Misdiagnosis of an Extragastrointestinal Stromal Tumor in the Rectovaginal Septum Marcos N. Mele´ndez, MD, Rocio Revello, MD, Marcos J. Cuerva, MD, Javier De Santiago, MD, PhD, and Ignacio Zapardiel, MD, PhD Gynecologic Oncology Unit, La Paz University Hospital, Madrid, Spain
h Abstract Gastrointestinal stromal tumors are very rare, representing 0.1% to 1% of gastrointestinal malignancies. Gastrointestinal stromal tumors outside the digestive tract comprise a very small fraction of all gastrointestinal stromal tumors, and their most common locations are the omentum, the mesentery, and, in few cases, the rectovaginal septum. Despite their low incidence, extragastrointestinal stromal tumors are potentially malignant tumors and they present a high rate of recurrences. This, added to the fact that they are often asymptomatic until advanced stages, determines an unfavorable prognosis. Case Report. We report a case of gastrointestinal stromal tumor located in the rectovaginal septum, which recurred after local excision; hence, a reintervention was needed. Conclusions. A correct differential diagnosis between extragastrointestinal stromal tumors and other similar pathologies such as leiomyomas or schwannomas is imperative based on their histology and immunohistochemistry. The correct diagnosis of extragastrointestinal stromal tumors allows to start adequate treatment and follow-up, preventing recurrence that determines their poor prognosis. h Introduction.
Key Words: extragastrointestinal stromal tumor, rectovaginal septum, imatinib mesylate
Reprint requests to: Ignacio Zapardiel, MD, PhD, Gynecologic Oncology Unit, La Paz University Hospital, Paseo Castellana 261, 28046, Madrid, Spain. E-mail: [email protected] The authors have declared they have no conflicts of interest. The authors did not receive financial support for this study.
Ó 2014, American Society for Colposcopy and Cervical Pathology Journal of Lower Genital Tract Disease, Volume 18, Number 3, 2014, e66Ye70
G
astrointestinal stromal tumors (GISTs) were originally confused with tumors derived from smooth muscle cells. They are potentially malignant tumors of the interstitial cells of Cajal [1]. Despite the fact that its incidence is only 10 to 20 cases per million population per year, they are the most frequent mesenchymal tumors in the gastrointestinal tract [2]. Gastrointestinal stromal tumors have been found across all ages. There are no differences between races, geographical distribution, or profession, and their most frequent location is the stomach, followed by the small intestine [3]. Recently, GISTs have also been described outside the gastrointestinal tract (extragastrointestinal stromal tumor [EGIST]). Extragastrointestinal stromal tumors comprise a very small fraction of all GISTs, and their most common locations are the omentum and the mesentery [4]. However, EGISTs have also been identified in the rectovaginal septum. Tumor sizes vary, and they are often asymptomatic until advanced stages. This, coupled with the high rate of recurrence of these tumors, determines a very unfavorable prognosis. There are currently 16 published cases of EGISTs in the rectovaginal septum [2, 5Y15] (see Table 1). We present a new case of EGISTs in the rectovaginal septum that was first wrongly diagnosed as a solitary fibrous tumor, influencing its final outcome.
CASE REPORT An 80-year-old woman with a 6-cm vulvar tumor presented at our institution. The patient complained of discomfort and a growth in her genital area without any other symptoms. A pelvic examination was performed
Copyright © 2014 American Society for Colposcopy and Cervical Pathology. Unauthorized reproduction of this article is prohibited.
Extragastrointestinal Stromal Tumor Misdiagnosis
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Table 1. Clinical Features, Treatment, and Follow-up of Rectovaginal EGIST Cases Published in the Literature Reference
Year
Age
Histology
Treatment
Outcomes
Nasu et al. [2] Ceballos et al. [5] Weppler et al. [6] Hsu and Chen [7] Hsu and Chen [7] Takano et al. [8] Lam et al. [9] Lam et al. [9] Lam et al. [9] Nagase et al. [10] Nagase et al. [10] Sanmartı´n et al. [11] Zhang et al. [12] Segura et al. [13] Pelz et al. [14] Va´zquez et al. [15] Mele´ndez et al. (this study)
2004 2004 2005 2006 2006 2006 2006 2006 2006 2007 2007 2009 2009 2010 2011 2012 2013
54 75 66 54 67 38 36 48 61 42 66 75 42 75 39 29 80
GIST GIST GIST GIST GIST GIST GIST GIST GIST GIST GIST GIST GIST GIST GIST GIST GIST
RR + local excision + LN LE Imatinib TAH + BSO + LN + RR + imatinib TAH + BSO + RR + imatinib Local excision ND ND ND Local excision Local excision + imatinib Local excision + imatinib TAH + local excision Imatinib Local excision + imatinib Local excision + imatinib Local excision + imatinib
NED 13 mo RE 7.5 y ND NED 2 y NED 6 mo NED 12 mo RE 2 y RE 10 y ND NED 4 y NED 6 mo NED 1 y NED 11 mo ND NED 44 mo NED 2 y ND
EGIST, extragastrointestinal stromal tumor; GIST, gastrointestinal stromal tumor; RR, resection of the rectum; LN, lymphadenectomy; NED, no evidence of disease; LE, local excision; RE, recidive; ND, not described; TAH, transabdominal hysterectomy; BSO, bilateral salpingo-oophorectomy.
during the first visit. Physical examination revealed a mass lesion in the rectovaginal septum, with predominant involvement of the posterior vaginal wall. The tumor was clearly visible and was 5 or 6 cm in diameter. We performed Pap smear of the vulva and the vagina, the results of which were normal; a pelvic ultrasound revealed no further lesions. No other tests were performed before surgery. The lesion was surgically excised, and we realized that the lesion had its origin 6 cm deep into the rectovaginal septum. The pathologic report revealed a mesenchymal tumor with fusiform cells, elongated core without atypia, and a significant pattern of expansive growth. It showed a very high mitotic index, up to 1 to 3 mitosis/high-power field (HPF), and the resection margin was less than 1 mm. Accordingly, a solitary fibrous tumor of the vulva was diagnosed. Because of the malignant potential of solitary fibrous tumors and the presence of risk factors such as the high mitotic index, the rate of proliferation, and the narrow resection margin, follow-up appointments every 6 months were decided. In every visit, pelvic examination, Pap smears of the vulva and the vagina, and routine blood sampling were performed. After 2 years of follow-up, a new 6-cm lesion on the area of the previous scar was found. The patient complained of a new growth in the vulvar area occurring during the last few months. She denied any abdominal pain, vaginal bleeding, or any other symptom. The patient underwent a second surgery where a 6 3-cm tumor was removed. An exhaustive pathological examination, with careful immunohistochemical analysis, was carried out. The tumor was positive for c-kit (CD117),
CD34, and caldesmon and negative for desmin, >-actin, and estrogen and progesterone receptors. The mitotic index was high: up to 5 mitosis/HPF. The diagnosis was GIST with intermediate risk for malignancy. With the diagnosis of EGIST in the rectovaginal septum, the patient started treatment with imatinib mesylate 400 mg/d. Pelvic magnetic resonance imaging, rectoscopy, abdominal computed tomography, positron emission tomography/computed tomography, and chest radiography were performed after the diagnosis of EGIST to detect any metastatic lesion. Physical and radiologic examination did not reveal any other primary site of disease or metastatic lesion. A magnetic resonance image showed a 3-cm tumor at the lower third of the rectum and a distortion of the rectovaginal septum. This finding was described as residual disease after surgery. No iliac or inguinal pathologic nodes were found. No additional surgical procedures were carried out. Follow-up appointments were set every 6 months. Pelvic magnetic resonance imaging, blood sampling, physical examination, and determination of serum tumor markers CA-125 and CA-19.9 were performed in each visit. Imaging tests, performed every 6 months, did not show any growth of the residual disease or new lesions. After 22 months of follow-up, there were no signs of local recurrence.
DISCUSSION Gastrointestinal stromal tumors are very rare, representing 0.1% to 1% of gastrointestinal malignancies
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[3]. However, it must be borne in mind that they are the most common mesenchymal tumors of the gastrointestinal tract [3]. Their most frequent location is the stomach (50%Y70%), followed by the small intestine (30%Y40%), esophagus (5%), and colon and rectum (5%Y10%) [16]. More than 90% of cases occur in patients older than 40 years, although they are described in all ages [3]. Tumor sizes are very variable and can be from 1 to 30 cm; mean size at diagnosis is from 5 to 8 cm [17]. Patients are often asymptomatic until advanced stages, when symptoms are constipation, intestinal hemorrhage, or changes in the urinary frequency. Extragastrointestinal stromal tumors represent 5% to 7% of all GISTs, and their most common locations are the omentum, the mesentery, the retroperitoneal space, and the bladder [4]. They have also been described in the rectovaginal septum, but this localization is extremely infrequent. In fact, only 16 cases have been published (see Table 1). Mean age at diagnosis is around the fifth decade of life, although cases from 29 to 75 years have been reported. Some cases presented constipation or changes in the urinary frequency, but most report no symptoms at the diagnosis like in our case. In almost all cases, the treatment consisted of surgical resection and imatinib mesylate to prevent a possible recurrence. In 3 cases, recurrences were found, and in others, the fact that no recurrences have been reported can be related to a short follow-up period. In one of the cases, the recurrence appeared 10 years after the removal of the tumor [12]. Because of their unusual clinical presentation, rectovaginal GISTs may pose a differential diagnostic challenge both to clinicians and to pathologists. The histopathologic differential diagnosis of GIST at this location is relatively limited and encompasses leiomyoma/ leiomyosarcoma, spindle cell carcinoma, spindle cell melanoma, solitary fibrous tumor, aggressive angiomyxoma, angiomyofibroblastoma, and angiofibroma [1, 9, 14]. In routine practice, most of these lesions are well distinguishable from GISTs given their characteristic histologic appearance and immunoprofiles. The key to the diagnosis of GIST is immunohistochemistry, and the positivity for KIT (CD117) deserves special consideration in this section [1]. CD117 is a proto-oncogene that encodes the tyrosine kinase receptor type III, whose ligand is c-kit. It is a marker of cell surface that can be found in the hematopoietic cells of the bone marrow, in mast cells, in melanocytes, and in the interstitial cells of Cajal [6]. Its presence is very evocative of GIST. Leiomyomas and leiomyosarcomas may closely mimic GIST histologically. Gastrointestinal stromal
tumors typically stain intensely for the CD117 molecule, which is an epitope of KIT. In contrast, desmoids, schwannomas (S-100Ypositive, KIT-negative), leiomyomas, and leiomyosarcomas (desmin-positive, KIT-negative) do not [18]. In GISTs, according to Fletcher et al. [18], CD117 appears diffusely in the cytoplasm in a punctate or Golgi-like pattern. H-Caldesmon, an otherwise specific smooth muscle marker, is expressed in around half of the GIST cases, thus being of no value in the differential diagnosis [14]. Melanomas at this anatomic site may express CD117, and a small proportion of the cases may harbor oncogenic c-KIT mutation. Thus, a careful pattern analysis, in particular, application of melanocytic markers (protein S-100, HMB45, and Melan A), is mandatory for this differentiation [14]. Although GISTs are stroma-poor tumors and solitary fibrous tumors tend to have more stroma, some tumors may have an overlapping histology. Both of them are immunoreactive for CD34. Immunoreactivity for CD117 (c-kit) has been shown to be a sensitive and specific marker for GISTs to be differentiated from solitary fibrous tumors. Thus, a careful pattern analysis is mandatory for this differentiation. Because GISTs respond to the tyrosine kinase inhibitor imatinib mesylate, differentiating them from solitary fibrous tumors is clinically relevant [19]. The treatment is mainly based on the total surgical removal of the tumor. Lymphadenectomy is not indicated because GISTs rarely spread through the lymphatic system. In addition to surgery, owing to the high rate of recurrences, treatment with imatinib mesylate 400 mg/d after surgery is advised [18]. Imatinib mesylate (Glivec), a tyrosine kinase inhibitor originally designed to treat chronic myelogenous leukemia, is the current treatment of choice for advanced GISTs [10]. Several clinical studies of imatinib for advanced GISTs have shown a high overall response rate, with a partial response rate and stable disease rate of 45% and 32%, respectively [10, 20, 21]. In addition, clinical response to imatinib therapy has been reported to correlate with the type of KIT mutation; patients with a mutation in KIT exon 11 seem to have a better response rate and longer interval of progression-free survival than patients whose mutation is in KIT exon 9 [10, 22]. The efficacy of imatinib as adjuvant therapy after optimal resection or as neoadjuvant therapy remains to be determined. Conventional chemotherapy and radiotherapy have not proven any use. Keeping the prognostic factors in mind is of high importance. The evidence is mostly based on GISTs, and
Copyright © 2014 American Society for Colposcopy and Cervical Pathology. Unauthorized reproduction of this article is prohibited.
Extragastrointestinal Stromal Tumor Misdiagnosis
there is small evidence for EGISTs. Tumor size greater than 10 cm is considered of high risk, but it does not seem to be as important as prognostic factor in the EGISTs as in the GISTs [3]. The most important prognostic factor for the GISTs and EGISTs is the mitotic index [14], with greater than 5 mitosis/HPF indicating poor prognosis. Another important risk factor is the Ki67. The higher the Ki67, the worse is the prognosis. Other prognostic factors are the presence of necrosis, tumor rupture during surgical resection, index of aneuploidies, and telomerase expression. Patients with fewer than two of the above histologic features experienced only a 5% adverse outcome (death from disease or tumor metastasis), whereas patients having two or more of the features had a 92% adverse outcome [4]. The behavior of stromal tumors differs by location, and there seems to be a general trend for increasingly aggressive behavior as one proceeds distally along the gastrointestinal tract [4, 23, 24]. For example, most GISTs located in the stomach have a good prognosis, whereas those in the small intestine have a significantly worse prognosis. In conclusion, despite the low frequency, the possible diagnosis of an EGIST must be taken into consideration in any mass at the level of the rectovaginal septum. Gynecologists as well as diagnostic pathologists should be aware of EGIST manifesting as a vaginal mass. Recognition of microscopic patterns and characteristic immunohistochemical phenotype is mandatory for establishing the correct diagnosis. In addition, the potential risk for recurrent disease indicates the need for a long-term follow-up. This has been the case of our patient, who had a relapse after complete resection of the tumor. The diagnosis of EGIST of the rectovaginal septum was not made in our case until the removal of the recurrence and an exhaustive immunohistochemical analysis was carried out. The right treatment with imatinib mesylate was only then started. No locoregional recurrence has appeared until the present time. However, the patient remains in follow-up, with pelvic magnetic resonance image showing residual disease that has not changed in 2 years.
REFERENCES 1. Miettinen M, Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol 2006;23:70Y83. 2. Nasu K, Ueda T, Kai S, Anai H, Kimura Y, Yokoyama S, et al. Gastrointestinal stromal tumor arising in the rectovaginal septum. Int J Gynecol Cancer 2004;14:373Y7. 3. Kim KM, Kang DW, Moon WS, Park JB, Park CK, Sohn JH, et al. Gastrointestinal Stromal Tumor Committee;
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The Korean Gastrointestinal Pathology Study Group. Gastrointestinal stromal tumors in Koreans: incidence and the clinical, pathologic and immunohistochemical findings. J Korean Med Sci 2005;20:977Y84. 4. Reith JD, Goldblum JR, Lyles RH, Weiss SW. Extragastrointestinal (soft tissue) stromal tumors: an analysis of 48 cases with emphasis on histologic predictors of outcome. Mod Pathol 2000;13:577Y85. 5. Ceballos KM, Francis JA, Mazurka JL. Gastrointestinal stromal tumor presenting as a recurrent vaginal mass. Arch Pathol Lab Med 2004;128:1442Y4. 6. 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;6:1169Y72. 7. Hsu S, Chen SS. Gastrointestinal stromal tumors presenting as gynecological tumors. Eur J Obstet Gynecol 2006; 125:139Y45. 8. Takano M, Saito K, Kita T, Furuya K, Aida S, Kikuchi Y. Preoperative needle biopsy and inmunohistochemical analysis for gastrointestinal stromal tumor of the rectum mimicking vaginal leiomyoma. Int J Gynecol Cancer 2006;16:927Y30. 9. Lam MM, Corless CL, Goldblum JR, Heinrich MC, Downs-Kelly E, Rubin BP. Extragastrointestinal stromal tumors presenting as vulvovaginal/rectovaginal septal masses: a diagnostic pitfall. Int J Gynecol Pathol 2006;25:288Y92. 10. Nagase S, Mikami Y, Moriya T, Niikura H, Yoshinaga K, Takano T, et al. Vaginal tumors with histologic and inmunocytochemical feature of gastrointestinal stromal tumor: two cases and review of the literature. Int J Gynecol Cancer 2007;17:928Y33. 11. Sanmartı´n JM, Sa´nchez MJR, Fuster NE, Lo´pez AS, Sa´nchez OCP, Hidalgo MAC, et al. Tumor del estroma gastrointestinal en el tabique rectovaginal, un desafı´o diagno´stico. Prog Obstet Ginecol 2010;53:288Y91. 12. 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: 399Y401. 13. Segura TB, Ferri J, Franco M, Paya´ A, Lluı´s F. Tumor de la estroma gastrointestinal en el tabique rectovaginal. Cir Esp 2010;87:402Y3. 14. Pelz AF, Agaimy A, Daniels M, Evert M, Schulz HU, Lu¨ders P, 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;42:586Y93. 15. Va´zquez J, Pe´rez-Pen˜a M, Gonza´lez B, Sa´nchez A. Gastrointestinal stromal tumor arising in the rectovaginal septum. J Low Genit Tract Dis 2012;16:158Y61. 16. Oliva E, Young RH, Amin MB, Clement PB. An inmunohistochemical analysis of endometrial stromal and smooth muscle tumors of the uterus. Am J Surg Pathol 2002; 26:403Y12.
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17. Wang L, Felix JC, Lee JL, Tan PY, Tourgeman DE, O’Meara AT, et al. The proto-oncogene c-kit is expressed in leiomyosarcomas of the uterus. Gynecol Oncol 2003;90:402Y6. 18. Fletcher CD, Berman JJ, Corless C, Gorstein F, Lasota J, Longley BJ, et al. Diagnosis of gastrointestinal stromal tumors: A consensus approach. Hum Pathol 2002;33:459Y65. 19. Shidham VB, Chivukula M, Gupta D, Rao RN, Komorowski R. Immunohistochemical comparison of gastrointestinal stromal tumor and solitary ?brous tumor. Arch Pathol Lab Medicine 2002;126:1189Y92. 20. Benjamin RS, Rankin C, Fletcher C, Blanke C, Von Mehren M, Maki R, et al. Phase III dose-randomized study of imatinib mesylate (STI571) for GIST: intergroup S0033 early results [abstract]. Proc Am Soc Clin Oncol 2003;22:814S. Abstract 3271.
21. Verweij J, Casali PG, Zalcberg J, LeCesne A, Reichardt P, Blay JY, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet 2004;364:1127Y34. 22. Corless CL, McGreevey L, Haley A, Town A, Heinrich MC. KIT mutations are common in incidental gastrointestinal stromal tumors one centimeter or less in size. Am J Pathol 2002;160:1567Y72. 23. Brainard JA, Goldblum JR. Stromal tumors of the jejunum and ileum: a clinicopathologic study of 39 cases. Am J Surg Pathol 1997;21:407Y16. 24. Goldblum JR, Appelman HD. Stromal tumors of the duodenum: a histologic and immunohistochemical study of 20 cases. Am J Surg Pathol 1995;19:71Y80.
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h Abstract Gastrointestinal stromal tumors are very rare, representing 0.1% to 1% of gastrointestinal malignancies. Gastrointestinal stromal tumors outside the digestive tract comprise a very small fraction of all gastrointestinal stromal tumors, and their most common locations are the omentum, the mesentery, and, in few cases, the rectovaginal septum. Despite their low incidence, extragastrointestinal stromal tumors are potentially malignant tumors and they present a high rate of recurrences. This, added to the fact that they are often asymptomatic until advanced stages, determines an unfavorable prognosis. Case Report. We report a case of gastrointestinal stromal tumor located in the rectovaginal septum, which recurred after local excision; hence, a reintervention was needed. Conclusions. A correct differential diagnosis between extragastrointestinal stromal tumors and other similar pathologies such as leiomyomas or schwannomas is imperative based on their histology and immunohistochemistry. The correct diagnosis of extragastrointestinal stromal tumors allows to start adequate treatment and follow-up, preventing recurrence that determines their poor prognosis. h Introduction.
Key Words: extragastrointestinal stromal tumor, rectovaginal septum, imatinib mesylate
Reprint requests to: Ignacio Zapardiel, MD, PhD, Gynecologic Oncology Unit, La Paz University Hospital, Paseo Castellana 261, 28046, Madrid, Spain. E-mail: [email protected] The authors have declared they have no conflicts of interest. The authors did not receive financial support for this study.
Ó 2014, American Society for Colposcopy and Cervical Pathology Journal of Lower Genital Tract Disease, Volume 18, Number 3, 2014, e66Ye70
G
astrointestinal stromal tumors (GISTs) were originally confused with tumors derived from smooth muscle cells. They are potentially malignant tumors of the interstitial cells of Cajal [1]. Despite the fact that its incidence is only 10 to 20 cases per million population per year, they are the most frequent mesenchymal tumors in the gastrointestinal tract [2]. Gastrointestinal stromal tumors have been found across all ages. There are no differences between races, geographical distribution, or profession, and their most frequent location is the stomach, followed by the small intestine [3]. Recently, GISTs have also been described outside the gastrointestinal tract (extragastrointestinal stromal tumor [EGIST]). Extragastrointestinal stromal tumors comprise a very small fraction of all GISTs, and their most common locations are the omentum and the mesentery [4]. However, EGISTs have also been identified in the rectovaginal septum. Tumor sizes vary, and they are often asymptomatic until advanced stages. This, coupled with the high rate of recurrence of these tumors, determines a very unfavorable prognosis. There are currently 16 published cases of EGISTs in the rectovaginal septum [2, 5Y15] (see Table 1). We present a new case of EGISTs in the rectovaginal septum that was first wrongly diagnosed as a solitary fibrous tumor, influencing its final outcome.
CASE REPORT An 80-year-old woman with a 6-cm vulvar tumor presented at our institution. The patient complained of discomfort and a growth in her genital area without any other symptoms. A pelvic examination was performed
Copyright © 2014 American Society for Colposcopy and Cervical Pathology. Unauthorized reproduction of this article is prohibited.
Extragastrointestinal Stromal Tumor Misdiagnosis
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Table 1. Clinical Features, Treatment, and Follow-up of Rectovaginal EGIST Cases Published in the Literature Reference
Year
Age
Histology
Treatment
Outcomes
Nasu et al. [2] Ceballos et al. [5] Weppler et al. [6] Hsu and Chen [7] Hsu and Chen [7] Takano et al. [8] Lam et al. [9] Lam et al. [9] Lam et al. [9] Nagase et al. [10] Nagase et al. [10] Sanmartı´n et al. [11] Zhang et al. [12] Segura et al. [13] Pelz et al. [14] Va´zquez et al. [15] Mele´ndez et al. (this study)
2004 2004 2005 2006 2006 2006 2006 2006 2006 2007 2007 2009 2009 2010 2011 2012 2013
54 75 66 54 67 38 36 48 61 42 66 75 42 75 39 29 80
GIST GIST GIST GIST GIST GIST GIST GIST GIST GIST GIST GIST GIST GIST GIST GIST GIST
RR + local excision + LN LE Imatinib TAH + BSO + LN + RR + imatinib TAH + BSO + RR + imatinib Local excision ND ND ND Local excision Local excision + imatinib Local excision + imatinib TAH + local excision Imatinib Local excision + imatinib Local excision + imatinib Local excision + imatinib
NED 13 mo RE 7.5 y ND NED 2 y NED 6 mo NED 12 mo RE 2 y RE 10 y ND NED 4 y NED 6 mo NED 1 y NED 11 mo ND NED 44 mo NED 2 y ND
EGIST, extragastrointestinal stromal tumor; GIST, gastrointestinal stromal tumor; RR, resection of the rectum; LN, lymphadenectomy; NED, no evidence of disease; LE, local excision; RE, recidive; ND, not described; TAH, transabdominal hysterectomy; BSO, bilateral salpingo-oophorectomy.
during the first visit. Physical examination revealed a mass lesion in the rectovaginal septum, with predominant involvement of the posterior vaginal wall. The tumor was clearly visible and was 5 or 6 cm in diameter. We performed Pap smear of the vulva and the vagina, the results of which were normal; a pelvic ultrasound revealed no further lesions. No other tests were performed before surgery. The lesion was surgically excised, and we realized that the lesion had its origin 6 cm deep into the rectovaginal septum. The pathologic report revealed a mesenchymal tumor with fusiform cells, elongated core without atypia, and a significant pattern of expansive growth. It showed a very high mitotic index, up to 1 to 3 mitosis/high-power field (HPF), and the resection margin was less than 1 mm. Accordingly, a solitary fibrous tumor of the vulva was diagnosed. Because of the malignant potential of solitary fibrous tumors and the presence of risk factors such as the high mitotic index, the rate of proliferation, and the narrow resection margin, follow-up appointments every 6 months were decided. In every visit, pelvic examination, Pap smears of the vulva and the vagina, and routine blood sampling were performed. After 2 years of follow-up, a new 6-cm lesion on the area of the previous scar was found. The patient complained of a new growth in the vulvar area occurring during the last few months. She denied any abdominal pain, vaginal bleeding, or any other symptom. The patient underwent a second surgery where a 6 3-cm tumor was removed. An exhaustive pathological examination, with careful immunohistochemical analysis, was carried out. The tumor was positive for c-kit (CD117),
CD34, and caldesmon and negative for desmin, >-actin, and estrogen and progesterone receptors. The mitotic index was high: up to 5 mitosis/HPF. The diagnosis was GIST with intermediate risk for malignancy. With the diagnosis of EGIST in the rectovaginal septum, the patient started treatment with imatinib mesylate 400 mg/d. Pelvic magnetic resonance imaging, rectoscopy, abdominal computed tomography, positron emission tomography/computed tomography, and chest radiography were performed after the diagnosis of EGIST to detect any metastatic lesion. Physical and radiologic examination did not reveal any other primary site of disease or metastatic lesion. A magnetic resonance image showed a 3-cm tumor at the lower third of the rectum and a distortion of the rectovaginal septum. This finding was described as residual disease after surgery. No iliac or inguinal pathologic nodes were found. No additional surgical procedures were carried out. Follow-up appointments were set every 6 months. Pelvic magnetic resonance imaging, blood sampling, physical examination, and determination of serum tumor markers CA-125 and CA-19.9 were performed in each visit. Imaging tests, performed every 6 months, did not show any growth of the residual disease or new lesions. After 22 months of follow-up, there were no signs of local recurrence.
DISCUSSION Gastrointestinal stromal tumors are very rare, representing 0.1% to 1% of gastrointestinal malignancies
Copyright © 2014 American Society for Colposcopy and Cervical Pathology. Unauthorized reproduction of this article is prohibited.
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[3]. However, it must be borne in mind that they are the most common mesenchymal tumors of the gastrointestinal tract [3]. Their most frequent location is the stomach (50%Y70%), followed by the small intestine (30%Y40%), esophagus (5%), and colon and rectum (5%Y10%) [16]. More than 90% of cases occur in patients older than 40 years, although they are described in all ages [3]. Tumor sizes are very variable and can be from 1 to 30 cm; mean size at diagnosis is from 5 to 8 cm [17]. Patients are often asymptomatic until advanced stages, when symptoms are constipation, intestinal hemorrhage, or changes in the urinary frequency. Extragastrointestinal stromal tumors represent 5% to 7% of all GISTs, and their most common locations are the omentum, the mesentery, the retroperitoneal space, and the bladder [4]. They have also been described in the rectovaginal septum, but this localization is extremely infrequent. In fact, only 16 cases have been published (see Table 1). Mean age at diagnosis is around the fifth decade of life, although cases from 29 to 75 years have been reported. Some cases presented constipation or changes in the urinary frequency, but most report no symptoms at the diagnosis like in our case. In almost all cases, the treatment consisted of surgical resection and imatinib mesylate to prevent a possible recurrence. In 3 cases, recurrences were found, and in others, the fact that no recurrences have been reported can be related to a short follow-up period. In one of the cases, the recurrence appeared 10 years after the removal of the tumor [12]. Because of their unusual clinical presentation, rectovaginal GISTs may pose a differential diagnostic challenge both to clinicians and to pathologists. The histopathologic differential diagnosis of GIST at this location is relatively limited and encompasses leiomyoma/ leiomyosarcoma, spindle cell carcinoma, spindle cell melanoma, solitary fibrous tumor, aggressive angiomyxoma, angiomyofibroblastoma, and angiofibroma [1, 9, 14]. In routine practice, most of these lesions are well distinguishable from GISTs given their characteristic histologic appearance and immunoprofiles. The key to the diagnosis of GIST is immunohistochemistry, and the positivity for KIT (CD117) deserves special consideration in this section [1]. CD117 is a proto-oncogene that encodes the tyrosine kinase receptor type III, whose ligand is c-kit. It is a marker of cell surface that can be found in the hematopoietic cells of the bone marrow, in mast cells, in melanocytes, and in the interstitial cells of Cajal [6]. Its presence is very evocative of GIST. Leiomyomas and leiomyosarcomas may closely mimic GIST histologically. Gastrointestinal stromal
tumors typically stain intensely for the CD117 molecule, which is an epitope of KIT. In contrast, desmoids, schwannomas (S-100Ypositive, KIT-negative), leiomyomas, and leiomyosarcomas (desmin-positive, KIT-negative) do not [18]. In GISTs, according to Fletcher et al. [18], CD117 appears diffusely in the cytoplasm in a punctate or Golgi-like pattern. H-Caldesmon, an otherwise specific smooth muscle marker, is expressed in around half of the GIST cases, thus being of no value in the differential diagnosis [14]. Melanomas at this anatomic site may express CD117, and a small proportion of the cases may harbor oncogenic c-KIT mutation. Thus, a careful pattern analysis, in particular, application of melanocytic markers (protein S-100, HMB45, and Melan A), is mandatory for this differentiation [14]. Although GISTs are stroma-poor tumors and solitary fibrous tumors tend to have more stroma, some tumors may have an overlapping histology. Both of them are immunoreactive for CD34. Immunoreactivity for CD117 (c-kit) has been shown to be a sensitive and specific marker for GISTs to be differentiated from solitary fibrous tumors. Thus, a careful pattern analysis is mandatory for this differentiation. Because GISTs respond to the tyrosine kinase inhibitor imatinib mesylate, differentiating them from solitary fibrous tumors is clinically relevant [19]. The treatment is mainly based on the total surgical removal of the tumor. Lymphadenectomy is not indicated because GISTs rarely spread through the lymphatic system. In addition to surgery, owing to the high rate of recurrences, treatment with imatinib mesylate 400 mg/d after surgery is advised [18]. Imatinib mesylate (Glivec), a tyrosine kinase inhibitor originally designed to treat chronic myelogenous leukemia, is the current treatment of choice for advanced GISTs [10]. Several clinical studies of imatinib for advanced GISTs have shown a high overall response rate, with a partial response rate and stable disease rate of 45% and 32%, respectively [10, 20, 21]. In addition, clinical response to imatinib therapy has been reported to correlate with the type of KIT mutation; patients with a mutation in KIT exon 11 seem to have a better response rate and longer interval of progression-free survival than patients whose mutation is in KIT exon 9 [10, 22]. The efficacy of imatinib as adjuvant therapy after optimal resection or as neoadjuvant therapy remains to be determined. Conventional chemotherapy and radiotherapy have not proven any use. Keeping the prognostic factors in mind is of high importance. The evidence is mostly based on GISTs, and
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Extragastrointestinal Stromal Tumor Misdiagnosis
there is small evidence for EGISTs. Tumor size greater than 10 cm is considered of high risk, but it does not seem to be as important as prognostic factor in the EGISTs as in the GISTs [3]. The most important prognostic factor for the GISTs and EGISTs is the mitotic index [14], with greater than 5 mitosis/HPF indicating poor prognosis. Another important risk factor is the Ki67. The higher the Ki67, the worse is the prognosis. Other prognostic factors are the presence of necrosis, tumor rupture during surgical resection, index of aneuploidies, and telomerase expression. Patients with fewer than two of the above histologic features experienced only a 5% adverse outcome (death from disease or tumor metastasis), whereas patients having two or more of the features had a 92% adverse outcome [4]. The behavior of stromal tumors differs by location, and there seems to be a general trend for increasingly aggressive behavior as one proceeds distally along the gastrointestinal tract [4, 23, 24]. For example, most GISTs located in the stomach have a good prognosis, whereas those in the small intestine have a significantly worse prognosis. In conclusion, despite the low frequency, the possible diagnosis of an EGIST must be taken into consideration in any mass at the level of the rectovaginal septum. Gynecologists as well as diagnostic pathologists should be aware of EGIST manifesting as a vaginal mass. Recognition of microscopic patterns and characteristic immunohistochemical phenotype is mandatory for establishing the correct diagnosis. In addition, the potential risk for recurrent disease indicates the need for a long-term follow-up. This has been the case of our patient, who had a relapse after complete resection of the tumor. The diagnosis of EGIST of the rectovaginal septum was not made in our case until the removal of the recurrence and an exhaustive immunohistochemical analysis was carried out. The right treatment with imatinib mesylate was only then started. No locoregional recurrence has appeared until the present time. However, the patient remains in follow-up, with pelvic magnetic resonance image showing residual disease that has not changed in 2 years.
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