Primary extragenital endometrial stromal sarcoma of the lung: first reported case and review of literature

Background: Endometrial stromal sarcomas arising in extrauterine and extraovarian sites, in the absence of a primary uterine lesion are quite rare, especially in the absence of endometriosis. They usually present as an abdominal or pelvic mass lesion. Case presentation: In 2007, a 45-year-old woman underwent total hysterectomy for in situ squamous cell carcinoma of the cervix. In 2014, an upper left pulmonary lobectomy was performed for a mass, which was provisionally diagnosed as primary carcinosarcoma of the lung. A second histological revision of the lung surgical specimen was performed in the Pathology Unit of our Institute. After extensive immunohistochemical analyses, the preferred diagnosis was spindle-cell sarcoma, consistent with high-grade extragenital endometrial stromal sarcoma (EESS). A review of all slides of the hysterectomy specimen confirms the original diagnosis: no evidence of stromal tumor was found. Afterwards, the patient developed multiple and metachronous pulmonary lesions and a scapular soft tissue mass, which showed the same morphophenotypic features of the first lung mass. The patient was treated with antiblastic therapy, surgical resection and radioablation, when appropriate. To date, the patient has no signs or symptoms. Conclusions:The authors present the first case of primary EESS arising in the lung with no association with endometriosis published to date. Detailed clinical history and follow-up are also described. Moreover, extensive literature review is reported, along with differential diagnoses, immunohistochemical and molecular findings, pathogenetic hypotheses and treatment options. The knowledge of EESS potential extrauterine location and of its peculiar morphophenotypic aspects are required for a correct diagnosis, and for choosing the most suitable treatment.

Extragenital endometrial stromal sarcoma, Lung, Immunohistochemistry, Case report

Endometrial stromal sarcoma (ESS) is an uncommon mesenchymal tumor of the uterus, which accounts for less than 1% of all uterine malignancies but it is the second most common uterine malignant mesenchymal tumor [1]. The latest World Health Organization Classi- fication [1], categorizes ESS into low-grade ESS (LGESS), high-grade ESS (HGESS) and undifferentiated endomet- rial sarcoma (UES). LGESS are typically composed of cytologically bland fusiform cells resembling stromal cells of proliferative-phase endometrium, intermingled with numerous small plexiform arterioles, permeating the myometrium as well as the intramyometrial or para- metrial vessels. The mitotic rate is usually lower than 5 mitoses/10HPF. They show an indolent course: recur- rences and metastases are rare and occur after long periods of time [1, 2]. In contrast, both HGESS and UES have a malignant behavior. They often exhibits myome- trial invasion, hemorrhage and necrosis, as well as marked nuclear pleomorphism with round cell morph- ology (and a minor component part of low-grade spindle cell morphology) and high mitotic activity with 10 mitoses/10HPF or higher. Patients are more likely to develop recurrences and die from disease. The most im- portant morphologic feature that distinguishes ESS from * Correspondence: [email protected] 1Pathology, IRCCS-National Cancer Institute, Via F. Gallini 2, 33081 Aviano, Italy Full list of author information is available at the end of the article © The Author(s). 2017 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. Alessandrini et al. Diagnostic Pathology (2017) 12:36 DOI 10.1186/s13000-017-0627-2 UES is that the latter lacks overt resemblance to proliferative endometrial stroma. Endometrial stromal sarcomas arising as primary tumors in extrauterine and extraovarian (i.e., extragenital endometrial stromal sarcomas) sites are quite rare, and reported in the English medical literature as small series or case reports (Table 1) [3 – 29]. The clinical-pathological features of primary EESS have not been widely investigated yet. To the authors ’ knowledge, this is the first case reported of EESS arising in the upper left lobe of the lung in a 45-year-old woman without associated endometriosis and in the absence of a primary genital ESS. An extensive review of literature is also reported, along with differential diagnoses, immu- nohistochemical and molecular findings, pathogenetic hypotheses and treatment options. Case presentation Clinical history In 2007, a 38-year-old female was hospitalized for an ulcerated uterine cervical lesion which, after cervical bi- opsies, showed an in situ squamous cell carcinoma. Subsequently, an abdominal CT scan revealed an en- larged, dishomogeneous uterus, with hypodense mass of 5 cm adjacent to the posterior wall of the bladder. Two months later, the patient underwent total abdominal hysterectomy with bilateral salpingectomy and pelvic lymphadenectomy. In the intraoperative phase, the uterus was found to be mobile and ovaries were normal. Neither enlarged lymph nodes nor peritoneal lesions or ascites were noted. On histological examination of the surgical specimen, a well-differentiated squamous cell carcinoma in situ of the cervix, measuring 4 mm in maximum diameter, with basaloid morphology, was identified. Three additional leiomyomata of the uterine corpus, besides the larger one already identified on CT scan, were also microscop- ically found. In 2014, the patient presented to medical observation with a pulmonary mass (Fig. 1). Upper left lobectomy was performed. The final pathologic diagnosis was carci- nosarcoma of the lung. A second histological revision of the lung surgical specimen was performed in March 2014 in the Pathology Unit of our Institute. The preferred diagnosis, after extensive immunohistochemical analyses, was spindle-cell sarcoma, consistent with high grade EESS. Post-operative staging with thoracic, abdominal and pelvic CT scan did no have any abnormal findings and a follow-up was proposed. After five months, a CT scan was performed: it revealed a left pulmonary lesion with a maximum diameter of 18 mm. Chemotherapy treatment with carboplatin AUC 5 and paclitaxel 175 mg/mq every three weeks was started. After three courses of antiblastic therapy, the lesion in the left lung appeared to be in- creased in volume (27 mm of diameter) on CT scan. After multidisciplinary discussion, a surgical intervention (atyp- ical segmentectomy of lower lobe of the left lung) was performed. Almost three months after surgical intervention, a new pulmonary lesion located in the right lung was detected by CT scan. The lesion was subsequently treated with radiofrequency ablation. As a consequence of the procedure, right pleural effusion after 24 h and after five days by the appearance of right pneumothorax after five days appeared. Shortly after tube insertion, additional radiographs were taken: they showeda rapid decrease in the size of the pneumothorax. The thoracic drainage was removed and patient was discharged from the hospital. After one month, a CT scan was repeated. The scan showed surgical and radiofrequency ablation effects and a new pulmonary lesion of uncertain nature, measuring 4– 5 mm of maximum diameter. Hormonal therapy with progestin (acetate medroxyprogesterone 1 gr daily) was prescribed. No radiological signs of progression were noted until December 2015, when new lung lesions located in the lower lobe of the right lung and upper lobe of the left lung were detected on CT scan. In January 2016, the patient referred the appearance of a soft tissue mass, rapidly enlarging, located in the left periscapular region. A tru-cut biopsy of the soft tissue lesion was performed: histological examination revealed a neoplastic lesion with spindlecell morphology, reminiscent of the upper left lobe EESS. A second line polychemotherapy with epirubicin and ifosfamide was started. After three courses of chemo- therapy, radiological evaluation through CT scan re- vealed a decrease of the diameter of the right lung lesion and the disappearance of the lesion in the left lung. At the follow-up visit, the patient was in good conditions well, with no clinical signs or symptoms of the disease and no pathological findings on CT scan; routine laboratory tests were normal. Signed written consent was obtained from the patient for this case report.

Two and half-micron sections from formalin-fixed paraf- fin embedded tissue of the resected lobe and of the hys- terectomy specimen were cut and immunohistochemical analysis was performed through an automated system (Benchmark-XT, Ventana, Tucson, AZ, US). The following primary antibodies were used: CD117 (pathway c-kit, clone 9.7, pre-diluted; Ventana, Tucson, AZ, US), Estrogen receptor (monoclonal anti- body, clone SP1, prediluted, Ventana), Progesteron receptor (monoclonal antibody, clone 1E2, prediluted, Alessandrini et al. Diagnostic Pathology (2017) 12:36 Page 2 of 9 Table 1 Clinical characteristics of EESS cases presented in Literature Ref Site N° of cases Age (Range) N° of cases with history of endometriosis N° of cases with history of gynecologic surgery N° of cases with concurrent endometriosis Treatment (N° of pts) Follow-up: time (range) and outcome (N° of pts) 3,6,17, 21,26 Pelvis 6 34 –50 2 1 4 resection + radioTX (1) resection (3) NA (2) 10 mo-1y; DOD (1), NED (2), NA(3) 6,13, 15, 17,18 Omentum, abdomen, retro-peritoneum, mesentery 54 6 –71 1 1 3 resection + radioTX (1) resection (4) 11 mo-4y; NED (3), NA(1); recurrence (1) 5,10,11, 12,14, 19,20, 21,23, 27, 28 Small bowel, colon, rectum 11 38 –80 3 5 6 resection + radioTX (1) resection + chemoTX (3) resection (6) NA (1) 4 mo-4y; DOD (1), NED (6), NA(2); recurrence (2) 22 omentum, mesentery, colon, liver, bladder, abdominal nodes, pelvis, vagina, aryepiglottic fold 38 cases EESS; age:27–81 (range) NA NA 14/38 cases resection + chemoTX +/− radioTX NED (12/38 cases, range : 15–174 mo) DOD (8/38 cases; range 36–336 mo); AWD (13/38 cases; range:6-145mo) 25 stomach 37 –54 NA 1 none resection NA 13 Liver 1 31 1 1 1 resection NED; 4 y 4,8,9, 16,17, 24 vagina 6 32 –45 none 1 none resection + radioTX (2) resection + chemoTX (1) resection (3) 18 mo-38 mo; NED (5), NA (1) 7,29 vulva 2 34 –50 none 2 1 Resection (2) 28 mo-6 y NED (2) TX therapy, NED no evidence of disease, DOD dead of disease, NA not available, mo months, y year/s, AWED alive with disease Alessandrini et al. Diagnostic Pathology (2017) 12:36 Page 3 of 9 Ventana), Ki67 (monoclonal antibody, clone 30.9, predi- luted, Ventana), CD10 (monoclonal antibody, clone Sp67, prediluted, Ventana), CD34 (monoclonal antibody, clone QBEND/10; 1:400 dilution; Neomarkers, Free- mont, CA, USA), CD31 (monoclonal antibody, clone JC70, Prediluted, Cell Marque, Rocklin, CA, US), Pankeratin (CkAE1/AE3/pCk26, pre-diluted, Ventana), MNF116 (monoclonal antibody, clone MNF116, predi- luted, Diagnostic Biosystem, Pleasanton, CA, US), smooth muscle actin (SMA) (monoclonal antibody, clone 1A4, 1:100 dilution; DAKO, Glostrup, Denmark/ Carpinteria, CA, US), H-Caldesmon (monoclonal anti- body, clone E89, prediluted, Ventana), S100 (polyclonal antibody, 1:400 dilution; DAKO), MDM2 (monoclonal antibody, clone IF2, 1:100 dilution, Calbiochem, Merk, Darmstardt, Germany), D2-40 (monoclonal antibody, clone podoplanin, prediluted, Cell Marque), CD99 (monoclonal antibody, clone o13, prediluted, Ventana), Myogenin (monoclonal antibody, clone FD5, 1:50 dilution, Cell Marque), Myoglobin (polyclonal, predi- luted, Ventana), Vimentin (monoclonal antibody, clone V9, prediluted, Ventana), Desmin (monoclonal antibody, clone De-R-11, prediluted, Ventana), TTF1 (monoclonal antibody, clone 8G9G3/1, prediluted, Ventana). The color was developed with 3.3 ′-diaminobenzidine (DAB), and the slides were counterstained with Meyer ’ s hematoxylin. Appropriate positive and negative controls were run concurrently. Morphological findings The histological examination of hematoxylin and eosin stained slides of the pulmonary lesion showed uniform spindle cells organized in a diffuse pattern (Fig. 2a, b, c), with mild atypia and foci of necrosis (Fig. 2d), in a back- ground of fibromyxoid stroma (Fig. 2d). The tumor cells had oval to round nuclei with inconspicuous nucleoli, and eosinophilic cytoplasms. Some small-sized thick- walled vessels were unevenly distributed among the stroma (Fig. 2a, d). Mitotic rate was high, ranging up to 20 mitoses per 10 high-power fields. Alveolar epithelium was focally entrapped by the neoplastic cells (Fig. 2a, c). Despite a thorough examination, endometriotic spots were not identified in the tumor or in adjacent non- neoplastic tissue. A review of all slides from the hysterectomy specimen, which included the large lesion identified on CT scan plus three additional microscopically found leiomyomas, confirmed the original diagnosis of squamous carcinoma in situ of the cervix with leiomyomas of the uterine wall. No evidence of ESS or endometrial stromal nodules was found. Immunophenotipic findings On immunohistochemical staining, the tumor cells showed patchy and intense immunoreactivity for CD10 (Fig. 3a), estrogen receptor (Fig. 3e), and progesterone receptor (Fig. 3f ), focal staining for CD99, and diffuse vimentin staining (Fig. 3b). Tumor cells also showed negative results for CD117, S-100 protein, and CD34, CD31, D2-40, MDM2, pan-keratin, H-caldesmon (posi- tive in small vessels) (Fig. 3c), MNF116 (positive in the entrapped epithelial alveolar elements), TTF-1 (positive in the entrapped epithelial alveolar elements) (Fig. 3d), myogenin and myoglobin. Ki67 percentage of positive Fig. 1 Thoracic CT scan showing a mass (50 mm of maximum diameter) in the upper left lobe Alessandrini et al. Diagnostic Pathology (2017) 12:36 Page 4 of 9 nuclei ranged from 20 to 40%. Limited smooth muscle differentiation was occasionally present and was focally positive for smooth muscle actin and desmin. The preferred diagnosis was EESS with high grade areas. CD10 was completely negative (Fig. 4b) whereas estro- gen and progesterone receptors (Fig. 4c, d, respectively) were positive, as expected, in leiomyomas from the pre- vious hysterectomy specimen. The periscapular soft tissue recurrence showed the same histological and immunohistochemical findings, except for the absence of staining for CD10, which dis- played a patchy staining on the lung specimen; therefore, its absence on a tru-cut biopsy of periscapular soft tis- sues could be due to sampling from a non-staining area.

Endometrial stromal sarcoma is a malignant tumor closely resembling stromal cells of proliferative-phase endometrial stromal cells. It is commonly associated with a delicate network of arterioles. Even when display- ing classical histological features, an unusual site of oc- currence may make the diagnosis challenging. Therefore, despite its rarity EESS should always be taken into con- sideration in the differential diagnosis for a woman with a thoracic or abdominal tumor with uniform cytologic- ally bland cells resembling normal endometrial stroma. On the other hand, in the gastrointestinal tract and extragenital sites, in the absence of endometriosis EESSs may be mistaken for other mesenchymal more common neoplasms [20], such as cellular leiomyoma and low- grade leiomyosarcoma, solitary fibrous tumor and gastrointestinal stromal tumor (Table 2). In such cases, a large panel of immunohistochemical markers could be of help in establishing the diagnosis (Table 2). Regardless of the site of presentation, also peculiar histological features may be challenging for diagnosis, when noted in EESS [22]. When tubules-like structures are identified within spindle cell proliferations, also endometriosis and adenosarcoma are additional diagnoses that should be considered. On the other hand, EESS also can have glandular differentiation. In this case periglandular stro- mal condensation around benign glands and polypoid fronds composed of cellular stroma imparting a leaf-like appearance are morphological features more characteristic of adenosarcoma. In the largest group of EESS described to date, one case arising in the larynx was initially diagnosed as monophasic synovial sarcoma [22] which is not usually included into the differential diagnoses of EESS as it fre- quently arises within the soft tissues of the limbs. Immu- nohistochemistry can once again be helpful (Table 2). Finally, the long time from primary genital ESS onset Fig. 2 a, b Panoramic view of the pulmonary lesion showing uniform spindle cells arranged in a fascicular pattern; alveolar epithelium is focally entrapped by the neoplastic cells (H&E, 100×); c, d some small thinwalled blood vessels resembling spiral arterioles of late secretory endometrium were unevenly distributed among the stroma (H&E, 100×);b, d, neoplastic cells show moderate atypia and foci of hyaline-type necrosis, in a background of fibromyxoid stroma);d, the tumor cells had oval to plump spindle-shaped nuclei with finely granular chromatins, inconspicuous nucleoli, and amphophilic cytoplasms (H&E, 200×) Alessandrini et al. Diagnostic Pathology (2017) 12:36 Page 5 of 9 and its recurrence and/or metastasis, requires a review of the clinical history of the patient and a second look at the slides from a previous hysterectomy specimen to rule out the possibility of an overlooked uterine ESS [2]. In our patient the hysterectomy specimen was exten- sively sampled and a review of all slides confirmed the original diagnosis. Several hypotheses are invoked to explain the patho- genesis of EESS. Since in many cases (Table 1) endomet- riosis was found to be adjacent to EESS, it could be speculated that primary EESS arises from an ectopic focus of endometrial stroma. However, our case and few others, (listed in Table 1), indicate that the absence of associated endometriosis does not preclude primary EESS at that site. In these cases, either EESS may arise from an underlying endometriosis hidden by sarcomatous overgrowth [22] or it might derive de novo from the peritoneal/pleural (in our case) surface or the coelomic or subcoelomic multipotential epithelium [30, 31]. Recent molecular studies showed that ESS can be genetically heterogeneous. The most common alteration carried by ESS is the t (7;17) (p15;q21) translocation, which results in JAZF1 – SUZ12 gene fusion (also known as JJAZ1) [32]. However, such rearrangements rarely occur in ESS displaying different morphological features e.g., myxoid, epithelioid, fibrous, smooth muscle, and sex-cord histologic variants: thisreveal that other un- known molecular changes may be involved in the disease phenotypic presentation [32]. Other gene fusionscon- cerning PHF1 and YWHAE genes, are much less frequent and are likely to be related with specific clinico- pathological features [33]. Although molecular testing Fig. 3 Neoplastic cells showed patchy and intense immunoreactivity for CD10 ( a, 100×), diffuse vimentin staining ( b, 100×), negative staining for H-Caldesmon (positive control staining in small vessels;upper left) ( c, 100×), negative staining for TTF-1 (positive nuclear staining in the entrapped epithelial alveolar elements; right) (d, 100×), moderately diffuse nuclear staining for estrogen receptor (e, 200×), moderately diffuse nuclear staining for progesterone receptor (f,2 0 0 × ) Alessandrini et al. Diagnostic Pathology (2017) 12:36 Page 6 of 9 for the t (7;17) (p15;q21) and associated gene fusion may be useful for confirming primary extrauterine endomet- rial stromal sarcoma, the low prevalence of the genetic aberration in this subset of patients limits the clinical utility of the analysis [21]. The behavior of EESS, compared to genital ESS, seems to be controversial. Although results are conflicting, it seems that the only feature associated with a worse prognosis is the presence of morphological features sug- gestive of dedifferentiation [22]. Given the rarity of these tumors, evidence-based data are not available to help guide treatment decisions. Surgery is generally regarded as the cornerstone of treat- ment for ESS. Complete cytoreductive surgery is recom- mended, especially in patients for whom this surgery could result in being residual-disease-free. Tumor-free margins are important in prognosis [34]. Extragenital ESS may have a high tendency for dissemination and metastasis in the omentum, mesentery, and abdominal or pelvic wall [20, 22]. Despite this, most patients with Fig. 4 Leiomyoma with classic morphology from previous hysterectomy specimen, showing intersecting fascicles of cigarshaped, spindle cells with eosinophilic cytoplasm (a, 200×); CD10 negative immunostaining (b, 200×); positive nuclear staining for estrogen receptor (c,2 0 0 × ) ,p o s i t i v en u c l e a r staining for progesterone receptor (d,2 0 0 × ) Table 2 Morphophenotypic features of the most common mesenchymal spindle cell neoplasms in the differential diagnosis of EESS Mesenchymal Neoplasm Morphological features Immunohistochemical markers Cellular leiomyoma/low-grade leiomyosarcoma characteristic intersecting fascicles of smooth muscle cigarshaped spindle cells with eosinophilic cytoplasm and perinuclear vacuolation, showing a smooth, pushing margin and large, irregular, thick-walled blood vessels muscle-specific actin +, smooth muscle actin +, desmin +, ER +, PgR+, CD10 −/+, H-caldesmon + Gastrointestinal stromal tumor spindle cells with long tapering nuclei and abundant clear or eosinophilic cytoplasm arranged in fascicles or sheets; characteristically well circumscribed with pushing borders CD34 +, DOG-1 +, CD117 +, CD10 -, ER -, PgR-; muscle-specific actin −/+, smooth muscle actin −/+, desmin −/+, Solitary fibrous tumor bland spindle cells haphazardly arranged in a dense collagenous matrix but lacks the peculiar characteristic vasculature of the ESS CD34 +, CD10 -, ER -, PgR- Monophasic synovial sarcoma most commonly involves the soft tissues of the extremities; CD99 +, EMA +, CD10 -, ER -, PgR- ESS monomorphous plump spindle cells forming short regular fascicles, evenly distributed arterioles and infiltrative border muscle-specific actin−/+, smooth muscle actin−/+, desmin −/+, ER +, PgR+, CD10 +, H-caldesmon - - negativity, −/+ focal positivity, + diffuse positivity, ER estrogen receptor, PgR Progesteron receptor, EMA epithelial membrane antigen Alessandrini et al. Diagnostic Pathology (2017) 12:36 Page 7 of 9 extrauterine ESS had prolonged disease-free intervals with late recurrences [20, 22]. The value of adjuvant therapy is controversial with no prospective studies showing a survival advantage associated with the use of chemotherapy or radiotherapy [34]. Nevertheless, adju- vant therapy is still considered in patients with meta- static or recurrent ESS. Radiotherapy may also have a palliative role [34].

In summary, we present in this study the first EESS of the lung reported to date. EESS is an uncommon tumor arising in women of any age, usually presents as a mass lesion in the abdomen or pelvic cavity. The knowledge of its potential extrauterine location and of peculiar morphophenotypic aspects are required for a correct diagnosis. Surgical resection is the most frequent treat- ment option, eventually followed by hormonal-therapy. EESS does not seem to have an aggressive behavior, and is likely to recur late after the initial treatment: therefore, a long-term clinical follow-up should be programmed. Abbreviations CT: Computed tomography; ESS: Endometrial stromal sarcoma; HGESS: High-grade endometrial stromal sarcoma; H&E: Hematoxylin-eosin; LGESS: Low-grade endometrial stromal sarcoma; UESS: Undifferentiated endometrial stromal sarcoma Acknowledgments We thank Ms Laura Zannier and Ms Antonella Selva for their invaluable technical assistance and Ms Anna Vallerugo, MA, for the English editing. Funding No funding was received for this case report. Availability of data and materials Please contact the Authors for data requests. Authors’ contributions LA analyzed the data, reviewed the literature, took the pictures and wrote and revised the manuscript as a major contributor. VC performed the final diagnosis on the revision of slides, interpreted the immunohistochemical staining of slides, wrote and revised the manuscript and contributes for important intellectual content. SS, FS, GM and GB gave information about clinical history and follow up; MU contributed to the radiological findings and images. PT, GM helped to the final draft of the manuscript. GM, FS contributed to revision of the manuscript. FI contributed to literature review. All authors have read and approved the final manuscript. Competing interests The authors declare that they have no competing interests. Consent for publication Informed consent was obtained from the patient for the publication of this case report and any accompanying images. Ethics approval and consent to participate Ethical approval for this study was obtained from the Scientific Committee Board of the Institute. Publisher’sN o t e Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Author details 1Pathology, IRCCS-National Cancer Institute, Via F. Gallini 2, 33081 Aviano, Italy. 2Gynecological Oncology Unit, IRCCS-National Cancer Institute, Aviano, Italy. 3Surgical Oncology, IRCCS-National Cancer Institute, Aviano, Italy.4Department of Medical Oncology, IRCCS-National Cancer Institute, Aviano, Italy. 5Department of Radiology, IRCCS-National Cancer Institute, Aviano, Italy. 6Oncopath Lab, Floridia, Siracusa, Italy. Received: 18 January 2017 Accepted: 17 April 2017

1. Kurman R, Carcangiu ML, Herrington C, et al. WHO classification of tumours of female reproductive organs. IARC WHO Classification of Tumours, No 6. Lyon: IARC press; 2014. 2. Oliva E, Clement PB, Young RH. Endometrial stromal tumors: an update on a group of tumors with a protean phenotype. Adv Anat Pathol. 2000;7(5): 257–81. 3. Ferraro LR, Hetz H, Carter H. Malignant endometriosis; pelvic endometriosis complicated by polypoid endometrioma of the colon and endometriotic sarcoma; report of a case and review of the literature. Obstet Gynecol. 1956;7(1):32–9. 4. Berkowitz RS, Ehrmann RL, Knapp RC. Endometrial stromal sarcoma arising from vaginal endometriosis. Obstet Gynecol. 1978;51(1 Suppl):34s –7. 5. Baiocchi G, Kavanagh JJ, Wharton JT. Endometrioid stromal sarcomas arising from ovarian and extraovarian endometriosis: report of two cases and review of the literature. Gynecol Oncol. 1990;36(1):147–51. 6. Fukunaga M, Ishihara A, Ushigome S. Extrauterine low-grade endometrial stromal sarcoma: report of three cases. Pathol Int. 1998;48(4):297 –302. 7. Irvin W, Pelkey T, Rice L, et al. Endometrial stromal sarcoma of the vulva arising in extraovarian endometriosis: a case report and literature review. Gynecol Oncol. 1998;71(2):313 –6. 8. Kondi-Paphitis A, Smyrniotis B, Liapis A, et al. Stromal sarcoma arising on endometriosis. A clinicopathological and immunohistochemical study of 4 cases. Eur J Gynaecol Oncol. 1998;19(6):588 –90. 9. Chang YC, Wang TY, Tzen CY. Endometrial stromal sarcoma of the vagina. Zhonghua Yi Xue Za Zhi (Taipei). 2000;63(9):714 –9. 10. 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(4):513–24. 11. Mourra N, Tiret E, Parc Y, et al. Endometrial stromal sarcoma of the rectosigmoid colon arising in extragonadal endometriosis and revealed by portal vein thrombosis. Arch Pathol Lab Med. 2001;125(8):1088 –90. 12. Bosincu L, Massarelli G, Cossu RP, et al. Rectal endometrial stromal sarcoma arising in endometriosis: report of a case. Dis Colon Rectum. 2001;44(6):890–2. 13. Khan AW, Craig M, Jarmulowicz M, et al. Liver tumours due to endometriosis and endometrial stromal sarcoma. HPB (Oxford). 2002;4(1):43–5. 14. Cho HY, Kim MK, Cho SJ, et al. Endometrial stromal sarcoma of the sigmoid colon arising in endometriosis: a case report with a review of literatures. J Korean Med Sci. 2002;17(3):412 –4. 15. Morrison C, Ramirez NC, Chan JK, et al. Endometrial stromal sarcoma of the retroperitoneum. Ann Diagn Pathol. 2002;6(5):312 –8. 16. Corpa MV, Serafini EP, Bacchi CE. Low-grade endometrial stromal sarcoma presenting as vaginal nodule. Ann Diagn Pathol. 2004;8(5):295 –8. 17. Kondi-Pafiti A, Spanidou-Carvouni H, Papadias K, et al. Malignant neoplasms arising in endometriosis: clinicopathological study of 14 cases. Clin Exp Obstet Gynecol. 2004;31(4):302–4. 18. Kovac D, Gasparovic I, Jasic M, et al. Endometrial stromal sarcoma arising in extrauterine endometriosis: a case report. Eur J Gynaecol Oncol. 2005; 26(1):113–6. 19. Rojas H, Wang J, Chase D, et al. Pathologic quiz case: a 46-year-old woman with 1-day history of abdominal pain and intestinal obstruction. Extrauterine low-grade endometrial stromal sarcoma. Arch Pathol Lab Med. 2005;129(2):e44–6. 20. Kim L, Choi SJ, Park IS, et al. Endometrial stromal sarcoma of the small bowel. Ann Diagn Pathol. 2008;12(2):128–33. 21. Amador-Ortiz C, Roma AA, Huettner PC, et al. JAZF1 and JJAZ1 gene fusion in primary extrauterine endometrial stromal sarcoma. Hum Pathol. 2011; 42(7):939–46. 22. Masand RP, Euscher ED, Deavers MT, et al. Endometrioid stromal sarcoma: a clinicopathologic study of 63 cases. Am J Surg Pathol. 2013;37(11):1635 –47. Alessandrini et al. Diagnostic Pathology (2017) 12:36 Page 8 of 9 23. Ayuso A, Fadare O, Khabele D. A case of extrauterine endometrial stromal sarcoma in the colon diagnosed three decades after hysterectomy for benign disease. Case Rep Obstet Gynecol. 2013;2013:202458. 24. Liu Z, Ding J, Li X, et al. Endometrial stromal sarcoma arising in vagina. Int J Clin Exp Pathol. 2013;6(12):2997 –3002. 25. Jin M, Reynolds JP, Odronic SI, et al. Primary gastric extra-uterine endometrial stromal sarcoma. Ann Diagn Pathol. 2014;18(3):187–90. 26. Ghosal T, Roy A, Kurian S. Primary extrauterine endometrial stromal sarcoma: Located in pelvic and abdominal tissue and arising in endometriosis. Indian J Pathol Microbiol. 2014;57(3):447 –9. 27. Wang Q, Zhao X, Han P. Endometrial stromal sarcoma arising in colorectal endometriosis: a case report and review ofthe literature. Case Rep Obstet Gynecol. 2015;2015:534273. 28. Son HJ, Kim JH, Kang DW, et al. Primary extrauterine endometrial stromal sarcoma in the sigmoid colon. Ann Coloproctol. 2015;31(2):68 –73. 29. Zaza KJ, Arafah MA, Al-Badawi IA. Vulvar extrauterine endometrial stromal sarcoma: a case report and literature review. Hematol Oncol Stem Cell Ther. 2015;8(3):125–9. 30. Norris HJ, Taylor HB. Mesenchymal tumors of the uterus. I. A clinical and pathological study of 53 endometrial stromal tumors. Cancer. 1966;19(6): 755–66. 31. Lauchlan SC. The secondary mullerian system. Obstet Gynecol Surv. 1972; 27(3):133–46. 32. Chiang S, Oliva E. Recent developments in uterine mesenchymal neoplasms. Histopathology. 2013;62(1):124–37. 33. Lee CH, Marino-Enriquez A, Ou W, et al. The clinicopathologic features of YWHAE-FAM22 endometrial stromal sarcomas: a histologically high-grade and clinically aggressive tumor. Am J Surg Pathol. 2012;36(5):641 –53. 34. Rauh-Hain JA, del Carmen MG. Endometrial stromal sarcoma: a systematic review. Obstet Gynecol. 2013;122(3):676–83. • 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: Alessandrini et al. Diagnostic Pathology (2017) 12:36 Page 9 of 9