Table of Contents
Definition / general | Essential features | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | 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: Ondič O. High grade endometrial stromal sarcoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/uterusESShighgrade.html. Accessed January 15th, 2021.
Definition / general
- Very rare biologically aggressive mesenchymal tumor of the uterus originating in the endometrial stroma
Essential features
- Rare and quite recently defined (Genes Chromosomes Cancer 2013;52:610, Am J Surg Pathol 2017;41:12, Mod Pathol 2018;31:674)
- Uniform high grade round or spindle cell areas
- Frequent positivity for BCOR, cyclin D1 and CD10; often negative or only focally positive for smooth muscle markers
- ZC3H7B-BCOR or YWHAE-NUTM2 fusions or BCOR internal tandem duplication (ITD)
ICD coding
Epidemiology
- Due to the rarity, the value of this data is limited
- YWHAE associated: age range 28 - 67, mean 50
- BCOR associated: age range 28 - 71, mean 54
- References: Mod Pathol 2018;31:674, Gynecol Oncol 2017;145:531
Sites
- Mostly uterine corpus
- Rarely uterine isthmus
Pathophysiology
- Gene rearrangement: YWHAE-NUTM2 (NUTM2 synonym FAM22)
- Gene rearrangement: ZC3H7B-BCOR (reciprocal)
- Gene internal tandem duplication (ITD): BCOR (Am J Surg Pathol 2018;42:335)
- Possibly other so far unknown or unconfirmed pathogenic gene fusions
- High grade transformation of low grade endometrial stromal sarcomas with JAZF1-SUZ12, JAZF1-PHF1, EPC1-PHF1 or BRD8-PHF1 (Mod Pathol 2020;33:1861)
Etiology
- Unknown
Clinical features
- Nonspecific presentation including pelvic pain, menorrhagia, postcoital bleeding
Diagnosis
- Hysterectomy
Radiology description
- Doppler ultrasound finding may imitate:
- Uterine leiomyosarcoma
- Endometrioid endometrial carcinoma with myometrial invasion
- As per PET / MR, it may be diagnosed as unspecified uterine malignancy with high metabolic activity
Radiology images
Contributed by Jan Kosťun, M.D., Pavel Vlasák, M.D. and Eva Ferdová, M.D.
Doppler ultrasound with sarcoma features
Doppler ultrasound with endometrioid cancer features
High metabolic activity tumor
Prognostic factors
- Stage (the single most important prognostic factor)
- Type of surgical procedure (morcellation is an unfavorable prognostic factor)
- Recurrence and overall prognosis cannot be assessed due to insufficient data
Case reports
- 40 year old woman with a 4 month history of recurrent right sided lower thoracic pain and a history of hysterectomy (BMC Cancer 2018;18:92)
- 41 year old woman presenting with a 6 month history of menorrhagia (Int J Gynecol Pathol 2019;38:420)
- 51 year old woman presenting with brown discharge and postcoital bleeding (Virchows Arch 2020;476:61)
Treatment
- Abdominal hysterectomy and bilateral adnexectomy
- Above followed by (mostly) doxorubicin or ifosfamide monotherapy or gemcitabine / docetaxel combination therapy (Obstet Gynecol 2013;122:676)
- Alternatively, oral antiangiogenic tyrosine kinase inhibitor (TKI) pazopanib (BMC Cancer 2018;18:92)
Gross description
- Pink to yellow-tan polypoid friable tumor involving the endometrium and variably invading the myometrium (Mod Pathol 2018;31:674, Virchows Arch 2020;476:61)
Gross images
Contributed by Ondrej Ondič, M.D., Ph.D.
High grade endometrial stromal sarcoma
Microscopic (histologic) description
- YWHAE-NUTM2 fusion (Am J Surg Pathol 2012;36:641):
- Cellular, mostly spindle cell tumor with a delicate and sometimes poorly visible network of short capillaries (Mod Pathol 2018;31:674, Am J Surg Pathol 2018;42:335)
- Patterns of myometrial invasion: tongue-like infiltrative or broad front (Virchows Arch 2020;476:61)
- High grade component: round cell or spindle cell with up to 50 mitotic figures per 10 high power fields, mild to severe nuclear pleiomorphism, variable micronecroses, focal myxoid change
- Low grade component: the variable size of the tumor area with uniform spindle cell proliferation with or without myxoid change (Am J Surg Pathol 2018;42:335)
- Special features:
- YWHAE-NUTM2: focal stroma collagenization (Am J Surg Pathol 2012;36:641)
- ZC3H7B-BCOR: focal cytoplasmic signet ring-like cell change, myxoid stromal change, microcystic change, pericytoma-like vessels, osseous metaplasia (Virchows Arch 2020;476:61, Pathology 2020 Aug 2 [Epub ahead of print])
- ITD BCOR: focal myxoid stromal change (Am J Surg Pathol 2018;42:335)
- High grade transformation of low grade endometrial stromal sarcomas lacking YWHAE and BCOR genetic abnormalities: focal myxoid stromal change (Mod Pathol 2020;33:1861)
Microscopic (histologic) images
Contributed by Ondrej Ondič, M.D., Ph.D.
Spindle cell morphology
High grade component
Myxoid stroma and signet ring-like change
Tongue-like infiltration
Small round cells
Positive stains
- BCOR: CD10, BCOR (maybe clone dependent), cyclin D1, SATB2 (to be validated) (Int J Gynecol Pathol 2018;37:372, Virchows Arch 2020;476:61, Pathology 2020 Aug 2 [Epub ahead of print])
- YWHAE: high grade component (cyclin D1, BCOR), low grade component (CD10, ER, PR)
Negative stains
- BCOR: desmin, h-caldesmon, alpha smooth muscle actin, ER, PR (weak focal positivity may be present), S100
- YWHAE: desmin, h-caldesmon, alpha smooth muscle actin, S100, CD10 (in high grade component)
Molecular / cytogenetics description
- Gene rearrangement involving BCOR, ZC3H7B, YWHAE, NUTM2A, NUTM2B genes, with breaks at different exons, can be detected by FISH showing split signal
- Internal tandem duplication (ITD) of BCOR gene - tandem duplications of different sizes affecting exon 15 (Am J Surg Pathol 2018;42:335, Mod Pathol 2020;33:1669)
- Rare BCOR gene rearrangement partners: BCOR- L3MBTL2, EP300- BCOR, BCOR- NUTM2G, BCOR- RALGPS1, BCOR- MAP7D2, RGAG1-BCOR, ING3- BCOR, BCOR- NUGGC, KMT2D- BCOR, CREBBP- BCOR (Gynecol Oncol 2020;157:357)
- Some BCOR rearranged cases present with co-occurence of associated alteration of CDK4 pathway members (CDK4 amplification or CDKN2A loss) (Gynecol Oncol 2020;157:357)
- In some cases there can be no gene rearrangement detected by the means of currently used NGS gene panels
Sample pathology report
- Uterus, hysterectomy and bilateral adnexectomy:
- ZC3H7B-BCOR rearranged high grade endometrial stromal sarcoma (see comment, see synoptic report)
- Comment: Polypoid high grade mesenchymal tumor consisting of a spindle cell population with focal myxoid stroma and up to 15 mitoses per 10 high power fields. Tumor border is tongue-like, infiltrating less than half of the myometrial wall thickness. Immunohistochemically, BCOR and CD10 are positive and desmin, h-caldesmon, alpha smooth muscle actin are negative. Molecular genetic testing confirmed reciprocal ZC3H7B-BCOR gene rearrangement.
Differential diagnosis
- Low grade endometrial stromal sarcoma:
- Prominent microvascular component
- Minimal nuclear atypia
- Typically have low mitotic count (< 5/10 high power fields)
- Positive: CD10, ER, PR
- Negative: BCOR, cyclin D1
- JAZF1 or PHF1 rearrangement identified by next generation sequencing
- The presence of high grade component indicates high grade transformation into HG ESS (Mod Pathol 2020;33:1861)
- Leiomyoma:
- No atypia or tumor cell necrosis
- Mitoses typically low (exception - mitotically active leiomyoma)
- Positive: desmin, alpha smooth muscle actin, h-caldesmon
- Negative: CD10
- Leiomyosarcoma:
- No stromal myxoid change
- Positive: desmin, alpha smooth muscle actin, h-caldesmon
- Negative: CD10
- Myxoid leiomyosarcoma:
- May see conventional smooth muscle component
- PLAG1 rearrangement or no rearrangement identified by next generation sequencing (Mod Pathol 2019;32:1688, Am J Surg Pathol 2019;43:382)
- Undifferentiated uterine sarcoma:
- No rearrangement identified by next generation sequencing (Am J Surg Pathol 2019;43:662)
- Uterine carcinosarcoma:
- Presence of malignant epithelial component
- Harbors mutations similar to endometrial carcinoma
- No rearrangement identified by next generation sequencing
- Inflammatory myofibroblastic tumor:
- Lymphoplasmacytic infiltrate
- Positive: ALK (in the vast majority of cases) (Virchows Arch 2018;473:583, Am J Surg Pathol 2020 Jun 19 [Epub ahead of print])
Additional references
Board review style question #1
A 51 year old woman presents with brown vaginal discharge. The surgical resection shows a cellular infiltrative spindle cell uterine neoplasm. Immunohistochemically, there is negative expression of smooth muscle actin, desmin, h-caldesmon paired with positive expression of CD10, cyclin D1, BCOR. NGS study reveals ZC3H7B-BCOR gene fusion. What is the correct diagnosis?
- Leiomyosarcoma
- Low grade endometrial stromal sarcoma
- Synovial sarcoma
- ZC3H7B-BCOR rearranged high grade endometrial stromal sarcoma
Board review style answer #1
D. ZC3H7B-BCOR rearranged high grade endometrial stromal sarcoma
Comment Here
Reference: High grade endometrial stromal sarcoma
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Reference: High grade endometrial stromal sarcoma
Board review style question #2
A subclassification of high grade endometrial stromal sarcoma as per WHO 2020 is based on
- Identification of specific gene rearrangement containing YWHAE or BCOR gene or internal tandem duplication (ITD) of BCOR gene
- Immunohistochemical co-expression of cyclin D1 and BCOR
- Immunohistochemical expression of BCOR
- Presence of myxoid stromal change
Board review style answer #2
A. Identification of specific gene rearrangement containing YWHAE or BCOR gene or internal tandem duplication (ITD) of BCOR gene
Comment Here
Reference: High grade endometrial stromal sarcoma
Comment Here
Reference: High grade endometrial stromal sarcoma
