{"paper_id":"76861e43-163c-45c3-ba96-b13d340839fd","body_text":"C A S E R E P O R T Open Access\nPrimary extra-uterine and extra-ovarian\nmullerian adenosarcoma: case report and\nliterature review\nVincenzo Dario Mandato 1*, Federica Torricelli 2, Valentina Mastrofilippo 3, Riccardo Valli 4, Lorenzo Aguzzoli 3\nand Giovanni Battista La Sala 1,5\nAbstract\nBackground: Extra-uterine mullerian adenosarcomas have varying biological behaviours depending on the\npresence of endometriosis or sarcomatous overgrowth . These behaviours manifest according to the tumours ’\nhistological characteristics and sites of origin. The best treatment and oncologic outcome have not been clarified because\nonly a few cases of extra-uterine and extra-ovarian adenosarcoma have been described in the literature. Here, we report a\ncase of primary peritoneal adenosarcoma with sarcomatous overgrowth and review all reported cases of adenosarcomas\narising outside of the uterus and outside the ovaries to identify the best treatment options and clarify outcomes.\nCase presentation:A 79-year-old woman was referred to our Department with an abdominal mass resembling a fibroid\nwith a haemorrhage. Her gynaecological history was negative. A transvaginal and transabdominal ultrasound examination\nrevealed a multicystic mass resembling an ovarian tumour arising from the pelvis and extending up to the abdomen. At\nlaparotomy a peritoneal mass arising from Douglas peritoneum was resected. The uterus and adnexa appeared normal,\nand a supra-cervical hysterectomy with bilateral salpingo-oophorectomy was performed. No macroscopic residual disease\nwas present. Final pathology diagnosed a malignant peripheral nerve sheath tumors with divergent differentiation. Four\nweeks later a new, multicystic mass was found. Due to the progressive poor condition, the patient died four months after\ndiagnosis. Histological slides were reviewed by external expert pathologists and the final diagnosis was of extra-genital\nadenosarcoma with sarcomatous overgrowth. Furthermore,we also collected and analysed articles written in English\nregarding extra-uterine and extra-ovarian adenosarcomas published between January 1974 and October 2016. PubMed\nw 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.\nConclusions:Only 41 cases has been reported in literature. Previous endometriosis and sarcomatous overgrowth showed\nan inverse effect on prognosis. Endometriosis was confirmed to have a positive effect on disease free survival Complete\nsurgical resection is the mainstay of treatment. A worldwide registry is urgently required to collect data to standardize\ntreatment and to obtain reliable data on prognosis.\nKeywords: Mullerian extra-uterine adenosarcoma, Mullerian extra-genital adenosarcoma, Survival, Vaginal adenosarcoma,\nSymptoms, Treatment, Review\n* Correspondence: dariomandato@gmail.com\n1Unit of Obstetrics and Gynecology, IRCCS- Azienda Unità Sanitaria Locale,\nViale Risorgimento n 80, Reggio Emilia, Italy\nFull list of author information is available at the end of the article\n© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0\nInternational License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and\nreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to\nthe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver\n(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.\nMandato et al. BMC Cancer  (2018) 18:134 \nDOI 10.1186/s12885-018-4037-y\n\nBackground\nMullerian adenosarcoma (AS) is a rare mesenchymal\nand epithelial neoplasm of low malignant potential typic-\nally occurring in the uterine corpus in perimenopausal\nor postmenopausal women [ 1]. It is a mixed tumour that\nusually arises as a solitary lesion with a benign but\nsometimes atypical glandular epithelium and low-grade\nsarcoma, usually of the endometrial stromal type [ 2].\nThe first case of AS was described in early 1974 by\nClement and Scully [ 3]. AS typically arises from the\ncorpus uterus, rarely from the cervix or ovary, and\nextremely rarely from the vagina or from extra-genital\nsites such as the peritoneum, retroperitoneum, bladder,\nliver or colon (T able1)[ 4–39].\nGenerally, uterine AS presents clinically indolent be-\nhaviour, whereas AS with sarcomatous overgrowth is\nextremely aggressive [ 31] and is characterized by re-\ncurrence and metastasis at an early stage [ 40, 41].\nSarcomatous overgrowth is characterized by the pres-\nence of a high-grade sarcomatous component in at\nleast 25% of the tumour [ 42].\nA recent national cancer database study reported\nsurvival data from 2205 women with AS arising from the\ncorpus uterus, cervix and ovary, but no consistent data re-\ngarding vaginal or extra-genital AS are available because\nthese are extremely rare sites for AS [ 43]. Uterine AS is\nthe rarest form of uterine sarcomas representing only\n∼0.2% of all uterine malignancies. It has an age-adjusted\nincidence of 2 per 1000,000 for Caucasians, 3 per\n1000,000 for African Americans, and 1 per 1000,000 for\nother ethnic groups in the US population [ 44, 45].\nExtra-genital AS is so rare that it has not been pos-\nsible to develop clear guidelines regarding treatment\nand prognosis [ 35].\nHere, we reported a case of primary peritoneal AS with\nsarcomatous overgrowth but no associated endometriosis\nand reviewed all cases of AS arising outside of the uterus\nand outside of the ovaries published since 1974 to identify\nthe best treatment options and clarify outcomes.\nMethods\nWe report the clinical data, preoperative imaging, patho-\nlogical findings and follow-up data for a case of primary\nperitoneal AS with sarcomatous overgrowth. We also\nperformed a systematic review of the literature to collect\nreports on AS arising outside of the uterus and outside\nof the ovaries. With the term “uterus” we mean the\nwhole organ without distinction between uterine corpus\nand cervix. We mean with the term “extra-uterine” all\nAS arising outside of the uterine corpus or of the cervix.\nSystematic review of the literature\nWe collected and analysed articles published on AS be-\ntween January 1974 and October 2016 using PubMed as a\ndatabase and the following search terms: “peritoneal\nmullerian adenosarcoma”, “primitive peritoneal mullerian\nadenosarcoma”, “primary peritoneal mullerian adenosar-\ncoma”, “extra-uterine mullerian adenosarcoma”, “primitive\nextra-uterine mulle rian adenosarcoma ”, “primary extra-\nuterine mullerian adenosarcoma”, “extra-uterine mesoder-\nmal adenosarcoma”, “primitive extra-uterine mesodermal\nadenosarcoma”, “primary extra-uterine mesodermal adeno-\nsarcoma”, “primary extra-genital adenosarcoma”, “primitive\nextra-genital adenosarcoma”, “primary extra-genital muller-\nian adenosarcoma”,a n d “primitive extra-genital mullerian\nadenosarcoma”. After selecting for cases arising outside of\nthe uterus and outside the ovaries, 32 reports of extra-\ngenital AS and 9 of vaginal AS were found and included in\nthis systematic review For each case the following data were\nextracted and collected in a d atabase: age, tumor size,\ntumor site, previous diagnosis of endometriosis, sarcoma-\ntous overgrowth, heterologous sarcomatous differentiation\ntherapy, presence of recurrences, recurrence site, treatment\nafter recurrence and follow up status and time. All dichoto-\nmic parameters were codified as 0 (absent) or 1 (present),\nwhile for all cases age was reported in years, follow up was\nreported in months and tumor size was reported in centi-\nmetres. When a patient experienced more than one recur-\nrence all events were reported. Missing data were indicated\nas not reported (NR) in database.\nStatistical analysis\nStatistical analysis was performed using R-3.2.3 software.\nAssociations between clinical and pathological parameters\nin different subgroups of patients were assessed using linear\nmodels and Fisher’s exact test.\nOverall survival (OS) was computed as the time period\nfrom the date of surgery to either the date of death or\nlast follow-up. Disease-free survival (DFS) was computed\nas the disease-free period from the date of surgery to the\ndate of relapse or last follow-up. Survival curves were\nplotted using the Kaplan –Meier method and differences\nbetween curves were assessed by Log-Rank test.\nTest were considered statistically significant with a P\nvalue lower than 0.05.\nCase presentation\nA 79-year-old woman was referred to the Department\nof Obstetrics and Gynecology with an abdominal mass\ndiscovered on a computed tomography scan (CT) per-\nformed following right iliac artery angioplasty. The scan\nrevealed a 16 × 11 cm mass resembling a fibroid with a\nhaemorrhage (Fig. 1).\nHer history included type 2 diabetes, hypertension, hyper-\ncholesterolemia, glaucoma, h ypothyroidism, and stage III\nchronic obstructive arteriopathy of the right leg, and she\nunderwent a left carotid thromboendarterectomy 1 year\nprior to admission. Her gynaecological history was negative.\nMandato et al. BMC Cancer  (2018) 18:134 Page 2 of 18\n\nTable 1 Clinical features of 41 patients with extra-genital mullerian adenosarcoma reported in the English literature and of the index case\nReference\nnumber\nAuthor Age\n(years)\nSite Size (cm) Tumour\nmarkers\nSigns and\nSymptoms at\npresentation\nTreatment Sarcomatous\novergrowth\nEndometriosis Hormonal\ntherapy\nFollow-up\n4 Douglas 18\ngravida\nRetroperitoneum 5 × 4.5 × 4 NR Anorexia,\nsuprapubic-low\nback pain, loss of\nweight, vaginal\nbleeding, preterm\ndelivery.\n24 weeks\nCHT (MTX) NR No No DOD 10 weeks later with\ndistant metastasis\n5a Clement 45 Right Pelvic\nperitoneum\n(pelvic mass that\nextended into\nthe rectum and\nthe bladder)\n7x7x5 NR Right lower leg\nthrombophlebitis,\nright paravaginal\nmass\nSurgery\n(partial tumour\nresection) + RT\nNR No No DOD 9 months later due\nto pelvic recurrence and\nvisceral metastasis\n5b Clement 73 Midline Pelvic\nperitoneum,\ndisplcing the\nbladder\nanteriorly\n14 NR Large pelvic mass\nwith bilateral\nhydronephrosis.\nInability to void\nSurgery (complete\ntumour resection)\nNR No No DOD 2 months later\n(postoperatively massive\ngastric bleeding\nnecessitating a subtotal\ngastrectomy occurred but after that the\npatient’s conditions\ndeteriorated gradually-\nautopsy not done-)\n5c Clement 58 Left Pelvic\nperitoneum\n16x15x8 NR Large pelvic mass.\nUrinary urgency,\nrectal pressure\nSurgery\n(partial tumour\nresection)\nNR Yes No AWD local recurrence\n15 months later (RT),\nlung metastases\n45 months later\n(resected)\n6 Bard 46 Right pelvic\nperitonum (the\nmass was\nadherent to the\nright bladder\nwall and\nsurrounded the\nright ureter)\n10 × 8 NR Weakness and\npelvic pain in the\nright lower\nextremity. Urinary\nincontinency\nBiopsy + RT NR NR No DOD 11 weeks later with\ndistant sepsis and\nmetastasis\n7 Kao 42 Left round\nligament\n10 NR NR Surgery (partial\ntumour resection)\n+ CHT (Cyt) + RT\nNR No No DOD after 10 months\ndue to the tumor\n8 Russell 29 Left Broad\nligament\n7x6x5 N.R. Lower abdominal\npain for 2 months\nand occasional\ndyspareunia\nSurgery (tumour\nresection)\nNR No No Recurrence after\n5 months treated with\nsurgery (hysterectomy,\nbilateral salpingo-\noophorectomy) + RT;\nDied of melanoma after 9 years.\n9 Kerner 32\ngravida\nBroad ligament 15x10x6 and\n10x7x4\nNR Abdominal pain at\n28 weeks\nSurgery (tumour\nresection)\nNo No No AWD omentum and infundibulopelvic\nligament recurrence 22 months later\n10 Vara 62 Bladder – NR Haematuria,\nweight loss,\nsuprapubic pain\nSurgery (radical\ncystectomy +\nurethrectomy)\nNR Yes No FOD 12 months\nMandato et al. BMC Cancer  (2018) 18:134 Page 3 of 18\n\nTable 1 Clinical features of 41 patients with extra-genital mullerian adenosarcoma reported in the English literature and of the index case (Continued)\nReference\nnumber\nAuthor Age\n(years)\nSite Size (cm) Tumour\nmarkers\nSigns and\nSymptoms at\npresentation\nTreatment Sarcomatous\novergrowth\nEndometriosis Hormonal\ntherapy\nFollow-up\n11 Roman 55 Retroperitoneal NR NR NR Surgery (tumour\nresection) + RT\nNR Yes No First abdominal recurrence 3 years later\n(resection by thoracoabdominal\napproach + MPA), a 5 cm perihepatic\nrecurrence 5 years later was completely\nresected, second perihepatic\nrecurrence 7 years from original\ntumour (resection of recurrence and\nTMX), 6 months later intrahepatic\nmetastasis (CHT for recurrences\n(cisplatin-ifosfamide, ifosfamide,\ndoxorubicin), later atrial tumour\n(resection of cardiac tumour and oral\ntherapy with etoposide).\nDied after 10 years from original\ntumour and 70 days after resection of\ncardiac tumour.\n12 De Jonge 16 Pelvic\nperitoneum and\ninfracolic\nomentum\nNR Ca 125 >\n190 U/ml\nSevere Abdominal\ndistension and\npain\nSurgery (tumour\nresection with\nextirpation of pelvic\nmass, left fallopian\ntube, infracolic\nomentum and\nappendix)\nYes No NR Three weeks after primary surgery a\npelvic mass recurred (CHT with\ndoxorubicin and ifosfamide), first\nrecurrence of the pouch of Douglas\n8 months later (CHT cisplatinum,\netoposide and ifosfamide), second\nrecurrence of the pouch of Douglas\n14 months later the first recurrence\n(bilateral salpingo-oophorectomy, ab\ndominal hysterectomy, pelvic and para-\naortic lymphadenectomy and hormonal\ntherapy) FOD 57 months after the last\ncycle of chemotherapy\n13 Benda 65 Vaginal apex 10x7x8 NR Pelvic pressure\nand urinary frequency\nSurgery\n(tumour\nresection)\nNR No No Three years later a 6 cm vaginal\nrecurrence was completely resected;\n5 yrs. after first recurrence a 12 cm\nvaginal recurrence was completely\nresected and a progesterone therapy\nwas delivered; 7 years after the second\nrecurrence a 17 cm pelvic recurrence\nwas partially resected and a TMX\n(2 weeks) therapy followed by P\n(2 weeks) therapy was delivered;\n10 months after the third recurrence a\nfourth pelvic recurrence was partially\nresected and treated with RT.\nAWD 16 years\n14 Ostor 49 Pouch of\nDouglas\n19x8x3 NR Right Iliac fossa\npain\nSurgery (tumour\nresection and\nabdominal\nhysterectomy and\nbilateral salpingo-\noophorectomy) Radio\ntherapy and Hormonal\ntherapy\n(Medroxyprogesterone)\nNR No No AWD recurrence 5 weeks later\n(chemotherapy cisplatin and\nifosfamide). Persistence of some\nnodularity on the pelvic floor\n18 months later\nMandato et al. BMC Cancer  (2018) 18:134 Page 4 of 18\n\nTable 1 Clinical features of 41 patients with extra-genital mullerian adenosarcoma reported in the English literature and of the index case (Continued)\nReference\nnumber\nAuthor Age\n(years)\nSite Size (cm) Tumour\nmarkers\nSigns and\nSymptoms at\npresentation\nTreatment Sarcomatous\novergrowth\nEndometriosis Hormonal\ntherapy\nFollow-up\n15 Inoue 54 Left paracolpium 15x11x10 Ca 125:\n860 U/ml\nBrownish vaginal\ndischarge\nSmall ulcer in the\nleft posterior fornix\nRT+\nSurgery (tumour\nresection+ total\nabdominal\nhysterectomy, bilateral\nadnexectomy,\nabdominal perineal\nresection with\ncolostomy)\nNR Yes No FOD 1 year later\n16 Judson 42 Vaginal cuff 6 × 3 NR Endometriosis\nrecurred three\ntimes and was\ntreated with\nsurgery, hormonal\ntherapy\n(megestrol,\ndanazol) and\nbrachytherapy.\nLesion coming out\nfrom vagina\nCHT (paclitaxel and\ncarboplatin followed by\nTMX)\nNR Yes No 12 months later a 4 cm vagina\nrecurrence was excised and a RT was\ndelivered than was FOD\n17 N ’Senda 54 Liver 20 × 12 CA 15 –3\nand CA\n19–9, were\nthree and\nfourfold\nnormal\nlevel\nrespectively\nRight-sided\nepigastric pain\nSurgery (tumour\nresection: A segment\n-IV enlarged right\nhepatectomy extended\nto adjacent diaphragm)\nNo Yes HRT FOD 24 months\n18 Kato 20 Abdominopelvic\nperitoneum\n23x23x14 CA 125:\n1000 IU/ml\nFatigue and\nconstipation\nSurgery (tumour\nresection)\nNR No No FOD 1 years later\n19a Yantiss 36 Sigmoid 10,5 NR Hypermenorrhoea,\n6 months\nabdominal pain\nSurgery (tumour and\nsigmoid resection)\nNR Yes NR FOD 36 months\n19b Yantiss\n2000\n50 Colon NR NR NR Surgery (tumour and\ncolon resection)\nNR Yes NR FOD 24 months\n19c Yantiss\n2000\n83 Small bowel 15 NR Abdominal mass\nobstruction\nSurgery (tumour and\nbowel resection)\nNR Yes NR NR\n19d Yantiss\n2000\n43 Small bowel 6.5 NR NR Surgery (incomplete\ntumour resection)\nNR NR ER T NR\n20 Visvalingam 50 Abdominopelvic\nperitoneum\n13 kg NV Painless\nabdominal\nswelling\nSurgery (tumour\nresection), Hormonal\ntherapy (progesterone)\nNR No No Ten months later a 50 cm pelvic\nrecurrence was resected (tumour\ndebulking, extrafascial hysterectomy,\nomentectomy, appendicectomy). DOD\n16 months later (Autopsy revealed\ntumor nodules throughout the\nabdominal and pelvic cavity limited\nto the peritoneal surface)\nMandato et al. BMC Cancer  (2018) 18:134 Page 5 of 18\n\nTable 1 Clinical features of 41 patients with extra-genital mullerian adenosarcoma reported in the English literature and of the index case (Continued)\nReference\nnumber\nAuthor Age\n(years)\nSite Size (cm) Tumour\nmarkers\nSigns and\nSymptoms at\npresentation\nTreatment Sarcomatous\novergrowth\nEndometriosis Hormonal\ntherapy\nFollow-up\n21 Anderon 46 Vagina 10 cm NR Removal of the vaginal\nmass, stalk and\nparavaginal tissue.\nNo Yes Yes FOD after a parametrium recurrence\nthat was treated with external\nradiotherapy and interstitial\nbrachytherapy.\n22 Dincer 50 Perisplenic\nPeritoneum\nNR NR Large bowel\nobstruction in a\nwoman with\nEndometriosis\ntreated with\naromatase\ninhibitor\nSurgery (partial tumour\nresection) +\nChemotherapy\n(anthracycline) +\nexperimental anti-\nangiogenesis agent\nYes Yes No DOD 13 months later due to no\nregression of the pelvic tumour\n23 Hines 43 Peritoneum\n(from posterior\ncul-de-sac\nthrough the\nmiddle to upper\nabdomen)\nNR Ca 125:\n824 IU/ml\nDysmenorrhea\nand endometriosis\nSurgery (tumour\nresection) + Hormonal\ntherapy\n(medroxyprogesterone\nacetate)\nNo Yes No FOD 10 months later\n24 Murugasu 23 Pouch of\nDouglas\n11 Ca 125:\n378 IU/ml;\nCEA: 13.\nRight-sided\npelvic pain\nSurgery (tumour\nresection),\nChemotherapy (Mesna,\nadriamycin, ifosfamide),\nRadiotherapy\nYes Yes No FOD 1 years later\n25 Liu 56 Vaginal Vault 16 NR Urinary\nincontinence\nand prolapse in\na woman with\nVaginal\nendometriosis\n(TAH, BSO).\nSurgery (tumour\nresection with adherent\nstructures including\nrectum and part of the\nbladder wall) +\nChemotherapy\n(ifosfamide and\ncisplatin) + Radiotherapy\nNo Yes ERT FOD\n26 Raffaelli 50 Rectovaginal\nseptum\nNot reported NR Deep dyspareunia,\nrectal pain,\nperiovulatory\npelvic pain in a\nwoman with\ndiagnosis of\nendometriosis\nSurgery (Hysterectomy,\nleft salpingo\noophorectomy and\npartial vaginectomy) +\nHormonal therapy\n(megestrol acetate)\nNo Yes No Pelvic recurrence 14 months after first\nsurgery (resection of the mass,\nchemotherapy with ifosfamide and\nepirubicin-stopped due to intolerance-\nand radiotherapy 52,90Gy-stopped due\nto toxic side effect)\nFOD 9 months after the last surgery\n27 Toyoshima 52 Vaginal cuff 11 cm High level\nof Ca125\nNeoadjuvant therapy\nand surgical removal of\nthe tumour, the vaginal\nwall and the greater\nomentum\nYes Yes No After a month the first lung recurrence\ntreated with chemotherapy, and then a\nsecond abdominal recurrence treated\nwith chemotherapy. DOD after\n9 months from surgery\n28 Kanngurn 48 Pelvic\nperitoneum\n26x26x10 cm NR Right lower\nquadrant pain\nSurgery (tumour\nresection, Hysterectomy,\nbilateral salpingo\noophorectomy) +\nChemotherapy\n(Bleomycin, Etoposide and\nCisplatinum × 7 cycles).\nYes No No Abdominal recurrence 8 months later\nduring the fourth cycle of therapy (13,\n5 × 7, 8 × 13 cm), lost at follow-up.\nMandato et al. BMC Cancer  (2018) 18:134 Page 6 of 18\n\nTable 1 Clinical features of 41 patients with extra-genital mullerian adenosarcoma reported in the English literature and of the index case (Continued)\nReference\nnumber\nAuthor Age\n(years)\nSite Size (cm) Tumour\nmarkers\nSigns and\nSymptoms at\npresentation\nTreatment Sarcomatous\novergrowth\nEndometriosis Hormonal\ntherapy\nFollow-up\n29 Chang 37 cul-de-sac 3.5 NR Vaginal bleeding in\na woman with\nendometriosis\n(TAH, BSO and\nhormonal therapy)\nSurgery (resection of\ncul-de-sac tumour, left\nanterior proctectomy,\ncoloanal anastomosis)\nNo yes yes FOD 36 months\n30 Milam 47 Right inguinal\nchannel\n12 × 4 CA 125:\n76,8\nPersistent and enlarged\ngroin mass\nSurgery (tumour\nresection)\nNo Yes HRT FOD 12 months later\n31 Huang 41 Mesentery of the\nterminal ileum,\nright colon and\npelvic sidewall\n10 NV Right lower\nquadrant pain and\nnausea\nSurgery (TAH,\nbilateral salpingo\noophorectomy,\nomentectomy,\nresection of cul-de-sac\nand sigmoid colon\nnodules, and pelvic and\npara-aortic lymph node\ndissection) + Chemo\ntherapy (ifosfamide+\ncisplatin)\nNo Yes No Peritoneal recurrence at 1 month and\nchemotherapy (liposomal doxorubicin)\nFOD for 18 months\n32 Han 34 Vagina 7 × 6 High value Tumour resection,\nhysterectomy and\nbilateral salpingo-\noophorectomy\nNo Yes No The patient had 4 vaginal recurrences.\nThe first was treated with\nchemotherapy, the second was treated\nwith surgery, the third with surgery\nand adjuvant therapy and the fourth\nwith chemotherapy. FOD\n33 Maeda 47 Left pelvic side\nwall\n3 NR (LDH\nlevel\n993 IU/ml)\nAcute lower\nabdominal pain\ndue to\npedunculated\nsubserosal myoma\nSurgery (tumour\nresection, bilateral\nsalpingo-\noophorectomy, total\nabdominal\nhysterectomy)\nYes Yes TMX Four weeks later 8 cm recurrent tumour\nin the right pelvis treated with salvage\nsurgery. One month after second\nsurgery recurrent tumour in pelvis and\nupper abdomen that was treated with\nsalvage chemotherapy (liposomal\ndoxorubicin), 5 cycles). FOD three\nmonths after chemotherapy.\n34 Patrelli 49 Pouch of\nDouglas\n10 × 6 CA 125\nand Ca 19 –\n9 slightly\nelevated\nPelvic pain Surgery (tumour\nresection)\nYes No No Eighteen months later recurrence of\nposterior vaginal fornix (resected),\n6 months after recurrence another\nposterior vaginal fornix recurrence\n(radical hysterectomy with bilateral\nsalpingo-oophorectomy, and pelvic\nlymphadenectomy and Radiotherapy-\n50Gy-) FOD\n35 Clarke 50 Pelvic\nperitoneum\n(partially\nadherent to the\nposterior uterine\nserosa)\n34x14x7 NR NR Surgery (omentectomy,\nappendicectomy,\nremoval of small bowel\nmesenteric implants)\nNR NR NR\n36 Karateke 26 Pouch of\nDouglas\n18 NR Lower abdominal\ndistention and left\nlower quadrant pain\nSurgery (tumour\nresection)\nNo Yes No FOD 24 months later\nMandato et al. BMC Cancer  (2018) 18:134 Page 7 of 18\n\nTable 1 Clinical features of 41 patients with extra-genital mullerian adenosarcoma reported in the English literature and of the index case (Continued)\nReference\nnumber\nAuthor Age\n(years)\nSite Size (cm) Tumour\nmarkers\nSigns and\nSymptoms at\npresentation\nTreatment Sarcomatous\novergrowth\nEndometriosis Hormonal\ntherapy\nFollow-up\n37 Yang 36 Rectum 2,5 × 2 NR Loose stool,\ndysmenorrhea,\ndeep dyspareunia,\nhaematochezia\nSurgery (tumour\nresection)\nNo Yes No FOD 60 months\n38 Kar 30 Omentum NR NR Abdominal\ndistension due to\nabdominal mass\nand free fluid\nSurgery (hysterectomy,\nbilateral salpingo\noophorectomy,\nomentectomy) and\npreoperative\nchemotherapy\nYes Yes No NR\n39 Pontrelli 58 Vagina 5 cm NR Bleeding vaginal\nlesion\nVaginectomy and\nparametrectomy using\nthe laparoscopic\napproach, total\ncolpectomy and partial\ncystectomy. After that\nthe patient was\ncandidate for progestin\ntherapy.\nYes Yes Yes FOD at November 2016\n40 Mandato 79 Abdominal\nPeritoneum\n16 × 11 NV Abdominal distension Surgery (tumour\nresection, bilateral\nsalpingo-\noophorectomy, total\nhysterectomy)\nResidual absent\nYes No No 4 weeks later had a pelvic recurrence; DOD\n4 months after diagnosis\nAbbreviations: 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,\nRT radiotherapy, Cyt cyclophosphamide, MPA medroxyprogesterone acetate\nMandato et al. BMC Cancer  (2018) 18:134 Page 8 of 18\n\nShe complained only of abdominal distension and pressure.\nA transvaginal and transabdominal ultrasound examination\nrevealed a multicystic mass resembling an ovarian tumour\narising from the pelvis and extending up to the abdomen.\nThree weeks later, a laparotomy was performed, and a peri-\ntoneal mass arising from Dou glas peritoneum was found\nand resected. The uterus and adnexa appeared normal, and\na supra-cervical hysterectomy with bilateral salpingo-\noophorectomy was performed. On frozen sections, the\nmass was identified as a primary sarcoma of the periton-\neum with areas of chondroliposarcoma and rhabdomyosar-\ncoma differenzation. No macroscopic residual disease was\npresent (R0). Final pathologydiagnosed a malignant periph-\neral nerve sheath tumors with divergent differentiation\n(osteosarcoma, chondrosarcoma, angiosarcoma rhabdo-\nmyosarcoma, glandular component), grade 3 according to\nthe French Federation of Cancer Centers Sarcoma Group\n(FNCLCC) grading system.\nAdjuvant chemotherapy was planned. Four weeks later,\na pre-chemotherapy CT scan revealed a new, multicystic\nmass (27 × 15 cm) (Fig. 2) with impregnation of the wall,\nstrictly adhering to the inferior side of the sigmoid colon\nand cecal profile and to the superior side of the bladder.\nThe mass protruded into the left inguinal canal by 2 cm.\nThe patient presented with bilateral hydroureterone-\nphrosis, fever due to wound infection, loss of appetite\nand weakness. Antibiotic therapy, bilateral stents, and\nsupport therapy were administered. Due to the progres-\nsive poor condition, the patient died 4 months after\ndiagnosis. Histological slides were reviewed by two ex-\nternal independent expert pathologists (A.P. Dei Tos,\nChief of Department of Pathology, Treviso Regional\nHospital, Treviso, Italy. C.D.M. Fletcher, Chief of Surgi-\ncal Pathology, Brigham And Women ’s Hospital, Boston,\nUSA) and the final diagnosis was of extra-genital AS\nwith sarcomatous overgrowth (Figs. 3 and 4).\nResults\nClinical features\nTable 1 shows the main clinical features of all 41 AS\ncases reported in literature and of our case.\nThe 41 affected patients ranged in age from 16 to\n83 years (mean, 44.5 years) at presentation, and 2/41\n(4.9%) patients were pregnant at the time of diagnosis.\nOverall, 12/32 (37.5%) patients presented with an extra-\ngenital AS arising from the pelvic peritoneum, 5/32 (15.6%)\npresented with an AS arising from the pouch of Douglas,\n2/32 (6.3%) presented with an AS arising from the retroper-\nitoneum, 3/32 (9.4%) presented with an AS arising from the\nbroad ligament, 3/32 (9.4%) presented with an AS arising\nfrom the colon, 2/32 (6.3%) presented with an AS arising\nfrom the small bowel, 1/32 (3.1%) presented with an AS\narising from the bladder, 1/32 (3.1%) presented with AS\narising from the omentum, 1/ 32 (3.1%) presented with an\nAS arising from the inguinal canal, 1/32 (3.1%) presented\nwith an AS arising from the liver, and 1/32 (3.1%) presented\nwith an AS arising from the mesentery of the terminal\nileum. Overall, 9/41 (21.9%) patients had an AS localized in\nthe vagina: 7/9 (77.8%) cases were in the vaginal cuff, 1/9\n(11.1%) case was in the paraco lpium, and 1/9 (11.1%) case\nwas in the recto-vaginal septum.\nInformation on tumour size was available for 33/41\n(80.5%) patients. The sized ranged from 2.5 to 34 cm\nwith a mean size of 12.2 cm (SD +/ − 6.0). Tumour\nweight was reported for 1 case (13 k) [ 20].\nSymptoms were reported for 34/41 (82.9%) patients.\nAbdominal/pelvic pain was reported for 14/34 (41.2%)\npatients, urinary disorders for 9/34 (26.5%), anorexia-\nweight loss for 3/34 (8.8%), abdominal pressure for 3/34\n(8.8%), dysmenorrhea for 2/34 (5.9%), bleeding for 4/34\n(11.8%), constipation for 1/34 (2.9%), low back pain for\n1/34 (2.9%), fatigue for 1/34 (2.9%) and thrombophlebitis\nfor 1/34 (2.9%).\nFig. 2 Pre-chemotherapy computed tomography scan taken 4 weeks\nafter surgery revealing a new, multicystic mass (27 × 15 cm)\nFig. 1 Computed tomography scan showing a mass of 16 × 11 cm\nMandato et al. BMC Cancer  (2018) 18:134 Page 9 of 18\n\nTumor markers were reported in 13/41 (31.7%) patients,\ntwo patients had normal value [ 20, 31] and 11 patients\nhad elevated value [ 12, 15, 17, 18, 23, 24, 27, 30, 32–34]\n(T able 1). Seven of eleven (63.6%) patients had elevated\nserum levels of CA 125 [ 12, 15, 18, 23, 27, 30, 32], 2/11\n(18.2%) patients had elevated serum levels of both CA 125\nand CA 19 –9[ 17, 34], 1/11 (9.1%) patient had elevated\nserum levels of both CA125 and CEA [ 24], 1/11 (9.1%)\nhad elevated serum level of LDH [ 33].\nOverall, 8/41 (19.5%) patients had received hormonal\ntherapy: two patients received hormone replacement ther-\napy (HRT) [ 17, 30], two patients received oestrogenic re-\nplacement therapy [19d,25], one patient received\ntamoxifen [ 16], one patient received oestrogen-progestin\ntherapy [ 39], and in two patients the hormonal therapy\nwas not specified [21, 29].\nTreatment\nAS was treated by surgical resection in 38/41 (92.7%) pa-\ntients: 5/38 (13.2%) patients underwent partial resection,\nand 33/38 (86.8%) underwent total resection. Of the 38\npatients who received surgical treatment, 18 (47.4%)\nunderwent resection of only the tumour [5abc, 7, 8, 9,\n11, 13, 18, 19d, 20, 22, 23, 24, 30, 34, 36, 37]; four\n(10.5%) underwent tumour resection, hysterectomy and\nbilateral salpingo-oophorectomy [ 14, 28, 32, 38]; and 16\n(42.1%) underwent extensive surgery involving other or-\ngans such as the bowel [12, 15, 19a, 19b, 19c, 25, 29, 31,\n35] and liver [ 17].\nMoreover, 12/38 (31.69%) patients had received\nprevious total hysterectomy with bilateral salpingo-\noophorectomy for benign disease [5A, 5B, 5C, 6,\n10,11,13,16,17,22,25, 29]; 15/38 (39.5%) patients re-\nceived total hysterectomy with bilateral salpingo-\noophorectomy for AS treatment [8,14,15,19A,19B,\n20,22,23,26,28,30 –33, 35,38]. Particularly, 13 patients\nwere younger than 40 years at the diagnosis of AS and\n4/13 (30.8%) underwent total hysterectomy with bilat-\neral oophorectomy for AS tr eatment. In 13/41 (31.7%)\npatients menopausal status was not reported. More-\nover, 17/41 (41.5%) [5a –c, 6, 10, 11, 13,16, 17, 19c, 21,\n22, 25, 27, 29, 30, 39] patients were in postmenopausal\nFig. 4 (a) Small areas with rhabdomyoblastic differentiation within the\nspindle cell areas (myogenin immunostain, haematoxylin counterstain,\n20X); (b) Epithelial clefts within the neoplastic undifferentiated spindle cells\nhighlighted by PAX8 immunohistochemical stain (PAX8 immunostain,\nhaematoxylin counterstain, 20X)\nFig. 3 Medium-power view of the neoplasia, showing both the epithelial\ncomponent and the undifferentiated spindle cell component, admixed\nwith areas of cartilaginous differentiation (haematoxylin-eosin stain, 10X)\nMandato et al. BMC Cancer  (2018) 18:134 Page 10 of 18\n\nstage, 11/41 (26.8%) patien ts were at premenopausal\nstage [ 4, 8, 9, 12, 14, 18, 24, 31, 36–38] and 4/11\n(36.4%) received bilateral salpingo-oophorectomy dur-\ning AS treatment [ 8, 14, 31, 38].\nOverall, 16/38 (36.6%) surgical patients received add-\nitional therapy: 13/38 (34.2%) received adjuvant therapy,\nand 3/38 (7.9%) received neo-adjuvant therapy [5a, 7, 11,\n14, 20, 22,23, 24, 25, 26, 28, 31, 39]. Additionally, 3/38\n(7.9%) patients received chemotherapy [ 22, 28, 31], 2/38\n(5.3%) patients received radiotherapy [5a, 11], 3/13\n(7.9%) patients received chemo-radiotherapy [ 7, 24, 25],\n4/38 (10.5%) patients received hormonal therapy [ 20, 23,\n26, 39], and 1/38 (2.6%) patient received radiotherapy\nand hormonal therapy [ 14]. In total, 2/38 (5.3%) patients\nwere treated with neoadjuvant chemotherapy [14\n(methotrexate), 27], and 1/38 (2.6%) patient was treated\nwith neoadjuvant radiotherapy [ 15].\nAS was not treated with surgery in 3/41 (7.3%) pa-\ntients. In the first patient AS was misdiagnosed with cor-\niocarcinoma and was treated with chemotherapy but at\npostmortem examination the final diagnosis of retroperi-\ntoneal AS was done [ 4]. The second patient had received\na hysterectomy for leiomyoma twenty years before\nunderwent to diagnostic laparoscopy for right pelvic\nmass. At laparoscopy both ovaries were normal and a bi-\nopsy of the mass diagnosed an AS. The second patient\nwas treated with only radiotherapy [ 6]. The third patient\nhad received a hysterectomy for leiomyoma 4 years be-\nfore multiple vaginal operations for recurrent vaginal\nendometriosis were performed [ 16]. The third patient\nwas treated with chemotherapy and hormonal therapy\n(tamoxifen) [ 16].\nRisk factors\nA total of 25/41 (61.0%) patients had received a previous\ndiagnosis of endometriosis [5c-10-11-15-16-17-19abc-21-\n22-23-24-25-26-27-29-30-31-32-33-36-37-38,39] (T able2).\nEndometriosis treatment was not reported for 18/25\n(72%) patients [5c,10,11,15,17,19abc,23,24,26,30,31,33,36\n,37,38], endometriosis was s urgically and hormonally\ntreated in 2/25 (8%) patients [ 29, 39], it was treated surgi-\ncally in 3/25 (12%) patients [ 21, 25, 27], it was treated hor-\nmonally (aromatase inhibitor) in 1/25 (4%) patient [22], and\nit was treated with surgery, hormonal therapy and brachy-\ntherapy in 1/25 (4%) patient [ 16]. Overall, 17/25 (68%)\npatients with endometriosis h ad an AS with extra-genital\nlocalization [5c-10-11-17-19abc-22-23-24-29-30-31-33-36-\n37-38], and 8/25 (32%) patients had a vaginally localized\ntumour [15–16–21-25-26-27-32-39]. Moreover, 8/25 (32%)\npatients showed elevated levels of tumour markers [ 15, 17,\n23, 24, 27, 30, 32, 33]. A total of 7/25 patients received pre-\nvious hormonal therapy [ 17, 21, 25, 29, 30, 33, 39]: 2/7\n(28,6%) received HRT [ 17, 30], 1/7 received (14.3%) ERT\n[25], 1/7 (14.3%) received TMX [ 33], 1/7 (14.3%) received\noestrogenic-progestinic therapy [ 39], and 2/7 (28,6%)\nreceived unspecified hormonal therapy [21, 29].\nOverall, 6/25 (24%) patients with endometriosis showed\nsarcomatous overgrowth [22, 24, 27, 33, 38, 39]: 13/25 (52%)\nwere only surgically treated [5c-10-17-19abc-21-29-30-32-\n33-36-37], 10/25 (40%) were treated with surgery and adju-\nvant therapy [11 –15–22-23-24-25-26-31-38-39], 1/25 (4%)\nwas treated with neoadjuvant chemotherapy and surgery\n[27], and 1/25 (4%) was treated with chemotherapy and\nhormonal therapy without surgery [16].\nHeterologous sarcomatous elements were present in 4/41\n(9.7%) patients [9, 12, 16, 18], endometriosis was present in\none patient [16,], sarcomatou s overgrowth was present in\none patient [ 12], surgery was performed in three cases [ 9,\n12, 18], one case received chemotherapy and tamoxifen [16].\nFollow-up data\nFollow-up information was available for 35/41 (85.4%)\npatients (Table 2); 1/41 (2.4%) patient died from a cause\nother than AS, and 5/41 (12.2%) were lost to follow-up.\nAt the time of follow-up, 22/35 (62.9%) patients were\nalive and free of disease (FOD), 9/35 (25.7%) patients\nhad died of disease (DOD), and 4/35 (11.4%) patients\nwere alive with disease (AWD).\nIn the group of nine DOD patients, 4/9 (44.4%) patients\ndied for relapse [5a,11, 20, 27], 1/9 (11.1%) [7] died for pro-\ngression of disease, 1/9 (11.1% ) patient died for treatment\ncomplication (postoperatively massive gastric bleeding) [5b],\n1/9 (11.1%) patient died for per sistent pelvic tumor [22r]\nand 2/9 (22.2%) patients died for distant metastasis [4, 6].\nInformation on follow-up time was available for 34\npatients: the mean follow-up was 27 months (range, 1 –\n192). Eighteen patients relapsed [5a, 5c, 8, 9, 11, 12, 13, 14,\n16, 20, 21, 26, 27, 28, 31, 32, 33, 34], and their mean DFS\nwas 11.8 months (range, 1 –36). Two cases were lost to\nfollow-up after recurrence. For the 9/35 (5.7%) patients\nwho died due to disease [4, 5a, 5b, 6, 7, 11, 20, 22, 27], 8/9\n(88.9%) patients had extra-genital AS, and 1/9 (11.1%) had\nvaginal AS [ 27]. Additionally, 2/9 (22.2%) patients showed\nboth sarcomatous overgrowth and endometriosis [ 22, 27].\nNone of these patients received previous hormonal ther-\napy. Of the patients who died because of AS, 4/9 (44.4%)\nhad experienced a relapse [5a, 11, 20, 27]. The number of\nrelapses ranged from one to five with a mean of two. The\nmost common localization for first relapse was the pelvis,\nbut one patient ’s first relapse was in the lung [ 27]. In\ntotal, 2/4 (50%) patients with relapse were surgically\ntreated [ 11, 20], 1/4 (25%) was not treated [5a], and 1/4\n(25%) received only chemotherapy. One patient [ 11]r e -\nlapsed additional times at prehepatic/intrahepatic sites\nand in the heart and received multimodal treatment;\nanother patient [ 27] had a second abdominal recur-\nrence and was treated with chemotherapy. Of the pa-\ntients who died from disease, the mean OS was\nMandato et al. BMC Cancer  (2018) 18:134 Page 11 of 18\n\n20.1 months (range, 2 –120), and of the subgroup of pa-\ntients who died after recurrence, the mean DFS was\n14 months (range, 1 –36). At the time of publication, 4/\n36 (11.1%) patients were alive with disease [5c, 9, 13,\n14]: 3/4 (75%) had an AS with extra-genital localization\n[5c, 9, 14], and 1/4 (25%) had an AS with vaginal\nlocalization [ 13]. None experienced sarcomatous over-\ngrowth, and 1/4 (25%) had a previous diagnosis of\nendometriosis [5c]. None had previously received hor-\nmonal therapy. All patients alive with disease had at\nleast one relapse. The number of relapses ranged from\none to four with a mean of 2.2 (Table 2). Overall, 22/35\n(62.9%) patients were FOD at the time of publication.\nOf these, 14/22 (63.6%) had not experienced relapse\n[10, 15, 17, 18, 19ab, 23, 24, 25, 29, 30, 36, 37, 39], 11/\n14 (78.5%) had an AS with extra-genital localization\n[10, 17, 18, 19ab, 23, 24, 29, 30, 36, 37], 3/14 (21.4%)\nhad an AS with vaginal localization [ 15, 25, 39], 2/14\n(14.3%) had a tumour with sarcomatous overgrowth\n[24], 13/14 (92.8%) had a previous diagnosis of endo-\nmetriosis [10, 15, 17, 19ab, 23, 24, 25, 29, 30, 36, 37,\n39], 9/14 (64.3%) were only surgically treated [10, 17,\n18, 19ab, 29, 30, 36, 37], and 5/14 (35.7%) were treated\nwith surgery and adjuvant therapy [ 15, 21, 24, 25, 39].\nAdditionally, 5/14 (35.7%) had previously underwent\nhormonal therapy [ 17, 25, 29, 30, 39]. Information on\nTable 2 Clinical features and follow up data of 41 extra-uterine and extra-ovarian mullerian adenosarcoma according to histological features\nTotal\npopulation\nEndometriosis P value Overgrowth P value Heterologous\nsarcomatous differentiation\nP value\nn =4 1\nn (%)\nNo n =1 6\nn (%)\nYes n =2 5\nn (%)\nNo n =3 2\nn (%)\nYes n =9\nn (%)\nNo n =3 7\nn (%)\nYes n =4\nn (%)\nAge (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\nSize (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\nSite 0.066 1 1\nExtra-genital 32 (78.0) 15 (93.8) 17 (68.0) 25 (78.1) 7 (77.8) 29 (78.4) 3 (75.0)\nVagina 9 (22.0) 1 (6.2) 8 (32.0) 7 (21.9) 2 (22.2) 8 (21.6) 1 (25.0)\nEndometriosis 1 0.281\nNo 16 (39.0) ––– 13(40.6) 3 (33.3) 13 (35.1) 3 (75.0)\nYes 25 (61.0) ––– 19 (59.4) 6 (66.7) 24 (64.9) 1 (25.0)\nOvergrowth 1 1\nNo 32 (78.0) 13 (81.3) 19(76.0) –– 29 (78.4) 3 (75.0)\nYes 9 (22.0) 3 (18.7) 6 (24.0) –– 8 (21.6) 1 (25.0)\nTreatment 0.557 1 0.101\nSurgery 22 (53.7) 9 (56.3) 13 (52.0) 18 (56.3) 4 (44.4) 19 (51.4) 3 (75.0)\nSurgery + additional\ntreatments\n16 (39.0) 5 (31.2) 11 (44.0) 11 (34.4) 5 (55.6) 16 (43.2) 0 (0.0)\nNo Surgery 3 (7.3) 2 (12.5) 1(4.0) 3 (9.4) 0 (0.0) 2 (5.4) 1 (25.0)\nSurgical Approach 0.345 1 0.327\nComplete resection 33 (80.5) 11 (68.8) 22 (88.0) 25 (78.1) 8 (88.9) 30 (81.1) 3 (75.0)\nPartial resection 5 (12.2) 3 (18.7) 2 (8.0) 4 (12.5) 1 (11.1) 5 (13.5) 0 (0.0)\nNo surgery 3 (7.3) 2 (12.5) 1 (4.0) 3 (9.4) 0 (0.0) 2 (5.4) 1 (25.0)\nLost in follow up 6 (14.6) 4 2 4 2 6 0\nStatus at last follow up\n(35 patients)\n0.002 0.843 0.278\nFOD 22 (62.9) 3 (25.0) 19 (82.6) 17 (60.7) 5 (71.4) 19 (61.3) 3 (75.0)\nAWD 4 (11.4) 3 (50.0) 1 (4.3) 4 (14.3) 0 (0.0) 3 (9.7) 1 (25.0)\nDOD 9 (25.7) 6 (25.0) 3 (13.0) 7 (25.0) 2 (28.6) 9 (29.0) 0 (0.0)\nRecurrence 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\nMore 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\nDeath 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 – *\nPatients with recurrence DFS\n(mean ± sd)\n47.9 ± 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\nAWD alive with disease, DOD died of disease, FOD free of disease\n*comparison was not possible, because no patients with heterologous sarcomatous differentiation dead during follow up\nMandato et al. BMC Cancer  (2018) 18:134 Page 12 of 18\n\nfollow-up time was available for 13 patients, and the\nmean follow-up was 21.9 months (range, 1 –60 months).\nA total of 8/22 (36.4%) patients were alive and FOD\ndespite having one or more relapses during follow-up\n[12, 16, 20, 26, 31, 32 33, 34]. Their number of relapses\nranged from one to four with a mean of 1.8. In 3/8\n(37.5%) patients, the first relapse was in the pelvis\n[12, 26, 33]; in 1/8 (12.5%) patient, it was in the peri-\ntoneum [ 31]; in 3/8 (37.5%) patients, it was in the va-\ngina [ 16, 32, 34]; and in 1/8 (12.5%) patient, it was in\nthe parametrium [ 21]. The first relapse was surgically\ntreated in 2/8 (25%) patients [ 33, 34], it was treated\nwith surgery and adjuvant therapy in 2/8 (25%)\npatients [ 16, 26], and it was treated with only chemo-\ntherapy [12, 31, 32] or only radiotherapy and brachyther-\napy [21] in 4/8 (50%) patients. Overall, 4/8 (50%) patients\nexperienced a second relapse [ 12, 32–34]: 1/4 (25%) pa-\ntient ’s second relapse location was in the pouch of\nDouglas [ 12], 1/4 (25%) patient ’s relapse was in the\npelvic peritoneum [ 33], and 2/4 (50%) patients ’ re-\nlapses were in the vagina [ 32, 34]. In 2/4 (50%) pa-\ntients, the second recurrence was treated only with\nchemotherapy [ 12, 33], whereas in 1/4 (25%) patient,\nit was treated with surgery a nd adjuvant therapy, and\nin 1/4 (25%) patient, it was surgically treated. In total,\n2/8 (25%) patients had a third relapse: one was in the\npouch of Douglas and was treated with surgery and\nhormonal therapy [ 34], and the other was in the va-\ngina and was treated with surgery and adjuvant ther-\napy [ 32]. Finally, 1/8 (12.5%) patient experienced a\nfourth vaginal relapse that was treated only with adju-\nvant therapy [ 32].\nInformation on follow-up time was available for six\npatients. They had a mean DFS of 7.8 months (range, 1 –\n18 months) and a mean total follow-up of 21.7 months\n(range, 1–57).\nOf the FOD patients who experienced at least one recur-\nrence during follow-up, 4/8 (50%) had AS with a peritoneal\nlocalization [12, 31, 33, 34] and 4/8 (50%) with a vaginal\nlocalization [16, 21, 26, 32], 3/8 (37.5%) showed sarcoma-\ntous overgrowth [12, 33, 34], and 6/8 (75%) had a diagnosis\nof endometriosis [ 16, 21, 26, 31–33]. In total, 5/8 (62.5%)\npatients were only surgically treated [ 12, 21, 32–34], 2/8\n(25%) were treated with surg ery and adjuvant therapy\n[26, 31], and 1/8 (12.5%) was treated only with chemo-\ntherapy and hormonal therapy [ 16]. Additionally, 2/8\n(25%) had previously received hormonal therapy.\nKaplan Meier curves were used to evaluate the impact of\nAS pathological characteristics(endometriosis, sarcomatous\novergrowth and site of localization) and AS treatment (no\nsurgery, surgery, complete rese ction, partial resection and\nadjuvant therapy) on OS (Fig. 5)a n dD F S( F i g .6). Statistical\ncomparison of OS Kaplan Meier curves showed a significant\ndifference in survival distribution (log-rankP value = 0.005)\nbetween patients who received different therapy; in particu-\nlar patients who received only surgery showed a trend of\nsurvival higher than those who received both surgery adju-\nvant therapy or only adjuvant therapy (Fig. 5d). Moreover,\npatients with AS treated with complete resection presented\nbetter OS than women with partially resected AS or not sur-\ngically treated AS (log-rankP value = 0.0005) (Fig.5e).\nEvaluation of Kaplan Meier curves referred to DFS\nshowed a significant difference in DFS distribution be-\ntween patients presenting or not presenting a previous\ndiagnosis of endometriosis (log-rank P value = 0.020).\nEndometriosis resulted to improve DFS of patients with\nextra-uterine AS (Fig. 6a).\nDiscussion\nSince 1974, when the first case of an extra-uterine AS\nwas described by Clement and Scully, only 41 cases of\nextra-uterine or extra-ovarian AS have been reported\n[3–34] (Table 1).\nHere, we reported on 32/41 (78.0%) patients with\nextra-genital AS and 9/41 (22.0%) patients with vaginal\nAS. The mean age was 44.5 years (range, 16 –83 years;\nSD +/ − 15). The extra-genital AS patients had a mean\nage of 42.8 years (range, 16 –83; + − 14.7), and the vagi-\nnal AS patients had a mean age of 50.8 years (range, 42 –\n65 years; SD +/ − 9.2). According to previous studies,\nextra-uterine AS occurs in younger women than uterine\nAS (median age, 58 years) [ 1–37].\nUnlike prior studies of uterine AS, for which bleeding\nwas the most common presentation symptom [ 1, 37], in\nour review, the most common presentation symptom re-\nsulted from the large abdominal masses of the AS growths\nin some patients, with some tumours reaching a size of\n34 cm [ 35]o r1 3k[ 20]. Typically, extra-uterine AS is a\nlarge, partly cystic mass with an irregular and lobulated\nsurface [1]. Heterologous elements have been reported in\nAS from all sites [ 22], which might cause misdiagnosis of\nchondroliposarcoma of the peritoneum. It should also be\nconsidered that evaluations of frozen sections are less\neffective when dealing with a huge mass (maximum size:\n27 cm). Heterologous elements may portend a poorer\nprognosis, particularly the rhabdomyoblastic differentiation\n[46]. Four AS patients included in our review presented\nheterologous elements [9, 12, 16, 18]. They were younger\nthan other AS patients, although 75% of patients recurred\n[9, 12, 16], 75% of patients were FOD [ 12, 16, 18]a tl a s t\nfollow-up (T able2).\nCA 125 was reported in 13/41 (31.7%) patients and\nwas found to be greater in 11/13 (84.6%) patients, sug-\ngesting an association with peritoneal involvement and\nsarcomatous overgrowth, as reported by Inoue [ 15]. In\nprior studies, CA 125 was reported in 5/10 (40%)\npatients [ 12, 24, 27, 33] ,a n di tw a sf o u n da th i g hl e v e l s\nin 4/4 (100%) patients [ 12, 23, 27, 30]. CA 125 titres\nMandato et al. BMC Cancer  (2018) 18:134 Page 13 of 18\n\nhave been well correlated with the clinical course of\nendometriosis associated with extra-uterine AS [ 30]. In\nour review, endometriosis was associated with AS in\n25/41 (61%) patients, being present in 8/9 (88%) pa-\ntients with vaginal AS and in 17/33 (51.5%) patients\nwith extra-genital AS.\nAS is the second most commo n gynaecological malig-\nnancy in patients with endometriosis after clear cell carcin-\noma of the ovary [ 30, 47]. A review of pathologic slides\nfrom 1000 cases of surgically proven endometriosis found a\n0.3% rate of AS in cases of extra-ovarian endometriosis [30,\n47]. In 2000, Zanetta suggested that chronic stimulation\nfrom endogenous or exogenous oestrogen may increase the\nlikelihood of endometriosis-associated carcinogenesis [48].\nIn our review, only 8/41 (19.5%) patients received hor-\nmonal therapy [17, 19d, 21, 25, 29, 30, 33,39] such as\nHRT [ 17, 30] ERT [19d, 25] or tamoxifen [ 16]. However,\nwe identified only two patients with AS associated with\nsevere refractory endometriosis who required surgery\nwith hormonal therapy [ 29] and one patient who\nFig. 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\nextra-uterine AS\nMandato et al. BMC Cancer  (2018) 18:134 Page 14 of 18\n\nrequired surgery with hormonal therapy and brachyther-\napy [ 16]. Nevertheless, old, recurrent and symptomatic\nendometriosis should be carefully monitored and pos-\nsibly excised radically [ 49].\nAlthough endometriosis may be involved in extra-\nuterine AS tumourigenesis, it is considered a favourable\nprognostic factor for this tumour type [ 29, 30]. Patients\nwith AS associated with endometriosis showed increased\nDFS than AS patients without endometriosis (Fig. 6a).\nNo endometriosis was found in our patient. In cases of\nextra-genital AS without en dometriosis, the tumour may\narise from pluripotent mesothelial and mesenchymal cells in\nt h ep e l v i cc a v i t y[5]. Our patient presented with an extra-\ngenital AS with sarcomatous overgrowth. Sarcomatous over-\ngrowth is characterized by the presence of a high-grade\nsarcomatous component in at least 25% of the tumour [ 42]\nand is associated with poor prognosis for both uterine and\nextra-uterine AS. In our review, patients with sarcomatous\novergrowth showed a worse DFS than patients without\novergrowth but log-rank P value between curves did not re-\nsult completely significant (Fig.6b).\nIn a recent retrospective study, patients with uterine\nAS showed a median OS of 161 months [ 43]. As\nreported by Murugasu [ 24], extra-genital AS is more ag-\ngressive than uterine AS, with AS recurring in 60% of\nextra-genital AS patients compared with 23% of uterine\nAS patients. In our review, 12/28 (42.9%) patients with\nextra-genital AS relapsed. Haematogenous metastases\nhave been found in 33% of extra-genital AS patients\ncompared to 2% of uterine AS patients. Death due to\ntumour occurred in 40% of extra-genital AS patients\ncompared to 10% of uterine AS patients [ 24]. In our re-\nview, 8/28 (28.6%) patients with extra-genital AS died of\ndisease. The aggressiveness of extra-genital AS may be\ndue to failure of the uterine myometrial wall as a barrier.\nExtra-genital AS is typically quite large at presentation\nand can easily spread to the peritoneum, to abdominal\nand pelvic organs, and to blood vessels. For this reason,\nit can easily cause bowel obstruction, and complete\ncytoreduction is not always easily achieved.\nSurgical treatment, particularly complete surgical re-\nsection, represents the best course of action for AS. Pa-\ntients with extra-uterine AS who received only surgery\nremained free of disease and never relapsed after treat-\nment. Patients who underwent complete resection\nshowed a better OS distribution than patients who\nFig. 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\nwith extra-uterine AS\nMandato et al. BMC Cancer  (2018) 18:134 Page 15 of 18\n\nunderwent partial resection (Fig. 5e). Endometriosis, sar-\ncomatous overgrowth, tumour size and age were not\ncorrelated with resection type. Because the number of\npatients who were not surgically treated was small, these\nresults require further confirmation.\nMoreover, survival seems to be not improved by bilateral\nsalpingooophorectomy. Ovarian preservation for uterine or\ncervical AS may be feasible among premenopausal women.\nIndeed, women who underwent hysterectomy with salpin-\ngooophorectomy for uterine AS did not have longer sur-\nvival than women who underwent only hysterectomy [ 43].\nThis finding was not tested in our review because we had a\nlot of missing data about postmenopausal status.\nThe OS of AS patients who received only surgery\nresulted more favourable than that of patients who re-\nceived surgery with additional treatment or who did not\nundergo surgery (Fig. 6b). Probably, patients submitted\nto an exclusive surgery presented a completely resectable\ndisease thanks to the biology of tumor or to the skills of\nsurgeon. However, there were no differences in DFS be-\ntween these three groups (Fig. 6b).\nDifferent adjuvant treatments were delivered. Three\npatients received chemotherapy alone (anthracycline\nwith an anti-angiogenesis agent [ 22]; bleomycin, etopo-\nside and cisplatinum [ 28]; ifosfamide with cisplatin [ 31]),\n3 received chemotherapy associated with radiotherapy\n(cytoxan + 4000 rad of radiotherapy [ 7]; mesna, adriamy-\ncin, ifosfamide, carboplatinum and pelvic radiotherapy\n[24]; ifosfamide and cisplatin plus pelvic radiotherapy\n[25]), and two received only radiotherapy [5a-11].\nUnfortunately, our review was limited by the low num-\nber of AS cases, by the lack of data and by short follow-up\ntime reported in literature therefore statistical analysis was\nlimited to Kaplan Meier curves comparison. Furthermore,\nour AS case was characterized by an extremely unusual\naggressive clinical course that it seems to be not represen-\ntative of AS common biological behavior. However, some\nindications may be suggested.\nConclusion\nIn summary, extra-uterine A S, particularly cases aris-\ning from extra-genital regions, is an extremely rare\ntumour. They are typically found in younger women\nthan are uterine AS, and they usually involve huge,\npolylobate masses that can easily spread into sur-\nrounding organs and blood vessels. For extra-uterine\nAS, endometriosis represents a positive prognostic\nfactor and sarcomatous overgrowth a negative prog-\nnostic factor; we could not asses the prognostic effect\nof heterologous sarcomatous elements for the scant\nnumber of cases included; however, independently of\nsarcomatous overgrowth, extra-uterine AS has a very\npoor prognosis. Although co mplete resection is not al-\nways feasible, surgery remains the mainstay treatment\nchoice, whereas adjuvant therapy does not appear to\nbe effective in prolonging OS. Surgical treatment of\nextra-uterine AS often requires an extensive surgery\ngiven the possible involving of multiple organs. More-\nover, AS patients can be pluri-operated because of\nprevious endometriosis treatment with consequent\nadditional difficulties during surgery. Therefore, since\nsurgery is the only treatment to have an impact on\nsurvival, patients should be centralized in qualified\nsurgical oncological centr es and operated by experi-\nenced surgeons to reduce morbidity and to achieve\nradical treatment. Nevertheless, centralization might\nallow the recovery of clin ical data and histological\nsamples allowing a revision and a definitive diagnosis.\nConsidering that in the last forty years less than forty\ncases have been reported in the literature, a worldwide\nregistry is urgently needed to collect data regarding\nthese rare AS to standardize treatment and obtain reli-\nable data on prognosis.\nAbbreviations\nAS: Adenosarcoma; AWD: Alive with disease; CI: Confidence interval; CT: Computed\ntomography scan; DFS: Disease-free survival; DOD: Died of disease; FOD: Free of\ndisease; HR: Hazard ratio; HRT: Hormone replacement therapy; OS: Overall survival;\nSD: Standard deviation\nAcknowledgements\nW 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\ndata, particularly Dr. Mauro Cozzolino and Dr. Rhonda Yantiss.\nFunding\nThe funding body had no role in the design of the study and collection,\nanalysis, and interpretation of data and in writing the manuscript.\nAvailability of data and materials\nData collected and analyzed during this study are included in this review and are\navailable from the corresponding author on reasonable request.\nAuthors’ contributions\nVDM conceived of the manuscript, performed operations, collected data, and wrote\nthe manuscript. FT performed statistical analysis and wrote the manuscript. VM\ncollected data and wrote the manuscript. RV performed pathological evaluation\nand wrote the manuscript. LA performed the operation and conceived of the\nmanuscript. GBL conceived of and revised the manuscript. All authors read and\napproved the final manuscript.\nEthics approval and consent to participate\nWritten informed consent was not necessary because our patient provided\nstandard written consent for the use of data, pictures and videos for\nteaching and research purposes at the time of laparotomy.\nConsent for publication\nNot applicable.\nCompeting interests\nThe authors declare that they have no competing interests. All authors deny any\nfound, financial and personal relationships with other people or organizations/\ncompanies that could inappropriately influence their work.\nPublisher’sN o t e\nSpringer Nature remains neutral with regard to jurisdictional claims in published\nmaps and institutional affiliations.\nMandato et al. BMC Cancer  (2018) 18:134 Page 16 of 18\n\nAuthor details\n1Unit of Obstetrics and Gynecology, IRCCS- Azienda Unità Sanitaria Locale,\nViale Risorgimento n 80, Reggio Emilia, Italy. 2Laboratory of Translational\nResearch, Azienda Unità Sanitaria Locale, IRCCS, Reggio Emilia, Italy. 3Unit of\nSurgical Gynecol Oncology, Azienda Unità Sanitaria Locale, IRCCS, Reggio\nEmilia, Italy. 4Unit of Pathology, Azienda Unità Sanitaria Locale, IRCCS, Reggio\nEmilia, Italy. 5Unit of Obstetrics and Gynecology, University of Modena e\nReggio Emilia, Reggio Emilia, Italy.\nReceived: 2 March 2017 Accepted: 23 January 2018\nReferences\n1. Clement PB, Scully RE. 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Mandato VD, Mastrofilippo V, Ciarlini G, Aguzzoli L, La Sala GB. Primary\nvaginal Adenosarcoma with Sarcomatous overgrowth arising in recurrent\nendometriosis: feasibility of laparoscopic treatment and review of the\nliterature. J Minim Invasive Gynecol. 2016;S1553-4650:31287 –0.\n•  We accept pre-submission inquiries \n  Our selector tool helps you to find the most relevant journal\n  We provide round the clock customer support \n  Convenient online submission\n  Thorough peer review\n  Inclusion in PubMed and all major indexing services \n  Maximum visibility for your research\nSubmit your manuscript at\nwww.biomedcentral.com/submit\nSubmit your next manuscript to BioMed Central \nand we will help you at every step:\nMandato et al. BMC Cancer  (2018) 18:134 Page 18 of 18","source_license":"CC0","license_restricted":false}