Endometrial Stromal Sarcoma 

Cancer / By

Endometrial Stromal Sarcoma

  •  rare and aggressive endometrial soft tissue cancer (subtype of uterine sarcoma)(1)

Types

  • low-grade(1)
    •  indolent course
    •  tends to have local or lymphovascular space invasion
    •  5-year survival rate 80%-100%
  • high-grade(1)
    •  based on mitotic activity (with 10 mitotic figures per 10 high-powered fields as threshold) and cellular atypia
    •  tends to invade more deeply and extensively into myometrium and metastasize early
    •  5-year survival rate 20%-55%

Epidemiology

Who is Most Affected

  •  middle- to older-aged women(1)

Incidence/Prevalence

  • rare – endometrial stromal sarcoma is type of uterine sarcoma(1)
    • uterine sarcomas
      •  make up about 3%-5% of all uterine cancers
      •  overall incidence of 17-44 cases per 1 million women per year
    •  endometrial stromal sarcoma rare type of uterine sarcoma
  • occult uterine sarcoma reported in 0.089% of women having hysterectomy for benign gynecological indications
    •  based on retrospective cohort study
    •  10,119 women (median age 39 years) having hysterectomy for benign gynecological indications (for abnormal bleeding in 77.8% and for leiomyoma in 22.2%) in single center were assessed
    •  0.089% had uterine sarcoma including 5 leiomyosarcomas, 2 endometrial stromal sarcomas, and 2 uterine adenosarcomas
    •  Reference – Obstet Gynecol 2016 Mar;127(3):468full-text

Possible Risk Factors

  • tamoxifen use may be associated with uterine sarcoma
    •  159 cases of uterine sarcoma in tamoxifen users have been reported
    •  reported cases are fewer than expected incidence (perhaps related to underreporting) but clinical trials suggest significantly increased incidence of 0.17 cases per 1,000 woman-years
    •  BLACK BOX WARNING added to tamoxifen labeling regarding uterine sarcoma, uterine adenocarcinoma, pulmonary embolism, and stroke
    •  Reference – N Engl J Med 2002 Jun 6;346(23):1832
  • ≥ 10 deliveries associated with increased risk of uterine sarcoma
    •  based on retrospective cohort study
    •  4,967 Finnish women with ≥ 10 deliveries followed for cancer incidence (104,807 person-years) through Finnish cancer registry and compared for cancer risk with reference population of 656 average Finnish women
    • ≥ 10 deliveries associated with
      •  lower total cancer incidence (standardized incidence ratio 0.76, 95% CI 0.73-0.79)
      •  increased incidence of uterine sarcoma (standardized incidence ratio 3.41, 95% CI 1.47-6.72)
    •  Reference – Obstet Gynecol 2014 Apr;123(4):811

Etiology and Pathogenesis

Pathogenesis

  •  arises from mesenchymal tissues(1)

History and Physical

History

Chief Concern (CC)

  •  irregular vaginal bleeding (most common concern)(1)
  •  pelvic mass(1)

Medication History

Physical

General Physical

  •  physical exam usually unremarkable

Pelvic

  •  may present as discrete mass or diffusely enlarged uterus(1)

Diagnosis

Making the Diagnosis

  •  endometrial biopsy – diagnosis usually made at time of surgery or on final pathologic review(1)
  •  no imaging or blood tests found to be reliable for diagnosis(1)

Differential Diagnosis

  • uterine leiomyosarcoma(1)
  • other very rare uterine sarcomas(1)
    •  rhabdomyosarcoma
    •  chondrosarcoma
    •  osteosarcoma
    •  liposarcoma
    •  fibrosarcoma

Testing Overview

  •  endometrial biopsy may miss tumor, due to presentation as discrete mass or diffusely enlarged uterus(1)

Biopsy and Pathology

  •  preoperative endometrial sampling has only 64% sensitivity in diagnosis(1)
  • low-grade(1)
    •  tends to have local or lymphovascular space invasion
    •  typical worm-like fashion
  • high-grade(1)
    •  based on mitotic activity (with 10 mitotic figures per 10 high-powered fields as threshold) and cellular atypia
    •  tends to invade more deeply and extensively into myometrium and metastasize early

Staging

  •  American Joint Committee on Cancer (AJCC) staging for corpus uterine leiomyosarcoma and endometrial stromal sarcoma, eighth edition

Table

Table 1: Clinical Staging

StageTNM
Stage IT1N0M0
Stage IAT1aN0M0
Stage IBT1bN0M0
Stage IIT2N0M0
Stage IIIAT3aN0M0
Stage IIIBT3bN0M0
Stage IIICT1-T3N1M0
Stage IVAT4Any NM0
Stage IVBAny TAny NM1
  • definitions of staging abbreviations
    • primary tumor (T)
      •  TX – primary tumor cannot be assessed
      •  T0 – no evidence of primary tumor
      • T1 – tumor limited to uterus
        •  T1a – tumor ≤ 5 cm in greatest dimension
        •  T1b – tumor > 5 cm
      • T2 – tumor extends beyond uterus, within pelvis
        •  T2a – tumor involves adnexa
        •  T2b – tumor involves other pelvic tissues
      • T3 – tumor infiltrates abdominal tissues
        •  T3a – 1 site
        •  T3b – > 1 site
      •  T4 – tumor invades bladder or rectum
    • regional lymph nodes (N)
      •  NX – regional lymph nodes cannot be assessed
      •  N0 – no regional lymph node metastasis
      •  N0 (i+) – isolated tumor cells in regional lymph node(s) < 0.2 mm
      •  N1 – regional lymph node metastasis
    • distant metastasis (M)
      •  M0 – no distant metastasis
      •  M1 – distant metastasis (excluding adnexa, pelvic, and abdominal tissues)

International Federation of Gynecology and Obstetrics (FIGO) staging for corpus uteri sarcoma, eighth edition

Table

Table 2: Clinical Staging

StageTNM
Stage IT1N0M0
Stage IAT1aN0M0
Stage IBT1bN0M0
Stage IIT2N0M0
Stage IIAT2aN0M0
Stage IIBT2bN0M0
Stage IIIT3N0M0
Stage IIIAT3aN0M0
Stage IIIBT3bN0M0
Stage IIICT1-T3N1M0
Stage IVAT4Any NM0
Stage IVBAny TAny NM1
  • definitions of staging abbreviations
    • primary tumor (T)
      •  TX – primary tumor cannot be assessed
      •  T0 – no evidence of primary tumor
      • T1 – tumor limited to uterus
        •  T1a – tumor ≤ 5 cm in greatest dimension
        •  T1b – tumor > 5 cm
      • T2 – tumor extends beyond uterus, within pelvis
        •  T2a – tumor involves adnexa
        •  T2b – tumor involves other pelvic tissues
      • T3 – tumor infiltrates abdominal tissues
        •  T3a – 1 site
        •  T3b – > 1 site
      •  T4 – tumor invades bladder or rectum
    • regional lymph nodes (N)
      •  NX – regional lymph nodes cannot be assessed
      •  N0 – no regional lymph node metastasis
      •  N0 (i+) – isolated tumor cells in regional lymph node(s) < 0.2 mm
      •  N1 – regional lymph node metastasis
    • distant metastasis (M)
      •  M0 – no distant metastasis
      •  M1 – distant metastasis (excluding adnexa, pelvic, and abdominal tissues)

Management

Management Overview

  •  surgery is main treatment modality
  • adjuvant therapies with limited evidence of efficacy include
    •  radiation
    •  chemotherapy
    •  hormonal therapy

Medications

  • reported chemotherapies used(1)
    • cyclophosphamide
    •  vincristine
    •  doxorubicin
    • dactinomycin
    • dacarbazine
    •  methotrexate
    •  progestin agents

Surgery and Procedures

  •  optimal surgery is total hysterectomy and bilateral salpingo-oophorectomy (BSO)(1)
  • ovarian preservation may be associated with increased tumor recurrence compared to BSO in adults with low-grade endometrial stromal sarcoma of uterus having hysterectomy (level 2 [mid-level] evidence)
    • based on systematic review of observational studies
    • systematic review of 17 observational studies (16 cohort and 1 case-control study) comparing ovarian preservation vs. BSO in 786 adults with low-grade endometrial stromal sarcoma of the uterus having hysterectomy
      • 75% had stage I disease
      • adjuvant therapies included radiation therapy in 16.6%, chemotherapy in 21.4%, and hormonal treatment in 20.9%
    • median or mean follow-up ranged from 35 to 130 months when reported
    • ovarian preservation associated with increased tumor recurrence rate (odds ratio [OR] 2.7, 95% CI 1.39-5.28) in analysis of 17 studies with 691 patients, results limited by significant heterogeneity
    • no significant differences in
      • mortality (odds ratio 0.8, 95% CI 0.18-3.47) in analysis of 3 studies with 162 patients, but confidence interval includes possibility of benefit or harm
      • tumor recurrence rate in analysis of 7 studies with 178 patients before menopause, but confidence interval includes possibility of benefit or harm
      • tumor recurrence rate in analysis of 8 studies with 196 patients with stage I-II sarcoma, but confidence interval includes possibility of benefit or harm
    • Reference – Int J Gynecol Cancer 2019 Jan;29(1):126
  •  successful pregnancy after fertility-sparing local resection and uterine reconstruction for low-grade endometrial stromal sarcoma in case report (Obstet Gynecol 2012 Aug;120(2 Pt 2):486)
  •  reaction to surgical implant foreign body masquerading as recurrent uterine sarcoma in case report (Obstet Gynecol 2011 Feb;117(2 Pt 2):450)

Radiation Therapy

  • adjuvant radiation therapy(1)
    •  may help control of local pelvic disease recurrence
    •  unclear benefit for overall survival

Other Management

  • enhanced recovery care may be associated with decreased need for postoperative analgesics, faster return of bowel function, and shorter hospital length of stay in patients having cytoreductive gynecologic surgery (level 2 [mid-level] evidence)
    • based on retrospective cohort study
    • 241 patients having gynecologic surgery who received enhanced recovery care (81 complex cytoreduction, 84 staging, and 76 vaginal surgery cases) were compared with 235 similar patients who did not receive enhanced care (78 complex cytoreductive, 80 staging, and 77 vaginal surgery cases)
    • enhanced recovery care included reduction of preoperative fasting, omission of bowel preparation, perioperative normovolemia, limited use of nasogastric tubes and drains, aggressive intraoperative multimodal analgesia to minimize opiate consumption, postoperative nausea and vomiting prophylaxis, early postoperative mobilization, and early enteral nutrition
    • comparing enhanced recovery vs. usual care in patients with complex cytoreduction
      • preoperative opioid use in 11.5% vs. 24.7% (p = 0.032)
      • opioid tolerance (defined as > 60 mg oral morphine equivalents daily) in 7.4% vs. 0% (p = 0.029)
      • mean postoperative day 1 hemoglobin 9.9 g/dL vs. 10.5 g/dL (p = 0.018)
      • postoperative hypotension in 60.5% vs. 75.6% (p = 0.041)
      • return of bowel function on mean postoperative day 3 vs. 4 (p < 0.001)
      • return to general diet on mean postoperative day 0 vs. 5 (p < 0.01)
      • mean length of stay 6.5 days vs. 10.7 days (p < 0.001)
    • similar but less pronounced results observed in staging and vaginal surgery cohorts
    • Reference – Obstet Gynecol 2013 Aug;122(2 Pt 1):319full-text

Complications and Prognosis

Complications

  •  disease recurrence(1)
  •  metastasis(1)

Prognosis

  • low-grade tumors(1)
    •  typically have indolent course
    •  surgery usually curative, however, may recur at > 5 years with case reports of up to 25 years
    •  overall survival rate range 80%-100%, including accounting for disease recurrence
  • high-grade tumors(1)
    •  more aggressive and with poorer prognosis than low-grade tumors
    •  recurrence common
    •  5-year survival rate range 20%-55%
  • nomogram may help predict 5-year and 10-year overall survival in women with low-grade endometrial stromal sarcoma (level 2 [mid-level] evidence)
    •  based on prognostic cohort study without independent validation and data to guide clinical use
    • 1,172 women diagnosed with low-grade (grade I or II) endometrial stromal sarcoma between 1988 and 2015 from Surveillance, Epidemiology, and End Results database were randomly assigned to derivation or internal validation cohort
      • derivation cohort included 821 women (median age 48 years) with median follow-up of 127 months
      • validation cohort included 351 women (median age 47 years) with median follow-up of 128 months
    • nomogram developed using 7 factors associated with overall survival in derivation cohort
      • age
      • tumor size
      • chemotherapy
      • Federation of Gynecology and Obstetrics (FIGO) criteria-based tumor staging
      • marital status
      • lymphadenectomy
      • radiotherapy
    • nomogram had strong discrimination for predicting overall survival in validation cohort (c-statistic 0.837)
    • see article for details of nomogram
    • Reference – Cancer Commun (Lond) 2020 Jul;40(7):301full-text
  •  patients with high-grade endometrial stromal sarcoma may have higher disease-free survival but not overall survival compared to patients with undifferentiated uterine sarcoma
    • based on retrospective cohort study
    • 71 patients with high-grade endometrial stromal sarcoma (median age 57 years) or undifferentiated uterine sarcoma (median age 58 years) who had surgery were assessed
    • median follow-up of 19 months
    • comparing patients with high-grade endometrial stromal sarcoma vs. undifferentiated uterine sarcoma
      • median disease-free survival 12 months vs. 6 months (p = 0.016)
      • median overall survival not reached vs. 22 months (not significant)
    • lymphovascular-space involvement associated with disease progression, recurrence, or death in patients with high-grade endometrial stromal sarcoma (hazard ratio 9.4, 95% CI 2.5-34.5)
    • Reference – Arch Gynecol Obstet 2021 Aug;304(2):475
  • 5-year survival 96% with low-grade endometrial sarcoma (level 2 [mid-level] evidence)
    •  based on retrospective cohort study
    •  848 women (mean age 55.2 years) with endometrial stromal sarcoma
    •  low-grade sarcoma defined as disease confined to uterus or FIGO stage I or II
    •  high-grade sarcoma defined as extrauterine disease or FIGO stage III or IV
    •  incidence lymph node metastasis 7% among women with low-grade sarcoma
    •  5-year survival in low-grade sarcoma 96% vs. 81% in high-grade sarcoma (p < 0.001)
    •  Reference – Obstet Gynecol 2008 Nov;112(5):1102
  •  5-year survival rate of 93% with low-grade endometrial stromal sarcoma reports based on case series of 14 patients World J Surg Oncol 2006 Aug 9;4:50
  •  efficacy of aggressive therapy limited by low response rates and limited duration of response in patients with metastatic recurrent disease(1)

Prevention and Screening

  •  not applicable

Guidelines and Resources

Guidelines

International Guidelines

United States Guidelines

  •  American Society for Radiation Oncology (ASTRO) evidence-based guideline on role of postoperative radiation therapy for endometrial cancer can be found at ASTRO 2014 PDF
  •  American College of Radiology (ACR) Appropriateness Criteria for pretreatment evaluation and follow-up of endometrial cancer can be found at ACR 2020 PDF.
  • American College of Obstetricians and Gynecologists (ACOG) Committee Opinion 601 on tamoxifen and uterine cancer can be found in Obstet Gynecol 2014 Jun;123(6):1394, reaffirmed 2020.
  • National Comprehensive Cancer Network (NCCN) statement on mitigating the impacts of anticancer drug shortages can be found at NCCN 2023 Jun 7 PDF
  •  National Comprehensive Cancer Network (NCCN) guideline on uterine neoplasms can be found at NCCN website (free registration required)
  • American Society of Clinical Oncology (ASCO) position on prioritization of antineoplastic agents in limited supply for first intervention can be found at ASCO, accessed 2023 Jun 13

United Kingdom Guidelines

Canadian Guidelines

  • Cancer Care Ontario (CCO) guideline on management of gynecologic sarcomas in Ontario can be found at CCO 2024 Jul
  •  Society of Obstetricians and Gynaecologists of Canada (SOGC) consensus clinical guideline on female sexual health can be found in J Obstet Gynaecol Can 2018 Jun;40(6):e451.
  •  Alberta Health Services (AHS) clinical practice guideline on uterine sarcoma can be found at AHS 2023 Jun PDF.
  •  Alberta Health Services (AHS) clinical practice guideline on endometrial cancer can be found at AHS 2015 Nov PDF.

European Guidelines

  • Deutsche Gesellschaft für Gynäkologie und Geburtshilfe e.V/Österreichische Gesellschaft für Gynäkologie und Geburtshilfe/Schweizerische Gesellschaft für Gynäkologie und Geburtshilfe (German Society for Gynecology and Obstetrics e.V./Austrian Society for Gynecology and Obstetrics/Swiss Society for Gynecology and Obstetrics) (DGGG/OEGGG/SGGG) S2k-leitlinie uterine sarkome (S2k guideline on uterine sarcoma can be found at Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF) 2024 Jul 1PDF [German]
  •  Haute Autorité de Santé (HAS) conseils sur cancer de l’endomètre se trouvent sur le site Haute Autorité de Santé 2010 Dec [French]
  • Spanish Group for Research in Sarcomas (Grupo Español de Investigación en Sarcomas [GEIS]) clinical practice guideline on diagnosis and treatment of patients with soft tissue sarcoma can be found in Cancer Chemother Pharmacol 2016 Jan;77(1):133full-text
  • European Society for Medical Oncology (ESMO) clinical guideline on soft tissue and visceral sarcomas: diagnosis, treatment, and follow-up can be found in Ann Oncol 2018 Oct 1;29(Supplement_4):iv51full-text
  •  Directorate of Health (DOH [Helsedirektoratet]) national clinical guideline on diagnosis, treatment, and follow-up of patients with sarcoma can be found at DOH 2015 [Norwegian]

Asian Guidelines

Mexican Guidelines

  •  Grupo de Investigación en Cáncer de Ovario y Tumores Ginecológicos de México (GICOM) consensus on endometrial cancer can be found in Rev Invest Clin 2010 Nov-Dec;62(6):583 [Spanish]

Central and South American Guidelines

  •  Federation of Gynecology Brazilian and Obstetrics/Brazilian Society of Oncology (Federação Brasileira das Associações de Ginecologia/Obstetrícia e Sociedade Brasileira de Cancerologia) guideline on treatment of endometrial carcinoma can be found in Rev Assoc Med Bras 2012 May-Jun;58(3):281full-text [English, Portuguese]

Review Articles

  •  to search MEDLINE for (Endometrial Stromal Sarcoma) with targeted search (Clinical Queries), click therapy, diagnosis, or prognosis

National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)

  • The CTCAE provides the definitions of terminology used for reporting of adverse events that occur during medical therapies or procedures, depending on their severity.
  • The CTCAE grading system for the severity of adverse events:
    • Grade 1 describes mild adverse events which fulfill ≥ 1 of the following criteria:
      • No symptoms or have mild symptoms
      • Clinical or diagnostic findings only
      • Not requiring interventions for management
    • Grade 2 describes moderate adverse events which fulfill ≥ 1 of the following criteria:
      • Requiring only minimal, local, or noninvasive intervention for management
      • Limiting age-appropriate instrumental activities of daily living (ADL)
    • Grade 3 describes adverse events that are severe or medically significant but not immediately life-threatening which fulfill ≥ 1 of the following criteria:
      • Requiring hospitalization
      • Prolonging of hospitalization
      • Disabling
      • Limiting self care ADL
    • Grade 4 describes life-threatening adverse events which require urgent interventions for management.
    • Grade 5 describes adverse events leading to death.
  • The CTCAE version 5 (November 27, 2017) table listing all the CTCAE definitions by organs or systems can be found at NCI website.

Patient Information

References

General References Used

  1. Lin JF, Slomovitz BM. Uterine sarcoma 2008. Curr Oncol Rep. 2008 Nov;10(6):512-8.

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