Ye D: CHEK2 mutation and risk of prostate cancer: a systematic review and meta-analysis. Int J Clin Exp Med 8 (9): 15708-15, 2015. [PUBMED Abstract]
64. Conti DV, Wang K, Sheng X, et al.: Two Novel Susceptibility Loci for Prostate Cancer in Men of African Ancestry. J Natl Cancer Inst 109 (8): , 2017. [PUBMED Abstract]
65. Mai PL, Best AF, Peters JA, et al.: Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni syndrome cohort. Cancer 122 (23): 3673-3681, 2016. [PUBMED Abstract]
66. Ruijs MW, Verhoef S, Rookus MA, et al.: TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes. J Med Genet 47 (6): 421-8, 2010. [PUBMED Abstract]
67. Bougeard G, Renaux-Petel M, Flaman JM, et al.: Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers. J Clin Oncol 33 (21): 2345-52, 2015. [PUBMED Abstract]
68. Cheng HH, Klemfuss N, Montgomery B, et al.: A Pilot Study of Clinical Targeted Next Generation Sequencing for Prostate Cancer: Consequences for Treatment and Genetic Counseling. Prostate 76 (14): 1303-11, 2016. [PUBMED Abstract]
69. Stacey SN, Sulem P, Jonasdottir A, et al.: A germline variant in the TP53 polyadenylation signal confers cancer susceptibility. Nat Genet 43 (11): 1098-103, 2011. [PUBMED Abstract]
70. Mittal RD, George GP, Mishra J, et al.: Role of functional polymorphisms of P53 and P73 genes with the risk of prostate cancer in a case-control study from Northern India. Arch Med Res 42 (2): 122-7, 2011. [PUBMED Abstract]
71. Xu B, Xu Z, Cheng G, et al.: Association between polymorphisms of TP53 and MDM2 and prostate cancer risk in southern Chinese. Cancer Genet Cytogenet 202 (2): 76-81, 2010. [PUBMED Abstract]
72. Maxwell KN, Cheng HH, Powers J, et al.: Inherited TP53 Variants and Risk of Prostate Cancer. Eur Urol 81 (3): 243-250, 2022. [PUBMED Abstract]
73. Rusak B, Kluźniak W, Wokołorczykv D, et al.: Inherited NBN Mutations and Prostate Cancer Risk and Survival. Cancer Res Treat 51 (3): 1180-1187, 2019. [PUBMED Abstract]
74. Wokołorczyk D, Kluźniak W, Huzarski T, et al.: Mutations in ATM, NBN and BRCA2 predispose to aggressive prostate cancer in Poland. Int J Cancer 147 (10): 2793-2800, 2020. [PUBMED Abstract]
75. Giri VN, Hegarty SE, Hyatt C, et al.: Germline genetic testing for inherited prostate cancer in practice: Implications for genetic testing, precision therapy, and cascade testing. Prostate 79 (4): 333-339, 2019. [PUBMED Abstract]
76. Nicolosi P, Ledet E, Yang S, et al.: Prevalence of Germline Variants in Prostate Cancer and Implications for Current Genetic Testing Guidelines. JAMA Oncol 5 (4): 523-528, 2019. [PUBMED Abstract]
77. Lang SH, Swift SL, White H, et al.: A systematic review of the prevalence of DNA damage response gene mutations in prostate cancer. Int J Oncol 55 (3): 597-616, 2019. [PUBMED Abstract]
78. Robinson D, Van Allen EM, Wu YM, et al.: Integrative clinical genomics of advanced prostate cancer. Cell 161 (5): 1215-28, 2015. [PUBMED Abstract]
79. Mandelker D, Zhang L, Kemel Y, et al.: Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing. JAMA 318 (9): 825-835, 2017. [PUBMED Abstract]
80. Schrader KA, Cheng DT, Joseph V, et al.: Germline Variants in Targeted Tumor Sequencing Using Matched Normal DNA. JAMA Oncol 2 (1): 104-11, 2016. [PUBMED Abstract]
81. Amundadottir LT, Sulem P, Gudmundsson J, et al.: A common variant associated with prostate cancer in European and African populations. Nat Genet 38 (6): 652-8, 2006. [PUBMED Abstract]
82. Schumacher FR, Feigelson HS, Cox DG, et al.: A common 8q24 variant in prostate and breast cancer from a large nested case-control study. Cancer Res 67 (7): 2951-6, 2007. [PUBMED Abstract]
83. Suuriniemi M, Agalliu I, Schaid DJ, et al.: Confirmation of a positive association between prostate cancer risk and a locus at chromosome 8q24. Cancer Epidemiol Biomarkers Prev 16 (4): 809-14, 2007. [PUBMED Abstract]
84. Wang L, McDonnell SK, Slusser JP, et al.: Two common chromosome 8q24 variants are associated with increased risk for prostate cancer. Cancer Res 67 (7): 2944-50, 2007. [PUBMED Abstract]
85. Yeager M, Orr N, Hayes RB, et al.: Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat Genet 39 (5): 645-9, 2007. [PUBMED Abstract]
86. Zheng SL, Sun J, Cheng Y, et al.: Association between two unlinked loci at 8q24 and prostate cancer risk among European Americans. J Natl Cancer Inst 99 (20): 1525-33, 2007. [PUBMED Abstract]
87. Savage SA, Greene MH: The evidence for prostate cancer risk loci at 8q24 grows stronger. J Natl Cancer Inst 99 (20): 1499-501, 2007. [PUBMED Abstract]
88. Salinas CA, Kwon E, Carlson CS, et al.: Multiple independent genetic variants in the 8q24 region are associated with prostate cancer risk. Cancer Epidemiol Biomarkers Prev 17 (5): 1203-13, 2008. [PUBMED Abstract]
89. Zheng SL, Hsing AW, Sun J, et al.: Association of 17 prostate cancer susceptibility loci with prostate cancer risk in Chinese men. Prostate 70 (4): 425-32, 2010. [PUBMED Abstract]
90. Zeegers MP, Khan HS, Schouten LJ, et al.: Genetic marker polymorphisms on chromosome 8q24 and prostate cancer in the Dutch population: DG8S737 may not be the causative variant. Eur J Hum Genet 19 (1): 118-20, 2011. [PUBMED Abstract]
91. Gudmundsson J, Sulem P, Manolescu A, et al.: Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24. Nat Genet 39 (5): 631-7, 2007. [PUBMED Abstract]
92. Haiman CA, Patterson N, Freedman ML, et al.: Multiple regions within 8q24 independently affect risk for prostate cancer. Nat Genet 39 (5): 638-44, 2007. [PUBMED Abstract]
93. Yeager M, Chatterjee N, Ciampa J, et al.: Identification of a new prostate cancer susceptibility locus on chromosome 8q24. Nat Genet 41 (10): 1055-7, 2009. [PUBMED Abstract]
94. Al Olama AA, Kote-Jarai Z, Giles GG, et al.: Multiple loci on 8q24 associated with prostate cancer susceptibility. Nat Genet 41 (10): 1058-60, 2009. [PUBMED Abstract]
95. Matejcic M, Saunders EJ, Dadaev T, et al.: Germline variation at 8q24 and prostate cancer risk in men of European ancestry. Nat Commun 9 (1): 4616, 2018. [PUBMED Abstract]
96. Conti DV, Darst BF, Moss LC, et al.: Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction. Nat Genet 53 (1): 65-75, 2021. [PUBMED Abstract]
97. Cook MB, Wang Z, Yeboah ED, et al.: A genome-wide association study of prostate cancer in West African men. Hum Genet 133 (5): 509-21, 2014. [PUBMED Abstract]
98. Haiman CA, Chen GK, Blot WJ, et al.: Characterizing genetic risk at known prostate cancer susceptibility loci in African Americans. PLoS Genet 7 (5): e1001387, 2011. [PUBMED Abstract]
99. Han Y, Signorello LB, Strom SS, et al.: Generalizability of established prostate cancer risk variants in men of African ancestry. Int J Cancer 136 (5): 1210-7, 2015. [PUBMED Abstract]
100. Han Y, Rand KA, Hazelett DJ, et al.: Prostate Cancer Susceptibility in Men of African Ancestry at 8q24. J Natl Cancer Inst 108 (7): , 2016. [PUBMED Abstract]
101. Takata R, Akamatsu S, Kubo M, et al.: Genome-wide association study identifies five new susceptibility loci for prostate cancer in the Japanese population. Nat Genet 42 (9): 751-4, 2010. [PUBMED Abstract]
102. Akamatsu S, Takata R, Haiman CA, et al.: Common variants at 11q12, 10q26 and 3p11.2 are associated with prostate cancer susceptibility in Japanese. Nat Genet 44 (4): 426-9, S1, 2012. [PUBMED Abstract]
103. Xu J, Mo Z, Ye D, et al.: Genome-wide association study in Chinese men identifies two new prostate cancer risk loci at 9q31.2 and 19q13.4. Nat Genet 44 (11): 1231-5, 2012. [PUBMED Abstract]
104. Takata R, Takahashi A, Fujita M, et al.: 12 new susceptibility loci for prostate cancer identified by genome-wide association study in Japanese population. Nat Commun 10 (1): 4422, 2019. [PUBMED Abstract]
105. Benafif S, Kote-Jarai Z, Eeles RA, et al.: A Review of Prostate Cancer Genome-Wide Association Studies (GWAS). Cancer Epidemiol Biomarkers Prev 27 (8): 845-857, 2018. [PUBMED Abstract]
106. Wang A, Shen J, Rodriguez AA, et al.: Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants. Nat Genet 55 (12): 2065-2074, 2023. [PUBMED Abstract]
107. Chou A, Darst BF, Wilkens LR, et al.: Association of Prostate-Specific Antigen Levels with Prostate Cancer Risk in a Multiethnic Population: Stability Over Time and Comparison with Polygenic Risk Score. Cancer Epidemiol Biomarkers Prev 31 (12): 2199-2207, 2022. [PUBMED Abstract]
108. Kachuri L, Hoffmann TJ, Jiang Y, et al.: Genetically adjusted PSA levels for prostate cancer screening. Nat Med 29 (6): 1412-1423, 2023. [PUBMED Abstract]
109. Nyberg T, Brook MN, Ficorella L, et al.: CanRisk-Prostate: A Comprehensive, Externally Validated Risk Model for the Prediction of Future Prostate Cancer. J Clin Oncol 41 (5): 1092-1104, 2023. [PUBMED Abstract]
110. Dite GS, Spaeth E, Murphy NM, et al.: Development and validation of a simple prostate cancer risk prediction model based on age, family history, and polygenic risk. Prostate 83 (10): 962-969, 2023. [PUBMED Abstract]
111. Black MH, Li S, LaDuca H, et al.: Validation of a prostate cancer polygenic risk score. Prostate 80 (15): 1314-1321, 2020. [PUBMED Abstract]
112. Yoon BW, Shin HT, Seo JH: Risk Allele Frequency Analysis and Risk Prediction of Single-Nucleotide Polymorphisms for Prostate Cancer. Genes (Basel) 13 (11): , 2022. [PUBMED Abstract]
113. Huntley C, Torr B, Sud A, et al.: Utility of polygenic risk scores in UK cancer screening: a modelling analysis. Lancet Oncol 24 (6): 658-668, 2023. [PUBMED Abstract]
114. Karunamuni RA, Huynh-Le MP, Fan CC, et al.: Performance of African-ancestry-specific polygenic hazard score varies according to local ancestry in 8q24. Prostate Cancer Prostatic Dis 25 (2): 229-237, 2022. [PUBMED Abstract]
115. Chen F, Madduri RK, Rodriguez AA, et al.: Evidence of Novel Susceptibility Variants for Prostate Cancer and a Multiancestry Polygenic Risk Score Associated with Aggressive Disease in Men of African Ancestry. Eur Urol 84 (1): 13-21, 2023. [PUBMED Abstract]
116. Zhang W, Nicholson T, Zhang K: Deciphering the Polygenic Basis of Racial Disparities in Prostate Cancer By an Integrative Analysis of Genomic and Transcriptomic Data. Cancer Prev Res (Phila) 15 (3): 161-171, 2022. [PUBMED Abstract]
117. Ruan X, Huang D, Huang J, et al.: Application of European-specific polygenic risk scores for predicting prostate cancer risk in different ancestry populations. Prostate 83 (1): 30-38, 2023. [PUBMED Abstract]
118. Darst BF, Shen J, Madduri RK, et al.: Evaluating approaches for constructing polygenic risk scores for prostate cancer in men of African and European ancestry. Am J Hum Genet 110 (7): 1200-1206, 2023. [PUBMED Abstract]
119. Siltari A, Lönnerbro R, Pang K, et al.: How Well do Polygenic Risk Scores Identify Men at High Risk for Prostate Cancer? Systematic Review and Meta-Analysis. Clin Genitourin Cancer 21 (2): 316.e1-316.e11, 2023. [PUBMED Abstract]
120. Chen F, Darst BF, Madduri RK, et al.: Validation of a multi-ancestry polygenic risk score and age-specific risks of prostate cancer: A meta-analysis within diverse populations. Elife 11: , 2022. [PUBMED Abstract]
121. Ruan X, Huang D, Huang J, et al.: Genetic risk assessment of lethal prostate cancer using polygenic risk score and hereditary cancer susceptibility genes. J Transl Med 21 (1): 446, 2023. [PUBMED Abstract]
122. Freedman ML, Monteiro AN, Gayther SA, et al.: Principles for the post-GWAS functional characterization of cancer risk loci. Nat Genet 43 (6): 513-8, 2011. [PUBMED Abstract]
123. Pomerantz MM, Beckwith CA, Regan MM, et al.: Evaluation of the 8q24 prostate cancer risk locus and MYC expression. Cancer Res 69 (13): 5568-74, 2009. [PUBMED Abstract]
124. Jia L, Landan G, Pomerantz M, et al.: Functional enhancers at the gene-poor 8q24 cancer-linked locus. PLoS Genet 5 (8): e1000597, 2009. [PUBMED Abstract]
125. Ahmadiyeh N, Pomerantz MM, Grisanzio C, et al.: 8q24 prostate, breast, and colon cancer risk loci show tissue-specific long-range interaction with MYC. Proc Natl Acad Sci U S A 107 (21): 9742-6, 2010. [PUBMED Abstract]
126. Sotelo J, Esposito D, Duhagon MA, et al.: Long-range enhancers on 8q24 regulate c-Myc. Proc Natl Acad Sci U S A 107 (7): 3001-5, 2010. [PUBMED Abstract]
127. Meyer KB, Maia AT, O’Reilly M, et al.: A functional variant at a prostate cancer predisposition locus at 8q24 is associated with PVT1 expression. PLoS Genet 7 (7): e1002165, 2011. [PUBMED Abstract]
128. Spisák S, Lawrenson K, Fu Y, et al.: CAUSEL: an epigenome- and genome-editing pipeline for establishing function of noncoding GWAS variants. Nat Med 21 (11): 1357-63, 2015. [PUBMED Abstract]
129. Hazelett DJ, Rhie SK, Gaddis M, et al.: Comprehensive functional annotation of 77 prostate cancer risk loci. PLoS Genet 10 (1): e1004102, 2014. [PUBMED Abstract]
130. Jiang J, Cui W, Vongsangnak W, et al.: Post genome-wide association studies functional characterization of prostate cancer risk loci. BMC Genomics 14 (Suppl 8): S9, 2013. [PUBMED Abstract]

This section addresses the impact of genetics on prostate cancer screening, surveillance, and treatment. For more information about prostate cancer screening, surveillance, and treatment, see Prostate Cancer Screening and Prostate Cancer Treatment.

References

1. Sartor O: Early detection of prostate cancer in African-American men with an increased familial risk of disease. J La State Med Soc 148 (4): 179-85, 1996. [PUBMED Abstract]
2. Matikainen MP, Schleutker J, Mörsky P, et al.: Detection of subclinical cancers by prostate-specific antigen screening in asymptomatic men from high-risk prostate cancer families. Clin Cancer Res 5 (6): 1275-9, 1999. [PUBMED Abstract]
3. Catalona WJ, Antenor JA, Roehl KA, et al.: Screening for prostate cancer in high risk populations. J Urol 168 (5): 1980-3; discussion 1983-4, 2002. [PUBMED Abstract]
4. Valeri A, Cormier L, Moineau MP, et al.: Targeted screening for prostate cancer in high risk families: early onset is a significant risk factor for disease in first degree relatives. J Urol 168 (2): 483-7, 2002. [PUBMED Abstract]
5. Narod SA, Dupont A, Cusan L, et al.: The impact of family history on early detection of prostate cancer. Nat Med 1 (2): 99-101, 1995. [PUBMED Abstract]
6. Giri VN, Beebe-Dimmer J, Buyyounouski M, et al.: Prostate cancer risk assessment program: a 10-year update of cancer detection. J Urol 178 (5): 1920-4; discussion 1924, 2007. [PUBMED Abstract]
7. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer Early Detection. Version 2.2023. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2023. Available online with free registration. Last accessed November 30, 2023.
8. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Version 2.2024. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2023. Available online with free registration. Last accessed September 18, 2024.
9. U.S. Preventative Services Task Force: Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Rockville, Md: U.S. Preventative Services Task Force, 2018. Available online. Last accessed May 8, 2025.
10. Wei JT, Barocas D, Carlsson S, et al.: Early Detection of Prostate Cancer: AUA/SUO Guideline Part I: Prostate Cancer Screening. J Urol 210 (1): 46-53, 2023. [PUBMED Abstract]
11. American Cancer Society: American Cancer Society Recommendations for Prostate Cancer Early Detection. American Cancer Society, 2023. Available online. Last accessed May 8, 2025.
12. Bancroft EK, Page EC, Castro E, et al.: Targeted prostate cancer screening in BRCA1 and BRCA2 mutation carriers: results from the initial screening round of the IMPACT study. Eur Urol 66 (3): 489-99, 2014. [PUBMED Abstract]
13. National Collaborating Centre for Cancer (UK): Prostate Cancer: Diagnosis and Treatment. Cardiff, UK: National Collaborating Centre for Cancer, 2008. Available online. Last accessed May 8, 2025.
14. Page EC, Bancroft EK, Brook MN, et al.: Interim Results from the IMPACT Study: Evidence for Prostate-specific Antigen Screening in BRCA2 Mutation Carriers. Eur Urol 76 (6): 831-842, 2019. [PUBMED Abstract]
15. Carlo MI, Giri VN, Paller CJ, et al.: Evolving Intersection Between Inherited Cancer Genetics and Therapeutic Clinical Trials in Prostate Cancer: A White Paper From the Germline Genetics Working Group of the Prostate Cancer Clinical Trials Consortium. JCO Precis Oncol 2018: , 2018. [PUBMED Abstract]
16. Annala M, Struss WJ, Warner EW, et al.: Treatment Outcomes and Tumor Loss of Heterozygosity in Germline DNA Repair-deficient Prostate Cancer. Eur Urol 72 (1): 34-42, 2017. [PUBMED Abstract]
17. Pomerantz MM, Spisák S, Jia L, et al.: The association between germline BRCA2 variants and sensitivity to platinum-based chemotherapy among men with metastatic prostate cancer. Cancer 123 (18): 3532-3539, 2017. [PUBMED Abstract]
18. Cheng HH, Pritchard CC, Boyd T, et al.: Biallelic Inactivation of BRCA2 in Platinum-sensitive Metastatic Castration-resistant Prostate Cancer. Eur Urol 69 (6): 992-5, 2016. [PUBMED Abstract]
19. Mateo J, Cheng HH, Beltran H, et al.: Clinical Outcome of Prostate Cancer Patients with Germline DNA Repair Mutations: Retrospective Analysis from an International Study. Eur Urol 73 (5): 687-693, 2018. [PUBMED Abstract]
20. Carter HB, Helfand B, Mamawala M, et al.: Germline Mutations in ATM and BRCA1/2 Are Associated with Grade Reclassification in Men on Active Surveillance for Prostate Cancer. Eur Urol 75 (5): 743-749, 2019. [PUBMED Abstract]
21. Marshall CH, Sokolova AO, McNatty AL, et al.: Differential Response to Olaparib Treatment Among Men with Metastatic Castration-resistant Prostate Cancer Harboring BRCA1 or BRCA2 Versus ATM Mutations. Eur Urol 76 (4): 452-458, 2019. [PUBMED Abstract]
22. Sokolova AO, Marshall CH, Lozano R, et al.: Efficacy of systemic therapies in men with metastatic castration resistant prostate cancer harboring germline ATM versus BRCA2 mutations. Prostate 81 (16): 1382-1389, 2021. [PUBMED Abstract]
23. Antonarakis ES, Lu C, Luber B, et al.: Germline DNA-repair Gene Mutations and Outcomes in Men with Metastatic Castration-resistant Prostate Cancer Receiving First-line Abiraterone and Enzalutamide. Eur Urol 74 (2): 218-225, 2018. [PUBMED Abstract]
24. Castro E, Romero-Laorden N, Del Pozo A, et al.: PROREPAIR-B: A Prospective Cohort Study of the Impact of Germline DNA Repair Mutations on the Outcomes of Patients With Metastatic Castration-Resistant Prostate Cancer. J Clin Oncol 37 (6): 490-503, 2019. [PUBMED Abstract]
25. de Bono J, Mateo J, Fizazi K, et al.: Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med 382 (22): 2091-2102, 2020. [PUBMED Abstract]
26. Hussain M, Mateo J, Fizazi K, et al.: Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer. N Engl J Med 383 (24): 2345-2357, 2020. [PUBMED Abstract]
27. Abida W, Patnaik A, Campbell D, et al.: Rucaparib in Men With Metastatic Castration-Resistant Prostate Cancer Harboring a BRCA1 or BRCA2 Gene Alteration. J Clin Oncol 38 (32): 3763-3772, 2020. [PUBMED Abstract]
28. de Bono JS, Mehra N, Scagliotti GV, et al.: Talazoparib monotherapy in metastatic castration-resistant prostate cancer with DNA repair alterations (TALAPRO-1): an open-label, phase 2 trial. Lancet Oncol 22 (9): 1250-1264, 2021. [PUBMED Abstract]

References

1. Ni Raghallaigh H, Eeles R: Genetic predisposition to prostate cancer: an update. Fam Cancer 21 (1): 101-114, 2022. [PUBMED Abstract]
2. Taylor KL, DiPlacido J, Redd WH, et al.: Demographics, family histories, and psychological characteristics of prostate carcinoma screening participants. Cancer 85 (6): 1305-12, 1999. [PUBMED Abstract]
3. Beebe-Dimmer JL, Wood DP, Gruber SB, et al.: Risk perception and concern among brothers of men with prostate carcinoma. Cancer 100 (7): 1537-44, 2004. [PUBMED Abstract]
4. Miller SM, Diefenbach MA, Kruus LK, et al.: Psychological and screening profiles of first-degree relatives of prostate cancer patients. J Behav Med 24 (3): 247-58, 2001. [PUBMED Abstract]
5. Montgomery GH, Erblich J, DiLorenzo T, et al.: Family and friends with disease: their impact on perceived risk. Prev Med 37 (3): 242-9, 2003. [PUBMED Abstract]
6. Bratt O, Damber JE, Emanuelsson M, et al.: Risk perception, screening practice and interest in genetic testing among unaffected men in families with hereditary prostate cancer. Eur J Cancer 36 (2): 235-41, 2000. [PUBMED Abstract]
7. Bancroft EK, Saya S, Page EC, et al.: Psychosocial impact of undergoing prostate cancer screening for men with BRCA1 or BRCA2 mutations. BJU Int 123 (2): 284-292, 2019. [PUBMED Abstract]
8. Cormier L, Reid K, Kwan L, et al.: Screening behavior in brothers and sons of men with prostate cancer. J Urol 169 (5): 1715-9, 2003. [PUBMED Abstract]
9. Vadaparampil ST, Jacobsen PB, Kash K, et al.: Factors predicting prostate specific antigen testing among first-degree relatives of prostate cancer patients. Cancer Epidemiol Biomarkers Prev 13 (5): 753-8, 2004. [PUBMED Abstract]
10. Bock CH, Peyser PA, Gruber SB, et al.: Prostate cancer early detection practices among men with a family history of disease. Urology 62 (3): 470-5, 2003. [PUBMED Abstract]
11. Jacobsen PB, Lamonde LA, Honour M, et al.: Relation of family history of prostate cancer to perceived vulnerability and screening behavior. Psychooncology 13 (2): 80-5, 2004. [PUBMED Abstract]
12. Roumier X, Azzouzi R, Valéri A, et al.: Adherence to an annual PSA screening program over 3 years for brothers and sons of men with prostate cancer. Eur Urol 45 (3): 280-5; author reply 285-6, 2004. [PUBMED Abstract]
13. Weinrich SP: Prostate cancer screening in high-risk men: African American Hereditary Prostate Cancer Study Network. Cancer 106 (4): 796-803, 2006. [PUBMED Abstract]
14. Ross LE, Uhler RJ, Williams KN: Awareness and use of the prostate-specific antigen test among African-American men. J Natl Med Assoc 97 (7): 963-71, 2005. [PUBMED Abstract]

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Risk Factors for Prostate Cancer

Updated statistics with new cancer cases and deaths for 2025 (cited American Cancer Society as reference 1).

Updated statistics with estimated new cancer cases and deaths for different racial and ethnic groups in 2025.

Risk Assessment for Prostate Cancer

Updated statistics with estimated new cancer cases and deaths for different racial and ethnic groups in 2025 (cited American Cancer Society as reference 1).

This summary is written and maintained by the PDQ Cancer Genetics Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

Note: The Summary of Evidence section summarizes the published evidence on this topic. The rest of the summary describes the evidence in more detail.

Other PDQ summaries on Primary Liver Cancer Treatment and Childhood Liver Cancer Treatment are also available.

References

1. Bray F, Laversanne M, Sung H, et al.: Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 74 (3): 229-263, 2024. [PUBMED Abstract]
2. American Cancer Society: Cancer Facts and Figures 2025. American Cancer Society, 2025. Available online. Last accessed January 16, 2025.
3. Surveillance Research Program, National Cancer Institute: SEER*Explorer: An interactive website for SEER cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed December 30, 2024.
4. Benvegnù L, Fattovich G, Noventa F, et al.: Concurrent hepatitis B and C virus infection and risk of hepatocellular carcinoma in cirrhosis. A prospective study. Cancer 74 (9): 2442-8, 1994. [PUBMED Abstract]
5. Ikeda K, Saitoh S, Koida I, et al.: A multivariate analysis of risk factors for hepatocellular carcinogenesis: a prospective observation of 795 patients with viral and alcoholic cirrhosis. Hepatology 18 (1): 47-53, 1993. [PUBMED Abstract]
6. Chiaramonte M, Stroffolini T, Vian A, et al.: Rate of incidence of hepatocellular carcinoma in patients with compensated viral cirrhosis. Cancer 85 (10): 2132-7, 1999. [PUBMED Abstract]
7. Yuan JM, Govindarajan S, Gao YT, et al.: Prospective evaluation of infection with hepatitis G virus in relation to hepatocellular carcinoma in Shanghai, China. J Infect Dis 182 (5): 1300-3, 2000. [PUBMED Abstract]
8. Di Bisceglie AM, Carithers RL, Gores GJ: Hepatocellular carcinoma. Hepatology 28 (4): 1161-5, 1998. [PUBMED Abstract]
9. Farinati F, Floreani A, De Maria N, et al.: Hepatocellular carcinoma in primary biliary cirrhosis. J Hepatol 21 (3): 315-6, 1994. [PUBMED Abstract]
10. Bugianesi E, Leone N, Vanni E, et al.: Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology 123 (1): 134-40, 2002. [PUBMED Abstract]
11. Fattovich G, Stroffolini T, Zagni I, et al.: Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 127 (5 Suppl 1): S35-50, 2004. [PUBMED Abstract]
12. Shiratori Y, Yoshida H, Omata M: Management of hepatocellular carcinoma: advances in diagnosis, treatment and prevention. Expert Rev Anticancer Ther 1 (2): 277-90, 2001. [PUBMED Abstract]

References

1. Zaman SN, Johnson PJ, Williams R: Silent cirrhosis in patients with hepatocellular carcinoma. Implications for screening in high-incidence and low-incidence areas. Cancer 65 (7): 1607-10, 1990. [PUBMED Abstract]
2. Primary liver cancer in Japan. Clinicopathologic features and results of surgical treatment. Liver Cancer Study Group of Japan. Ann Surg 211 (3): 277-87, 1990. [PUBMED Abstract]
3. Collier J, Sherman M: Screening for hepatocellular carcinoma. Hepatology 27 (1): 273-8, 1998. [PUBMED Abstract]
4. Zhou L, Liu J, Luo F: Serum tumor markers for detection of hepatocellular carcinoma. World J Gastroenterol 12 (8): 1175-81, 2006. [PUBMED Abstract]
5. Sherman M, Peltekian KM, Lee C: Screening for hepatocellular carcinoma in chronic carriers of hepatitis B virus: incidence and prevalence of hepatocellular carcinoma in a North American urban population. Hepatology 22 (2): 432-8, 1995. [PUBMED Abstract]
6. Oka H, Tamori A, Kuroki T, et al.: Prospective study of alpha-fetoprotein in cirrhotic patients monitored for development of hepatocellular carcinoma. Hepatology 19 (1): 61-6, 1994. [PUBMED Abstract]
7. Pateron D, Ganne N, Trinchet JC, et al.: Prospective study of screening for hepatocellular carcinoma in Caucasian patients with cirrhosis. J Hepatol 20 (1): 65-71, 1994. [PUBMED Abstract]
8. McMahon BJ, Bulkow L, Harpster A, et al.: Screening for hepatocellular carcinoma in Alaska natives infected with chronic hepatitis B: a 16-year population-based study. Hepatology 32 (4 Pt 1): 842-6, 2000. [PUBMED Abstract]
9. Soresi M, Magliarisi C, Campagna P, et al.: Usefulness of alpha-fetoprotein in the diagnosis of hepatocellular carcinoma. Anticancer Res 23 (2C): 1747-53, 2003 Mar-Apr. [PUBMED Abstract]
10. Di Bisceglie AM, Hoofnagle JH: Elevations in serum alpha-fetoprotein levels in patients with chronic hepatitis B. Cancer 64 (10): 2117-20, 1989. [PUBMED Abstract]
11. Chalasani N, Horlander JC, Said A, et al.: Screening for hepatocellular carcinoma in patients with advanced cirrhosis. Am J Gastroenterol 94 (10): 2988-93, 1999. [PUBMED Abstract]
12. Peterson MS, Baron RL, Marsh JW, et al.: Pretransplantation surveillance for possible hepatocellular carcinoma in patients with cirrhosis: epidemiology and CT-based tumor detection rate in 430 cases with surgical pathologic correlation. Radiology 217 (3): 743-9, 2000. [PUBMED Abstract]
13. Moon AM, Weiss NS, Beste LA, et al.: No Association Between Screening for Hepatocellular Carcinoma and Reduced Cancer-Related Mortality in Patients With Cirrhosis. Gastroenterology 155 (4): 1128-1139.e6, 2018. [PUBMED Abstract]
14. Dodd GD, Miller WJ, Baron RL, et al.: Detection of malignant tumors in end-stage cirrhotic livers: efficacy of sonography as a screening technique. AJR Am J Roentgenol 159 (4): 727-33, 1992. [PUBMED Abstract]
15. Aghoram R, Cai P, Dickinson JA: Alpha-foetoprotein and/or liver ultrasonography for screening of hepatocellular carcinoma in patients with chronic hepatitis B. Cochrane Database Syst Rev 9: CD002799, 2012. [PUBMED Abstract]
16. Zhang BH, Yang BH, Tang ZY: Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol 130 (7): 417-22, 2004. [PUBMED Abstract]
17. Chen JG, Parkin DM, Chen QG, et al.: Screening for liver cancer: results of a randomised controlled trial in Qidong, China. J Med Screen 10 (4): 204-9, 2003. [PUBMED Abstract]

Two kinds of harms or complications may result from screening. Direct harms may result from complications of liver biopsy done as part of the diagnostic workup. Such complications are reported in 0.06% to 0.32% of patients, and they typically occur within the first few hours after the biopsy. Complications include hemorrhage, bile peritonitis, penetration of viscera, and pneumothorax. Rarely, death occurs as a direct result of liver biopsy (0.009%–0.12%). About one third of patients experience pain at the site of entry, in the right upper quadrant, or in the right shoulder.[1] Needle aspiration cytology and liver biopsy are rarely associated with needle-track implantation of malignant cells. Lead-time bias (earlier diagnosis in the natural history of hepatocellular carcinoma [HCC] rather than improved survival from earlier diagnosis and treatment), length bias (earlier detection of slower-growing and less aggressive tumors through screening), and/or overdiagnosis of HCC (detection of tumors that will not affect morbidity or mortality) may wholly or partially account for the improved 5-year and 10-year survival rates reported.

References

1. Tobkes AI, Nord HJ: Liver biopsy: review of methodology and complications. Dig Dis 13 (5): 267-74, 1995 Sep-Oct. [PUBMED Abstract]

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Significance

Updated statistics with estimated new cases and deaths for 2025 (cited Bray et al. as reference 1 and American Cancer Society as reference 2).

This summary is written and maintained by the PDQ Screening and Prevention Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

Note: The Overview section summarizes the published evidence on this topic. The rest of the summary describes the evidence in more detail.

Other PDQ summaries containing information related to liver (hepatocellular) cancer prevention include the following:

References

1. London WT, McGlynn K: Liver cancer. In: Schottenfeld D, Fraumeni JF Jr, eds.: Cancer Epidemiology and Prevention. 3rd ed. Oxford University Press, 2006, pp 763-86.
2. El-Serag HB, Kanwal F: Epidemiology of hepatocellular carcinoma in the United States: where are we? Where do we go? Hepatology 60 (5): 1767-75, 2014. [PUBMED Abstract]
3. Fattovich G, Stroffolini T, Zagni I, et al.: Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 127 (5 Suppl 1): S35-50, 2004. [PUBMED Abstract]
4. Hartke J, Johnson M, Ghabril M: The diagnosis and treatment of hepatocellular carcinoma. Semin Diagn Pathol 34 (2): 153-159, 2017. [PUBMED Abstract]
5. Donato F, Tagger A, Gelatti U, et al.: Alcohol and hepatocellular carcinoma: the effect of lifetime intake and hepatitis virus infections in men and women. Am J Epidemiol 155 (4): 323-31, 2002. [PUBMED Abstract]
6. Ascha MS, Hanouneh IA, Lopez R, et al.: The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology 51 (6): 1972-8, 2010. [PUBMED Abstract]
7. White DL, Kanwal F, El-Serag HB: Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol 10 (12): 1342-1359.e2, 2012. [PUBMED Abstract]
8. Perumpail RB, Wong RJ, Ahmed A, et al.: Hepatocellular Carcinoma in the Setting of Non-cirrhotic Nonalcoholic Fatty Liver Disease and the Metabolic Syndrome: US Experience. Dig Dis Sci 60 (10): 3142-8, 2015. [PUBMED Abstract]
9. Chuang SC, Lee YC, Hashibe M, et al.: Interaction between cigarette smoking and hepatitis B and C virus infection on the risk of liver cancer: a meta-analysis. Cancer Epidemiol Biomarkers Prev 19 (5): 1261-8, 2010. [PUBMED Abstract]
10. Calzadilla Bertot L, Adams LA: The Natural Course of Non-Alcoholic Fatty Liver Disease. Int J Mol Sci 17 (5): , 2016. [PUBMED Abstract]
11. Streba LA, Vere CC, Rogoveanu I, et al.: Nonalcoholic fatty liver disease, metabolic risk factors, and hepatocellular carcinoma: an open question. World J Gastroenterol 21 (14): 4103-10, 2015. [PUBMED Abstract]
12. Kim D, Touros A, Kim WR: Nonalcoholic Fatty Liver Disease and Metabolic Syndrome. Clin Liver Dis 22 (1): 133-140, 2018. [PUBMED Abstract]
13. Kao JH: Hepatitis B vaccination and prevention of hepatocellular carcinoma. Best Pract Res Clin Gastroenterol 29 (6): 907-17, 2015. [PUBMED Abstract]
14. Singal AK, Salameh H, Kuo YF, et al.: Meta-analysis: the impact of oral anti-viral agents on the incidence of hepatocellular carcinoma in chronic hepatitis B. Aliment Pharmacol Ther 38 (2): 98-106, 2013. [PUBMED Abstract]
15. Chen JG, Egner PA, Ng D, et al.: Reduced aflatoxin exposure presages decline in liver cancer mortality in an endemic region of China. Cancer Prev Res (Phila) 6 (10): 1038-45, 2013. [PUBMED Abstract]
16. Kanwal F, Kramer J, Asch SM, et al.: Risk of Hepatocellular Cancer in HCV Patients Treated With Direct-Acting Antiviral Agents. Gastroenterology 153 (4): 996-1005.e1, 2017. [PUBMED Abstract]
17. Lafaro KJ, Demirjian AN, Pawlik TM: Epidemiology of hepatocellular carcinoma. Surg Oncol Clin N Am 24 (1): 1-17, 2015. [PUBMED Abstract]
18. El-Serag HB: Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology 142 (6): 1264-1273.e1, 2012. [PUBMED Abstract]
19. Grewal P, Viswanathen VA: Liver cancer and alcohol. Clin Liver Dis 16 (4): 839-50, 2012. [PUBMED Abstract]
20. Bosetti C, Turati F, La Vecchia C: Hepatocellular carcinoma epidemiology. Best Pract Res Clin Gastroenterol 28 (5): 753-70, 2014. [PUBMED Abstract]
21. Rinella ME: Nonalcoholic fatty liver disease: a systematic review. JAMA 313 (22): 2263-73, 2015. [PUBMED Abstract]
22. Mittal S, El-Serag HB, Sada YH, et al.: Hepatocellular Carcinoma in the Absence of Cirrhosis in United States Veterans is Associated With Nonalcoholic Fatty Liver Disease. Clin Gastroenterol Hepatol 14 (1): 124-31.e1, 2016. [PUBMED Abstract]
23. Jinjuvadia R, Patel S, Liangpunsakul S: The association between metabolic syndrome and hepatocellular carcinoma: systemic review and meta-analysis. J Clin Gastroenterol 48 (2): 172-7, 2014. [PUBMED Abstract]
24. Qu C, Chen T, Fan C, et al.: Efficacy of neonatal HBV vaccination on liver cancer and other liver diseases over 30-year follow-up of the Qidong hepatitis B intervention study: a cluster randomized controlled trial. PLoS Med 11 (12): e1001774, 2014. [PUBMED Abstract]
25. McGlynn KA, Petrick JL, London WT: Global epidemiology of hepatocellular carcinoma: an emphasis on demographic and regional variability. Clin Liver Dis 19 (2): 223-38, 2015. [PUBMED Abstract]
26. Li DK, Ren Y, Fierer DS, et al.: The short-term incidence of hepatocellular carcinoma is not increased after hepatitis C treatment with direct-acting antivirals: An ERCHIVES study. Hepatology 67 (6): 2244-2253, 2018. [PUBMED Abstract]
27. Carrat F, Fontaine H, Dorival C, et al.: Clinical outcomes in patients with chronic hepatitis C after direct-acting antiviral treatment: a prospective cohort study. Lancet 393 (10179): 1453-1464, 2019. [PUBMED Abstract]
28. Li X, Sheng L, Liu L, et al.: Statin and the risk of hepatocellular carcinoma in patients with hepatitis B virus or hepatitis C virus infection: a meta-analysis. BMC Gastroenterol 20 (1): 98, 2020. [PUBMED Abstract]
29. Tsan YT, Lee CH, Wang JD, et al.: Statins and the risk of hepatocellular carcinoma in patients with hepatitis B virus infection. J Clin Oncol 30 (6): 623-30, 2012. [PUBMED Abstract]
30. Tsan YT, Lee CH, Ho WC, et al.: Statins and the risk of hepatocellular carcinoma in patients with hepatitis C virus infection. J Clin Oncol 31 (12): 1514-21, 2013. [PUBMED Abstract]
31. Simon TG, Duberg AS, Aleman S, et al.: Lipophilic Statins and Risk for Hepatocellular Carcinoma and Death in Patients With Chronic Viral Hepatitis: Results From a Nationwide Swedish Population. Ann Intern Med 171 (5): 318-327, 2019. [PUBMED Abstract]
32. Simon TG, Bonilla H, Yan P, et al.: Atorvastatin and fluvastatin are associated with dose-dependent reductions in cirrhosis and hepatocellular carcinoma, among patients with hepatitis C virus: Results from ERCHIVES. Hepatology 64 (1): 47-57, 2016. [PUBMED Abstract]
33. Singh S, Singh PP, Singh AG, et al.: Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis. Gastroenterology 144 (2): 323-32, 2013. [PUBMED Abstract]

In the United States, liver cancer, regardless of histology, accounts for about 2% of cancer diagnoses and 5% of cancer deaths. Although liver cancer is not among the top ten diagnosed cancers in the United States,[1] it is the sixth-leading cause of cancer deaths.[1] About 42,240 new cases of liver cancer and 30,090 deaths are expected to occur in the United States in 2025.[2] Hepatocellular cancer accounts for about 70% of all liver cancers in the United States.[2] In 1975, liver cancer incidence in the United States was 2.64 per 100,000. In 2021, the rate had risen more than threefold to 8.39 per 100,000.[3] Five-year survival rates vary by stage, from a high of 37.3% for localized disease to a low of 3.3% for distant disease.[1] In the United States, rates of liver cancer incidence and liver cancer death are lowest in White individuals and highest in American Indian or Alaska Native individuals. Rates are also higher in Hispanic individuals than in non-Hispanic individuals.[1]

Worldwide, liver cancer is the sixth most common cancer and the third leading cause of cancer-related death.[4] Liver cancer resulted in about 865,269 new cases and 757,948 deaths in 2022;[4] in most countries, the liver annual incidence and mortality rates are nearly identical.[4] It is the fifth most frequently diagnosed cancer in adult men and the ninth most commonly diagnosed cancer in women.[4] The incidence of liver varies widely according to geographic location.[4] High-incidence regions include Northern and Western Africa (Egypt, the Gambia, Guinea) and Eastern and South-Eastern Asia (Mongolia, Cambodia, and Vietnam). Liver incidence is low in North and South America, most of Europe, Australia, and parts of the Middle East.[4,5] In all parts of the world, liver is more common in men than in women.[4,5]

References

1. National Cancer Institute: SEER Stat Fact Sheets: Liver and Intrahepatic Bile Duct Cancer. Bethesda, Md: National Cancer Institute. Available online. Last accessed December 5, 2024.
2. American Cancer Society: Cancer Facts and Figures 2025. American Cancer Society, 2025. Available online. Last accessed January 16, 2025.
3. Surveillance Research Program, National Cancer Institute: SEER*Explorer: An interactive website for SEER cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed December 30, 2024.
4. Bray F, Laversanne M, Sung H, et al.: Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 74 (3): 229-263, 2024. [PUBMED Abstract]
5. Jemal A, Bray F, Center MM, et al.: Global cancer statistics. CA Cancer J Clin 61 (2): 69-90, 2011 Mar-Apr. [PUBMED Abstract]

References

1. Lafaro KJ, Demirjian AN, Pawlik TM: Epidemiology of hepatocellular carcinoma. Surg Oncol Clin N Am 24 (1): 1-17, 2015. [PUBMED Abstract]
2. London WT, McGlynn K: Liver cancer. In: Schottenfeld D, Fraumeni JF Jr, eds.: Cancer Epidemiology and Prevention. 3rd ed. Oxford University Press, 2006, pp 763-86.
3. Centers for Disease Control and Prevention: Hepatitis B FAQs for the Public. Atlanta, GA: Centers for Disease Control and Prevention, Division of Viral Hepatitis, 2016. Available online. Last accessed December 5, 2024.
4. U.S. Department of Health and Human Services: Hepatitis B Basic Information. Washington, DC: U.S. Department of Health and Human Services, 2017. Available online. Last accessed December 5, 2024.
5. Mittal S, El-Serag HB: Epidemiology of hepatocellular carcinoma: consider the population. J Clin Gastroenterol 47 (Suppl): S2-6, 2013. [PUBMED Abstract]
6. El-Serag HB: Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology 142 (6): 1264-1273.e1, 2012. [PUBMED Abstract]
7. Ferlay J, Soerjomataram I, Dikshit R, et al.: Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136 (5): E359-86, 2015. [PUBMED Abstract]
8. El-Serag HB, Kanwal F: Epidemiology of hepatocellular carcinoma in the United States: where are we? Where do we go? Hepatology 60 (5): 1767-75, 2014. [PUBMED Abstract]
9. Centers for Disease Control and Prevention: Hepatitis C FAQs for Health Professionals. Atlanta, GA: Centers for Disease Control and Prevention, Division of Viral Hepatitis, 2017. Available online. Last accessed December 5, 2024.
10. Ghouri YA, Mian I, Rowe JH: Review of hepatocellular carcinoma: Epidemiology, etiology, and carcinogenesis. J Carcinog 16: 1, 2017. [PUBMED Abstract]
11. Huang YT, Jen CL, Yang HI, et al.: Lifetime risk and sex difference of hepatocellular carcinoma among patients with chronic hepatitis B and C. J Clin Oncol 29 (27): 3643-50, 2011. [PUBMED Abstract]
12. Scaglione S, Kliethermes S, Cao G, et al.: The Epidemiology of Cirrhosis in the United States: A Population-based Study. J Clin Gastroenterol 49 (8): 690-6, 2015. [PUBMED Abstract]
13. Hartke J, Johnson M, Ghabril M: The diagnosis and treatment of hepatocellular carcinoma. Semin Diagn Pathol 34 (2): 153-159, 2017. [PUBMED Abstract]
14. Fattovich G, Stroffolini T, Zagni I, et al.: Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 127 (5 Suppl 1): S35-50, 2004. [PUBMED Abstract]
15. Saffioti F, Pinzani M: Development and Regression of Cirrhosis. Dig Dis 34 (4): 374-81, 2016. [PUBMED Abstract]
16. Grewal P, Viswanathen VA: Liver cancer and alcohol. Clin Liver Dis 16 (4): 839-50, 2012. [PUBMED Abstract]
17. Donato F, Tagger A, Gelatti U, et al.: Alcohol and hepatocellular carcinoma: the effect of lifetime intake and hepatitis virus infections in men and women. Am J Epidemiol 155 (4): 323-31, 2002. [PUBMED Abstract]
18. McGlynn KA, Petrick JL, London WT: Global epidemiology of hepatocellular carcinoma: an emphasis on demographic and regional variability. Clin Liver Dis 19 (2): 223-38, 2015. [PUBMED Abstract]
19. Liu Y, Wu F: Global burden of aflatoxin-induced hepatocellular carcinoma: a risk assessment. Environ Health Perspect 118 (6): 818-24, 2010. [PUBMED Abstract]
20. Chen JG, Egner PA, Ng D, et al.: Reduced aflatoxin exposure presages decline in liver cancer mortality in an endemic region of China. Cancer Prev Res (Phila) 6 (10): 1038-45, 2013. [PUBMED Abstract]
21. Diehl AM, Day C: Cause, Pathogenesis, and Treatment of Nonalcoholic Steatohepatitis. N Engl J Med 377 (21): 2063-2072, 2017. [PUBMED Abstract]
22. White DL, Kanwal F, El-Serag HB: Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol 10 (12): 1342-1359.e2, 2012. [PUBMED Abstract]
23. Ascha MS, Hanouneh IA, Lopez R, et al.: The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology 51 (6): 1972-8, 2010. [PUBMED Abstract]
24. Younossi ZM, Koenig AB, Abdelatif D, et al.: Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 64 (1): 73-84, 2016. [PUBMED Abstract]
25. Lee YC, Cohet C, Yang YC, et al.: Meta-analysis of epidemiologic studies on cigarette smoking and liver cancer. Int J Epidemiol 38 (6): 1497-511, 2009. [PUBMED Abstract]
26. Cancer. In: U.S. Department of Health and Human Services: The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General. U.S. Department of Health and Human Services, CDC, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2014, pp 139-351. Also available online. Last accessed December 5, 2024.
27. Koh WP, Robien K, Wang R, et al.: Smoking as an independent risk factor for hepatocellular carcinoma: the Singapore Chinese Health Study. Br J Cancer 105 (9): 1430-5, 2011. [PUBMED Abstract]
28. Chuang SC, Lee YC, Hashibe M, et al.: Interaction between cigarette smoking and hepatitis B and C virus infection on the risk of liver cancer: a meta-analysis. Cancer Epidemiol Biomarkers Prev 19 (5): 1261-8, 2010. [PUBMED Abstract]
29. Harrison SA, Bacon BR: Relation of hemochromatosis with hepatocellular carcinoma: epidemiology, natural history, pathophysiology, screening, treatment, and prevention. Med Clin North Am 89 (2): 391-409, 2005. [PUBMED Abstract]
30. Villanueva A, Newell P, Hoshida Y: Inherited hepatocellular carcinoma. Best Pract Res Clin Gastroenterol 24 (5): 725-34, 2010. [PUBMED Abstract]
31. Campos MA, Wanner A, Zhang G, et al.: Trends in the diagnosis of symptomatic patients with alpha1-antitrypsin deficiency between 1968 and 2003. Chest 128 (3): 1179-86, 2005. [PUBMED Abstract]
32. Lomas DA, Evans DL, Finch JT, et al.: The mechanism of Z alpha 1-antitrypsin accumulation in the liver. Nature 357 (6379): 605-7, 1992. [PUBMED Abstract]
33. Nelson DR, Teckman J, Di Bisceglie AM, et al.: Diagnosis and management of patients with α1-antitrypsin (A1AT) deficiency. Clin Gastroenterol Hepatol 10 (6): 575-80, 2012. [PUBMED Abstract]
34. Limmer J, Fleig WE, Leupold D, et al.: Hepatocellular carcinoma in type I glycogen storage disease. Hepatology 8 (3): 531-7, 1988 May-Jun. [PUBMED Abstract]
35. Harber LC, Bickers DR: Photosensitivity Diseases: Principles of Diagnosis and Treatment. Saunders, 1981.
36. Linet MS, Gridley G, Nyrén O, et al.: Primary liver cancer, other malignancies, and mortality risks following porphyria: a cohort study in Denmark and Sweden. Am J Epidemiol 149 (11): 1010-5, 1999. [PUBMED Abstract]
37. Huster D: Wilson disease. Best Pract Res Clin Gastroenterol 24 (5): 531-9, 2010. [PUBMED Abstract]
38. Pfeiffenberger J, Mogler C, Gotthardt DN, et al.: Hepatobiliary malignancies in Wilson disease. Liver Int 35 (5): 1615-22, 2015. [PUBMED Abstract]

References

1. Younossi ZM, Stepanova M, Afendy M, et al.: Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin Gastroenterol Hepatol 9 (6): 524-530.e1; quiz e60, 2011. [PUBMED Abstract]
2. Dyson JK, Anstee QM, McPherson S: Non-alcoholic fatty liver disease: a practical approach to diagnosis and staging. Frontline Gastroenterol 5 (3): 211-218, 2014. [PUBMED Abstract]
3. Rinella ME: Nonalcoholic fatty liver disease: a systematic review. JAMA 313 (22): 2263-73, 2015. [PUBMED Abstract]
4. Calzadilla Bertot L, Adams LA: The Natural Course of Non-Alcoholic Fatty Liver Disease. Int J Mol Sci 17 (5): , 2016. [PUBMED Abstract]
5. Younossi ZM, Koenig AB, Abdelatif D, et al.: Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 64 (1): 73-84, 2016. [PUBMED Abstract]
6. Baffy G, Brunt EM, Caldwell SH: Hepatocellular carcinoma in non-alcoholic fatty liver disease: an emerging menace. J Hepatol 56 (6): 1384-91, 2012. [PUBMED Abstract]
7. Mittal S, El-Serag HB, Sada YH, et al.: Hepatocellular Carcinoma in the Absence of Cirrhosis in United States Veterans is Associated With Nonalcoholic Fatty Liver Disease. Clin Gastroenterol Hepatol 14 (1): 124-31.e1, 2016. [PUBMED Abstract]
8. Kim D, Touros A, Kim WR: Nonalcoholic Fatty Liver Disease and Metabolic Syndrome. Clin Liver Dis 22 (1): 133-140, 2018. [PUBMED Abstract]
9. Aguilar M, Bhuket T, Torres S, et al.: Prevalence of the metabolic syndrome in the United States, 2003-2012. JAMA 313 (19): 1973-4, 2015. [PUBMED Abstract]
10. Jinjuvadia R, Patel S, Liangpunsakul S: The association between metabolic syndrome and hepatocellular carcinoma: systemic review and meta-analysis. J Clin Gastroenterol 48 (2): 172-7, 2014. [PUBMED Abstract]
11. Rahman R, Hammoud GM, Almashhrawi AA, et al.: Primary hepatocellular carcinoma and metabolic syndrome: An update. World J Gastrointest Oncol 5 (9): 186-94, 2013. [PUBMED Abstract]
12. Schlesinger S, Aleksandrova K, Pischon T, et al.: Abdominal obesity, weight gain during adulthood and risk of liver and biliary tract cancer in a European cohort. Int J Cancer 132 (3): 645-57, 2013. [PUBMED Abstract]
13. Welzel TM, Graubard BI, Zeuzem S, et al.: Metabolic syndrome increases the risk of primary liver cancer in the United States: a study in the SEER-Medicare database. Hepatology 54 (2): 463-71, 2011. [PUBMED Abstract]
14. Chen Y, Wang X, Wang J, et al.: Excess body weight and the risk of primary liver cancer: an updated meta-analysis of prospective studies. Eur J Cancer 48 (14): 2137-45, 2012. [PUBMED Abstract]
15. Streba LA, Vere CC, Rogoveanu I, et al.: Nonalcoholic fatty liver disease, metabolic risk factors, and hepatocellular carcinoma: an open question. World J Gastroenterol 21 (14): 4103-10, 2015. [PUBMED Abstract]
16. Wang P, Kang D, Cao W, et al.: Diabetes mellitus and risk of hepatocellular carcinoma: a systematic review and meta-analysis. Diabetes Metab Res Rev 28 (2): 109-22, 2012. [PUBMED Abstract]
17. Wainwright P, Scorletti E, Byrne CD: Type 2 Diabetes and Hepatocellular Carcinoma: Risk Factors and Pathogenesis. Curr Diab Rep 17 (4): 20, 2017. [PUBMED Abstract]
18. Ferlay J, Soerjomataram I, Dikshit R, et al.: Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136 (5): E359-86, 2015. [PUBMED Abstract]

References

1. Kao JH: Hepatitis B vaccination and prevention of hepatocellular carcinoma. Best Pract Res Clin Gastroenterol 29 (6): 907-17, 2015. [PUBMED Abstract]
2. World Health Organization: Hepatitis B Fact Sheet. Geneva, Switzerland: World Health Organization, 2017. Available online. Last accessed December 5, 2024.
3. Qu C, Chen T, Fan C, et al.: Efficacy of neonatal HBV vaccination on liver cancer and other liver diseases over 30-year follow-up of the Qidong hepatitis B intervention study: a cluster randomized controlled trial. PLoS Med 11 (12): e1001774, 2014. [PUBMED Abstract]
4. Chang MH, You SL, Chen CJ, et al.: Long-term Effects of Hepatitis B Immunization of Infants in Preventing Liver Cancer. Gastroenterology 151 (3): 472-480.e1, 2016. [PUBMED Abstract]
5. McGlynn KA, Petrick JL, London WT: Global epidemiology of hepatocellular carcinoma: an emphasis on demographic and regional variability. Clin Liver Dis 19 (2): 223-38, 2015. [PUBMED Abstract]
6. Leuridan E, Van Damme P: Hepatitis B and the need for a booster dose. Clin Infect Dis 53 (1): 68-75, 2011. [PUBMED Abstract]
7. Perrillo R: Benefits and risks of interferon therapy for hepatitis B. Hepatology 49 (5 Suppl): S103-11, 2009. [PUBMED Abstract]
8. Terrault NA, Lok ASF, McMahon BJ, et al.: Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 67 (4): 1560-1599, 2018. [PUBMED Abstract]
9. Lai CL, Yuen MF: Prevention of hepatitis B virus-related hepatocellular carcinoma with antiviral therapy. Hepatology 57 (1): 399-408, 2013. [PUBMED Abstract]
10. Huang DQ, Li X, Le MH, et al.: Natural History and Hepatocellular Carcinoma Risk in Untreated Chronic Hepatitis B Patients With Indeterminate Phase. Clin Gastroenterol Hepatol 20 (8): 1803-1812.e5, 2022. [PUBMED Abstract]
11. Huang DQ, Tran A, Yeh ML, et al.: Antiviral therapy substantially reduces HCC risk in patients with chronic hepatitis B infection in the indeterminate phase. Hepatology 78 (5): 1558-1568, 2023. [PUBMED Abstract]
12. Singal AK, Salameh H, Kuo YF, et al.: Meta-analysis: the impact of oral anti-viral agents on the incidence of hepatocellular carcinoma in chronic hepatitis B. Aliment Pharmacol Ther 38 (2): 98-106, 2013. [PUBMED Abstract]
13. Coffin CS, Rezaeeaval M, Pang JX, et al.: The incidence of hepatocellular carcinoma is reduced in patients with chronic hepatitis B on long-term nucleos(t)ide analogue therapy. Aliment Pharmacol Ther 40 (11-12): 1262-9, 2014. [PUBMED Abstract]
14. Gordon SC, Lamerato LE, Rupp LB, et al.: Antiviral therapy for chronic hepatitis B virus infection and development of hepatocellular carcinoma in a US population. Clin Gastroenterol Hepatol 12 (5): 885-93, 2014. [PUBMED Abstract]
15. Chen JG, Egner PA, Ng D, et al.: Reduced aflatoxin exposure presages decline in liver cancer mortality in an endemic region of China. Cancer Prev Res (Phila) 6 (10): 1038-45, 2013. [PUBMED Abstract]

References

1. Simmons B, Saleem J, Hill A, et al.: Risk of Late Relapse or Reinfection With Hepatitis C Virus After Achieving a Sustained Virological Response: A Systematic Review and Meta-analysis. Clin Infect Dis 62 (6): 683-694, 2016. [PUBMED Abstract]
2. Kanwal F, Kramer J, Asch SM, et al.: Risk of Hepatocellular Cancer in HCV Patients Treated With Direct-Acting Antiviral Agents. Gastroenterology 153 (4): 996-1005.e1, 2017. [PUBMED Abstract]
3. Buonomo AR, Gentile I, Borgia G: Direct acting antiviral agents and hepatocellular carcinoma development: don’t take it for granted. Transl Gastroenterol Hepatol 2: 101, 2017. [PUBMED Abstract]
4. Mei Z, Liang M, Li L, et al.: Effects of statins on cancer mortality and progression: A systematic review and meta-analysis of 95 cohorts including 1,111,407 individuals. Int J Cancer 140 (5): 1068-1081, 2017. [PUBMED Abstract]
5. Singh S, Singh PP, Singh AG, et al.: Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis. Gastroenterology 144 (2): 323-32, 2013. [PUBMED Abstract]
6. Li X, Sheng L, Liu L, et al.: Statin and the risk of hepatocellular carcinoma in patients with hepatitis B virus or hepatitis C virus infection: a meta-analysis. BMC Gastroenterol 20 (1): 98, 2020. [PUBMED Abstract]
7. Zamani SA, Graubard BI, Hyer M, et al.: Use of cholesterol-lowering medications in relation to risk of primary liver cancer in the Clinical Practice Research Datalink. Cancer 130 (20): 3506-3518, 2024. [PUBMED Abstract]

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Incidence, Mortality, and Survival

Updated statistics with estimated new cases and deaths for 2025 (cited American Cancer Society as reference 2).

Updated statistics with estimated new cases and deaths worldwide in 2022 (cited Bray et al. as reference 4).

This summary is written and maintained by the PDQ Screening and Prevention Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

Cancer of the bile duct (also called cholangiocarcinoma) is extremely rare. The true incidence of bile duct cancer is unknown because establishing an accurate diagnosis is difficult.

Traditionally, bile duct tumors located within the liver were classified with hepatocellular carcinoma as primary liver tumors.[1] In contrast, bile duct tumors located outside of the liver were classified with gallbladder cancer as extrahepatic biliary tract tumors.[1] The classification of bile duct tumors has changed to include intrahepatic tumors of the bile ducts and extrahepatic tumors (perihilar and distal) of the bile ducts.

Approximately 50% of cholangiocarcinomas arise in the bile ducts of the perihilar region, 40% in the distal region, and 10% in the intrahepatic region.

Many bile duct cancers are multifocal. In most patients, the tumor cannot be completely removed by surgery and is incurable. Palliative measures such as resection, radiation therapy (e.g., brachytherapy or external-beam radiation therapy), or stenting procedures may maintain adequate biliary drainage and allow for improved quality of life.

Anatomy

The biliary system consists of a network of ducts that carry bile from the liver to the small bowel and is classified by its anatomical location (Figure 1). Bile is produced by the liver and is important for fat digestion.

Intrahepatic bile duct

The bile ducts located within the liver are called intrahepatic bile ducts. Tumors of the intrahepatic bile ducts originate in small intrahepatic ductules or large intrahepatic ducts that are proximal to the bifurcation of the right and left hepatic ducts. These tumors are also known as intrahepatic cholangiocarcinomas.

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Extrahepatic bile duct

The bile ducts located outside of the liver are called extrahepatic bile ducts. They include part of the right and left hepatic ducts that are outside of the liver, the common hepatic duct, and the common bile duct. The extrahepatic bile ducts can be further divided into the perihilar (hilum) region and distal region.

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• Perihilar (hilum) region. The hilum is the region where the right and left hepatic ducts exit the liver and join to form the common hepatic duct that is proximal to the origin of the cystic duct. Tumors of this region are also known as perihilar cholangiocarcinomas or Klatskin tumors.
• Distal region. This region includes the common bile duct and inserts into the small intestine. Tumors of this region are also known as extrahepatic cholangiocarcinomas (Figure 2).

References

1. Siegel R, Ma J, Zou Z, et al.: Cancer statistics, 2014. CA Cancer J Clin 64 (1): 9-29, 2014 Jan-Feb. [PUBMED Abstract]
2. de Groen PC, Gores GJ, LaRusso NF, et al.: Biliary tract cancers. N Engl J Med 341 (18): 1368-78, 1999. [PUBMED Abstract]
3. Stain SC, Baer HU, Dennison AR, et al.: Current management of hilar cholangiocarcinoma. Surg Gynecol Obstet 175 (6): 579-88, 1992. [PUBMED Abstract]
4. Wakai T, Shirai Y, Moroda T, et al.: Impact of ductal resection margin status on long-term survival in patients undergoing resection for extrahepatic cholangiocarcinoma. Cancer 103 (6): 1210-6, 2005. [PUBMED Abstract]
5. Klempnauer J, Ridder GJ, von Wasielewski R, et al.: Resectional surgery of hilar cholangiocarcinoma: a multivariate analysis of prognostic factors. J Clin Oncol 15 (3): 947-54, 1997. [PUBMED Abstract]
6. Bhuiya MR, Nimura Y, Kamiya J, et al.: Clinicopathologic studies on perineural invasion of bile duct carcinoma. Ann Surg 215 (4): 344-9, 1992. [PUBMED Abstract]
7. Rosen CB, Nagorney DM, Wiesner RH, et al.: Cholangiocarcinoma complicating primary sclerosing cholangitis. Ann Surg 213 (1): 21-5, 1991. [PUBMED Abstract]
8. Shirabe K, Mano Y, Taketomi A, et al.: Clinicopathological prognostic factors after hepatectomy for patients with mass-forming type intrahepatic cholangiocarcinoma: relevance of the lymphatic invasion index. Ann Surg Oncol 17 (7): 1816-22, 2010. [PUBMED Abstract]
9. Isa T, Kusano T, Shimoji H, et al.: Predictive factors for long-term survival in patients with intrahepatic cholangiocarcinoma. Am J Surg 181 (6): 507-11, 2001. [PUBMED Abstract]