Introduction
High-grade endometrial stromal sarcoma (HGESS) is a rare mesenchymal tumor that typically occurs in the uterus but occasionally arises at other gynecologic or pelvic locations.1 With the extensive application of molecular techniques, the diagnosis of HGESS has shifted from a morphology-based scheme to a paradigm that amalgamates molecular features, each with its own immunophenotype.2 Besides YWHAE-NUTM2A/B fusion HGESS, BCOR-rearranged HGESSs, such as ZC3H7B-BCOR,3BCOR ITD,4 and EPC1-BCOR,5 are new entities of HGESS. The histomorphology of HGESS expands from high-grade oval-shaped cells to high-grade oval or spindle-shaped cells. HGESS with ZC3H7B-BCOR fusion is the most common type among the new entities. Recognition of this rare tumor is of great clinical importance because of its aggressive biological behavior and susceptibility to recurrence and metastasis.3,6 Gastrointestinal stromal tumor (GIST) is one of the most common mesenchymal tumors in the abdominopelvic cavity. The diagnosis of GIST is mainly based on the combination of morphology with a cluster of differentiation 117 (CD117)- and/or discovered on gastrointestinal stromal tumor 1(DOG1)-positive immunophenotype. About 85% of GISTs have gain-of-function mutations in the KIT proto-oncogene, receptor tyrosine kinase (CKIT) or platelet-derived growth factor receptor, alpha polypeptide (PDGFRA) oncogene. Therefore, patients with GIST could benefit from targeted therapy with receptor tyrosine kinase inhibitors.7
Here, we report a case of molecularly confirmed ZC3H7B-BCOR HGESS in primary extrauterine, with morphologic and immunohistochemical findings resembling a GIST. The manuscript was prepared according to the CARE guideline and the checklist was completed.
Case presentation
The patient was a 51-year-old woman who presented with multiple abdominal masses and had undergone debulking surgery at a local hospital. Postoperatively, a pathological diagnosis of GIST was made. Pathological consultation was then performed for further diagnosis and treatment. She had a history of subtotal hysterectomy with double adnexectomy for uterine leiomyoma 9 months ago and without a family history of tumors. A computed tomographic scan showed extensive pelvic and abdominal masses, with the largest tumor measuring 9.6 cm × 6.1 cm, which invaded the rectum and left ureter (Fig. 1a).
By reviewing the histology, the tumor was composed of spindle cells arranged in haphazard fascicles without hyalinized collagenous stroma (Fig. 1b). The tumor cells had moderate eosinophilic cytoplasm, elongated nuclei and inconspicuous nucleoli (Fig. 1c). The myxoid intracellular and extracellular matrix could be found (Fig. 1d), and some even formed a myxoid lake locally (Fig. 1e). Cytoplasmic vacuolation sometimes generated a signet-ring-like appearance. There were abundant mitotic figures (>30/5 mm2) (Fig. 1f). No hemorrhage or necrosis was observed. Immunohistochemical staining showed diffusely and moderately to strongly positive staining for CD117 (Fig. 1g) and DOG1 (Fig. 1h), variably focal staining for smooth muscle actin and negative staining for desmin, CD34, S-100 and SRY-box transcription factor-10. The proliferation index of Ki-67 (Fig. 1i) was about 60%. The tumor was initially diagnosed as a GIST. Unexpectedly, no CKIT or PDGFRA driver mutations were detected, but amplification of murine double minute 2 (MDM2) and cyclin-dependent kinase 4 (CDK4) was detected via next-generation sequencing (NGS) of DNA before imatinib treatment. Furthermore, ZC3H7B-BCOR was detected via sequential NGS of RNA (Fig. 2a), which was used to determine whether it was a specific type of sarcoma. Histology, immunohistochemistry, and molecular tests were performed on the same tissue block, and the genetic alterations identified by NGS of DNA and RNA are summarized in Table 1. Additional immunostaining showed that CD10 (Fig. 2b) was diffusely positive, while the estrogen receptor (ER) (Fig. 2c) was negative and the progesterone receptor (PR) (Fig. 2d) was weakly positive. HGESS with ZC3H7B-BCOR fusion was definitively diagnosed.
Table 1Genetic alterations in this ZC3H7B-BCOR high-grade endometrial stromal sarcomas
| Method | Fusion | Amplification | Mutation |
|---|
| RNA NGS | ZC3H7B:exon10-BCOR:exon7 | ✗ | ✗ |
| DNA NGS | ✗ | CDK4 | RECQL4 exon5 stop_gained |
| | MDM2 | LYN exon9 missense_variant |
| | ERBB3 | PDCD1LG2 exon5 missense_variant |
| | | ERBB4 exon19 synonymous_varian |
| | | RECQL4 exon14 splice_acceptor_variant |
The patient returned to the local hospital for therapy. She was alive 2 months after the initial presentation, but refused further follow-up.
The study was performed in accordance with the ethical standards of the institutions to which we are affiliated and the Declaration of Helsinki (revised in 2013).
Discussion
The diagnosis of this case was challenging due to complexities in morphology, immunohistology, and molecular testing. While this case exhibited histological and immunohistochemical similarities with GIST, the prognosis and treatment strategies for these conditions are completely distinct.
The occurrence of HGESS with ZC3H7B-BCOR fusion in an extrauterine location is extremely rare, making it an unexpected finding. The morphological features of this case were similar to those of the previously reported ZC3H7B-BCOR fusion HGESS, characterized by uniform spindle cells arranged in haphazard fascicles with intermediate-sized ovoid to spindle nuclei, inconspicuous nucleoli, and frequent brisk mitotic activity. The cytoplasm ranges from scant to moderate and eosinophilic to more abundant and blue-gray. Myxoid stroma is frequently observed, with the occasional presence of collagen plaques.3 These features are often shared by myxoid leiomyosarcoma and GIST, which are common in the abdominopelvic cavity. The above morphologic characteristics, especially the myxoid matrix, as well as the female sex, should be considered HGESS.
A notable challenge in this case was the coexpression of CD117 and DOG1 in spindle tumor cells. Pathologists often use CD117 in combination with DOG1 as an approach to eliminate pitfalls in the diagnosis of GIST because CD117 may be expressed in various tumors, such as leiomyosarcoma, mesothelioma, dedifferentiated liposarcoma and solitary fibrous tumors.8 Unexpectedly, the dual expression of the group became the worst pitfall in this particular case. In the context of differential diagnosis, the expression of CD117 and DOG1 was examined in HGESS with YWHAE-NUTM2A/B fusion. Most (12/14) cases with high-grade round cells displayed moderate to strong membranous/cytoplasmic CD117 staining, while the remaining two cases with pure low-grade fibroblastic components were negative for CD117. Conversely, all 14 cases were negative for DOG1.9 Among the reported cases of ZC3H7B-BCOR fusion HGESS, only two cases were negative for CD117.6,10 The expression of DOG1 in the ZC3H7B-BCOR fusion HGESS is largely unknown. To our knowledge, DOG 1 was only stained and was positive in our case. However, further studies are needed. When the tumor cells expressed CD117, no mutations involving CKIT were found, raising suspicion about the diagnosis. The marker CD10 is valuable because it’s consistently positive in the ZC3H7B-BCOR fusion HGESS. BCOR was typically expressed in the YWHAE-NUTM2A/B fusion HGESS, but only half of the sarcomas with BCOR rearrangements displayed BCOR positivity. A panel of CD10, cyclin D1, ER, and PR is essential when considering HGESS.2
RNA NGS is preferred for its excellent performance in gene fusion detection when sarcoma is suspected. The identification of ZC3H7B-BCOR fusion through RNA NGS provided crucial insight and confidence to overthrow the diagnosis of GIST, characterized by spindle tumor cells expressing both CD117 and DOG1. Initially, DNA NGA was performed to determine whether the patient was suitable for targeted therapy. However, the absence of CKIT and PDGFRA mutations, along with the presence of MDM2 and CDK4 gene amplification, prompted the consideration of a special sarcoma. The incidences of MDM2 and CDK4 gene amplification have been reported in 45% and 38% of BCOR-rearranged cases respectively.11 It’s also worth highlighting that molecular detection becomes more essential in differential diagnosis as the distinction between low-grade and high-grade ESS is increasingly defined by genetics.
Conclusions
In summary, we presented a special ZC3H7B-BCOR HGESS in extrauterine expressing both CD117 and DOG1, which is a diagnostic pitfall that needs to be considered because it may lead to misdiagnosis and incorrect clinical treatment.
Abbreviations
- BCOR:
b-cell lymphoma-6 corepressor
- CD:
cluster of differentiation
- CDK:
cyclin-dependent kinase
- CKIT:
KIT proto-oncogene, receptor tyrosine kinase
- DNA:
deoxyribonucleic acid
- DOG:
discovered on gastrointestinal stromal tumor
- ER:
estrogen receptor
- ERBB:
human epidermal growth factor receptor
- GIST:
gastrointestinal stromal tumor
- HGESS:
high-grade endometrial stromal sarcoma
- LYN:
lck/yes-related novel protein-tyrosine kinase
- MDM:
murine double minute
- NGS:
next-generation sequencing
- PDCD1LG2:
programmed cell death 1 ligand 2
- PDGFRA:
platelet-derived growth factor receptor, alpha polypeptide
- PR:
progesterone receptor
- RECQL:
recQ like helicase
- RNA:
ribonucleic acid
- ZC3H7B:
zinc finger CCCH-type containing 7B
Declarations
Ethical statement
The study was performed in accordance with the ethical standards of the institutions to which we are affiliated and the Declaration of Helsinki (revised in 2013). Written informed consent was obtained from the patient for publication of this case report.
Funding
None.
Conflict of interest
The authors declare that they have no conflicts of interest.
Authors’ contributions
Writing the manuscript (YW, JY), assisting in data collection (PY), assisted in section staining (HZ), performing the molecular analysis (WL). All authors have made a significant contribution to this study and have approved the final manuscript.