JAZF1-SUZ12 rearrangement positive low grade endometrial stromal sarcoma with extrauterine presentation and multiple metastases: A diagnostic and therapeutic dilemma
Cancer Genetics and Therapeutics
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Primary Categories:
- Cancer
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Secondary Categories:
- Cancer
Introduction
Endometrial stromal sarcomas (ESS)are an infrequent group of mesenchymal tumors that accounts for 0.2% of tumors of the female genital tract and 11% of primary uterine sarcomas. Low-grade endometrial stromal sarcoma (LGESS) classically exhibits a proliferative morphology and has an indolent course. However, morphological variation of extrauterine tumors presents a diagnostic challenge. Herein, we present a rare case of low grade endometrial stromal sarcoma presenting as extensive extrauterine lesions as bilateral bulky adnexal masses with multiple metastases.This report highlights the significance of important morphological features, immunohistochemistry and molecular profile in the diagnosis of low grade endometrial stromal sarcoma with an aggressive presentation.
Case Presentation
A 36-year-old female presented with complaint of pain and fullness in lower abdomen for 4 months with no significant past history. Tumor markers profile showed a mildly increased CA-125 level of 72.5u/ml while rest AFP, Beta-Hcg, LDH and CEA were within normal limits. On per vaginal examination soft 2*2 cm ulceroproliferative growth was noted over both lips of cervix .
Diagnostic Workup
CECT revealed a well-defined solid cystic heterogeneously enhancing lesion in right adnexa measuring 1 x 19 mm extending into the abdomen at umbilicus level and displacing the adjacent bowel loops. Right ovary was not visualised separately from the lesion. Outside MRI findings revealed a large complex abdominopelvic cystic mass m/s 12x21x21 cm with solid component m/s 68x30mm with a bulky uterus and a hypointense lesion m/s 22x25mm in left lateral wall of uterus likely fibroid. Endometrial biopsy revealed no evidence of malignancy and cervical biopsy showed features of endocervicitis. Subsequently patient underwent staging laparotomy with total abdominal hysterectomy with bilateral salpingo-oopherectomy with B/L adnexectomy with omentectomy and peritonectomy. Grossly a polypoid mass measuring 6x2.5x2cm was noted arising from endometrium and both the ovaries were entirely replaced by the multinodular growth. Microscopic examination demonstrated dense proliferation of spindle cells with little nuclear atypia, arranged in whorled pattern around abundant arterioles, with absence of mitosis and necrosis. Similar tumor deposits was identified on appendix, omentum and peritoneum. Additionally, ovarian mass sections showed some thecomatous areas. Differentials considered were granulosa cell tumor, leiomyosarcoma and endometrial stromal sarcoma. Further immunohistochemistry revealed positivity for CD10, CyclinD1, ER and PR while negative for Inhibin, SF1, AE1:AE3, Calretinin and BCOR which favored the diagnosis of LG-ESS. However in view of diffuse Cyclin D1 positivity and aggressive presentation, clinicians requested to rule ot high grade ESS. The diagnosis of LG-ESS was finally confirmed by fluorescence in situ hybridization (FISH) testing, which revealed a characteristic JAZF1-SUZ12 gene rearrangement.
Treatment and Management
The patient underwent staging laparotomy with total abdominal hysterectomy with bilateral salpingo-oopherectomy with B/L adnexectomy with omentectomy and peritonectomy.
After the surgery, she was treated with medications that included anti-inflammatory, anticoagulation, gastric protection, fluid supplementation, water and electrolyte balance. The patient was discharged on the sixth day after the operation and did not complain of any complications. Endocrine therapy was started with oral letrozole 2.5 mg OD tablets after the histopathological diagnosis of low grade ESS and cytogenetics confirmation of JAZF1-SUZ12 rearrangement was rendered.
Outcome and Follow-Up
The patient is being followed up at a regular interval of 3 months and the last imaging (FDG-PETscan) revealed no evidence of disease recurrence or residual disease till now. Patient is alive with complete remission.
Discussion
The index case presented with abdominal fullness and pain. While often indolent in behavior, ESS is malignant and can spread to the vagina, fallopian tubes, ovaries, bladder and ureters. Up to 30% of women with low grade ESS have an extra uterine disease at presentation. Preoperative diagnosis is often difficult and around 75% are diagnosed as benign leiomyoma. Endometrial curettage and HPE do not help due to similarity with normal endometrium. Besides, the tumor has a propensity to grow through intramural sections of the uterus instead of intracavitary part. This prevents accurate histopathological diagnosis preoperatively. Ultrasound and magnetic resonance imaging are inconclusive and the diagnosis is usually uterine leiomyoma or pelvic mass.Endometrial stromal tumors mainly occur in the uterus and are categorized based on tumor morphology, immunophenotype, and molecular pathology as follows: endometrial stromal nodules, LGESS, high-grade ESS, and undifferentiated uterine sarcoma[9]. LGESS is a rare malignant tumor that shares morphologic resemblance with endometrial stroma in the proliferative phase. LGESS is capable of infiltrative growth with or without lymphovascular invasion.
At presentation, the patient had no known history of ESS. In the absence of uterine tissue, we initially considered a diagnosis of primary extrauterine ESS (EESS), a type of extrauterine ESS with no accompanying intrauterine lesions.However after sampling the resection specimen of abdominal hysterectomy with bilateral salpingo-oophorectomy ,a small endometrial nodule was identified which further modified our diagnosis as uterine LG-ESS with ovarian and multiple metastases in appendix and omentum.In our case the tumors exhibited variable morphologies at different sites and variable IHC expression of CD10 and Cylin D1 as well,thus posing a morphological and immunohistochemical contrast whether the tumor is low grade or high grade as few areas of tumor sampled from ovarian mass showed mitotically active spindle cell neoplasm with Cyclin D1 expression.However other areas from uterine nodule showed diffuse ER and CD10 expression.As a result to confirm the diagnosis,the molecular test was performed which finally confirmed the JAZF1/SUZ12 rearrangement in low grade ESS ,thus helping the clinician to chose the best treatment option for this patient as surgery with hormonal therapy.Chemotherapy was not offered to patient as patient responded very well after hormonal therapy with complete metabolic response both at primary and metastatic sites.
The morphology of LGESS may vary according to tumor location. LGESS with fibroblast differentiation is rare and may be easily misdiagnosed as GIST or leiomyosarcoma. Based on our findings, we suggest performing IHC or molecular analyses for LGESS diagnostic certainty. A clear and correct diagnosis is critical to support appropriate treatment, improve prognosis, and guide patient care. As LGESS usually has a favorable prognosis, the choice of surgical approach, especially for young female patients, is controversial. Surgery including hysterectomy and bilateral salpingo-oopherectomy is considered the initial standard management.
Conclusion
CONCLUSIONS:
By reporting our case, we wish to stress the necessity for a high degree of suspicion to diagnose this tumor even in younger women. A prompt diagnosis and timely intervention are keys to improve patient survival.To the best of our knowledge, this is the first documented case of metastatic endometrial stromal sarcoma of uterus presenting as a huge abdominopelvic mass mimicking primary ovarian neoplasm. An unexpected extra-uterine location and unusual presentation of ESS may make the diagnosis challenging, despite classic histological features. Morphological, immunohistochemical, and molecular findings must be combined to render the correct diagnosis for optimal treatment and patient care.
Areas of future research: Combined with the recently described YWHAE/FAM22 gene fusion, the JAZF1/SUZ12 fusion could differentiate between LG-ESS and HG-ESS. Since the prognosis and the 5-year survival rate of LG-ESSs and HG-ESSs are drastically different, the precise distinction between these entities is clinically very important. Although it is very challenging to foresee the whole potential benefit behind these new findings, further investigations in this field will certainly provide novel insights into our understanding of ESSs pathogenesis. Elucidation of the functions of fusion genes/proteins in uterine sarcomas will further improve our understanding of the oncogenic process in these malignancies. This might lead to the identification of new therapeutic targets for the treatment of uterine sarcoma
Endometrial stromal sarcomas (ESS)are an infrequent group of mesenchymal tumors that accounts for 0.2% of tumors of the female genital tract and 11% of primary uterine sarcomas. Low-grade endometrial stromal sarcoma (LGESS) classically exhibits a proliferative morphology and has an indolent course. However, morphological variation of extrauterine tumors presents a diagnostic challenge. Herein, we present a rare case of low grade endometrial stromal sarcoma presenting as extensive extrauterine lesions as bilateral bulky adnexal masses with multiple metastases.This report highlights the significance of important morphological features, immunohistochemistry and molecular profile in the diagnosis of low grade endometrial stromal sarcoma with an aggressive presentation.
Case Presentation
A 36-year-old female presented with complaint of pain and fullness in lower abdomen for 4 months with no significant past history. Tumor markers profile showed a mildly increased CA-125 level of 72.5u/ml while rest AFP, Beta-Hcg, LDH and CEA were within normal limits. On per vaginal examination soft 2*2 cm ulceroproliferative growth was noted over both lips of cervix .
Diagnostic Workup
CECT revealed a well-defined solid cystic heterogeneously enhancing lesion in right adnexa measuring 1 x 19 mm extending into the abdomen at umbilicus level and displacing the adjacent bowel loops. Right ovary was not visualised separately from the lesion. Outside MRI findings revealed a large complex abdominopelvic cystic mass m/s 12x21x21 cm with solid component m/s 68x30mm with a bulky uterus and a hypointense lesion m/s 22x25mm in left lateral wall of uterus likely fibroid. Endometrial biopsy revealed no evidence of malignancy and cervical biopsy showed features of endocervicitis. Subsequently patient underwent staging laparotomy with total abdominal hysterectomy with bilateral salpingo-oopherectomy with B/L adnexectomy with omentectomy and peritonectomy. Grossly a polypoid mass measuring 6x2.5x2cm was noted arising from endometrium and both the ovaries were entirely replaced by the multinodular growth. Microscopic examination demonstrated dense proliferation of spindle cells with little nuclear atypia, arranged in whorled pattern around abundant arterioles, with absence of mitosis and necrosis. Similar tumor deposits was identified on appendix, omentum and peritoneum. Additionally, ovarian mass sections showed some thecomatous areas. Differentials considered were granulosa cell tumor, leiomyosarcoma and endometrial stromal sarcoma. Further immunohistochemistry revealed positivity for CD10, CyclinD1, ER and PR while negative for Inhibin, SF1, AE1:AE3, Calretinin and BCOR which favored the diagnosis of LG-ESS. However in view of diffuse Cyclin D1 positivity and aggressive presentation, clinicians requested to rule ot high grade ESS. The diagnosis of LG-ESS was finally confirmed by fluorescence in situ hybridization (FISH) testing, which revealed a characteristic JAZF1-SUZ12 gene rearrangement.
Treatment and Management
The patient underwent staging laparotomy with total abdominal hysterectomy with bilateral salpingo-oopherectomy with B/L adnexectomy with omentectomy and peritonectomy.
After the surgery, she was treated with medications that included anti-inflammatory, anticoagulation, gastric protection, fluid supplementation, water and electrolyte balance. The patient was discharged on the sixth day after the operation and did not complain of any complications. Endocrine therapy was started with oral letrozole 2.5 mg OD tablets after the histopathological diagnosis of low grade ESS and cytogenetics confirmation of JAZF1-SUZ12 rearrangement was rendered.
Outcome and Follow-Up
The patient is being followed up at a regular interval of 3 months and the last imaging (FDG-PETscan) revealed no evidence of disease recurrence or residual disease till now. Patient is alive with complete remission.
Discussion
The index case presented with abdominal fullness and pain. While often indolent in behavior, ESS is malignant and can spread to the vagina, fallopian tubes, ovaries, bladder and ureters. Up to 30% of women with low grade ESS have an extra uterine disease at presentation. Preoperative diagnosis is often difficult and around 75% are diagnosed as benign leiomyoma. Endometrial curettage and HPE do not help due to similarity with normal endometrium. Besides, the tumor has a propensity to grow through intramural sections of the uterus instead of intracavitary part. This prevents accurate histopathological diagnosis preoperatively. Ultrasound and magnetic resonance imaging are inconclusive and the diagnosis is usually uterine leiomyoma or pelvic mass.Endometrial stromal tumors mainly occur in the uterus and are categorized based on tumor morphology, immunophenotype, and molecular pathology as follows: endometrial stromal nodules, LGESS, high-grade ESS, and undifferentiated uterine sarcoma[9]. LGESS is a rare malignant tumor that shares morphologic resemblance with endometrial stroma in the proliferative phase. LGESS is capable of infiltrative growth with or without lymphovascular invasion.
At presentation, the patient had no known history of ESS. In the absence of uterine tissue, we initially considered a diagnosis of primary extrauterine ESS (EESS), a type of extrauterine ESS with no accompanying intrauterine lesions.However after sampling the resection specimen of abdominal hysterectomy with bilateral salpingo-oophorectomy ,a small endometrial nodule was identified which further modified our diagnosis as uterine LG-ESS with ovarian and multiple metastases in appendix and omentum.In our case the tumors exhibited variable morphologies at different sites and variable IHC expression of CD10 and Cylin D1 as well,thus posing a morphological and immunohistochemical contrast whether the tumor is low grade or high grade as few areas of tumor sampled from ovarian mass showed mitotically active spindle cell neoplasm with Cyclin D1 expression.However other areas from uterine nodule showed diffuse ER and CD10 expression.As a result to confirm the diagnosis,the molecular test was performed which finally confirmed the JAZF1/SUZ12 rearrangement in low grade ESS ,thus helping the clinician to chose the best treatment option for this patient as surgery with hormonal therapy.Chemotherapy was not offered to patient as patient responded very well after hormonal therapy with complete metabolic response both at primary and metastatic sites.
The morphology of LGESS may vary according to tumor location. LGESS with fibroblast differentiation is rare and may be easily misdiagnosed as GIST or leiomyosarcoma. Based on our findings, we suggest performing IHC or molecular analyses for LGESS diagnostic certainty. A clear and correct diagnosis is critical to support appropriate treatment, improve prognosis, and guide patient care. As LGESS usually has a favorable prognosis, the choice of surgical approach, especially for young female patients, is controversial. Surgery including hysterectomy and bilateral salpingo-oopherectomy is considered the initial standard management.
Conclusion
CONCLUSIONS:
By reporting our case, we wish to stress the necessity for a high degree of suspicion to diagnose this tumor even in younger women. A prompt diagnosis and timely intervention are keys to improve patient survival.To the best of our knowledge, this is the first documented case of metastatic endometrial stromal sarcoma of uterus presenting as a huge abdominopelvic mass mimicking primary ovarian neoplasm. An unexpected extra-uterine location and unusual presentation of ESS may make the diagnosis challenging, despite classic histological features. Morphological, immunohistochemical, and molecular findings must be combined to render the correct diagnosis for optimal treatment and patient care.
Areas of future research: Combined with the recently described YWHAE/FAM22 gene fusion, the JAZF1/SUZ12 fusion could differentiate between LG-ESS and HG-ESS. Since the prognosis and the 5-year survival rate of LG-ESSs and HG-ESSs are drastically different, the precise distinction between these entities is clinically very important. Although it is very challenging to foresee the whole potential benefit behind these new findings, further investigations in this field will certainly provide novel insights into our understanding of ESSs pathogenesis. Elucidation of the functions of fusion genes/proteins in uterine sarcomas will further improve our understanding of the oncogenic process in these malignancies. This might lead to the identification of new therapeutic targets for the treatment of uterine sarcoma