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Hepatic endometrial stromal sarcoma
Accepted Manuscript Title: Hepatic Endometrial Stromal Sarcoma Authors: Nick Baniak, Scott Adams, Rajni Chibbar, Cheng-Han Lee, Rani Kanthan PII: DOI: Reference:
S0344-0338(18)30378-9 https://doi.org/10.1016/j.prp.2018.05.008 PRP 52066
To appear in: Received date: Revised date: Accepted date:
31-3-2018 8-5-2018 8-5-2018
Please cite this article as: Nick Baniak, Scott Adams, Rajni Chibbar, Cheng-Han Lee, Rani Kanthan, Hepatic Endometrial Stromal Sarcoma, Pathology - Research and Practice https://doi.org/10.1016/j.prp.2018.05.008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Hepatic Endometrial Stromal Sarcoma
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Nick Baniak, MDa, Scott Adams, MDb, Rajni Chibbar, MD, PhD, FRCPCa, Cheng-Han Lee, MD, PhD, FRCPCc, Rani Kanthan, MBBS, MS, FRCS, FRCPSC, FCAP, M.Eda a
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Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Saskatoon, Canada b Department of Medical Imaging, College of Medicine, University of Saskatchewan, Saskatoon, Canada c Department of Pathology, BC Cancer Agency, Vancouver, British Columbia, Canada Dr. Baniak: [email protected] Dr. Adams: [email protected] Dr. Chibbar: [email protected] Dr. Lee: [email protected] Dr. Kanthan: [email protected]
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Corresponding Author: Dr. Nick Baniak Resident, Department of Pathology & Laboratory Medicine, University of Saskatchewan, 103 Hospital Drive, Saskatoon, SK, Canada S7N 0W8. Email: [email protected] Phone: 306-270-1988 Fax: 306-655-2223
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Conflict of Interest: None declared Funding: None declared
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Abstract Endometrial stromal sarcomas are rare tumors that may recur or metastasize many years after their initial presentation. Though most recurrences are within the pelvis, distant metastases can occur, and are most common to the lungs. Metastases to the liver are extremely rare. Herein we report two cases of endometrial stromal sarcoma with metastases to the liver without a prior history of endometriosis, accompanied by their histology, immunohistochemistry, and molecular analysis in the context of a relevant literature review. Abbreviations
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ESS – endometrial stromal sarcoma, IHC – immunohistochemistry, ER – estrogen receptor, PR – progesterone receptor, NSE – neuron specific enolase, FFPE - formalin-fixed paraffin embedded, EESS - extra-uterine endometrial stromal sarcoma
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Key Words Endometrial stromal sarcoma; extra-pelvic; metastases; JAZF1-SUZ12 rearrangement
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Introduction Endometrial stromal sarcomas (ESSs), though rare tumors, are the second most common uterine mesenchymal malignancy [1-4], representing less than one percent of all uterine cancers and 15% of all uterine sarcomas [4]. ESS primarily affects perimenopausal women and is usually a slow-growing indolent disease with a favorable 5-year disease-specific survival [2-4]. Recurrent disease may occur after long tumor-free intervals, sometimes more than 20 years after the initial diagnosis [5]. Although recurrence typically occurs locally in the abdomen/pelvis, distant metastases can occur, most commonly to the lungs [6, 7]. In addition, metastases have been reported in the bladder [2], heart [1], spine [8], colon [9], breast [10], bone [11], and brain [12]. Metastasis to liver has been very infrequently reported, especially in the absence of a synchronous history of endometriosis. Liver is one of the commonest organ sites for metastatic disease, most frequently by metastatic carcinomas, though melanomas and lymphomas can also spread to the liver. Sarcoma metastasis to the liver, while rare, do occur [13], presenting as either multiple lesions or as a solitary mass. Most cases can be diagnosed with standard morphology and immunohistochemistry. In addition, correlating the clinical history can be very important in elucidating the correct diagnosis. We report on two cases of metastatic ESS to the liver. The clinical, histologic, immunophenotypic and molecular characteristics are summarized in Table 1.
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Materials and Methods The databases in Saskatoon and Regina, Saskatchewan were searched back to 1996 for ESS cases and their clinical and histological characteristics. Of 32 cases, 10 had extra-pelvic metastases, two of which involved the liver. A central pathology review was completed along with immunohistochemistry (IHC) and genetic analysis. IHC stains used in the pathological analysis of these lesions included HepPar, CD10, Cyclin D1, ER (estrogen receptor), PR (progesterone receptor), Ki67, p53, Vimentin, CK7, CK20, CD45, S100, NSE (neuron specific enolase), desmin, actin, calponin, inhibin, and calretinin, the specifics of which are summarized in Table 2. For genetic analysis, a RNA-based assay for detecting the presence of fusion transcript using Nanostring Element based technology was used. A detailed description of the methods and its reliability in detecting JAZF1-SUZ12, YWHAE-NUTM2A/B and ZC3H7B-BCOR/BCORZC3H7B fusions have been previously published (PMID: 29104083). Briefly, RNA was extracted from paraffin scrolls or cores obtained from formalin-fixed paraffin embedded (FFPE) tumor tissue with a High Pure FFPET RNA isolation kit (Roche, Laval, QC, Canada). A total of 100-300 ng of RNA was hybridized to the tagged probe set to produce hybridized RNA/probe mixture, which is then cleaned and bound to a streptavidin-coated cartridge in a NanoString Prep Station (NanoString Technologies, Seattle, WA, USA). Following the prep station completion, the cartridge was sealed and transferred to a NanoString Digital Analyzer device (NanoString Technologies) for optical barcodes counting in a second generation NanoString Digital Analyzer 2
(NanoString Technologies, Seattle, WA, USA). A sample ratio of 5.0 or above was considered positive for the corresponding gene fusion. A sample ratio below 5.0 was considered negative for that fusion. A literature review of the English language was completed in Medline and PubMed, with the search terms ‘Endometrial stromal sarcoma’, ‘liver’, and ‘metastases/ neoplasm metastases’. The resulting papers and their relevant references were reviewed.
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Results Case 1 The first patient is 20-year-old female who was initially found in 2000 to have a large pelvic mass with suspicion of invasion into the bladder. A bladder biopsy showed a poorly differentiated neoplasm composed of small uniform “round” cells showing focally brisk mitotic activity infiltrating the bladder wall. CD45, S100, NSE, desmin and actin were all negative. A uterine ESS was favored based on clinical and radiological correlation. A hysterectomy, bilateral salpingectomy and oophorectomy, cystectomy, pelvic lymph node dissection, and a liver wedge biopsy were performed. The liver showed nodular hyperplasia and the ovary, fallopian tube, and lymph nodes were unremarkable. The hysterectomy showed a high grade ESS of the uterus that involves the cervix and invades into the posterior wall of the urinary bladder, and extending to adnexal margins. The tumour was composed of nodules and infiltrating masses of monomorphic ovoid to spindled cells with scant amounts of cytoplasm and associated with extensive necrosis. Within the left adnexal tissue was positive lymphovascular invasion. Upon external consultation, the tumor was classified a low grade ESS of the uterus because of minimal nuclear atypia. The patient’s first recurrence was a left pelvic mass in 2006, which was resected and confirmed to be ESS. A PET scan in late 2014 identified another soft tissue mass in the left perirectal region (3.8 x 2.6 cm) suspicious for local tumour recurrence, which was confirmed on biopsy. A CT scan in early 2015 showed multiple parenchymal lesions within the liver (Figure 1A) in keeping with metastatic disease, with the largest being 3.2 x 3.1 cm and an increase in the size of the perirectal mass to 4.1 x 2.8 cm. A biopsy of the liver lesion showed metastatic ESS. The morphology resembled the previous primary and recurrent tumors (Figure 1B), with CD10 and PR immunopositivity (Figures 1C and 1D). The cyclin D1 was negative. The patient subsequently underwent four cycles of chemotherapy with Ifosfamide and Adriamycin, followed by Pazopanib. Gemcitabine was given in late 2015 after additional clinical consultation. The patient was transferred to her home hospital where her condition deteriorated. In March 2016, a chest x-ray showed elevation of the right hemidiaphgram and nodular opacities within both lower lung zones suspicious for lung metastases. The patient passed away shortly afterwards. Molecular testing on the liver biopsy failed to demonstrate ESS genetic fusion due to poor RNA quality and quantity. There was only 91ng of RNA input and 2 or more of the control genes had less than 25% and the overall average was below 30%. Case 2 The second patient was a 48-year-old female who was first found to have bilateral complex adnexal masses highly suspicious for malignancy in early 2015. Her CA-125 was 89. Initial CT imaging (Figure 2A) in February showed three hypodense lesions within the liver, all concerning for metastatic disease. The largest lesion (2 x 2 m) was well defined and near the upper aspect of
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the right lobe. The second well defined lesion (3.8 x 2.5 cm) in segment 7 was also heterogeneous and hypodense. A third lesion (1.1 cm) was present in the inferior aspect of the right lobe. The uterus was unremarkable. The left ovary/adnexal region had a large complex mass (10 x 11.4 x 6.1 cm) that was predominantly solid with some cystic components. A similar appearing mass (14.3 x 11.4 x 7.1 cm) was seen in the right ovary/adnexal region. She subsequently underwent a total abdominal hysterectomy, omentectomy, appendectomy, debulking of lymph nodes, multiple peritoneal biopsies, and a sup-optimal cytoreduction of one of the liver metastases. Final pathology as described below showed a high grade left ovarian endometrioid stromal sarcoma metastatic to the rectosigmoid colon, descending colon, appendix, liver, and omentum. The patient was given 4 cycles of chemotherapy (Adriamycin and Ifosfamide with Mesna). A subsequent CT scan again demonstrated the three liver lesions – 2.5 x 2.2 cm, 3.1 x 1.4 cm, and 1.7 x 1.3 cm. The patient was then referred to a liver surgeon at a different institution, where she had a resection of a liver metastasis and biopsies of the deeper lesions, ablation radiation, and started on Letrozole in December 2015. A CT scan in October 2016 and PET scan the following month showed interval stability and a slight decrease in size of the lesions. Imaging in August 2017 again showed interval stability of the liver lesions and no new evidence of metastatic disease or recurrent disease in the pelvis. The initial pathology was reported as a high grade ESS of the ovary arising in a background of endometriosis. The tumour was composed of monomorphic round to ovoid cells with scant cytoplasm and a conspicuous vascular stromal network. The tumor showed up to 23 mitoses/10hpf and was positive for ER, PR, CD10, focally positive for SMA and desmin, and negative for inhibin, calretinin, and cyclin D1. The pathology from the second surgery showed the lesion in segment 3 to be a residual cystic cavity lined by foreign body giant cells and fibroblastic tissue in keeping with her previous surgery. Neoplastic cells were not identified. Tru-cut biopsies of the deep lesions in segment 6 and 7 showed the same findings. Within dilated cystic spaces, there were small scattered focal areas of dense condensation of dark blue spindle cells reminiscent of endometrial stroma in the subcapsular region (Figure 2B). The cells were strongly positive for CD10, vimentin, calponin, and ER (Figures 2C and 2D). The expression of Ki67 was low in many areas (up to 40%). With the context of proven metastatic ESS, these were considered recurrent/residual foci of ESS. Subsequent molecular testing showed both the original tumour in the ovary, the original liver lesion and second surgery liver lesion all to harbor JAZF1-SUZ12 fusion (Figure 3). Given the lack of cyclin D1 expression and characteristic fusion, this case also represented a low-grade ESS rather than the high-grade ESS originally reported.
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Discussion ESSs are divided into low grade and high grade categories. Most cases of low grade ESS harbor a t(7;17) (p21;q15), which results in genetic fusion between 5’ potion of JAZF1 and 3’ portion of SUZ12 (JJAZ1) [4]. High grade ESS is characterized by a genetic fusion between the YWHAE and NUTM2A/B (previously known as FAM22A/B) genes that results from t(10;17) (q22;p13) [4, 14] and high-grade ESS is associated with an aggressive clinical behavior and poor prognosis [3]. Compared to low grade, they have more frequent and earlier recurrences, and their prognosis is intermediate between low-grade ESS and undifferentiated uterine sarcoma [4]. While high-grade ESS exhibits higher grade histologic features compared to low-grade ESS, the distinction on histology can sometimes be challenging, especially given their rarity [15]. Immunohistochemistry can aid in the diagnosis. Low grade ESS usually shows diffuse positive
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staining for ER, PR, and CD10 [14-16]. Conversely, ER, PR, and CD10 are usually negative in the high-grade component of high-grade ESS, but can be positive if there is a low-grade component present [16]. The cyclin D1 immunostain is quite discriminatory in this context [15, 16]. The highgrade component shows strong diffuse nuclear cyclin D1 positivity in more than 70% of tumor cells, and the low-grade spindle cell component shows weak to variable, heterogeneous cyclin D1 expression. Conventional ESSs are typically negative for cyclin D1 expression [14, 15]. Furthermore, the differential of a high-grade ESS would include other high-grade typically pleomorphic uterine sarcomas including undifferentiated endometrial sarcoma and leiomyosarcoma, a setting in which cyclin D1 expression is of limited diagnostic value [15]. Notably, although cyclin D1 immunostaining extent and intensity in YWHAE-FAM22 ESS is comparable to that in mantle cell lymphoma, the mechanism of cyclin D1 overexpression in YWHAE-FAM22 ESS has not been determined [15]. Despite high-grade ESS having a worse prognosis with more frequent and earlier recurrences, low-grade ESS can also metastasize and result in a poor outcome, as evidenced in the index cases. Nevertheless, having an ancillary study available, such as JAZF1- SUZ12 fusion, to confirm the diagnosis may aid in risk prediction in morphologically ambiguous cases. As more patients are documented and molecular techniques become more available, perhaps genetic signatures will become the primary method of risk prediction. ESS involving the liver has been reported infrequently (Table 3) [17-20]. Of the four previous reports documenting a total of six patients, three were not metastatic disease, but rather ESS evolving from endometriosis that involved the liver. Comparing our cases to the literature is not possible due to the low number and incomplete documentation. Due to the rarity of the cases, and the availability of ancillary techniques, we attempted to characterize the lesions fully. The ancillary techniques in one case were completely supportive for metastatic ESS, with a documented history, characteristic IHC, and positive fusion for low grade ESS, which correlates with the histology and negative cyclin D1. The other case could not be fully documented due to poor RNA quality resulting in indeterminate molecular analysis. When trying to differentiate metastatic ESS from primary extra-uterine endometrial stromal sarcoma (EESS), a uterine primary needs to be excluded. A primary uterine tumour can be excluded if a hysterectomy is done concurrently. Similarly, if the hysterectomy occurred previously, the slides can be reviewed if available [20]. If there is a uterine tumour and endometriosis, there is a possibility of synchronous tumours since EESS are often associated with foci of endometriosis [20, 21]. The largest series of primary EESS to date showed that the tumor was associated with endometriosis in 30 of 50 cases, suggesting an origin from ectopic endometrial stroma. In the absence of a uterine primary, when no endometriosis is identified, the tumor may have originated from stromal endometriosis or overgrowth of the tumor obscured the underlying endometriosis [20]. Alternatively, it has also been postulated that EESS could arise de novo from coelomic or sub-coelomic multipotential epithelium [20, 22]. The differential diagnosis of ESS includes endometrial stromal nodule, highly cellular leiomyoma, highly cellular intravenous leiomyomatosis, cellular endometrial polyp, sex-cord stromal tumours, low-grade Mullerian adenosarcomas and adenomyosis [23]. In the retroperitoneum, other neoplasms in the differential include peripheral nerve sheath tumors, gastrointestinal stromal tumor, fibrosarcoma, and monophasic synovial sarcoma [24]. The diagnosis of metastatic ESS can occur many months to years after the original diagnosis. Additionally, the metastatic lesion may present prior to the primary being discovered. Therefore, pathologists entertaining the diagnosis of distant involvement by ESS cannot always
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rely on a clinical history [2, 25]. Moreover, making the diagnosis can be problematic because of small biopsy size and various histological features [25]. Histologic features of recurrent or metastatic ESS generally parallel those of the initial tumors, resembling stromal cells in normal proliferative endometrium [2]. However, recurrent tumors may demonstrate more nuclear pleomorphism and atypia compared with the primary tumor or show areas of high-grade features or leiomyomatous differentiation [26]. Thus, without a known clinical history, it is often very difficult to accurately diagnose metastatic ESS [25]. Due to low numbers, evidence based guidelines for treatment is not available [18, 27] and the treatment modality for recurrent or distant metastatic ESS remains unclear [6, 28]. It has been suggested that the indolent growth makes cytoreductive surgery, including repeated surgery, appropriate for late recurrent disease [2]. The value of adjuvant therapy is controversial, but nevertheless considered [27]. In one series of metastatic pulmonary ESS, treatment modalities included surgery, selective embolization, chemo, hormonal therapy, and radiation [6]. Other reports have also advocated using progestin, alone or in combination with GnRH agonists as adjuvant therapy and for treatment of recurrent disease [28-30]. However, the optimal dose, regimen, and duration of hormonal treatment are not well established [28].
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Acknowledgements None
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Conclusion Although, pulmonary metastases are the most common distant metastatic location for ESS, other sites, including the liver are possible, and must be kept in mind in hepatic lesions in relevant cases. Correctly identifying hepatic ESS can be challenging, especially when the original clinical history may be misleading and when recurrences occur after a prolonged interval. Even with classic features, an unusual site can lead to a difficult diagnosis. A combination of detailed history, imaging, histology, and IHC will assist in the differential diagnosis of endometriosis-related ESS versus metastatic ESS. Furthermore, characteristic molecular alterations, if accessible, can facilitate diagnosis.
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Figure Legends
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Figure 1 A – Contrast-enhanced axial CT image showing a low-density lesion in the periphery of the liver with surrounding cystic changes. B – Hematoxylin and eosin stained section showing ESS involving the liver at medium power C – CD10 immunohistochemistry showing positive staining in ESS involving the liver (*) at low power. D – PR immunohistochemistry showing positive staining in ESS involving the liver (**) at low power.
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Figure 2 A – Contrast-enhanced axial CT image showing hypodense lesions within the liver; the largest lesion demonstrates heterogeneous enhancement and measures 3.8 x 2.5 cm. B – Hematoxylin and eosin stained section showing ESS involving the liver at medium power C – ER immunohistochemistry showing positive staining in ESS involving the liver at low power. D – CD10 immunohistochemistry showing positive staining in ESS involving the liver at low power.
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Figure 3 – Molecular analysis showing the characteristic JAZF1-SUZ12 fusion seen in low grade ESS.
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Table 1 – Cases of ESS with distant metastases with clinical, molecular, and IHC data Diagnosis Age at Site of Original Metastatic Case to ER PR CD10 Diagnosis Metastasis Mutation Mutation Metastasis Liver, 1 20 72 mo NA* NA* +,- +,+ +,+ Colon, Appendix, JAZF1JAZF1+, 2 48 0 mo Colon, +,+ +,+ SUZ12 SUZ12 NA Liver *Poor RNA quality
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Control CB-1 Breast Breast CB-1 Liver Appendix Breast Appendix CB-1 Appendix CB-1 CB-1 NA Appendix CB-1 Appendix NA CB-1
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Antibody Manufacturer Source Clone Dilution Cyclin D1 Dako Rabbit EP12 1:30 ER Dako Rabbit EP1 1:50 PR NCL Mouse 16 1:150 CD10 Dako Mouse 5636 0 Hep Par Dako Mouse OCH1E5 1:1000 Ki-67 Dako Mouse MIB-1 1:60 p53 Dako Mouse DO-7 0 Vimentin Dako Mouse V9 0 CK7 Dako Mouse OV-TL12/30 1:70 CK20 Dako Mouse Ks20.8 1:100 CD45 Dako Mouse 2B11+PD7/26 1:400 S100 Dako Rabbit NA 0 NSE Dako Mouse BBS/NC/V1-H14 0 Desmin Dako Mouse D33 1:50 Actin Dako Mouse 1A4 0 1 Calponin Dako Mouse CALP 1:700 Inhibin Dako Mouse R1 0 Calretinin Dako Mouse DAK Calret 1 1:450 Table 2 – Characteristics of the antibodies used for immunohistochemical analysis.
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*CB-1 – control block 1, appendix, tonsil, liver, kidney
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Table 3 – Cases of ESS involving the liver from the literature (ANED – alive with no evidence of disease; NA – not applicable). Site of Diagnosis to Age History Primary Follow-up Metastasis Metastasis 31 Endometriosis Liver NA NA 48mo ANED 61 Endometriosis Liver NA NA 48mo ANED Peritoneum, TAH+BSO, 68 Uterine small bowel, 342mo ANED leiomyomas colon, liver Recurrent Passed 24mo 52 menorrhagia, Uterine Liver, lung 24mo after enlarging uterus hysterectomy Omentum, liver, 174mo 42 Endometriosis small bowel, NA NA ANED mesentery, colon 63 Unknown Adnexa Liver Not specified Lost to FU
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S0344-0338(18)30378-9 https://doi.org/10.1016/j.prp.2018.05.008 PRP 52066
To appear in: Received date: Revised date: Accepted date:
31-3-2018 8-5-2018 8-5-2018
Please cite this article as: Nick Baniak, Scott Adams, Rajni Chibbar, Cheng-Han Lee, Rani Kanthan, Hepatic Endometrial Stromal Sarcoma, Pathology - Research and Practice https://doi.org/10.1016/j.prp.2018.05.008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Hepatic Endometrial Stromal Sarcoma
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Nick Baniak, MDa, Scott Adams, MDb, Rajni Chibbar, MD, PhD, FRCPCa, Cheng-Han Lee, MD, PhD, FRCPCc, Rani Kanthan, MBBS, MS, FRCS, FRCPSC, FCAP, M.Eda a
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Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Saskatoon, Canada b Department of Medical Imaging, College of Medicine, University of Saskatchewan, Saskatoon, Canada c Department of Pathology, BC Cancer Agency, Vancouver, British Columbia, Canada Dr. Baniak: [email protected] Dr. Adams: [email protected] Dr. Chibbar: [email protected] Dr. Lee: [email protected] Dr. Kanthan: [email protected]
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Corresponding Author: Dr. Nick Baniak Resident, Department of Pathology & Laboratory Medicine, University of Saskatchewan, 103 Hospital Drive, Saskatoon, SK, Canada S7N 0W8. Email: [email protected] Phone: 306-270-1988 Fax: 306-655-2223
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Conflict of Interest: None declared Funding: None declared
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Abstract Endometrial stromal sarcomas are rare tumors that may recur or metastasize many years after their initial presentation. Though most recurrences are within the pelvis, distant metastases can occur, and are most common to the lungs. Metastases to the liver are extremely rare. Herein we report two cases of endometrial stromal sarcoma with metastases to the liver without a prior history of endometriosis, accompanied by their histology, immunohistochemistry, and molecular analysis in the context of a relevant literature review. Abbreviations
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ESS – endometrial stromal sarcoma, IHC – immunohistochemistry, ER – estrogen receptor, PR – progesterone receptor, NSE – neuron specific enolase, FFPE - formalin-fixed paraffin embedded, EESS - extra-uterine endometrial stromal sarcoma
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Key Words Endometrial stromal sarcoma; extra-pelvic; metastases; JAZF1-SUZ12 rearrangement
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Introduction Endometrial stromal sarcomas (ESSs), though rare tumors, are the second most common uterine mesenchymal malignancy [1-4], representing less than one percent of all uterine cancers and 15% of all uterine sarcomas [4]. ESS primarily affects perimenopausal women and is usually a slow-growing indolent disease with a favorable 5-year disease-specific survival [2-4]. Recurrent disease may occur after long tumor-free intervals, sometimes more than 20 years after the initial diagnosis [5]. Although recurrence typically occurs locally in the abdomen/pelvis, distant metastases can occur, most commonly to the lungs [6, 7]. In addition, metastases have been reported in the bladder [2], heart [1], spine [8], colon [9], breast [10], bone [11], and brain [12]. Metastasis to liver has been very infrequently reported, especially in the absence of a synchronous history of endometriosis. Liver is one of the commonest organ sites for metastatic disease, most frequently by metastatic carcinomas, though melanomas and lymphomas can also spread to the liver. Sarcoma metastasis to the liver, while rare, do occur [13], presenting as either multiple lesions or as a solitary mass. Most cases can be diagnosed with standard morphology and immunohistochemistry. In addition, correlating the clinical history can be very important in elucidating the correct diagnosis. We report on two cases of metastatic ESS to the liver. The clinical, histologic, immunophenotypic and molecular characteristics are summarized in Table 1.
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Materials and Methods The databases in Saskatoon and Regina, Saskatchewan were searched back to 1996 for ESS cases and their clinical and histological characteristics. Of 32 cases, 10 had extra-pelvic metastases, two of which involved the liver. A central pathology review was completed along with immunohistochemistry (IHC) and genetic analysis. IHC stains used in the pathological analysis of these lesions included HepPar, CD10, Cyclin D1, ER (estrogen receptor), PR (progesterone receptor), Ki67, p53, Vimentin, CK7, CK20, CD45, S100, NSE (neuron specific enolase), desmin, actin, calponin, inhibin, and calretinin, the specifics of which are summarized in Table 2. For genetic analysis, a RNA-based assay for detecting the presence of fusion transcript using Nanostring Element based technology was used. A detailed description of the methods and its reliability in detecting JAZF1-SUZ12, YWHAE-NUTM2A/B and ZC3H7B-BCOR/BCORZC3H7B fusions have been previously published (PMID: 29104083). Briefly, RNA was extracted from paraffin scrolls or cores obtained from formalin-fixed paraffin embedded (FFPE) tumor tissue with a High Pure FFPET RNA isolation kit (Roche, Laval, QC, Canada). A total of 100-300 ng of RNA was hybridized to the tagged probe set to produce hybridized RNA/probe mixture, which is then cleaned and bound to a streptavidin-coated cartridge in a NanoString Prep Station (NanoString Technologies, Seattle, WA, USA). Following the prep station completion, the cartridge was sealed and transferred to a NanoString Digital Analyzer device (NanoString Technologies) for optical barcodes counting in a second generation NanoString Digital Analyzer 2
(NanoString Technologies, Seattle, WA, USA). A sample ratio of 5.0 or above was considered positive for the corresponding gene fusion. A sample ratio below 5.0 was considered negative for that fusion. A literature review of the English language was completed in Medline and PubMed, with the search terms ‘Endometrial stromal sarcoma’, ‘liver’, and ‘metastases/ neoplasm metastases’. The resulting papers and their relevant references were reviewed.
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Results Case 1 The first patient is 20-year-old female who was initially found in 2000 to have a large pelvic mass with suspicion of invasion into the bladder. A bladder biopsy showed a poorly differentiated neoplasm composed of small uniform “round” cells showing focally brisk mitotic activity infiltrating the bladder wall. CD45, S100, NSE, desmin and actin were all negative. A uterine ESS was favored based on clinical and radiological correlation. A hysterectomy, bilateral salpingectomy and oophorectomy, cystectomy, pelvic lymph node dissection, and a liver wedge biopsy were performed. The liver showed nodular hyperplasia and the ovary, fallopian tube, and lymph nodes were unremarkable. The hysterectomy showed a high grade ESS of the uterus that involves the cervix and invades into the posterior wall of the urinary bladder, and extending to adnexal margins. The tumour was composed of nodules and infiltrating masses of monomorphic ovoid to spindled cells with scant amounts of cytoplasm and associated with extensive necrosis. Within the left adnexal tissue was positive lymphovascular invasion. Upon external consultation, the tumor was classified a low grade ESS of the uterus because of minimal nuclear atypia. The patient’s first recurrence was a left pelvic mass in 2006, which was resected and confirmed to be ESS. A PET scan in late 2014 identified another soft tissue mass in the left perirectal region (3.8 x 2.6 cm) suspicious for local tumour recurrence, which was confirmed on biopsy. A CT scan in early 2015 showed multiple parenchymal lesions within the liver (Figure 1A) in keeping with metastatic disease, with the largest being 3.2 x 3.1 cm and an increase in the size of the perirectal mass to 4.1 x 2.8 cm. A biopsy of the liver lesion showed metastatic ESS. The morphology resembled the previous primary and recurrent tumors (Figure 1B), with CD10 and PR immunopositivity (Figures 1C and 1D). The cyclin D1 was negative. The patient subsequently underwent four cycles of chemotherapy with Ifosfamide and Adriamycin, followed by Pazopanib. Gemcitabine was given in late 2015 after additional clinical consultation. The patient was transferred to her home hospital where her condition deteriorated. In March 2016, a chest x-ray showed elevation of the right hemidiaphgram and nodular opacities within both lower lung zones suspicious for lung metastases. The patient passed away shortly afterwards. Molecular testing on the liver biopsy failed to demonstrate ESS genetic fusion due to poor RNA quality and quantity. There was only 91ng of RNA input and 2 or more of the control genes had less than 25% and the overall average was below 30%. Case 2 The second patient was a 48-year-old female who was first found to have bilateral complex adnexal masses highly suspicious for malignancy in early 2015. Her CA-125 was 89. Initial CT imaging (Figure 2A) in February showed three hypodense lesions within the liver, all concerning for metastatic disease. The largest lesion (2 x 2 m) was well defined and near the upper aspect of
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the right lobe. The second well defined lesion (3.8 x 2.5 cm) in segment 7 was also heterogeneous and hypodense. A third lesion (1.1 cm) was present in the inferior aspect of the right lobe. The uterus was unremarkable. The left ovary/adnexal region had a large complex mass (10 x 11.4 x 6.1 cm) that was predominantly solid with some cystic components. A similar appearing mass (14.3 x 11.4 x 7.1 cm) was seen in the right ovary/adnexal region. She subsequently underwent a total abdominal hysterectomy, omentectomy, appendectomy, debulking of lymph nodes, multiple peritoneal biopsies, and a sup-optimal cytoreduction of one of the liver metastases. Final pathology as described below showed a high grade left ovarian endometrioid stromal sarcoma metastatic to the rectosigmoid colon, descending colon, appendix, liver, and omentum. The patient was given 4 cycles of chemotherapy (Adriamycin and Ifosfamide with Mesna). A subsequent CT scan again demonstrated the three liver lesions – 2.5 x 2.2 cm, 3.1 x 1.4 cm, and 1.7 x 1.3 cm. The patient was then referred to a liver surgeon at a different institution, where she had a resection of a liver metastasis and biopsies of the deeper lesions, ablation radiation, and started on Letrozole in December 2015. A CT scan in October 2016 and PET scan the following month showed interval stability and a slight decrease in size of the lesions. Imaging in August 2017 again showed interval stability of the liver lesions and no new evidence of metastatic disease or recurrent disease in the pelvis. The initial pathology was reported as a high grade ESS of the ovary arising in a background of endometriosis. The tumour was composed of monomorphic round to ovoid cells with scant cytoplasm and a conspicuous vascular stromal network. The tumor showed up to 23 mitoses/10hpf and was positive for ER, PR, CD10, focally positive for SMA and desmin, and negative for inhibin, calretinin, and cyclin D1. The pathology from the second surgery showed the lesion in segment 3 to be a residual cystic cavity lined by foreign body giant cells and fibroblastic tissue in keeping with her previous surgery. Neoplastic cells were not identified. Tru-cut biopsies of the deep lesions in segment 6 and 7 showed the same findings. Within dilated cystic spaces, there were small scattered focal areas of dense condensation of dark blue spindle cells reminiscent of endometrial stroma in the subcapsular region (Figure 2B). The cells were strongly positive for CD10, vimentin, calponin, and ER (Figures 2C and 2D). The expression of Ki67 was low in many areas (up to 40%). With the context of proven metastatic ESS, these were considered recurrent/residual foci of ESS. Subsequent molecular testing showed both the original tumour in the ovary, the original liver lesion and second surgery liver lesion all to harbor JAZF1-SUZ12 fusion (Figure 3). Given the lack of cyclin D1 expression and characteristic fusion, this case also represented a low-grade ESS rather than the high-grade ESS originally reported.
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Discussion ESSs are divided into low grade and high grade categories. Most cases of low grade ESS harbor a t(7;17) (p21;q15), which results in genetic fusion between 5’ potion of JAZF1 and 3’ portion of SUZ12 (JJAZ1) [4]. High grade ESS is characterized by a genetic fusion between the YWHAE and NUTM2A/B (previously known as FAM22A/B) genes that results from t(10;17) (q22;p13) [4, 14] and high-grade ESS is associated with an aggressive clinical behavior and poor prognosis [3]. Compared to low grade, they have more frequent and earlier recurrences, and their prognosis is intermediate between low-grade ESS and undifferentiated uterine sarcoma [4]. While high-grade ESS exhibits higher grade histologic features compared to low-grade ESS, the distinction on histology can sometimes be challenging, especially given their rarity [15]. Immunohistochemistry can aid in the diagnosis. Low grade ESS usually shows diffuse positive
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staining for ER, PR, and CD10 [14-16]. Conversely, ER, PR, and CD10 are usually negative in the high-grade component of high-grade ESS, but can be positive if there is a low-grade component present [16]. The cyclin D1 immunostain is quite discriminatory in this context [15, 16]. The highgrade component shows strong diffuse nuclear cyclin D1 positivity in more than 70% of tumor cells, and the low-grade spindle cell component shows weak to variable, heterogeneous cyclin D1 expression. Conventional ESSs are typically negative for cyclin D1 expression [14, 15]. Furthermore, the differential of a high-grade ESS would include other high-grade typically pleomorphic uterine sarcomas including undifferentiated endometrial sarcoma and leiomyosarcoma, a setting in which cyclin D1 expression is of limited diagnostic value [15]. Notably, although cyclin D1 immunostaining extent and intensity in YWHAE-FAM22 ESS is comparable to that in mantle cell lymphoma, the mechanism of cyclin D1 overexpression in YWHAE-FAM22 ESS has not been determined [15]. Despite high-grade ESS having a worse prognosis with more frequent and earlier recurrences, low-grade ESS can also metastasize and result in a poor outcome, as evidenced in the index cases. Nevertheless, having an ancillary study available, such as JAZF1- SUZ12 fusion, to confirm the diagnosis may aid in risk prediction in morphologically ambiguous cases. As more patients are documented and molecular techniques become more available, perhaps genetic signatures will become the primary method of risk prediction. ESS involving the liver has been reported infrequently (Table 3) [17-20]. Of the four previous reports documenting a total of six patients, three were not metastatic disease, but rather ESS evolving from endometriosis that involved the liver. Comparing our cases to the literature is not possible due to the low number and incomplete documentation. Due to the rarity of the cases, and the availability of ancillary techniques, we attempted to characterize the lesions fully. The ancillary techniques in one case were completely supportive for metastatic ESS, with a documented history, characteristic IHC, and positive fusion for low grade ESS, which correlates with the histology and negative cyclin D1. The other case could not be fully documented due to poor RNA quality resulting in indeterminate molecular analysis. When trying to differentiate metastatic ESS from primary extra-uterine endometrial stromal sarcoma (EESS), a uterine primary needs to be excluded. A primary uterine tumour can be excluded if a hysterectomy is done concurrently. Similarly, if the hysterectomy occurred previously, the slides can be reviewed if available [20]. If there is a uterine tumour and endometriosis, there is a possibility of synchronous tumours since EESS are often associated with foci of endometriosis [20, 21]. The largest series of primary EESS to date showed that the tumor was associated with endometriosis in 30 of 50 cases, suggesting an origin from ectopic endometrial stroma. In the absence of a uterine primary, when no endometriosis is identified, the tumor may have originated from stromal endometriosis or overgrowth of the tumor obscured the underlying endometriosis [20]. Alternatively, it has also been postulated that EESS could arise de novo from coelomic or sub-coelomic multipotential epithelium [20, 22]. The differential diagnosis of ESS includes endometrial stromal nodule, highly cellular leiomyoma, highly cellular intravenous leiomyomatosis, cellular endometrial polyp, sex-cord stromal tumours, low-grade Mullerian adenosarcomas and adenomyosis [23]. In the retroperitoneum, other neoplasms in the differential include peripheral nerve sheath tumors, gastrointestinal stromal tumor, fibrosarcoma, and monophasic synovial sarcoma [24]. The diagnosis of metastatic ESS can occur many months to years after the original diagnosis. Additionally, the metastatic lesion may present prior to the primary being discovered. Therefore, pathologists entertaining the diagnosis of distant involvement by ESS cannot always
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rely on a clinical history [2, 25]. Moreover, making the diagnosis can be problematic because of small biopsy size and various histological features [25]. Histologic features of recurrent or metastatic ESS generally parallel those of the initial tumors, resembling stromal cells in normal proliferative endometrium [2]. However, recurrent tumors may demonstrate more nuclear pleomorphism and atypia compared with the primary tumor or show areas of high-grade features or leiomyomatous differentiation [26]. Thus, without a known clinical history, it is often very difficult to accurately diagnose metastatic ESS [25]. Due to low numbers, evidence based guidelines for treatment is not available [18, 27] and the treatment modality for recurrent or distant metastatic ESS remains unclear [6, 28]. It has been suggested that the indolent growth makes cytoreductive surgery, including repeated surgery, appropriate for late recurrent disease [2]. The value of adjuvant therapy is controversial, but nevertheless considered [27]. In one series of metastatic pulmonary ESS, treatment modalities included surgery, selective embolization, chemo, hormonal therapy, and radiation [6]. Other reports have also advocated using progestin, alone or in combination with GnRH agonists as adjuvant therapy and for treatment of recurrent disease [28-30]. However, the optimal dose, regimen, and duration of hormonal treatment are not well established [28].
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Acknowledgements None
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Conclusion Although, pulmonary metastases are the most common distant metastatic location for ESS, other sites, including the liver are possible, and must be kept in mind in hepatic lesions in relevant cases. Correctly identifying hepatic ESS can be challenging, especially when the original clinical history may be misleading and when recurrences occur after a prolonged interval. Even with classic features, an unusual site can lead to a difficult diagnosis. A combination of detailed history, imaging, histology, and IHC will assist in the differential diagnosis of endometriosis-related ESS versus metastatic ESS. Furthermore, characteristic molecular alterations, if accessible, can facilitate diagnosis.
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Figure Legends
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Figure 1 A – Contrast-enhanced axial CT image showing a low-density lesion in the periphery of the liver with surrounding cystic changes. B – Hematoxylin and eosin stained section showing ESS involving the liver at medium power C – CD10 immunohistochemistry showing positive staining in ESS involving the liver (*) at low power. D – PR immunohistochemistry showing positive staining in ESS involving the liver (**) at low power.
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Figure 2 A – Contrast-enhanced axial CT image showing hypodense lesions within the liver; the largest lesion demonstrates heterogeneous enhancement and measures 3.8 x 2.5 cm. B – Hematoxylin and eosin stained section showing ESS involving the liver at medium power C – ER immunohistochemistry showing positive staining in ESS involving the liver at low power. D – CD10 immunohistochemistry showing positive staining in ESS involving the liver at low power.
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Figure 3 – Molecular analysis showing the characteristic JAZF1-SUZ12 fusion seen in low grade ESS.
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Table 1 – Cases of ESS with distant metastases with clinical, molecular, and IHC data Diagnosis Age at Site of Original Metastatic Case to ER PR CD10 Diagnosis Metastasis Mutation Mutation Metastasis Liver, 1 20 72 mo NA* NA* +,- +,+ +,+ Colon, Appendix, JAZF1JAZF1+, 2 48 0 mo Colon, +,+ +,+ SUZ12 SUZ12 NA Liver *Poor RNA quality
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-, NA
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Control CB-1 Breast Breast CB-1 Liver Appendix Breast Appendix CB-1 Appendix CB-1 CB-1 NA Appendix CB-1 Appendix NA CB-1
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Antibody Manufacturer Source Clone Dilution Cyclin D1 Dako Rabbit EP12 1:30 ER Dako Rabbit EP1 1:50 PR NCL Mouse 16 1:150 CD10 Dako Mouse 5636 0 Hep Par Dako Mouse OCH1E5 1:1000 Ki-67 Dako Mouse MIB-1 1:60 p53 Dako Mouse DO-7 0 Vimentin Dako Mouse V9 0 CK7 Dako Mouse OV-TL12/30 1:70 CK20 Dako Mouse Ks20.8 1:100 CD45 Dako Mouse 2B11+PD7/26 1:400 S100 Dako Rabbit NA 0 NSE Dako Mouse BBS/NC/V1-H14 0 Desmin Dako Mouse D33 1:50 Actin Dako Mouse 1A4 0 1 Calponin Dako Mouse CALP 1:700 Inhibin Dako Mouse R1 0 Calretinin Dako Mouse DAK Calret 1 1:450 Table 2 – Characteristics of the antibodies used for immunohistochemical analysis.
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*CB-1 – control block 1, appendix, tonsil, liver, kidney
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Table 3 – Cases of ESS involving the liver from the literature (ANED – alive with no evidence of disease; NA – not applicable). Site of Diagnosis to Age History Primary Follow-up Metastasis Metastasis 31 Endometriosis Liver NA NA 48mo ANED 61 Endometriosis Liver NA NA 48mo ANED Peritoneum, TAH+BSO, 68 Uterine small bowel, 342mo ANED leiomyomas colon, liver Recurrent Passed 24mo 52 menorrhagia, Uterine Liver, lung 24mo after enlarging uterus hysterectomy Omentum, liver, 174mo 42 Endometriosis small bowel, NA NA ANED mesentery, colon 63 Unknown Adnexa Liver Not specified Lost to FU
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