Primary extra-uterine and extra-ovarian mullerian adenosarcoma: case report and literature review

Background: Extra-uterine mullerian adenosarcomas have varying biological behaviours depending on the presence of endometriosis or sarcomatous overgrowth . These behaviours manifest according to the tumours ’ histological characteristics and sites of origin. The best treatment and oncologic outcome have not been clarified because only a few cases of extra-uterine and extra-ovarian adenosarcoma have been described in the literature. Here, we report a case of primary peritoneal adenosarcoma with sarcomatous overgrowth and review all reported cases of adenosarcomas arising outside of the uterus and outside the ovaries to identify the best treatment options and clarify outcomes. Case presentation:A 79-year-old woman was referred to our Department with an abdominal mass resembling a fibroid with a haemorrhage. Her gynaecological history was negative. A transvaginal and transabdominal ultrasound examination revealed a multicystic mass resembling an ovarian tumour arising from the pelvis and extending up to the abdomen. At laparotomy a peritoneal mass arising from Douglas peritoneum was resected. The uterus and adnexa appeared normal, and a supra-cervical hysterectomy with bilateral salpingo-oophorectomy was performed. No macroscopic residual disease was present. Final pathology diagnosed a malignant peripheral nerve sheath tumors with divergent differentiation. Four weeks later a new, multicystic mass was found. Due to the progressive poor condition, the patient died four months after diagnosis. Histological slides were reviewed by external expert pathologists and the final diagnosis was of extra-genital adenosarcoma with sarcomatous overgrowth. Furthermore,we also collected and analysed articles written in English regarding extra-uterine and extra-ovarian adenosarcomas published between January 1974 and October 2016. PubMed w a su s e da sad a t a b a s ef o rt h i ss e a r c h .C l i n i c a la n dp a t h o l o g ical characteristics, treatments and outcomes were assessed. Conclusions:Only 41 cases has been reported in literature. Previous endometriosis and sarcomatous overgrowth showed an inverse effect on prognosis. Endometriosis was confirmed to have a positive effect on disease free survival Complete surgical resection is the mainstay of treatment. A worldwide registry is urgently required to collect data to standardize treatment and to obtain reliable data on prognosis.

Mullerian extra-uterine adenosarcoma, Mullerian extra-genital adenosarcoma, Survival, Vaginal adenosarcoma, Symptoms, Treatment, Review * Correspondence: [email protected] 1Unit of Obstetrics and Gynecology, IRCCS- Azienda Unità Sanitaria Locale, Viale Risorgimento n 80, Reggio Emilia, Italy Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Mandato et al. BMC Cancer (2018) 18:134 DOI 10.1186/s12885-018-4037-y

Mullerian adenosarcoma (AS) is a rare mesenchymal and epithelial neoplasm of low malignant potential typic- ally occurring in the uterine corpus in perimenopausal or postmenopausal women [ 1]. It is a mixed tumour that usually arises as a solitary lesion with a benign but sometimes atypical glandular epithelium and low-grade sarcoma, usually of the endometrial stromal type [ 2]. The first case of AS was described in early 1974 by Clement and Scully [ 3]. AS typically arises from the corpus uterus, rarely from the cervix or ovary, and extremely rarely from the vagina or from extra-genital sites such as the peritoneum, retroperitoneum, bladder, liver or colon (T able1)[ 4–39]. Generally, uterine AS presents clinically indolent be- haviour, whereas AS with sarcomatous overgrowth is extremely aggressive [ 31] and is characterized by re- currence and metastasis at an early stage [ 40, 41]. Sarcomatous overgrowth is characterized by the pres- ence of a high-grade sarcomatous component in at least 25% of the tumour [ 42]. A recent national cancer database study reported survival data from 2205 women with AS arising from the corpus uterus, cervix and ovary, but no consistent data re- garding vaginal or extra-genital AS are available because these are extremely rare sites for AS [ 43]. Uterine AS is the rarest form of uterine sarcomas representing only ∼0.2% of all uterine malignancies. It has an age-adjusted incidence of 2 per 1000,000 for Caucasians, 3 per 1000,000 for African Americans, and 1 per 1000,000 for other ethnic groups in the US population [ 44, 45]. Extra-genital AS is so rare that it has not been pos- sible to develop clear guidelines regarding treatment and prognosis [ 35]. Here, we reported a case of primary peritoneal AS with sarcomatous overgrowth but no associated endometriosis and reviewed all cases of AS arising outside of the uterus and outside of the ovaries published since 1974 to identify the best treatment options and clarify outcomes.

We report the clinical data, preoperative imaging, patho- logical findings and follow-up data for a case of primary peritoneal AS with sarcomatous overgrowth. We also performed a systematic review of the literature to collect reports on AS arising outside of the uterus and outside of the ovaries. With the term “uterus” we mean the whole organ without distinction between uterine corpus and cervix. We mean with the term “extra-uterine” all AS arising outside of the uterine corpus or of the cervix. Systematic review of the literature We collected and analysed articles published on AS be- tween January 1974 and October 2016 using PubMed as a database and the following search terms: “peritoneal mullerian adenosarcoma”, “primitive peritoneal mullerian adenosarcoma”, “primary peritoneal mullerian adenosar- coma”, “extra-uterine mullerian adenosarcoma”, “primitive extra-uterine mulle rian adenosarcoma ”, “primary extra- uterine mullerian adenosarcoma”, “extra-uterine mesoder- mal adenosarcoma”, “primitive extra-uterine mesodermal adenosarcoma”, “primary extra-uterine mesodermal adeno- sarcoma”, “primary extra-genital adenosarcoma”, “primitive extra-genital adenosarcoma”, “primary extra-genital muller- ian adenosarcoma”,a n d “primitive extra-genital mullerian adenosarcoma”. After selecting for cases arising outside of the uterus and outside the ovaries, 32 reports of extra- genital AS and 9 of vaginal AS were found and included in this systematic review For each case the following data were extracted and collected in a d atabase: age, tumor size, tumor site, previous diagnosis of endometriosis, sarcoma- tous overgrowth, heterologous sarcomatous differentiation therapy, presence of recurrences, recurrence site, treatment after recurrence and follow up status and time. All dichoto- mic parameters were codified as 0 (absent) or 1 (present), while for all cases age was reported in years, follow up was reported in months and tumor size was reported in centi- metres. When a patient experienced more than one recur- rence all events were reported. Missing data were indicated as not reported (NR) in database. Statistical analysis Statistical analysis was performed using R-3.2.3 software. Associations between clinical and pathological parameters in different subgroups of patients were assessed using linear models and Fisher’s exact test. Overall survival (OS) was computed as the time period from the date of surgery to either the date of death or last follow-up. Disease-free survival (DFS) was computed as the disease-free period from the date of surgery to the date of relapse or last follow-up. Survival curves were plotted using the Kaplan –Meier method and differences between curves were assessed by Log-Rank test. Test were considered statistically significant with a P value lower than 0.05. Case presentation A 79-year-old woman was referred to the Department of Obstetrics and Gynecology with an abdominal mass discovered on a computed tomography scan (CT) per- formed following right iliac artery angioplasty. The scan revealed a 16 × 11 cm mass resembling a fibroid with a haemorrhage (Fig. 1). Her history included type 2 diabetes, hypertension, hyper- cholesterolemia, glaucoma, h ypothyroidism, and stage III chronic obstructive arteriopathy of the right leg, and she underwent a left carotid thromboendarterectomy 1 year prior to admission. Her gynaecological history was negative. Mandato et al. BMC Cancer (2018) 18:134 Page 2 of 18 Table 1 Clinical features of 41 patients with extra-genital mullerian adenosarcoma reported in the English literature and of the index case

number Author Age (years) Site Size (cm) Tumour markers Signs and Symptoms at presentation Treatment Sarcomatous overgrowth Endometriosis Hormonal therapy Follow-up 4 Douglas 18 gravida Retroperitoneum 5 × 4.5 × 4 NR Anorexia, suprapubic-low back pain, loss of weight, vaginal bleeding, preterm delivery. 24 weeks CHT (MTX) NR No No DOD 10 weeks later with distant metastasis 5a Clement 45 Right Pelvic peritoneum (pelvic mass that extended into the rectum and the bladder) 7x7x5 NR Right lower leg thrombophlebitis, right paravaginal mass Surgery (partial tumour resection) + RT NR No No DOD 9 months later due to pelvic recurrence and visceral metastasis 5b Clement 73 Midline Pelvic peritoneum, displcing the bladder anteriorly 14 NR Large pelvic mass with bilateral hydronephrosis. Inability to void Surgery (complete tumour resection) NR No No DOD 2 months later (postoperatively massive gastric bleeding necessitating a subtotal gastrectomy occurred but after that the patient’s conditions deteriorated gradually- autopsy not done-) 5c Clement 58 Left Pelvic peritoneum 16x15x8 NR Large pelvic mass. Urinary urgency, rectal pressure Surgery (partial tumour resection) NR Yes No AWD local recurrence 15 months later (RT), lung metastases 45 months later (resected) 6 Bard 46 Right pelvic peritonum (the mass was adherent to the right bladder wall and surrounded the right ureter) 10 × 8 NR Weakness and pelvic pain in the right lower extremity. Urinary incontinency Biopsy + RT NR NR No DOD 11 weeks later with distant sepsis and metastasis 7 Kao 42 Left round ligament 10 NR NR Surgery (partial tumour resection) + CHT (Cyt) + RT NR No No DOD after 10 months due to the tumor 8 Russell 29 Left Broad ligament 7x6x5 N.R. Lower abdominal pain for 2 months and occasional dyspareunia Surgery (tumour resection) NR No No Recurrence after 5 months treated with surgery (hysterectomy, bilateral salpingo- oophorectomy) + RT; Died of melanoma after 9 years. 9 Kerner 32 gravida Broad ligament 15x10x6 and 10x7x4 NR Abdominal pain at 28 weeks Surgery (tumour resection) No No No AWD omentum and infundibulopelvic ligament recurrence 22 months later 10 Vara 62 Bladder – NR Haematuria, weight loss, suprapubic pain Surgery (radical cystectomy + urethrectomy) NR Yes No FOD 12 months Mandato et al. BMC Cancer (2018) 18:134 Page 3 of 18 Table 1 Clinical features of 41 patients with extra-genital mullerian adenosarcoma reported in the English literature and of the index case (Continued)

number Author Age (years) Site Size (cm) Tumour markers Signs and Symptoms at presentation Treatment Sarcomatous overgrowth Endometriosis Hormonal therapy Follow-up 11 Roman 55 Retroperitoneal NR NR NR Surgery (tumour resection) + RT NR Yes No First abdominal recurrence 3 years later (resection by thoracoabdominal approach + MPA), a 5 cm perihepatic recurrence 5 years later was completely resected, second perihepatic recurrence 7 years from original tumour (resection of recurrence and TMX), 6 months later intrahepatic metastasis (CHT for recurrences (cisplatin-ifosfamide, ifosfamide, doxorubicin), later atrial tumour (resection of cardiac tumour and oral therapy with etoposide). Died after 10 years from original tumour and 70 days after resection of cardiac tumour. 12 De Jonge 16 Pelvic peritoneum and infracolic omentum NR Ca 125 > 190 U/ml Severe Abdominal distension and pain Surgery (tumour resection with extirpation of pelvic mass, left fallopian tube, infracolic omentum and appendix) Yes No NR Three weeks after primary surgery a pelvic mass recurred (CHT with doxorubicin and ifosfamide), first recurrence of the pouch of Douglas 8 months later (CHT cisplatinum, etoposide and ifosfamide), second recurrence of the pouch of Douglas 14 months later the first recurrence (bilateral salpingo-oophorectomy, ab dominal hysterectomy, pelvic and para- aortic lymphadenectomy and hormonal therapy) FOD 57 months after the last cycle of chemotherapy 13 Benda 65 Vaginal apex 10x7x8 NR Pelvic pressure and urinary frequency Surgery (tumour resection) NR No No Three years later a 6 cm vaginal recurrence was completely resected; 5 yrs. after first recurrence a 12 cm vaginal recurrence was completely resected and a progesterone therapy was delivered; 7 years after the second recurrence a 17 cm pelvic recurrence was partially resected and a TMX (2 weeks) therapy followed by P (2 weeks) therapy was delivered; 10 months after the third recurrence a fourth pelvic recurrence was partially resected and treated with RT. AWD 16 years 14 Ostor 49 Pouch of Douglas 19x8x3 NR Right Iliac fossa pain Surgery (tumour resection and abdominal hysterectomy and bilateral salpingo- oophorectomy) Radio therapy and Hormonal therapy (Medroxyprogesterone) NR No No AWD recurrence 5 weeks later (chemotherapy cisplatin and ifosfamide). Persistence of some nodularity on the pelvic floor 18 months later Mandato et al. BMC Cancer (2018) 18:134 Page 4 of 18 Table 1 Clinical features of 41 patients with extra-genital mullerian adenosarcoma reported in the English literature and of the index case (Continued)

number Author Age (years) Site Size (cm) Tumour markers Signs and Symptoms at presentation Treatment Sarcomatous overgrowth Endometriosis Hormonal therapy Follow-up 15 Inoue 54 Left paracolpium 15x11x10 Ca 125: 860 U/ml Brownish vaginal discharge Small ulcer in the left posterior fornix RT+ Surgery (tumour resection+ total abdominal hysterectomy, bilateral adnexectomy, abdominal perineal resection with colostomy) NR Yes No FOD 1 year later 16 Judson 42 Vaginal cuff 6 × 3 NR Endometriosis recurred three times and was treated with surgery, hormonal therapy (megestrol, danazol) and brachytherapy. Lesion coming out from vagina CHT (paclitaxel and carboplatin followed by TMX) NR Yes No 12 months later a 4 cm vagina recurrence was excised and a RT was delivered than was FOD 17 N ’Senda 54 Liver 20 × 12 CA 15 –3 and CA 19–9, were three and fourfold normal level respectively Right-sided epigastric pain Surgery (tumour resection: A segment -IV enlarged right hepatectomy extended to adjacent diaphragm) No Yes HRT FOD 24 months 18 Kato 20 Abdominopelvic peritoneum 23x23x14 CA 125: 1000 IU/ml Fatigue and constipation Surgery (tumour resection) NR No No FOD 1 years later 19a Yantiss 36 Sigmoid 10,5 NR Hypermenorrhoea, 6 months abdominal pain Surgery (tumour and sigmoid resection) NR Yes NR FOD 36 months 19b Yantiss 2000 50 Colon NR NR NR Surgery (tumour and colon resection) NR Yes NR FOD 24 months 19c Yantiss 2000 83 Small bowel 15 NR Abdominal mass obstruction Surgery (tumour and bowel resection) NR Yes NR NR 19d Yantiss 2000 43 Small bowel 6.5 NR NR Surgery (incomplete tumour resection) NR NR ER T NR 20 Visvalingam 50 Abdominopelvic peritoneum 13 kg NV Painless abdominal swelling Surgery (tumour resection), Hormonal therapy (progesterone) NR No No Ten months later a 50 cm pelvic recurrence was resected (tumour debulking, extrafascial hysterectomy, omentectomy, appendicectomy). DOD 16 months later (Autopsy revealed tumor nodules throughout the abdominal and pelvic cavity limited to the peritoneal surface) Mandato et al. BMC Cancer (2018) 18:134 Page 5 of 18 Table 1 Clinical features of 41 patients with extra-genital mullerian adenosarcoma reported in the English literature and of the index case (Continued)

number Author Age (years) Site Size (cm) Tumour markers Signs and Symptoms at presentation Treatment Sarcomatous overgrowth Endometriosis Hormonal therapy Follow-up 21 Anderon 46 Vagina 10 cm NR Removal of the vaginal mass, stalk and paravaginal tissue. No Yes Yes FOD after a parametrium recurrence that was treated with external radiotherapy and interstitial brachytherapy. 22 Dincer 50 Perisplenic Peritoneum NR NR Large bowel obstruction in a woman with Endometriosis treated with aromatase inhibitor Surgery (partial tumour resection) + Chemotherapy (anthracycline) + experimental anti- angiogenesis agent Yes Yes No DOD 13 months later due to no regression of the pelvic tumour 23 Hines 43 Peritoneum (from posterior cul-de-sac through the middle to upper abdomen) NR Ca 125: 824 IU/ml Dysmenorrhea and endometriosis Surgery (tumour resection) + Hormonal therapy (medroxyprogesterone acetate) No Yes No FOD 10 months later 24 Murugasu 23 Pouch of Douglas 11 Ca 125: 378 IU/ml; CEA: 13. Right-sided pelvic pain Surgery (tumour resection), Chemotherapy (Mesna, adriamycin, ifosfamide), Radiotherapy Yes Yes No FOD 1 years later 25 Liu 56 Vaginal Vault 16 NR Urinary incontinence and prolapse in a woman with Vaginal endometriosis (TAH, BSO). Surgery (tumour resection with adherent structures including rectum and part of the bladder wall) + Chemotherapy (ifosfamide and cisplatin) + Radiotherapy No Yes ERT FOD 26 Raffaelli 50 Rectovaginal septum Not reported NR Deep dyspareunia, rectal pain, periovulatory pelvic pain in a woman with diagnosis of endometriosis Surgery (Hysterectomy, left salpingo oophorectomy and partial vaginectomy) + Hormonal therapy (megestrol acetate) No Yes No Pelvic recurrence 14 months after first surgery (resection of the mass, chemotherapy with ifosfamide and epirubicin-stopped due to intolerance- and radiotherapy 52,90Gy-stopped due to toxic side effect) FOD 9 months after the last surgery 27 Toyoshima 52 Vaginal cuff 11 cm High level of Ca125 Neoadjuvant therapy and surgical removal of the tumour, the vaginal wall and the greater omentum Yes Yes No After a month the first lung recurrence treated with chemotherapy, and then a second abdominal recurrence treated with chemotherapy. DOD after 9 months from surgery 28 Kanngurn 48 Pelvic peritoneum 26x26x10 cm NR Right lower quadrant pain Surgery (tumour resection, Hysterectomy, bilateral salpingo oophorectomy) + Chemotherapy (Bleomycin, Etoposide and Cisplatinum × 7 cycles). Yes No No Abdominal recurrence 8 months later during the fourth cycle of therapy (13, 5 × 7, 8 × 13 cm), lost at follow-up. Mandato et al. BMC Cancer (2018) 18:134 Page 6 of 18 Table 1 Clinical features of 41 patients with extra-genital mullerian adenosarcoma reported in the English literature and of the index case (Continued)

number Author Age (years) Site Size (cm) Tumour markers Signs and Symptoms at presentation Treatment Sarcomatous overgrowth Endometriosis Hormonal therapy Follow-up 29 Chang 37 cul-de-sac 3.5 NR Vaginal bleeding in a woman with endometriosis (TAH, BSO and hormonal therapy) Surgery (resection of cul-de-sac tumour, left anterior proctectomy, coloanal anastomosis) No yes yes FOD 36 months 30 Milam 47 Right inguinal channel 12 × 4 CA 125: 76,8 Persistent and enlarged groin mass Surgery (tumour resection) No Yes HRT FOD 12 months later 31 Huang 41 Mesentery of the terminal ileum, right colon and pelvic sidewall 10 NV Right lower quadrant pain and nausea Surgery (TAH, bilateral salpingo oophorectomy, omentectomy, resection of cul-de-sac and sigmoid colon nodules, and pelvic and para-aortic lymph node dissection) + Chemo therapy (ifosfamide+ cisplatin) No Yes No Peritoneal recurrence at 1 month and chemotherapy (liposomal doxorubicin) FOD for 18 months 32 Han 34 Vagina 7 × 6 High value Tumour resection, hysterectomy and bilateral salpingo- oophorectomy No Yes No The patient had 4 vaginal recurrences. The first was treated with chemotherapy, the second was treated with surgery, the third with surgery and adjuvant therapy and the fourth with chemotherapy. FOD 33 Maeda 47 Left pelvic side wall 3 NR (LDH level 993 IU/ml) Acute lower abdominal pain due to pedunculated subserosal myoma Surgery (tumour resection, bilateral salpingo- oophorectomy, total abdominal hysterectomy) Yes Yes TMX Four weeks later 8 cm recurrent tumour in the right pelvis treated with salvage surgery. One month after second surgery recurrent tumour in pelvis and upper abdomen that was treated with salvage chemotherapy (liposomal doxorubicin), 5 cycles). FOD three months after chemotherapy. 34 Patrelli 49 Pouch of Douglas 10 × 6 CA 125 and Ca 19 – 9 slightly elevated Pelvic pain Surgery (tumour resection) Yes No No Eighteen months later recurrence of posterior vaginal fornix (resected), 6 months after recurrence another posterior vaginal fornix recurrence (radical hysterectomy with bilateral salpingo-oophorectomy, and pelvic lymphadenectomy and Radiotherapy- 50Gy-) FOD 35 Clarke 50 Pelvic peritoneum (partially adherent to the posterior uterine serosa) 34x14x7 NR NR Surgery (omentectomy, appendicectomy, removal of small bowel mesenteric implants) NR NR NR 36 Karateke 26 Pouch of Douglas 18 NR Lower abdominal distention and left lower quadrant pain Surgery (tumour resection) No Yes No FOD 24 months later Mandato et al. BMC Cancer (2018) 18:134 Page 7 of 18 Table 1 Clinical features of 41 patients with extra-genital mullerian adenosarcoma reported in the English literature and of the index case (Continued)

number Author Age (years) Site Size (cm) Tumour markers Signs and Symptoms at presentation Treatment Sarcomatous overgrowth Endometriosis Hormonal therapy Follow-up 37 Yang 36 Rectum 2,5 × 2 NR Loose stool, dysmenorrhea, deep dyspareunia, haematochezia Surgery (tumour resection) No Yes No FOD 60 months 38 Kar 30 Omentum NR NR Abdominal distension due to abdominal mass and free fluid Surgery (hysterectomy, bilateral salpingo oophorectomy, omentectomy) and preoperative chemotherapy Yes Yes No NR 39 Pontrelli 58 Vagina 5 cm NR Bleeding vaginal lesion Vaginectomy and parametrectomy using the laparoscopic approach, total colpectomy and partial cystectomy. After that the patient was candidate for progestin therapy. Yes Yes Yes FOD at November 2016 40 Mandato 79 Abdominal Peritoneum 16 × 11 NV Abdominal distension Surgery (tumour resection, bilateral salpingo- oophorectomy, total hysterectomy) Residual absent Yes No No 4 weeks later had a pelvic recurrence; DOD 4 months after diagnosis Abbreviations: AWD alive with disease, DOD died of disease, NER no evidence of recurrence, UK unknown, NR not reported, NV normal value, FOD free of disease, CHT chemotherapy, MTX methotrexate, RT radiotherapy, Cyt cyclophosphamide, MPA medroxyprogesterone acetate Mandato et al. BMC Cancer (2018) 18:134 Page 8 of 18 She complained only of abdominal distension and pressure. A transvaginal and transabdominal ultrasound examination revealed a multicystic mass resembling an ovarian tumour arising from the pelvis and extending up to the abdomen. Three weeks later, a laparotomy was performed, and a peri- toneal mass arising from Dou glas peritoneum was found and resected. The uterus and adnexa appeared normal, and a supra-cervical hysterectomy with bilateral salpingo- oophorectomy was performed. On frozen sections, the mass was identified as a primary sarcoma of the periton- eum with areas of chondroliposarcoma and rhabdomyosar- coma differenzation. No macroscopic residual disease was present (R0). Final pathologydiagnosed a malignant periph- eral nerve sheath tumors with divergent differentiation (osteosarcoma, chondrosarcoma, angiosarcoma rhabdo- myosarcoma, glandular component), grade 3 according to the French Federation of Cancer Centers Sarcoma Group (FNCLCC) grading system. Adjuvant chemotherapy was planned. Four weeks later, a pre-chemotherapy CT scan revealed a new, multicystic mass (27 × 15 cm) (Fig. 2) with impregnation of the wall, strictly adhering to the inferior side of the sigmoid colon and cecal profile and to the superior side of the bladder. The mass protruded into the left inguinal canal by 2 cm. The patient presented with bilateral hydroureterone- phrosis, fever due to wound infection, loss of appetite and weakness. Antibiotic therapy, bilateral stents, and support therapy were administered. Due to the progres- sive poor condition, the patient died 4 months after diagnosis. Histological slides were reviewed by two ex- ternal independent expert pathologists (A.P. Dei Tos, Chief of Department of Pathology, Treviso Regional Hospital, Treviso, Italy. C.D.M. Fletcher, Chief of Surgi- cal Pathology, Brigham And Women ’s Hospital, Boston, USA) and the final diagnosis was of extra-genital AS with sarcomatous overgrowth (Figs. 3 and 4).

Clinical features Table 1 shows the main clinical features of all 41 AS cases reported in literature and of our case. The 41 affected patients ranged in age from 16 to 83 years (mean, 44.5 years) at presentation, and 2/41 (4.9%) patients were pregnant at the time of diagnosis. Overall, 12/32 (37.5%) patients presented with an extra- genital AS arising from the pelvic peritoneum, 5/32 (15.6%) presented with an AS arising from the pouch of Douglas, 2/32 (6.3%) presented with an AS arising from the retroper- itoneum, 3/32 (9.4%) presented with an AS arising from the broad ligament, 3/32 (9.4%) presented with an AS arising from the colon, 2/32 (6.3%) presented with an AS arising from the small bowel, 1/32 (3.1%) presented with an AS arising from the bladder, 1/32 (3.1%) presented with AS arising from the omentum, 1/ 32 (3.1%) presented with an AS arising from the inguinal canal, 1/32 (3.1%) presented with an AS arising from the liver, and 1/32 (3.1%) presented with an AS arising from the mesentery of the terminal ileum. Overall, 9/41 (21.9%) patients had an AS localized in the vagina: 7/9 (77.8%) cases were in the vaginal cuff, 1/9 (11.1%) case was in the paraco lpium, and 1/9 (11.1%) case was in the recto-vaginal septum. Information on tumour size was available for 33/41 (80.5%) patients. The sized ranged from 2.5 to 34 cm with a mean size of 12.2 cm (SD +/ − 6.0). Tumour weight was reported for 1 case (13 k) [ 20]. Symptoms were reported for 34/41 (82.9%) patients. Abdominal/pelvic pain was reported for 14/34 (41.2%) patients, urinary disorders for 9/34 (26.5%), anorexia- weight loss for 3/34 (8.8%), abdominal pressure for 3/34 (8.8%), dysmenorrhea for 2/34 (5.9%), bleeding for 4/34 (11.8%), constipation for 1/34 (2.9%), low back pain for 1/34 (2.9%), fatigue for 1/34 (2.9%) and thrombophlebitis for 1/34 (2.9%). Fig. 2 Pre-chemotherapy computed tomography scan taken 4 weeks after surgery revealing a new, multicystic mass (27 × 15 cm) Fig. 1 Computed tomography scan showing a mass of 16 × 11 cm Mandato et al. BMC Cancer (2018) 18:134 Page 9 of 18 Tumor markers were reported in 13/41 (31.7%) patients, two patients had normal value [ 20, 31] and 11 patients had elevated value [ 12, 15, 17, 18, 23, 24, 27, 30, 32–34] (T able 1). Seven of eleven (63.6%) patients had elevated serum levels of CA 125 [ 12, 15, 18, 23, 27, 30, 32], 2/11 (18.2%) patients had elevated serum levels of both CA 125 and CA 19 –9[ 17, 34], 1/11 (9.1%) patient had elevated serum levels of both CA125 and CEA [ 24], 1/11 (9.1%) had elevated serum level of LDH [ 33]. Overall, 8/41 (19.5%) patients had received hormonal therapy: two patients received hormone replacement ther- apy (HRT) [ 17, 30], two patients received oestrogenic re- placement therapy [19d,25], one patient received tamoxifen [ 16], one patient received oestrogen-progestin therapy [ 39], and in two patients the hormonal therapy was not specified [21, 29]. Treatment AS was treated by surgical resection in 38/41 (92.7%) pa- tients: 5/38 (13.2%) patients underwent partial resection, and 33/38 (86.8%) underwent total resection. Of the 38 patients who received surgical treatment, 18 (47.4%) underwent resection of only the tumour [5abc, 7, 8, 9, 11, 13, 18, 19d, 20, 22, 23, 24, 30, 34, 36, 37]; four (10.5%) underwent tumour resection, hysterectomy and bilateral salpingo-oophorectomy [ 14, 28, 32, 38]; and 16 (42.1%) underwent extensive surgery involving other or- gans such as the bowel [12, 15, 19a, 19b, 19c, 25, 29, 31, 35] and liver [ 17]. Moreover, 12/38 (31.69%) patients had received previous total hysterectomy with bilateral salpingo- oophorectomy for benign disease [5A, 5B, 5C, 6, 10,11,13,16,17,22,25, 29]; 15/38 (39.5%) patients re- ceived total hysterectomy with bilateral salpingo- oophorectomy for AS treatment [8,14,15,19A,19B, 20,22,23,26,28,30 –33, 35,38]. Particularly, 13 patients were younger than 40 years at the diagnosis of AS and 4/13 (30.8%) underwent total hysterectomy with bilat- eral oophorectomy for AS tr eatment. In 13/41 (31.7%) patients menopausal status was not reported. More- over, 17/41 (41.5%) [5a –c, 6, 10, 11, 13,16, 17, 19c, 21, 22, 25, 27, 29, 30, 39] patients were in postmenopausal Fig. 4 (a) Small areas with rhabdomyoblastic differentiation within the spindle cell areas (myogenin immunostain, haematoxylin counterstain, 20X); (b) Epithelial clefts within the neoplastic undifferentiated spindle cells highlighted by PAX8 immunohistochemical stain (PAX8 immunostain, haematoxylin counterstain, 20X) Fig. 3 Medium-power view of the neoplasia, showing both the epithelial component and the undifferentiated spindle cell component, admixed with areas of cartilaginous differentiation (haematoxylin-eosin stain, 10X) Mandato et al. BMC Cancer (2018) 18:134 Page 10 of 18 stage, 11/41 (26.8%) patien ts were at premenopausal stage [ 4, 8, 9, 12, 14, 18, 24, 31, 36–38] and 4/11 (36.4%) received bilateral salpingo-oophorectomy dur- ing AS treatment [ 8, 14, 31, 38]. Overall, 16/38 (36.6%) surgical patients received add- itional therapy: 13/38 (34.2%) received adjuvant therapy, and 3/38 (7.9%) received neo-adjuvant therapy [5a, 7, 11, 14, 20, 22,23, 24, 25, 26, 28, 31, 39]. Additionally, 3/38 (7.9%) patients received chemotherapy [ 22, 28, 31], 2/38 (5.3%) patients received radiotherapy [5a, 11], 3/13 (7.9%) patients received chemo-radiotherapy [ 7, 24, 25], 4/38 (10.5%) patients received hormonal therapy [ 20, 23, 26, 39], and 1/38 (2.6%) patient received radiotherapy and hormonal therapy [ 14]. In total, 2/38 (5.3%) patients were treated with neoadjuvant chemotherapy [14 (methotrexate), 27], and 1/38 (2.6%) patient was treated with neoadjuvant radiotherapy [ 15]. AS was not treated with surgery in 3/41 (7.3%) pa- tients. In the first patient AS was misdiagnosed with cor- iocarcinoma and was treated with chemotherapy but at postmortem examination the final diagnosis of retroperi- toneal AS was done [ 4]. The second patient had received a hysterectomy for leiomyoma twenty years before underwent to diagnostic laparoscopy for right pelvic mass. At laparoscopy both ovaries were normal and a bi- opsy of the mass diagnosed an AS. The second patient was treated with only radiotherapy [ 6]. The third patient had received a hysterectomy for leiomyoma 4 years be- fore multiple vaginal operations for recurrent vaginal endometriosis were performed [ 16]. The third patient was treated with chemotherapy and hormonal therapy (tamoxifen) [ 16]. Risk factors A total of 25/41 (61.0%) patients had received a previous diagnosis of endometriosis [5c-10-11-15-16-17-19abc-21- 22-23-24-25-26-27-29-30-31-32-33-36-37-38,39] (T able2). Endometriosis treatment was not reported for 18/25 (72%) patients [5c,10,11,15,17,19abc,23,24,26,30,31,33,36 ,37,38], endometriosis was s urgically and hormonally treated in 2/25 (8%) patients [ 29, 39], it was treated surgi- cally in 3/25 (12%) patients [ 21, 25, 27], it was treated hor- monally (aromatase inhibitor) in 1/25 (4%) patient [22], and it was treated with surgery, hormonal therapy and brachy- therapy in 1/25 (4%) patient [ 16]. Overall, 17/25 (68%) patients with endometriosis h ad an AS with extra-genital localization [5c-10-11-17-19abc-22-23-24-29-30-31-33-36- 37-38], and 8/25 (32%) patients had a vaginally localized tumour [15–16–21-25-26-27-32-39]. Moreover, 8/25 (32%) patients showed elevated levels of tumour markers [ 15, 17, 23, 24, 27, 30, 32, 33]. A total of 7/25 patients received pre- vious hormonal therapy [ 17, 21, 25, 29, 30, 33, 39]: 2/7 (28,6%) received HRT [ 17, 30], 1/7 received (14.3%) ERT [25], 1/7 (14.3%) received TMX [ 33], 1/7 (14.3%) received oestrogenic-progestinic therapy [ 39], and 2/7 (28,6%) received unspecified hormonal therapy [21, 29]. Overall, 6/25 (24%) patients with endometriosis showed sarcomatous overgrowth [22, 24, 27, 33, 38, 39]: 13/25 (52%) were only surgically treated [5c-10-17-19abc-21-29-30-32- 33-36-37], 10/25 (40%) were treated with surgery and adju- vant therapy [11 –15–22-23-24-25-26-31-38-39], 1/25 (4%) was treated with neoadjuvant chemotherapy and surgery [27], and 1/25 (4%) was treated with chemotherapy and hormonal therapy without surgery [16]. Heterologous sarcomatous elements were present in 4/41 (9.7%) patients [9, 12, 16, 18], endometriosis was present in one patient [16,], sarcomatou s overgrowth was present in one patient [ 12], surgery was performed in three cases [ 9, 12, 18], one case received chemotherapy and tamoxifen [16]. Follow-up data Follow-up information was available for 35/41 (85.4%) patients (Table 2); 1/41 (2.4%) patient died from a cause other than AS, and 5/41 (12.2%) were lost to follow-up. At the time of follow-up, 22/35 (62.9%) patients were alive and free of disease (FOD), 9/35 (25.7%) patients had died of disease (DOD), and 4/35 (11.4%) patients were alive with disease (AWD). In the group of nine DOD patients, 4/9 (44.4%) patients died for relapse [5a,11, 20, 27], 1/9 (11.1%) [7] died for pro- gression of disease, 1/9 (11.1% ) patient died for treatment complication (postoperatively massive gastric bleeding) [5b], 1/9 (11.1%) patient died for per sistent pelvic tumor [22r] and 2/9 (22.2%) patients died for distant metastasis [4, 6]. Information on follow-up time was available for 34 patients: the mean follow-up was 27 months (range, 1 – 192). Eighteen patients relapsed [5a, 5c, 8, 9, 11, 12, 13, 14, 16, 20, 21, 26, 27, 28, 31, 32, 33, 34], and their mean DFS was 11.8 months (range, 1 –36). Two cases were lost to follow-up after recurrence. For the 9/35 (5.7%) patients who died due to disease [4, 5a, 5b, 6, 7, 11, 20, 22, 27], 8/9 (88.9%) patients had extra-genital AS, and 1/9 (11.1%) had vaginal AS [ 27]. Additionally, 2/9 (22.2%) patients showed both sarcomatous overgrowth and endometriosis [ 22, 27]. None of these patients received previous hormonal ther- apy. Of the patients who died because of AS, 4/9 (44.4%) had experienced a relapse [5a, 11, 20, 27]. The number of relapses ranged from one to five with a mean of two. The most common localization for first relapse was the pelvis, but one patient ’s first relapse was in the lung [ 27]. In total, 2/4 (50%) patients with relapse were surgically treated [ 11, 20], 1/4 (25%) was not treated [5a], and 1/4 (25%) received only chemotherapy. One patient [ 11]r e - lapsed additional times at prehepatic/intrahepatic sites and in the heart and received multimodal treatment; another patient [ 27] had a second abdominal recur- rence and was treated with chemotherapy. Of the pa- tients who died from disease, the mean OS was Mandato et al. BMC Cancer (2018) 18:134 Page 11 of 18 20.1 months (range, 2 –120), and of the subgroup of pa- tients who died after recurrence, the mean DFS was 14 months (range, 1 –36). At the time of publication, 4/ 36 (11.1%) patients were alive with disease [5c, 9, 13, 14]: 3/4 (75%) had an AS with extra-genital localization [5c, 9, 14], and 1/4 (25%) had an AS with vaginal localization [ 13]. None experienced sarcomatous over- growth, and 1/4 (25%) had a previous diagnosis of endometriosis [5c]. None had previously received hor- monal therapy. All patients alive with disease had at least one relapse. The number of relapses ranged from one to four with a mean of 2.2 (Table 2). Overall, 22/35 (62.9%) patients were FOD at the time of publication. Of these, 14/22 (63.6%) had not experienced relapse [10, 15, 17, 18, 19ab, 23, 24, 25, 29, 30, 36, 37, 39], 11/ 14 (78.5%) had an AS with extra-genital localization [10, 17, 18, 19ab, 23, 24, 29, 30, 36, 37], 3/14 (21.4%) had an AS with vaginal localization [ 15, 25, 39], 2/14 (14.3%) had a tumour with sarcomatous overgrowth [24], 13/14 (92.8%) had a previous diagnosis of endo- metriosis [10, 15, 17, 19ab, 23, 24, 25, 29, 30, 36, 37, 39], 9/14 (64.3%) were only surgically treated [10, 17, 18, 19ab, 29, 30, 36, 37], and 5/14 (35.7%) were treated with surgery and adjuvant therapy [ 15, 21, 24, 25, 39]. Additionally, 5/14 (35.7%) had previously underwent hormonal therapy [ 17, 25, 29, 30, 39]. Information on Table 2 Clinical features and follow up data of 41 extra-uterine and extra-ovarian mullerian adenosarcoma according to histological features Total population Endometriosis P value Overgrowth P value Heterologous sarcomatous differentiation P value n =4 1 n (%) No n =1 6 n (%) Yes n =2 5 n (%) No n =3 2 n (%) Yes n =9 n (%) No n =3 7 n (%) Yes n =4 n (%) Age (mean ± SD), years 44.5 ± 15.0 43.1 ± 15.8 45.5 ± 12.7 0.597 45.4 ± 13.9 41.4 ± 14.6 0.463 46.4 ± 13.0 27.5 ± 11.8 0.009 Size (mean ± SD), mm 12.2 ± 6.9 13.4 ± 8.3 11.0 ± 5.3 0.319 12.5 ± 6.7 11.0 ± 8.1 0.659 11.9 ± 6.8 14.7 ± 8.5 0.517 Site 0.066 1 1 Extra-genital 32 (78.0) 15 (93.8) 17 (68.0) 25 (78.1) 7 (77.8) 29 (78.4) 3 (75.0) Vagina 9 (22.0) 1 (6.2) 8 (32.0) 7 (21.9) 2 (22.2) 8 (21.6) 1 (25.0) Endometriosis 1 0.281 No 16 (39.0) ––– 13(40.6) 3 (33.3) 13 (35.1) 3 (75.0) Yes 25 (61.0) ––– 19 (59.4) 6 (66.7) 24 (64.9) 1 (25.0) Overgrowth 1 1 No 32 (78.0) 13 (81.3) 19(76.0) –– 29 (78.4) 3 (75.0) Yes 9 (22.0) 3 (18.7) 6 (24.0) –– 8 (21.6) 1 (25.0) Treatment 0.557 1 0.101 Surgery 22 (53.7) 9 (56.3) 13 (52.0) 18 (56.3) 4 (44.4) 19 (51.4) 3 (75.0) Surgery + additional treatments 16 (39.0) 5 (31.2) 11 (44.0) 11 (34.4) 5 (55.6) 16 (43.2) 0 (0.0) No Surgery 3 (7.3) 2 (12.5) 1(4.0) 3 (9.4) 0 (0.0) 2 (5.4) 1 (25.0) Surgical Approach 0.345 1 0.327 Complete resection 33 (80.5) 11 (68.8) 22 (88.0) 25 (78.1) 8 (88.9) 30 (81.1) 3 (75.0) Partial resection 5 (12.2) 3 (18.7) 2 (8.0) 4 (12.5) 1 (11.1) 5 (13.5) 0 (0.0) No surgery 3 (7.3) 2 (12.5) 1 (4.0) 3 (9.4) 0 (0.0) 2 (5.4) 1 (25.0) Lost in follow up 6 (14.6) 4 2 4 2 6 0 Status at last follow up (35 patients) 0.002 0.843 0.278 FOD 22 (62.9) 3 (25.0) 19 (82.6) 17 (60.7) 5 (71.4) 19 (61.3) 3 (75.0) AWD 4 (11.4) 3 (50.0) 1 (4.3) 4 (14.3) 0 (0.0) 3 (9.7) 1 (25.0) DOD 9 (25.7) 6 (25.0) 3 (13.0) 7 (25.0) 2 (28.6) 9 (29.0) 0 (0.0) Recurrence 18 (51.4) 9 (56.2) 9 (36.0) 0.184 13 (40.6) 5 (55.5) 0.447 15 (45.5) 3 (75.0) 0.340 More than 1 recurrence 9 (25.7) 4 (28.6) 5 (21.7) 1 5 (17.9) 4 (57.1) 0.294 7 (18.9) 2 (50.0) 1 Death patients OS (mean ± sd) 7.0 ± 5.7 46.3 ± 63.9 0.151 6.0 ± 4.0 16.7 ± 17.8 0.179 20.1 ± 37.8 – * Patients with recurrence DFS (mean ± sd) 47.9 ± 63.6 28.0 ± 41.3 0.486 12.2 ± 11.4 11.4 ± 12.6 0.897 11.9 ± 12.1 11.6 ± 10.5 1 AWD alive with disease, DOD died of disease, FOD free of disease *comparison was not possible, because no patients with heterologous sarcomatous differentiation dead during follow up Mandato et al. BMC Cancer (2018) 18:134 Page 12 of 18 follow-up time was available for 13 patients, and the mean follow-up was 21.9 months (range, 1 –60 months). A total of 8/22 (36.4%) patients were alive and FOD despite having one or more relapses during follow-up [12, 16, 20, 26, 31, 32 33, 34]. Their number of relapses ranged from one to four with a mean of 1.8. In 3/8 (37.5%) patients, the first relapse was in the pelvis [12, 26, 33]; in 1/8 (12.5%) patient, it was in the peri- toneum [ 31]; in 3/8 (37.5%) patients, it was in the va- gina [ 16, 32, 34]; and in 1/8 (12.5%) patient, it was in the parametrium [ 21]. The first relapse was surgically treated in 2/8 (25%) patients [ 33, 34], it was treated with surgery and adjuvant therapy in 2/8 (25%) patients [ 16, 26], and it was treated with only chemo- therapy [12, 31, 32] or only radiotherapy and brachyther- apy [21] in 4/8 (50%) patients. Overall, 4/8 (50%) patients experienced a second relapse [ 12, 32–34]: 1/4 (25%) pa- tient ’s second relapse location was in the pouch of Douglas [ 12], 1/4 (25%) patient ’s relapse was in the pelvic peritoneum [ 33], and 2/4 (50%) patients ’ re- lapses were in the vagina [ 32, 34]. In 2/4 (50%) pa- tients, the second recurrence was treated only with chemotherapy [ 12, 33], whereas in 1/4 (25%) patient, it was treated with surgery a nd adjuvant therapy, and in 1/4 (25%) patient, it was surgically treated. In total, 2/8 (25%) patients had a third relapse: one was in the pouch of Douglas and was treated with surgery and hormonal therapy [ 34], and the other was in the va- gina and was treated with surgery and adjuvant ther- apy [ 32]. Finally, 1/8 (12.5%) patient experienced a fourth vaginal relapse that was treated only with adju- vant therapy [ 32]. Information on follow-up time was available for six patients. They had a mean DFS of 7.8 months (range, 1 – 18 months) and a mean total follow-up of 21.7 months (range, 1–57). Of the FOD patients who experienced at least one recur- rence during follow-up, 4/8 (50%) had AS with a peritoneal localization [12, 31, 33, 34] and 4/8 (50%) with a vaginal localization [16, 21, 26, 32], 3/8 (37.5%) showed sarcoma- tous overgrowth [12, 33, 34], and 6/8 (75%) had a diagnosis of endometriosis [ 16, 21, 26, 31–33]. In total, 5/8 (62.5%) patients were only surgically treated [ 12, 21, 32–34], 2/8 (25%) were treated with surg ery and adjuvant therapy [26, 31], and 1/8 (12.5%) was treated only with chemo- therapy and hormonal therapy [ 16]. Additionally, 2/8 (25%) had previously received hormonal therapy. Kaplan Meier curves were used to evaluate the impact of AS pathological characteristics(endometriosis, sarcomatous overgrowth and site of localization) and AS treatment (no surgery, surgery, complete rese ction, partial resection and adjuvant therapy) on OS (Fig. 5)a n dD F S( F i g .6). Statistical comparison of OS Kaplan Meier curves showed a significant difference in survival distribution (log-rankP value = 0.005) between patients who received different therapy; in particu- lar patients who received only surgery showed a trend of survival higher than those who received both surgery adju- vant therapy or only adjuvant therapy (Fig. 5d). Moreover, patients with AS treated with complete resection presented better OS than women with partially resected AS or not sur- gically treated AS (log-rankP value = 0.0005) (Fig.5e). Evaluation of Kaplan Meier curves referred to DFS showed a significant difference in DFS distribution be- tween patients presenting or not presenting a previous diagnosis of endometriosis (log-rank P value = 0.020). Endometriosis resulted to improve DFS of patients with extra-uterine AS (Fig. 6a).

Since 1974, when the first case of an extra-uterine AS was described by Clement and Scully, only 41 cases of extra-uterine or extra-ovarian AS have been reported [3–34] (Table 1). Here, we reported on 32/41 (78.0%) patients with extra-genital AS and 9/41 (22.0%) patients with vaginal AS. The mean age was 44.5 years (range, 16 –83 years; SD +/ − 15). The extra-genital AS patients had a mean age of 42.8 years (range, 16 –83; + − 14.7), and the vagi- nal AS patients had a mean age of 50.8 years (range, 42 – 65 years; SD +/ − 9.2). According to previous studies, extra-uterine AS occurs in younger women than uterine AS (median age, 58 years) [ 1–37]. Unlike prior studies of uterine AS, for which bleeding was the most common presentation symptom [ 1, 37], in our review, the most common presentation symptom re- sulted from the large abdominal masses of the AS growths in some patients, with some tumours reaching a size of 34 cm [ 35]o r1 3k[ 20]. Typically, extra-uterine AS is a large, partly cystic mass with an irregular and lobulated surface [1]. Heterologous elements have been reported in AS from all sites [ 22], which might cause misdiagnosis of chondroliposarcoma of the peritoneum. It should also be considered that evaluations of frozen sections are less effective when dealing with a huge mass (maximum size: 27 cm). Heterologous elements may portend a poorer prognosis, particularly the rhabdomyoblastic differentiation [46]. Four AS patients included in our review presented heterologous elements [9, 12, 16, 18]. They were younger than other AS patients, although 75% of patients recurred [9, 12, 16], 75% of patients were FOD [ 12, 16, 18]a tl a s t follow-up (T able2). CA 125 was reported in 13/41 (31.7%) patients and was found to be greater in 11/13 (84.6%) patients, sug- gesting an association with peritoneal involvement and sarcomatous overgrowth, as reported by Inoue [ 15]. In prior studies, CA 125 was reported in 5/10 (40%) patients [ 12, 24, 27, 33] ,a n di tw a sf o u n da th i g hl e v e l s in 4/4 (100%) patients [ 12, 23, 27, 30]. CA 125 titres Mandato et al. BMC Cancer (2018) 18:134 Page 13 of 18 have been well correlated with the clinical course of endometriosis associated with extra-uterine AS [ 30]. In our review, endometriosis was associated with AS in 25/41 (61%) patients, being present in 8/9 (88%) pa- tients with vaginal AS and in 17/33 (51.5%) patients with extra-genital AS. AS is the second most commo n gynaecological malig- nancy in patients with endometriosis after clear cell carcin- oma of the ovary [ 30, 47]. A review of pathologic slides from 1000 cases of surgically proven endometriosis found a 0.3% rate of AS in cases of extra-ovarian endometriosis [30, 47]. In 2000, Zanetta suggested that chronic stimulation from endogenous or exogenous oestrogen may increase the likelihood of endometriosis-associated carcinogenesis [48]. In our review, only 8/41 (19.5%) patients received hor- monal therapy [17, 19d, 21, 25, 29, 30, 33,39] such as HRT [ 17, 30] ERT [19d, 25] or tamoxifen [ 16]. However, we identified only two patients with AS associated with severe refractory endometriosis who required surgery with hormonal therapy [ 29] and one patient who Fig. 5 Impact of (a) endometriosis, (b) sarcomatous overgrowth, (c) site of tumor localization, (d)t r e a t m e n t ,(e)s u r g i c a la p p r o a c ho nO So fp a t i e n t sw i t h extra-uterine AS Mandato et al. BMC Cancer (2018) 18:134 Page 14 of 18 required surgery with hormonal therapy and brachyther- apy [ 16]. Nevertheless, old, recurrent and symptomatic endometriosis should be carefully monitored and pos- sibly excised radically [ 49]. Although endometriosis may be involved in extra- uterine AS tumourigenesis, it is considered a favourable prognostic factor for this tumour type [ 29, 30]. Patients with AS associated with endometriosis showed increased DFS than AS patients without endometriosis (Fig. 6a). No endometriosis was found in our patient. In cases of extra-genital AS without en dometriosis, the tumour may arise from pluripotent mesothelial and mesenchymal cells in t h ep e l v i cc a v i t y[5]. Our patient presented with an extra- genital AS with sarcomatous overgrowth. Sarcomatous over- growth is characterized by the presence of a high-grade sarcomatous component in at least 25% of the tumour [ 42] and is associated with poor prognosis for both uterine and extra-uterine AS. In our review, patients with sarcomatous overgrowth showed a worse DFS than patients without overgrowth but log-rank P value between curves did not re- sult completely significant (Fig.6b). In a recent retrospective study, patients with uterine AS showed a median OS of 161 months [ 43]. As reported by Murugasu [ 24], extra-genital AS is more ag- gressive than uterine AS, with AS recurring in 60% of extra-genital AS patients compared with 23% of uterine AS patients. In our review, 12/28 (42.9%) patients with extra-genital AS relapsed. Haematogenous metastases have been found in 33% of extra-genital AS patients compared to 2% of uterine AS patients. Death due to tumour occurred in 40% of extra-genital AS patients compared to 10% of uterine AS patients [ 24]. In our re- view, 8/28 (28.6%) patients with extra-genital AS died of disease. The aggressiveness of extra-genital AS may be due to failure of the uterine myometrial wall as a barrier. Extra-genital AS is typically quite large at presentation and can easily spread to the peritoneum, to abdominal and pelvic organs, and to blood vessels. For this reason, it can easily cause bowel obstruction, and complete cytoreduction is not always easily achieved. Surgical treatment, particularly complete surgical re- section, represents the best course of action for AS. Pa- tients with extra-uterine AS who received only surgery remained free of disease and never relapsed after treat- ment. Patients who underwent complete resection showed a better OS distribution than patients who Fig. 6 Impact of (a) endometriosis, (b) sarcomatous overgrowth, (c) site of tumor localization, (d)t r e a t m e n t ,(e)s u r g i c a la p p r o a c ho nD F So fp a t i e n t s with extra-uterine AS Mandato et al. BMC Cancer (2018) 18:134 Page 15 of 18 underwent partial resection (Fig. 5e). Endometriosis, sar- comatous overgrowth, tumour size and age were not correlated with resection type. Because the number of patients who were not surgically treated was small, these

require further confirmation. Moreover, survival seems to be not improved by bilateral salpingooophorectomy. Ovarian preservation for uterine or cervical AS may be feasible among premenopausal women. Indeed, women who underwent hysterectomy with salpin- gooophorectomy for uterine AS did not have longer sur- vival than women who underwent only hysterectomy [ 43]. This finding was not tested in our review because we had a lot of missing data about postmenopausal status. The OS of AS patients who received only surgery resulted more favourable than that of patients who re- ceived surgery with additional treatment or who did not undergo surgery (Fig. 6b). Probably, patients submitted to an exclusive surgery presented a completely resectable disease thanks to the biology of tumor or to the skills of surgeon. However, there were no differences in DFS be- tween these three groups (Fig. 6b). Different adjuvant treatments were delivered. Three patients received chemotherapy alone (anthracycline with an anti-angiogenesis agent [ 22]; bleomycin, etopo- side and cisplatinum [ 28]; ifosfamide with cisplatin [ 31]), 3 received chemotherapy associated with radiotherapy (cytoxan + 4000 rad of radiotherapy [ 7]; mesna, adriamy- cin, ifosfamide, carboplatinum and pelvic radiotherapy [24]; ifosfamide and cisplatin plus pelvic radiotherapy [25]), and two received only radiotherapy [5a-11]. Unfortunately, our review was limited by the low num- ber of AS cases, by the lack of data and by short follow-up time reported in literature therefore statistical analysis was limited to Kaplan Meier curves comparison. Furthermore, our AS case was characterized by an extremely unusual aggressive clinical course that it seems to be not represen- tative of AS common biological behavior. However, some indications may be suggested.

In summary, extra-uterine A S, particularly cases aris- ing from extra-genital regions, is an extremely rare tumour. They are typically found in younger women than are uterine AS, and they usually involve huge, polylobate masses that can easily spread into sur- rounding organs and blood vessels. For extra-uterine AS, endometriosis represents a positive prognostic factor and sarcomatous overgrowth a negative prog- nostic factor; we could not asses the prognostic effect of heterologous sarcomatous elements for the scant number of cases included; however, independently of sarcomatous overgrowth, extra-uterine AS has a very poor prognosis. Although co mplete resection is not al- ways feasible, surgery remains the mainstay treatment choice, whereas adjuvant therapy does not appear to be effective in prolonging OS. Surgical treatment of extra-uterine AS often requires an extensive surgery given the possible involving of multiple organs. More- over, AS patients can be pluri-operated because of previous endometriosis treatment with consequent additional difficulties during surgery. Therefore, since surgery is the only treatment to have an impact on survival, patients should be centralized in qualified surgical oncological centr es and operated by experi- enced surgeons to reduce morbidity and to achieve radical treatment. Nevertheless, centralization might allow the recovery of clin ical data and histological samples allowing a revision and a definitive diagnosis. Considering that in the last forty years less than forty cases have been reported in the literature, a worldwide registry is urgently needed to collect data regarding these rare AS to standardize treatment and obtain reli- able data on prognosis. Abbreviations AS: Adenosarcoma; AWD: Alive with disease; CI: Confidence interval; CT: Computed tomography scan; DFS: Disease-free survival; DOD: Died of disease; FOD: Free of disease; HR: Hazard ratio; HRT: Hormone replacement therapy; OS: Overall survival; SD: Standard deviation

W ea r eg r a t e f u lt oo u rC o l l e a g u e sw h oa n s w e r e do u rr e q u e s tt ou p d a t ef o l l o w - u p data, particularly Dr. Mauro Cozzolino and Dr. Rhonda Yantiss. Funding The funding body had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. Availability of data and materials Data collected and analyzed during this study are included in this review and are available from the corresponding author on reasonable request. Authors’ contributions VDM conceived of the manuscript, performed operations, collected data, and wrote the manuscript. FT performed statistical analysis and wrote the manuscript. VM collected data and wrote the manuscript. RV performed pathological evaluation and wrote the manuscript. LA performed the operation and conceived of the manuscript. GBL conceived of and revised the manuscript. All authors read and approved the final manuscript. Ethics approval and consent to participate Written informed consent was not necessary because our patient provided standard written consent for the use of data, pictures and videos for teaching and research purposes at the time of laparotomy. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. All authors deny any found, financial and personal relationships with other people or organizations/ companies that could inappropriately influence their work. Publisher’sN o t e Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Mandato et al. BMC Cancer (2018) 18:134 Page 16 of 18 Author details 1Unit of Obstetrics and Gynecology, IRCCS- Azienda Unità Sanitaria Locale, Viale Risorgimento n 80, Reggio Emilia, Italy. 2Laboratory of Translational Research, Azienda Unità Sanitaria Locale, IRCCS, Reggio Emilia, Italy. 3Unit of Surgical Gynecol Oncology, Azienda Unità Sanitaria Locale, IRCCS, Reggio Emilia, Italy. 4Unit of Pathology, Azienda Unità Sanitaria Locale, IRCCS, Reggio Emilia, Italy. 5Unit of Obstetrics and Gynecology, University of Modena e Reggio Emilia, Reggio Emilia, Italy. Received: 2 March 2017 Accepted: 23 January 2018

1. Clement PB, Scully RE. Mullerian adenosarcoma of the uterus: a clinicopathologic analysis of 100 cases with a review of the literature. Hum Pathol. 1990;21:363 –81. 2. D'Angelo E, Prat J. Uterine sarcomas: a review. Gynecol Oncol. 2010;116:131 –9. 3. Clement PB, Scully RE. Mullerian adenosarcoma of the uterus: a clinicopathologic analysis of ten cases of a distinctive type of mullerian mixed tumor. Cancer. 1974;34:1138 –49. 4. Douglas GW, Kastin AJ, Huntington RW Jr. Carcinoma arising in a retroperitoneal muellerian cyst, with widespread metastasis during pregnancy. Am J Obstet Gynecol. 1965;91:210 –6. 5. Clement PB, Scully RE. Extrauterine mesodermal (müllerian) adenosarcoma: a clinicopathologic analysis of five cases. Am J Clin Pathol. 1978;69:276 –83. 6. Bard ES, Bard DS, Vargas-Cortes F. Extrauterine Müllerian adenosarcoma; a clinicopathologic report of a case with distant metastases and review of the literature. Gynecol Oncol. 1978;6:261 –74. 7. Kao GF, Norris HJ. Benign and low grade variants of mixed mesodermal tumor (adenosarcoma) of the ovary and adnexal region. Cancer. 1978;42:1314–24. 8. Russell P, Slavutin L, Laverty CR, Cooper-Booth J. Extrauterine mesodermal (müllerian) adenosarcoma. A case report. Pathology. 1979;11:557 –60. 9. Kerner H, Lichtig C, Beck D. Extrauterine Mullerian adenosarcoma of the peritoneal mesothelium: a clinicopathologic and electron microscopic study. Obstet Gynecol. 1989;73:510. 10. Vara AR, Ruzics EP, Moussabeck O, Martin DC. Endometrioid adenosarcoma of the bladder arising from endometriosis. J Urol. 1990;143:813 –5. 11. Roman LD, Mitchell MF, Tornos C, Glover A, Kavanagh JJ. Dedifferentiated Extrauterine Adenosarcoma responsive to chemotherapy. Gynecol Oncol. 1993;49:389–94. 12. de Jonge MJ, van Dam PA, Van Marck E, Prove A, van Oosterom AT. Primary extrauterine mullerian adenosarcoma of the peritoneum. Gynecol Oncol. 1995;57:126–30. 13. Benda JA, Veronezi-Gurwell A, Wilcox M, Buller R. An unusual extrauterine variant of adenosarcoma with multiple recurrences over 16 years. Gynecol Oncol. 1994;53:131–7. 14. Ostor AG, Nirenberg A, Ashdown ML, Murphy DJ. Extragenital adenosarcoma arising in the pouch of Douglas. Gynecol Oncol. 1994;53:373–5. 15. Inoue M, Fukuda H, Tanizawa O. Adenosarcomas originating from sites other than uterine endometrium. Int J Gynaecol Obstet. 1995;48:299 –306. 16. Judson PL, Temple AM, Fowler WC Jr, Novothy DB, FunkHouser WK Jr. Vaginal adenosarcoma arising from endometriosis. Gynecol Oncol. 2000;76:123–5. 17. N'Senda P, Wendum D, Balladur P, Dahan H, Tubiana JM, Arrivè L. Adenosarcoma arising in hepatic endometriosis. Eur Radiol. 2000;10:1287 –9. 18. Kato N, Zhe J, Endoh Y, Motoyama T. Extrauterine Mullerian adenosarcoma of the peritoneum with an extensive rhabdomyosarcomatous element and a marked myxoid change. Pathol Int. 2000;50:347 –51. 19. Yantiss RK, Clement PB, Young RH. Neoplastic and pre-neoplastic changes in gastrointestinal endometriosis: a study of 17 cases. Am J Surg Pathol. 2000;24:513–24. 20. Visvalingam S, Jaworski R, Blumenthal N, Chan F. Primary peritoneal mesodermal adenosarcoma: report of a case and review of the literature. Gynecol Oncol. 2001;81:500 –5. 21. Anderson J, Behbakht K, De Geest K, Bitterman P. Adenosarcoma in a patient with vaginal endometriosis. Obstet Gynecol. 2001;98:964 –6. 22. Dincer AD, Timmins P, Pietrocola D, Fisher H, Ambros RA. Primary peritoneal mullerian adenosarcoma with sarcomatous overgrowth associated with endometriosis: a case report. Int J Gynecol Pathol. 2002;2:65 –8. 23. Hines BJ, Porges RF, Mittal K, Muggia FM, Curtin JP. Use of Medroxyprogesterone acetate in the treatment of Mullerian adenosarcoma: a case report. Gynecol Oncol. 2002;85:192 –5. 24. Murugasu A, Miller J, Proietto A, Millar E. Extragenital mullerian adenosarcoma with sarcomatous overgrowth arising in an endometriotic cyst in the pouch of Douglas. Int J Gynecol Cancer. 2003;13:371 –5. 25. Liu L, Davidson S, Singh M. Mullerian adenosarcoma of vagina arising in persistent endometriosis: report of a case and review of the literature. Gynecol Oncol. 2003;90:486 –90. 26. Raffaelli R, Piazzola E, Zanconato G, Fedele L. A rare case of extrauterine adenosarcoma arising in endometriosis of the rectovaginal septum. Fertil Steril. 2004;81:1142 –4. 27. Toyoshima M, Akahira J, Moriya T, Hayakawa S, Yaegashi N. Primary vaginal adenosarcoma with sarcomatous overgrowth. Gynecol Oncol. 2004;95:759 –61. 28. Kanngurn S, Somran J, Art-Ong C, Lamlertthon W, Porncharoenpong S. Primary peritoneal adenosarcoma with stromal overgrowth and fetal type cartilage: a case report and literature review. J Med Assoc Thail. 2005;88:849–54. 29. Chang HY, Chagchien CC, Chen HH, Lin H, Huang CC. Extrauterine mullerian adenosarcoma associated with endometriosis and rectal villotubular adenoma: report of a case and review of the literature. Int J Gynecol Cancer. 2005;15:361–5. 30. Milam MR, Atkinson JB, Currie JL. Adenosarcoma arising in inguinal endometriosis. Obstet Gynecol. 2006;108:753 –5. 31. Huang GS, Arend RC, Sakaris A, Hebert TM, Goldberg GL. Extragenital adenosarcoma: a case report, review of the literature, and management discussion. Gynecol Oncol. 2009;115:472 –5. 32. Han X, Leng J, Guo L, Xiang Y, Lang J. V aginal adenosarcoma arising from refractory endometriosis: a case report. Aust N Z J Obstet Gynaecol. 2010;50:574–6. 33. Maeda M, Mabuchi S, Matsumoto Y, Hisamatsu T, Ohashi H, Kimura T. Activity of pegylated liposomal doxorubicin for extragenital mullerian adenosarcoma with sarcomatous overgrowth: a case report an a review of the literature. Eur J Gynaecol Oncol. 2011;32:542 –6. 34. Patrelli TS, Sillini EM, Gizzo S, Beretta R, Franchi L, Thai E, et al. Extragenital Mullerian adenosarcoma with pouch of Douglas location. BMC Cancer. 2011;11:171. 35. Clarke BA, Mulligan AM, Irving JA, McCluggage WG, Oliva E. Mullerian adenosarcomas with unusual growth patterns: staging issues. Int J Gynecol Pathol. 2011;30:340 –7. 36. Karateke A, Kahramanoqlu I, Bilgiç R. Extragenital mullerian adenosarcoma in the pouch of douglas. Balkan Med J. 2014;31:100 –4. 37. Yang C, Oh HK, Kim D. Mullerian adenosarcoma arising from rectal endometriosis. Ann Coloproctol. 2014;30:232 –6. 38. Kar R, Verma SK, Papa D, Sylvia MT. Extrauterine adenosarcoma arising in omental endometriosis: rare site of occurrence of a rare tumor. Indian J Pathol Microbiol. 2014;57:640 –1. 39. Pontrelli G, Cozzolino M, Stepniewska A, Bruni F, Pesci A, Ceccaroni M. Primary vaginal Adenosarcoma with Sarcomatous overgrowth arising in recurrent endometriosis: feasibility of laparoscopic treatment and review of the literature. J Minim Invasive Gynecol. 2016;23:833 –8. 40. Krivak TC, Seidman JD, McBroom JW, MacKoul PJ, Aye LM, Rose GS. Uterine adenosarcoma with sarcomatous overgrowth versus uterine carcinosarcoma: comparison of treatment and survival. Gynecol Oncol. 2001;83:89–94. 41. Carroll A, Ramirez PT, Westin SN, Soliman PT, Munsell MF, Nick AM, et al. Uterine adenosarcoma: an analysis on management, outcomes, and risk factors for recurrence. Gynecol Oncol. 2014;135:455 –61. 42. Clement PB. Müllerian adenosarcomas of the uterus with sarcomatous overgrowth. A clinicopathological analysis of 10 cases. Am J Surg Pathol. 1989;13:28–38. 43. Seagle BL, Kanis M, Strohl AE, Shahabi S. Survival of women with Mullerian adenosarcoma: a National Cancer Data Base study. Gynecol Oncol. 2016; S0090-8258:31485–8. 44. Brooks SE, Zhan M, Cote T, Baquet CR. Surveillance, epidemiology, and end

analysis of 2677 cases of uterine sarcoma 1989 –1999. Gynecol Oncol. 2004;93:204–8. 45 45. Nathenson MJ, Ravi V, Fleming N, Wang WL, Conley A. Uterine Adenosarcoma: a Review. Curr Oncol Rep. 2016;18:68. 46. Seagle BL, Falter KJ 2nd, Lee SJ, Frimer M, Samuelson R, Shahabi S. Mullerian adenosarcoma of the cervix: report of two large tumors with sarcomatous overgrowth or heterologous elements. Gynecol Oncol Case Rep. 2014;9:7–10. 47. Stern RC, Dash R, Bentley RC, Snyder MJ, Haney AF, Robboy SJ. Malignancy in endometriosis: frequency and comparison of ovarian and extraovarian types. Int J Gynecol Pathol. 2001;20:133 –9. Mandato et al. BMC Cancer (2018) 18:134 Page 17 of 18 48. Zanetta GM, Webb MJ, Li H, Keeney GL. Hyperestrogenism: a relevant risk factor for the development of cancer from endometriosis. Gynecol Oncol. 2000;79:18–22. 49. Mandato VD, Mastrofilippo V, Ciarlini G, Aguzzoli L, La Sala GB. Primary vaginal Adenosarcoma with Sarcomatous overgrowth arising in recurrent endometriosis: feasibility of laparoscopic treatment and review of the literature. J Minim Invasive Gynecol. 2016;S1553-4650:31287 –0. • We accept pre-submission inquiries  Our selector tool helps you to find the most relevant journal  We provide round the clock customer support  Convenient online submission  Thorough peer review  Inclusion in PubMed and all major indexing services  Maximum visibility for your research Submit your manuscript at www.biomedcentral.com/submit Submit your next manuscript to BioMed Central and we will help you at every step: Mandato et al. BMC Cancer (2018) 18:134 Page 18 of 18