Uterine Leiomyosarcoma with a Novel RAB2A-PLAG1 Gene Fusion

doi:10.21203/rs.3.rs-2443563/v2

Download PDF

Case Report

Uterine Leiomyosarcoma with a Novel RAB2A-PLAG1 Gene Fusion

https://doi.org/10.21203/rs.3.rs-2443563/v2

This work is licensed under a CC BY 4.0 License

Version 2

posted

You are reading this older preprint version

Read the latest preprint version →

Uterine leiomyosarcoma (ULMS) constitutes 1% of all uterine malignancies and is the most common subtype of uterine sarcoma. In some cases, distinguishing ULMS from endometrial stromal sarcoma (ESS) can be challenging as they may display histological and immunohistochemical overlap. In such cases, molecular studies such as RNA sequencing to detect gene rearrangements can help arrive at the definitive diagnosis. We report a unique case on ULMS with a novel RAB2A-PLAG1 gene fusion, which to our knowledge, is the first case reported in the English literature.

Case Presentation:

An 80-year-old woman presented to our hospital with a one-month history of pelvic pain and abnormal uterine bleeding. Imaging was notable for a large necrotic uterine mass, a thickened endometrium, and uterine fibroids. A subsequent endometrial biopsy (EMB) revealed an unremarkable transformation zone epithelium. After 4 months, the patient presented with persistent symptoms. One solid mass within the endometrium was found on imaging. Endometrial curettage (EMC) revealed a malignant uterine mesenchymal neoplasm with histologic findings suggestive of ULMS and ESS. The patient underwent a total hysterectomy with bilateral salpingo-oophorectomy. Immunohistochemical study performed on the resection specimen was inconclusive. RNA sequencing identified a novel RAB2A-PLAG1 gene fusion, and a diagnosis of ULMS was rendered.

Conclusion:

This is the first case of a ULMS with RAB2A-PLAG1 gene fusion. Pathologists should be cognizant of the extensive morphologic and immunophenotypic overlap between various uterine mesenchymal neoplasms. In challenging cases, molecular studies are crucial in allowing the pathologist to arrive at the final diagnosis.

Pathology

Uterine Leiomyosarcoma

Endometrium

endometrial stromal sarcoma

Molecular genetic

RAB21-PLAG1 gene fusion

Uterine leiomyosarcoma (ULMS) is a rare and clinically aggressive cancer with a poor prognosis and accounts for 1% of all uterine malignancies [1]. ULMS is a malignant neoplasm with three distinct histologic subtypes: spindle, epithelioid, and myxoid [1]. Accurate and timely diagnosis is important to institute an appropriate management plan for a better outcome. It can be challenging to distinguish leiomyosarcoma from other mesenchymal uterine neoplasms such as endometrial stromal sarcoma (ESS) as they may exhibit a similar histology and immunohistochemical profile [2]. In such cases, molecular studies can help achieve a definitive diagnosis. It has been shown that ~25% of the uterine myxoid leiomyosarcomas harbor TRPS1-PLAG1 and RAD51B-PLAG1 gene fusions [3]. To our knowledge, no ULMS with RAB2A-PLAG1 gene fusion has been previously reported in the English literature.

An 80-year-old woman was referred to our hospital with a one-month history of pelvic pain and abnormal uterine bleeding. She had a history of diabetes mellitus, hypertension, and dyslipidemia. The patient had no known gynecologic history. Imaging revealed a large necrotic uterine mass, thickened endometrium (thickness: 1.53 cm), and fibroids with no evident lymphadenopathy. A subsequent endometrial biopsy (EMB) revealed an unremarkable transformation zone epithelium.

The patient came back after 4 months with persistent complaints. A contrast computed tomography (CT) scan of the abdomen and pelvis was performed which revealed a large solid mass within the endometrium (size: 10.4 x 11.1 cm) with no evidence of metastatic disease. Endometrial curettage demonstrated a malignant mesenchymal neoplasm that was positive for CD10, desmin, and vimentin and lacked expression of SMA, SMMH, synaptophysin, and chromogranin. AE1/AE3 highlighted rare foci.

The patient underwent a total hysterectomy with bilateral salpingo-oophorectomy. The hysterectomy specimen was notable for a 10.8 cm rubbery focally calcified tan-white mass histologically composed of high-grade spindle and epithelioid cells (1A and 1B) with myxoid hypocellular (1C) and hyalinized areas (1D). The mitotic activity was >25/10HPF (1E). Immunohistochemically, the neoplastic cells expressed CD10, caldesmon, desmin (patchy), SMA (weak focal), and CAM5.2 (patchy) (Fig. 2) while they were negative for ER, PR, HMB45, AE1/AE3, WT1, cyclin D1, BCOR, myogenin, pan-NTRK, and ALK. P53 staining showed a wild type expression pattern. Ki67 staining indicated a high proliferative rate in these tumors (Fig 2). Histology and immunohistochemistry could not definitively differentiate between leiomyosarcoma and high grade ESS. RNA sequencing identified a RAB2A-PLAG1 gene fusion. In light of the histology and ancillary studies, a diagnosis of ULMS was rendered.

Uterine sarcomas constitute <10% of uterine malignancies while majority of them are either ULMS or ESS [1]. ULMS, a rare and aggressive cancer with poor prognosis, accounts for 1% of all uterine malignancies and is the most common subtype of uterine sarcoma with an annual incidence of 0.64/100,000 [2]. The age at onset is usually 50-55 years [2]. ULMS is associated with an increased mortality rate due to frequent recurrence and distant metastasis with a 5-year survival rate of 57% and 16% for stage I and stage IV, respectively [4]. Leiomyosarcoma can occur anywhere in the pelvis including the cervix, urinary bladder, or uterus with the most common location being in the uterus as seen in this patient [5]. ULMS can present with abnormal vaginal bleeding (56%), palpable pelvic mass (54%), and pelvic pain (22%) [6]. Since these symptoms mimic other benign uterine tumors in presentation, they often cause a delayed diagnosis. This patient had persistent pelvic pain and abnormal uterine bleeding for 4 months which led to further diagnostic workup for uterine malignancy. Laboratory and imaging studies cannot reliably diagnose ULMS. While uterine fibroids usually do not develop into ULMS, they may co-exist as found in this patient [7]. In a few patients, lactate dehydrogenase or CA-125 are elevated, which are non-specific findings and unreliable predictors of ULMS. MRI is a reliable method for the preliminary diagnosis of uterine tumors [8]. All patients should undergo imaging studies such as MRI to rule out the metastatic disease of ULMS. MRI in this patient did not detected metastatic disease. The absence of metastatic disease helps in staging the disease and directing appropriate treatment. There are different modalities to diagnose uterine mesenchymal sarcomas such as histological examination, immunohistochemistry (IHC), and/or molecular studies. ULMS is histologically composed of spindle cells with a blunt terminal nucleus and active mitotic activity of 10 mitoses per 10 high power fields, which corresponds to the histologic findings in this patient.

Histologically distinguishing ULMS from other uterine mesenchymal neoplasms (such as ESS) often poses a diagnostic complexity. In such cases with equivalent features, the IHC panel is used as an adjunct to morphology. Routinely, the following IHC panel is used to differentiate ULMS from ESS such as estrogen receptor (ER), progesterone receptor (PR), desmin, smooth muscle actin (SMA), h-caldesmon and CD10 [9,10,11,12]. However, no immunomarker is sensitive and specific enough to diagnose and distinguish these neoplasms, thereby, an IHC panel of markers are performed. We performed an IHC panel in this patient as the histologic features were inconclusive. While IHC helped us elucidate this case as a high-grade uterine sarcoma, we still could not conclude a confirmatory diagnosis due to the overlapping IHC features between ULMS and ESS. It is important to distinguish them since both have a different clinical course and management, for example, ESS has an indolent disease course that responds to hormonal treatment because of ER, and PR expression [13]. On the other hand, ULMS has a clinically aggressive course with high mortality. [13].

There is an extensive morphologic and immunophenotypic overlap between various uterine mesenchymal neoplasms. The use of novel antibodies such as GEM and transgelin is discussed in the medical literature to distinguish the tumors [13]. A growing body of evidence suggests using novel gene expression signatures to differentiate ESS from ULMS. For example, the following genes are only overexpressed in ULMS such as SLCA7A10/ASC1, EFNB3, CCND2, ECEL1, ITM2A, NPW, PLAG1, and GCGR [13]. PLAG-1 rearrangement can distinguish ULMS from ESS [14]. It has been shown that ~25% of the uterine myxoid leiomyosarcomas harbor TRPS1-PLAG1 and RAD51B-PLAG1 gene fusions [3]. These gene rearrangements can be detected utilizing FISH or sequencing of fusion transcripts [3]. Targeted RNA sequencing methods which were used in this patient, can detect both known and novel fusions and thus, significantly improve in analytical sensitivity [3].

In this patient, A RAB2A-PLAG1 gene fusion was identified, which confirmed the diagnosis of ULMS. The RAB2A-PLAG1 gene fusion has not been previously reported in the English literature.

This is the first case reported of a ULMS with RAB2A-PLAG1 gene fusion. Pathologists should be cognizant of the extensive morphologic and immunophenotypic overlap between various uterine mesenchymal neoplasms. In challenging cases, molecular analysis is crucial in allowing the pathologist to arrive at the final diagnosis. Targeted RNA sequencing is the preferred method which can detect both known and novel fusion facilitating the accuracy of diagnosis. Our case report will inform future genome studies in oncologic research in formulating their hypothesis with the potential for new diagnostic and therapeutic approaches.

Brooks SE, Zhan M, Cote T, et al. Surveillance, epidemiology, and end results analysis of 2677 cases of uterine sarcoma 1989–1999. Gynecol Oncol 2004;93:204–8.
Echt G, Jepson J, Steel J, Langholz B, Luxton G, Hernandez W, et al. Treatment of uterine sarcomas. Cancer. (1990) 66(1):35–9.
Arias-Stella III JA, Benayed R, Oliva E, Young RH, Hoang LN, Lee CH, Jungbluth AA, Frosina D, Soslow RA, Antonescu CR, Ladanyi M. Novel PLAG1 gene rearrangement distinguishes a subset of uterine myxoid leiomyosarcoma from other uterine myxoid mesenchymal tumors. The American journal of surgical pathology. 2019 Mar;43(3):382.
Kapp DS, Shin JY, Chan JK. Prognostic factors and survival in 1396 patients with uterine leiomyosarcomas: emphasis on impact of lymphadenectomy and oophorectomy. Cancer. (2008) 112(4):820–30.
Corcoran S, Hogan AM, Nemeth T, Bennani F, Sullivan FJ, Khan W, et al. Isolated cutaneous metastasis of uterine leiomyosarcoma: Case report and review of literature. Diagn Pathol. 2012;7:85.
Giuntoli RL 2nd, Metzinger DS, DiMarco CS, Cha SS, Sloan JA, Keeney GL, et al. Retrospective review of 208 patients with leiomyosarcoma of the uterus: prognostic indicators, surgical management, and adjuvant therapy. Gynecol Oncol (2003) 89(3):460–9.
Harry VN, Narayansingh GV, Parkin DE. Uterine leiomyosarcomas: A review of the diagnostic and therapeutic pitfalls. Obstet Gynaecol. 2007;9:88–94.
Hricak H, Tscholakoff D, Heinrichs L, Fisher MR, Dooms GC, Reinhold C, et al. Uterine leiomyomas: correlation of MR, histopathologic findings, and symptoms. Radiology. (1986) 158(2):385–91.
Leitao MM, Soslow RA, Nonaka D, et al. Tissue microarray immunohistochemical expression of estrogen, progesterone, and androgen receptors in uterine leiomyomata and leiomyosarcoma. Cancer 2004;101:1455–62.
Kelley TW, Borden EC, Goldblum JR. Estrogen and progesterone receptor expression in uterine and extrauterine leiomyosarcomas. An immunohistochemical study. Appl Immunohistochem Mol Morphol 2004;12:338–41.
Chu PG, Arber DA, Weiss LM, et al. Utility of CD10 in distinguishing between endometrial stromal sarcoma and uterine smooth muscle tumors: An immunohistochemical comparison of 34 cases. Mod Pathol 2001;14:465–71.
Rush DS, Tan J, Baergen RN, et al. h-Caldesmon, a novel smooth muscle-specific antibody, distinguishes between cellular leiomyoma and endometrial stromal sarcoma. Am J Surg Pathol 2001;25:253–8.
Hwang H, Matsuo K, Duncan K, Pakzamir E, Pham HQ, Correa A, Fedenko A, Mhawech-Fauceglia P. Immunohistochemical panel to differentiate endometrial stromal sarcoma, uterine leiomyosarcoma and leiomyoma: something old and something new. Journal of clinical pathology. 2015 Sep 1;68(9):710-7.
Arias-Stella III JA, Benayed R, Oliva E, Young RH, Hoang LN, Lee CH, Jungbluth AA, Frosina D, Soslow RA, Antonescu CR, Ladanyi M. Novel PLAG1 gene rearrangement distinguishes a subset of uterine myxoid leiomyosarcoma from other uterine myxoid mesenchymal tumors. The American journal of surgical pathology. 2019 Mar;43(3):382.

Download PDF

Version 2

posted

You are reading this older preprint version

Read the latest preprint version →

Uterine Leiomyosarcoma with a Novel RAB2A-PLAG1 Gene Fusion

Status:

Version 2

Abstract

Figures

Introduction

Case Presentation

Discussion

Conclusion

References

Status:

Version 2