Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Positive stains | Negative stains | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Özen Ö, Ayhan A. Endometrial stromal neoplasms. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/uterusessgeneral.html. Accessed April 16th, 2021.
Definition / general
- Uterine tumors of endometrial stromal derivation, subclassified by the presence of permeative infiltrative growth into the myometrium or lymphovascular spaces, which clinically reflects its behavior and alters the therapy
- Benign and low grade endometrial stromal tumors divided into endometrial stromal tumor and endometrial stromal nodule
- Sarcomas are classified into low grade endometrial stromal sarcoma, high grade endometrial stromal sarcoma and undifferentiated uterine sarcoma by the IARC: WHO Classification of Tumours of the Female Reproductive Organs (Medicine), 4th Edition, 2014 based on resemblance to / or lack of proliferative type endometrial stroma (Virchows Arch 2018;473:665, Histopathology 2013;62:124)
Essential features
- Represents the second most common category of uterine mesenchymal tumors
- Due to a greater understanding of tumor genetics, mutations have unifying features for several subgroups:
- Most common genetic alteration for low grade endometrial stromal tumors is (7;17) resulting in JAZF1-SUZ12 changes and those areas with sex cord morphology contain PHF1 gene rearrangements
- BCOR alterations and ZC3H7B-BCOR categorize high grade as a distinct entity (Int J Gynecol Pathol 2018 Jun 12 [Epub ahead of print])
- YWHAE-FAM22 is seen in undifferentiated endometrial / uterine sarcoma (Oncotarget 2017;8:4062)
- When invasion cannot be assessed in a biopsy / curettage specimen, it is recommended to report as endometrial stromal tumor, defer definitive classification to the hysterectomy specimen (Adv Anat Pathol 2014;21:383)
Terminology
- First described by Norris and Taylor as endolymphatic stromal myosis for low grade and stromal sarcoma for high grade (Cancer 1966;19:755) (terms no longer recommended)
- Benign and low grade endometrial stromal tumors may be classified as endometrial stromal tumor and endometrial stromal nodule
- Endometrial stromal nodule: no or minimal myoinvasion (< 3 mm) and < 3 protrusions in number, no lymphovascular invasion
- Endometrial stromal tumor with limited infiltration: more infiltration than endometrial stromal nodule but does not qualify as stromal sarcoma, no lymphovascular invasion
- Endometrial stromal sarcoma: endometrial stromal nodule with myometrial or lymphovascular invasion
- High grade endometrial stromal sarcoma with variable morphology, high grade sarcoma not otherwise specified subgrouping by morphology and ancillary tests; combination of low grade and high grade components
- Recently may be classified based on the genetic alteration, for which also several morphologic implications
- YWHAE-FAM22 endometrial stromal sarcoma (undifferentiated endometrial stromal sarcoma, uniform type)
- ZC3H7B-FAM22 endometrial stromal sarcoma
- BCOR-ITD endometrial stromal sarcoma
ICD coding
Epidemiology
- All three subtypes of endometrial stromal sarcoma comprise 6 - 20% of uterine sarcomas and < 1% of all the uterus primary malignancies (Adv Anat Pathol 2014;21:383, Nucci: Diagnostic Pathology - Gynecological, 2nd Edition, 2018)
- Low grade endometrial stromal sarcoma is the most common subtype
- Wide age range for all, only BCOR internal tandem duplication (BCOR-ITD)
- May have relation to hyperestrogenism, tamoxifen therapy and radiation of endometriosis
Sites
- Occurs most commonly in the uterus but may also occur in cervix (Int J Gynecol Pathol 2014;33:253)
- May also occasionally occur in the ovary and peritoneum or colon, often associated with endometriosis (Int J Gynecol Pathol 2017;36:433, Ann Coloproctol 2015;31:68, Zhonghua Bing Li Xue Za Zhi 2005;34:824)
Pathophysiology
- Low and high grade are of endometrial stromal derivation
- Histogenesis is unknown for undifferentiated uterine sarcoma but rare tumors are shown to be endometrial stromal derivation by microRNA studies (Am J Surg Pathol 2019;43:662, Pathologe 2019;40:36, Pathology 2018;50:162)
Etiology
- Some cases have been reported in women with ovarian polycystic disease and after estrogen use or tamoxifen therapy (Gynecol Endocrinol 2005;20:200, J Obstet Gynaecol Res 2013;39:424, Comput Med Imaging Graph 2006;30:315)
- There have been reported cases of radiation induced sarcomas occurring long after treatment for other cancers (Int J Gynaecol Obstet 2018;143:51)
Clinical features
- Mean age at diagnosis: (BMC Cancer 2018;18:1247, Int J Gynecol Pathol 2019 Feb 21 [Epub ahead of print])
- Low grade: 52 years
- High grade: 50 years
- Undifferentiated : 60 years (typically postmenopausal)
- Commonly presents with vaginal bleeding (Helv Chir Acta 1984;50:683)
- Patients with high grade and undifferentiated often have extrauterine disease at the time of presentation (Eur J Gynaecol Oncol 2014;35:646, United European Gastroenterol J 2013;1:184)
Diagnosis
- Curettage specimens are not adequate to diagnose low grade endometrial stromal sarcoma
- Since endometrial stromal nodule and low grade endometrial stromal sarcoma have similar morphologic, immunohistochemical and molecular features and are distinguished on the basis of a myoinvasive growth pattern and lymphovascular invasion, thorough sampling of the tumor-myometrial interface on hysterectomy specimens is important (Adv Anat Pathol 2014;21:383, Int J Gynecol Pathol 2019 Feb 21 [Epub ahead of print])
Radiology description
- Ultrasonography: mixed echogenicity / not reliable, may lead to incorrect diagnosis of adenomyosis or uterine leiomyoma
- Transvaginal color Doppler: low impedance flow compared with other benign tumors
- MRI: irregular margin, nodular extensions at margin, into myometrium or into ligaments, fallopian tubes, ovaries and along the vessels; low signal intensity bands at T2 at the site of myometrial involvement representing preserved myometrial bundles (AJR Am J Roentgenol 2004;182:1531, Adv Anat Pathol 2000;7:257)
Prognostic factors
- Tumor stage is the most important prognostic factor (Int J Gynaecol Obstet 2018;143:51, Asian Pac J Cancer Prev 2015;16:881, Gynecol Oncol 2014;132:70)
- Low grade: 5 year disease specific survival is 90% for stages I and II and 50% for stages III and IV
- High grade: prognosis intermediate between low grade and undifferentiated, have earlier and more frequent recurrences (often < 1 year)
- Undifferentiated: present with high stage disease (> 60%) (Gynecol Oncol 2017;146:254, Oncol Res Treat 2018;41:687)
Case reports
- 46 year old woman with YWHAE-NUTM2A/B low grade tumor confined to the endometrium (Int J Gynecol Pathol 2017;36:165)
- 47 year old woman with coexisting mixed type endometrial carcinomas (Medicine (Baltimore) 2017;96:e8928)
- 47 year old woman with endometrial stromal sarcoma arising in colorectal endometriosis (Int J Gynecol Pathol 2017;36:433)
- 51 year old woman with atypical paracaval recurrence (Anticancer Res 2015;35:3405)
- Elderly woman with low grade tumor mimicking low grade fibromyxoid sarcoma (Int J Surg Pathol 2018;26:525)
Treatment
- Low grade and high grade, stage I: hysterectomy and bilateral salpingo-oophorectomy (Adv Anat Pathol 2014;21:383); may also receive adjuvant radiation or hormonal treatment with progestational agents or aromatase inhibitors
- Undifferentiated: should be treated by hysterectomy and bilateral salpingo-oophorectomy and adjuvant radiation or chemotherapy
Gross description
- Usually polypoid or intramural with a fleshy tan-yellow cut surface (J Clin Pathol 2007;60:235, Mymensingh Med J 2015;24:178)
- High grade frequently shows grossly evident myometrial invasion (J Clin Diagn Res 2017;11:ED03)
- Necrosis and hemorrhage are frequently present in high grade tumors (Indian J Surg Oncol 2019;10:91)
Gross images
Microscopic (histologic) description
- Low grade endometrial stromal sarcoma:
- Consists of well differentiated endometrial stromal cells exhibiting only mild nuclear atypia and infiltrates the myometrium as irregular tongues, often with lymphovascular invasion (Int J Gynaecol Obstet 2018;143:51)
- Tumor cell necrosis is rarely seen
- Low mitotic activity (usually < 5/10 HPFs)
- Smooth muscle differentiation, fibromyxoid change, sex cord-like differentiation and endometrioid type glands may be present (Int J Gynecol Pathol.1992;11:163, J Clin Pathol 2001;54:481, Histopathology 2009;54:365)
- High grade endometrial stromal sarcoma:
- Consists predominantly of high grade round cells and sometimes associated with a low grade most commonly fibromyxoid spindle cell component (Int J Gynaecol Obstet 2018;143:51)
- Mitotic activity is striking (typically > 10/10 HPFs)
- Necrosis is usually present
- Rarely, areas of conventional low grade endometrial stromal sarcoma are seen
- Undifferentiated endometrial sarcoma:
- Exhibits myometrial invasion, severe nuclear pleomorphism, high mitotic activity or tumor cell necrosis and lack smooth muscle or endometrial stromal differentiation (Int J Gynaecol Obstet 2018;143:51)
Microscopic (histologic) images
Positive stains
- Low grade endometrial stromal sarcoma:
- CD10: strongly immunoreactive
- Smooth muscle actin: usually positive
- Estrogen receptors (only alpha isoform), progesterone receptors, androgen receptors and WT1
- High grade endometrial stromal sarcoma:
- Undifferentiated uterine sarcoma:
- CD10: variably positive
Negative stains
- Low grade endometrial stromal sarcoma:
- h-caldesmon and HDAC8
- Desmin: 30% positive
- Nuclear beta catenin: up to 40% positive
- High grade endometrial stromal sarcoma:
- h-caldesmon and HDAC8
- DOG1, CD10, estrogen receptor and progesterone receptor
- Undifferentiated uterine sarcoma:
- Estrogen receptor and progesterone receptor: weakly positive or negative
- Pancytokeratin (AE1 / AE3), CK7:
- Usually negative (sex cord-like and epithelial differentiation may show variable positivity)
Molecular / cytogenetics description
- Low grade: most common cytogenetic abnormality is a recurrent translocation involving chromosomes 7 and 17 t(7;17) (p15;q21)], which results in a fusion between JAZF1-SUZ12
- High grade: typically harbors the YWHAE-FAM22 genetic fusion as a result of t(10;17) (q22;p13)
- Undifferentiated: exhibits a complex karyotype with no specific translocation pattern (Int J Cancer 2015;136:1608)
Sample pathology report
- Uterus, hysterectomy:
- Endometrial stromal sarcoma (with smooth muscle differentiation or with sex cord elements or with glandular element), low grade (see synoptic report)
- Comment: Tumor cells are positive for CD10, ER and PR and negative for h-caldesmon and desmin.
- Endometrial stromal sarcoma (with smooth muscle differentiation or with sex cord elements or with glandular element), low grade (see synoptic report)
Differential diagnosis
- Endometrial polyp:
- Thick walled vessels in a compact inactive stroma (Adv Anat Pathol 2014;21:383)
- Adenomyosis, gland poor or intravascular:
- Gland poor: atrophic stromal cells surrounded by hypertrophic smooth muscle Adv Anat Pathol 2014;21:383)
- Has adjacent smooth muscle hypertrophy and lacks a characteristic arborizing vascular network
- Intravascular adenomyosis: carefully search for typical adenomyosis in the background
- Endometrial stromal nodule:
- A tumor with myoinvasion that is < 3 mm and < 3 interdigitations at the tumor / myometrial junction is consistent with the diagnosis of an endometrial stromal nodule (Virchows Arch 2018;473:665, Mod Pathol 2016;29:S104)
- It is difficult to assess myoinvasion in biopsy or curettage specimen
- Highly cellular leiomyoma:
- Presence of an intersecting fascicular growth pattern and thick, large blood vessels and cleft-like spaces throughout the tumor favor smooth muscle tumor (Oncology 2018;94:1)
- Positive for desmin and h-caldesmon, negative for CD10
- Epithelioid leiomyosarcoma:
- Positive for desmin, caldesmon and also often keratin and epithelial membrane antigen (EMA), negative for cyclin D1 (Int J Mol Sci 2019;20:E1136)
- PEComa:
- Typically circumscribed and consisting of epithelioid and spindled cells (Adv Anat Pathol 2014;21:383)
- Positive for HMB45 and smooth muscle markers, negative for CD10
- Undifferentiated carcinoma:
- Typically consists of solid sheets of high grade dyscohesive cells (Adv Anat Pathol 2014;21:383)
- Keratin expression favors carcinoma
- Mixed epithelial and mesenchymal tumors (carcinosarcoma and adenosarcoma):
- Cystically dilated glands with periglandular stromal condensation (Histopathology 2015;67:1)
- Glands greater in number and less haphazardly placed
- Extensive sampling is important to detect epithelial elements
- Uterine tumors resembling ovarian sex cord tumors (UTROSCT):
- Rare tumor characterized by sex cord-like elements that resemble epithelial cells arranged in cords, tubules or sheets (Gynecol Oncol Rep 2016;19:34, Histopathology 2017;71:751, Diagn Cytopathol 2019;47:603)
- Lacks endometrial stromal differentiation and the specific translocations seen in endometrial stromal sarcoma
- Immunohistochemical staining patterns of CD10, inhibin and cytokeratin may be similar
Additional references
Board review style question #1
- A 51 year old woman presented with vaginal bleeding and workup revealed a large uterine mass. Hysterectomy and bilateral salpingo-oophorectomy is performed. Pathology is consistent with a low grade endometrial sarcoma. Which of the following statements is correct?
- Harbors the YWHAE-FAM22 genetic fusion
- Tumor cells strongly immunoreactive for CD10, negative for ER and PR
- Tumor consists of high grade round-cells with brisk mitotic activity
- Uterine mass showing irregular infiltrating borders to the myometrium
Board review style answer #1
D. Uterine mass showing irregular infiltrating borders to the myometrium
Comment Here
Reference: Endometrial stromal neoplasms
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Reference: Endometrial stromal neoplasms
Board review style question #2
- Which of the following statements about endometrial stroma sarcoma is correct?
- High grade endometrial stromal sarcoma is the most common subtype
- Hormonal treatment is the only standard therapy for stage I tumors
- Mitotic rate is the most important prognostic factor for the prognosis
- Thorough sampling of the tumor-myometrial interface is essential to diagnose low grade endometrial stromal sarcoma
Board review style answer #2
D. Thorough sampling of the tumor-myometrial interface is essential to diagnose low grade endometrial stromal sarcoma
Comment Here
Reference: Endometrial stromal neoplasms
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Reference: Endometrial stromal neoplasms