Gastrointestinal stromal tumors (GISTs) are the commonest mesenchymal tumors in gastrointestinal tract, with the most common sites at the stomach (70%), small intestine (20–30%) and others (<10%), including esophagus, colon, rectum, and extragastrointestinal sites.[2,3] GISTs outside the gastrointestinal tract are referred to as extragastrointestinal stromal tumors (EGISTs), comprising only 5% to 7% of GISTs. GISTs or EGISTs rarely occur in the gynecological tract, and sometimes are difficult to distinguish since their origins are unclear. We herein report a case of GIST, which is manifested as a vaginal mass, and patient has written informed consent for publication of the case. To further understand the disease, a systematic literature review was conducted to identify the similar cases and summarize the clinical findings and treatment plan.
2 Clinical case
A 78-year-old woman, gravida 7, para 3, without significant past medical history was referred to our hospital with persistent vaginal bleeding and difficulty of micturition for ten days. Hemoglobin level was 11.0 g/dl on the day of admission. Pelvic-rectal examination revealed a hard, unmovable mass lesion protruding from the right lateral and posterior vaginal wall. The inferior border of the tumor extended to 2 cm above the anus verge. A computerized tomography was performed and demonstrated a heterogeneous soft tissue mass (6.3 cm × 5.3 cm) with suspicious rectal and vaginal wall invasion, resulting in hydrocolpos, without pelvic or inguinal lymph node involvement (Fig. 1). Serum tumor markers (CA-125 = 16.1 U/ml, CEA = 2.9 ng/ml, SCC = 0.7 ng/ml) were within normal limits. Cervical biopsy through colposcopy was done and showed atypical spindle cells. Immunohistochemical staining of p40, actin, and S100 were negative. Due to inadequate specimen and suspected cervical cancer, a loop electrosurgical excision procedure was performed, and neither spindle cell neoplasm nor evidence of malignancy was identified under pathologic examination. Upon equivocal diagnosis of spindle cell tumor with obstructive micturition, exploratory laparotomy was performed, and the tumor was completely resected. Grossly, the specimen contained an 8.5 × 6 × 3 cm gray-tan necrotic soft tissue with direct invasion to the rectal mucosal (Fig. 2). Microscopically, the tumor consisted of fascicular, spindle-shaped cells. The mitotic count was 7 mitoses per 50 high-power fields (HPFs). Immunohistochemical analysis was strongly and diffusely positive for CD117, DOG1, and h-Caldesmon, but negative for S-100 and smooth muscle actin (SMA) (Fig. 3). The diagnosis was GIST with high risk of malignancy, most likely arising from rectum. The specimens from uterine, bilateral fallopian tubes, and ovaries were unremarkable. The postoperative course was uneventful, and the patient was referred to Department of Medical Oncology for imatinib treatment. To date, the patient has survived without the disease for more than 3 years.
3 Literature search and results
To further understand the disease and treatment strategy, a detailed systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline was conducted to identify the similar cases and summarize the clinical findings, initial diagnosis, and treatment plan. The final search was conducted in October 2018. Electronic medical database, PubMed, and Embase were searched for all related literature, using combinations of the following terms: “gastrointestinal Stromal tumor” or “extragastrointestinal Stromal tumor” and “vaginal” or “rectovaginal septum” or “gynecological.” Filters were set to find all available English language articles, without limitation on time of publication. Inclusion criteria for the present literature review included case reports, case series, and case characteristic studies, concerning female patients with a diagnosis of GISTs or EGISTs at rectovaginal space (Fig. 4). Two independent reviewers (M Cheng and C-H Liu) selected the identified studies based on the title and abstract. The following data were collected from all included studies: first author's surname, publication year, sample size, treatment strategies, morphological and immunohistochemical characteristics of the GISTs or EGISTs. We display a flowchart in Figure 1 that summarizes study identification and selection according to PRISMA. Ethics committee approval was not necessary for a systematic review.
The clinicopathological characteristics of previous and the current cases are summarized in Table 1. Only 22 GISTs/EGISTs, including the current case, presenting as vaginal or rectovaginal septal masses have been reported in English since 2004.[4–21] The mean age of patients was 54 years, and the mean tumor size was 6.2 cm. GISTs located in the vagina and retro-vaginal septal space were found in 32% (7/22) and 68% (15/22) of patients, respectively. Cases that received complete resection of tumors and those who had either adjuvant or neoadjuvant targeted therapy included 77% (17/22) and 41% (9/22), respectively. Aside from the current case, a total of 6 patients underwent lesion biopsy at preoperative stage, including 3 new and 3 recurrent cases.[5,6,8,15,16,21] In all new cases (n = 18), there were three cases that were precisely diagnosed before definite treatment (3/18,16.7%).[4,6–14,17–21]
In the current case, we noted an approximate tumor size of 8.5 cm, 7 mitoses per 50 HPFs and tumor rupture under pathological evaluation, and the tumor was defined as a highly malignant GIST according to National Institutes of Health (NIH) consensus classification. Rectal mucosa perforation at the site of lesion was regarded as rapid tumor progression after colonoscopy examination (a 7-day interval). Gastrointestinal stromal tumors (GISTs) from the rectovaginal space are rare and often misleading. The current literature review has shown the low possibility of achieving pretreatment diagnosis. The current case also failed to make accurate preoperative diagnosis.
The clinical manifestations of GISTs originating from rectovaginal space have nonspecific symptoms including bleeding of mass, pain, abdominal distension, and compression effect leading to urinary frequency and constipation. Imaging studies such as computed tomography or magnetic resonance image can provide some clues for clinicians preoperatively. GIST on computed tomography is characterized by well-circumscribed soft tissue mass with heterogeneous density and the low-attenuation parts often suggest necrosis or hemorrhage. Magnetic resonance imaging often shows uniform intermediate enhancement on T1-weighted images and heterogeneous high enhancement on T2-weighted images if necrosis or hemorrhage exists. Although the current case displays the typical features of GIST on computed tomography, these findings were nonspecific, and a pathological proof was essential to confirm the diagnosis.
All previously reported cases demonstrated spindle cells under histologic evaluation, and there were 5 cases (5/21, 24%) having initial diagnosis as leiomyosarcoma or leiomyoma,[5,7,11,12] suggesting the potentially significant diagnostic pitfall before treatment. GISTs and smooth muscle tumors share similar pathological characteristics as fascicular spindle cells. To distinguish GISTs from smooth muscle tumors, conventional histology plus immunohistochemistry might be helpful. Histologically, smooth muscle tumors usually display eosinophilic cytoplasm, whereas GISTs tend to present pale pink cytoplasm in fibrillary pattern. Using immunohistochemistry, leiomyomas and leiomyosarcomas are typically positive for smooth muscle actin, desmin and negative for CD117. Other mesenchymal neoplasms including aggressive schwannomas, angiomyxoma, angiofibroblastoma, and dermatofibrosarcoma protuberans should also be taken into consideration. Schwannomas of rectovaginal septum also show spindle-cell pattern; however, schwannomas are strongly positive for S100 and negative for CD 117. Angiomyxomas and angiofibroblastomas are immunoreactive for actin and desmin, but negative for CD117. Dermatofibrosarcoma protuberans is positive for CD34, which is also seen in the majority of GISTs, but appear negative for CD117. Melanoma and carcinoma should be included in differential diagnosis. Positive CD117 and S100 were frequently presented in melanoma. The current case revealed negative staining of S100 and p40 in biopsy specimen, ruling out melanoma and squamous cell carcinoma, respectively. Furthermore, the absence of pathological finding in cervical conization excluded the possibility of cervical cancer. The diagnosis of GIST was primarily based on immunochemistry, and it was more distinguishable from other mesenchymal tumors by a typical panel of positive immunohistochemical staining including CD117 (95%), DOG1 (98%), CD34 (70%), SMA (50%), S100 (10%), and desmin (5%).[23,24] CD 117 positivity implies the mutation of KIT gene, which is a proto-oncogene encoding type III transmembrane tyrosine kinase receptor and a distinctive feature of GISTs. However, it should be noted that CD117 alone is not sufficient to make the definite diagnosis of GISTs, since a number of spindle cell tumors including Kaposi's sarcoma, melanoma also demonstrate immunoreactive CD117. DOG1 displays both high sensitivity and excellent specificity for GISTs, with false positive rate < 1% in spindle cell tumors The combination use of CD117 and DOG1 staining is reliable in confirming the diagnosis of GISTs. CD34, SMA, and S100 immunostaining act as complementary diagnostic tests if either CD117 or DOG1 staining shows negative result.
The current treatment of choice for vaginal smooth muscle tumors is a margin-free resection of primary tumor and the possible site for uterine sarcoma included, suggesting the variant and individualized extent of surgical excision based on clinical evaluation. On the other hand, the standard treatment for GIST is an en bloc tumor excision with negative margins and segmental resection of the primary site. Regarding the issue of preserving reproductive organs, a precise diagnosis before treatment is relevant for making optimized surgical plan.
The constitutive activation of KIT due to gain-of-function mutation is the target of anti-tyrosine kinase therapy.[30–33] Adjuvant imatinib therapy has been shown to improve recurrence-free survival rate for patients with high risk of recurrence after complete resection of primary GIST.[34–39] Several retrospective studies have suggested that the administration of neoadjuvant imatinib may reduce surgical morbidity in patients with advanced primary GISTs,[40–44] which could be potentially beneficial for patients with confirmed preoperative diagnosis.
The diagnosis of soft tissue stromal tumors is challenging owing to complex histology and diverse entities. Histological evaluation of biopsy specimens is often inadequate for reaching accurate diagnosis. Therefore, immunochemistry plays a crucial role in distinguishing GISTs from other mesenchymal neoplasms. The combined use of CD117 and DOG1 staining is helpful in making precise diagnosis before treatment. Despite its rarity, GISTs should be considered as one of the possible differential diagnoses in patients presenting with vaginal or rectovaginal septal masses during gynecologic examination with the view of a better surgical plan for preserving reproductive organs and accessibility for targeted therapy.
Data curation: Min Cheng, Chia-Hao Liu, Pei-Fen Lo, Peng-Hui Wang.
Formal analysis: Peng-Hui Wang.
Funding acquisition: Yi-Jen Chen, Peng-Hui Wang.
Investigation: Huann-Cheng Horng, Pei-Fen Lo.
Methodology: Min Cheng, Chia-Hao Liu, Huann-Cheng Horng.
Project administration: Peng-Hui Wang.
Supervision: Wen-Ling Lee, Peng-Hui Wang.
Validation: Huann-Cheng Horng, Yi-Jen Chen, Pei-Fen Lo.
Writing – original draft: Min Cheng, Peng-Hui Wang.
Writing – review & editing: Min Cheng, Chia-Hao Liu, Wen-Ling Lee, Peng-Hui Wang.
Peng-Hui Wang orcid: 0000-0002-6048-8541.
. Nishida T, Blay JY, Hirota S, et al. The standard diagnosis, treatment, and follow-up of gastrointestinal stromal tumors based on guidelines. Gastric Cancer 2016;19:3–14.
. Miettinen M, Sarlomo-Rikala M, Lasota J. Gastrointestinal stromal tumors: recent advances in understanding of their biology. Hum Pathol 1999;30:1213–20.
. Reith JD, Goldblum JR, Lyles RH, et al. (Soft Tissue) Stromal tumors: an analysis of 48 cases with emphasis on histologic predictors of outcome. Mod Pathol 2000;13:577.
. Nasu K, Ueda T, Kai S, et al. Gastrointestinal stromal tumor
arising in the rectovaginal septum. Int J Gynecol Cancer 2004;14:373–7.
. Ceballos KM, Francis JA, Mazurka JL. Gastrointestinal stromal tumor
presenting as a recurrent vaginal mass. Arch Pathol Lab Med 2004;128:1442–4.
. Weppler EH, Gaertner EM. Malignant extragastrointestinal stromal tumor presenting as a vaginal mass: report of an unusual case with literature review. Int J Gynecol Cancer 2005;15:1169–72.
. Lam MM, Corless CL, Goldblum JR, et al. Extragastrointestinal stromal tumors presenting as vulvovaginal/rectovaginal septal masses: a diagnostic pitfall. Int J Gynecol Pathol 2006;25:288–92.
. Takano M, Saito K, Kita T, et al. Preoperative needle biopsy and immunohistochemical analysis for gastrointestinal stromal tumor
of the rectum mimicking vaginal leiomyoma. J Gynecol Cancer 2006;16:927–30.
. Hsu S, Chen SS, Chen YZ. Gastrointestinal stromal tumors presenting as gynecological tumors. Eur J Obstet Gynecol Reprod Biol 2006;125:139–40.
. Kim YJ, Jeong YY, Kim SM. Extragastrointestinal stromal tumor arising from the vagina: MR findings. Eur Radiol 2006;16:1860–1.
. Nagase S, Mikami Y, Moriya T, et al. Vaginal tumors with histologic and immunocytochemical feature of gastrointestinal stromal tumor
: two cases and review of the literature. J Gynecol Cancer 2007;17:928–33.
. Molina I, Seamon LG, Copeland LJ, et al. Reclassification of leiomyosarcoma as an extra-gastrointestinal stromal tumor
of the gynecologic tract. Int J Gynecol Pathol 2009;28:458–63.
. Zhang W, Peng Z, Xu L. Extragastrointestinal stromal tumor arising in the rectovaginal septum: report of an unusual case with literature review. Gynecol Oncol 2009;113:399–401.
. Shafiq Q, Mohamed I. Concomitant occurrence of the left atrial myxoma and gastrointestinal stromal tumor
(GIST): a case report. Internet J Cardiol 2009;7:
. Fregnani JH, de Oliveira AT, de Lima Vazquez V, et al. Is the gastrointestinal stromal tumor
arising in the rectovaginal septum an extragastrointestinal entity? A time for reflection. Int J Colorectal Dis 2011;26:387–9.
. Pelz AF, Agaimy A, Daniels M, et al. Gastrointestinal stromal tumor
presenting as a rectovaginal mass. Clinicopathologic and molecular-genetic characterization of a rare tumor with a literature review. Hum Pathol 2011;42:586–93.
. Vazquez J, Perez-Pena M, Gonzalez B, et al. Gastrointestinal stromal tumor
arising in the rectovaginal septum. J Low Genit Tract Dis 2012;16:158–61.
. Munoz M, Echeverri C, Ramirez PT, et al. Extragastrointestinal stromal tumor in the rectovaginal septum in an adolescent. Gynecol Oncol Case Rep 2013;5:67–9.
. Melendez MN, Revello R, Cuerva MJ, et al. Misdiagnosis of an extragastrointestinal stromal tumor in the rectovaginal septum. J Low Genit Tract Dis 2014;18:e66–70.
. Liu QY, Kan YZ, Zhang MY, et al. Primary extragastrointestinal stromal tumor arising in the vaginal wall: significant clinicopathological characteristics of a rare aggressive soft tissue neoplasm. World J Clin Cases 2016;4:118–23.
. Hanayneh W, Starr J, George TJ Jr, et al. Extragastrointestinal stromal tumors of the pelvic cavity and the vagina: two case reports and review of the literature. Gynecol Oncol Rep 2018;25:3–7.
. Miettinen M, Sobin LH, Sarlomo-Rikala M. Immunohistochemical spectrum of GISTs at different sites and their differential diagnosis with a reference to CD117 (KIT). Mod Pathol 2000;13:1134–42.
. Fulop E, Marcu S, Milutin D, et al. Gastrointestinal stromal tumors: review on morphology, diagnosis and management. Rom J Morphol Embryol 2009;50:319–26.
. West RB, Corless CL, Chen X, et al. The novel marker, DOG1, is expressed ubiquitously in gastrointestinal stromal tumors irrespective of KIT or PDGFRA mutation status. Am J Pathol 2004;165:107–13.
. Novelli M, Rossi S, Rodriguez-Justo M, et al. DOG1 and CD117 are the antibodies of choice in the diagnosis of gastrointestinal stromal tumours. Histopathology 2010;57:259–70.
. Espinosa I, Lee CH, Kim MK, et al. A novel monoclonal antibody against DOG1 is a sensitive and specific marker for gastrointestinal stromal tumors. Am J Surg Pathol 2008;32:210–8.
. Suh MJ, Park DC. Leiomyosarcoma of the vagina: a case report and review from the literature. J Gynecol Oncol 2008;19:261–4.
. Ngan HY, Fisher C, Blake P, et al. Vaginal sarcoma: the Royal Marsden experience. Int J Gynecol Cancer 1994;4:337–41.
. van der Zwan SM, DeMatteo RP. Gastrointestinal stromal tumor
: 5 years later. Cancer 2005;104:1781–8.
. Wu CC, Weng CS, Hsu YT, et al. Antitumor effects of BMS-777607 on ovarian cancer cells with constitutively activated c-MET. Taiwan J Obstet Gynecol 2019;58:145–52.
. Lim L, Wu CC, Hsu YT, et al. Clinical significance of c-Met and phospho-c-Met (Tyr1234/1235) in ovarian cancer. Taiwan J Obstet Gynecol 2019;58:105–10.
. Chang CM, Wang PH, Horng HC. Gene set-based analysis of mucinous ovarian carcinoma. Taiwan J Obstet Gynecol 2017;56:210–6.
. Su W, Zhang X, Cai X, et al. BIM deletion polymorphism predicts poor response to EGFR-TKIs in nonsmall cell lung cancer: an updated meta-analysis. Medicine (Baltimore) 2019;98:e14568.
. Dematteo RP, Ballman KV, Antonescu CR, et al. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet 2009;373:1097–104.
. Hsieh YY, Yen CC, Yeh CN, et al. Effective salvage therapy of imatinib-resistant gastrointestinal stromal tumor
with combination of imatinib and pegylated liposomal doxorubicin. J Chin Med Assoc 2011;74:272–4.
. Chen YY, Peng FS, Lin HH, et al. Gastrointestinal stromal tumor
mimicking ovarian malignancy in a woman with type I neurofibromatosis. Taiwan J Obstet Gynecol 2015;54:330–1.
. Tjhoi WEH, Li K, Shou CH, et al. Long-term adjuvant imatinib treatment for a patient who underwent complete resection of a localized recurrent gastrointestinal stromal tumor
after preoperative imatinib treatment: a case report. Medicine (Baltimore) 2019;98:e14477.
. Lu J, Dai Y, Zheng HL, et al. What is the appropriate duration of adjuvant imatinib mesylate treatment for primary gastrointestinal stromal tumors classified according to the strict definition of tumor rupture? Medicine (Baltimore) 2019;98:e14177.
. Nie Y, Sun W, Xiao Z, et al. Complete response to sunitinib for more than three years in a patient with a jejunum gastrointestinal stromal tumor
: a case report. Medicine (Baltimore) 2019;98:e14060.
. Sicklick JK, Lopez NE. Optimizing surgical and imatinib therapy for the treatment of gastrointestinal stromal tumors. J Gastrointest Surg 2013;17:1997–2006.
. Qiu HB, Zhou ZG, Feng XY, et al. Advanced gastrointestinal stromal tumor
patients benefit from palliative surgery after tyrosine kinase inhibitors therapy. Medicine (Baltimore) 2018;97:e9097.
. Tang J, Zhao R, Zheng X, et al. Using the recurrence risk score by Joensuu to assess patients with gastrointestinal stromal tumor
treated with adjuvant imatinib: a retrospective cohort study. Medicine (Baltimore) 2018;97:e11400.
. Lu J, Chen S, Li X, et al. Gastrointestinal stromal tumors: fibrinogen levels are associated with prognosis of patients as blood-based biomarker. Medicine (Baltimore) 2018;97:e0568.
. Yin X, Shen C, Yin Y, et al. Giant gastric stromal tumor mimicking as a posterior mediastinal mass: a case report and literature review. Medicine (Baltimore) 2018;97:e12816.