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
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)
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
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