Endometrial stromal neoplasms

Uterus
Stromal tumors
Endometrial stromal neoplasms

Authors: Özlem Isiksacan Özen, M.D., Ayse Ayhan, M.D., Ph.D.

Topic Completed: 29 July 2019

Minor changes: 14 December 2019

Copyright: 2019, PathologyOutlines.com, Inc.

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Table of Contents

Cite this page: Özen Ö, Ayhan A. Endometrial stromal neoplasms. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/uterusessgeneral.html. Accessed May 24th, 2020.

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

8931/3 - low grade endometrial stromal sarcoma
8930/3 - high grade endometrial stromal sarcoma
8805/3 - undifferentiated uterine sarcoma

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

Contributed by Ayse Ayhan, M.D., Ph.D.

Low grade endometrial stromal sarcoma

High grade endometrial stromal sarcoma

Undifferentiated uterine sarcoma

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

Contributed by Ayse Ayhan, M.D., Ph.D.

Low grade endometrial stromal sarcoma

CD10

Cyclin D1

High grade endometrial stromal sarcoma

Estrogen receptor (alpha isoform)

Progesterone receptor

Unusual features in endometrial stromal sarcoma

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:
- Cyclin D1 (> 70% nuclei) nuclei strongly positive
- c-Kit strongly positive
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.

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

Am J Surg Pathol 2012;36:641, Arch Pathol Lab Med 2017;141:528, Uptodate.com: Classification and treatment of endometrial stromal sarcoma and related tumors and uterine adenosarcoma [Accessed 28 May 2019]

Board review style question #1

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 answer #1

D. Uterine mass showing irregular infiltrating borders to the myometrium

Comment Here

Reference: Endometrial stromal neoplasms

Board review style question #2

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 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