Gastrointestinal stromal tumor presenting as a pelvic mass

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Gynecologic Oncology 91 (2003) 630 – 635

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Case Report

Gastrointestinal stromal tumor presenting as a pelvic mass Israel Zighelboim, M.D.,a,* Gwendolyn Henao, M.D.,a Anand Kunda, M.D.,b Carolina Gutierrez, M.D.,b and Creighton Edwards, M.D.a a

Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Baylor College of Medicine, Houston, TX 77030, USA b Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA Received 23 April 2003

Abstract Background. Gastrointestinal stromal tumors (GISTs) are c-kit-positive tumors that may arise anywhere in the tubular gastrointestinal tract. Around 5% of the cases arise elsewhere in the abdominal cavity. Tumors originating in the omentum and mesentery have been reported. Case. A 31-year-old woman presented with pelvic pain, a palpable pelvic mass, and elevated CA-125. Imaging showed innumerable pelvic and abdominal masses. Histopathology showed a GIST that was positive for c-kit and vimentin and negative for desmin and smooth muscle actin. The patient was started on imatinib mesylate. Six months after diagnosis the tumor has remained stable. Conclusions. GI stromal tumors (GIST) may initially present as pelvic mass with elevated CA-125. Imatinib mesylate is the current mainstay therapy for GISTs after surgery. © 2003 Elsevier Inc. All rights reserved. Keywords: Gastrointestinal stromal tumor; GIST; Pelvic mass; CA-125; Imatinib mesylate; STI-571

Introduction In the 1980s the term “stromal tumor” was applied to a variety of mesenchymal neoplasms of the gastrointestinal tract that had been previously called leiomyomas or leiomyosarcomas. Although still uncertain at the time, the term gastrointestinal stromal tumor (GIST) was progressively adopted to describe certain tumors that shared histologic features and a possible common origin from myogenic and neural elements in the gastrointestinal tract. In the late 1990s, a gain-of-function mutation (c-kit) was described at the level of the transmembrane tyrosine kinase (KIT) in these tumors [1]. The expression and presence of the c-kit protein was also normally found in the interstitial cells of Cajal, or the “pacemaker cells” of the gastrointestinal tract. This association suggests that these cells represent the common origin for GISTs [2]. The introduction of a molecule * Corresponding author. Department of Obstetrics and Gynecology, Baylor College of Medicine, 6550 Fannin, Suite 901, Houston TX 77030. Fax: ⫹1-713-798-6044. E-mail address: [email protected] (I. Zighelboim). 0090-8258/$ – see front matter © 2003 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2003.08.025

(STI-571; imatinib mesylate) capable of selectively inhibiting the activated KIT protein has brought this group of tumors to the spotlight of cancer molecular biologists, pathologists, pharmacologists, and clinicians. We report a case of a large metastatic gastrointestinal stromal tumor that presented as a large pelvic mass in a young female.

Case report A 31-year-old hispanic female G1P1 presented to the emergency department with history of lower abdominal pain for 20 days. The pain was initially localized in the left lower quadrant and then radiated to the whole pelvis by the time of evaluation. She also reported dysuria and hematuria for which she received treatment for a urinary tract infection the week before at an outside clinic. The patient was seen by her primary care physician 2 weeks before presentation and was found to have a “large left ovarian mass” and free fluid on a pelvic ultrasound. A CA-125 that had been done at that time was reported as 52 U/mL. Her past medical history was

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Fig. 1. CT Scan of the pelvis with contrast showing innumerable pelvic masses.

negative except for an uncomplicated cesarean section 23 months before her current presentation. On initial presentation to our hospital, a pelvic exam revealed left adnexal fullness and a 12-week-size pelvic mass, which extended from the midline to the left lower quadrant. An ultrasound performed in the emergency department showed multiple confluent echogenic masses throughout the pelvis. The largest of these masses measured approximately 4 cm. Color Doppler images of the masses demonstrated moderate vascularity. The uterus measured 12

cm in length. The right ovary measured 3.9 ⫻ 2.6 ⫻ 5.9 cm and appeared normal. The left ovary was not visualized. Free fluid was present in pelvic and abdominal cavities. A CT scan of the abdomen and pelvis was ordered to better characterize the masses, revealing innumerable abdominal and pelvic masses measuring 79 –90 Hounsfield Units (Fig. 1). At the time, these masses were thought, based on their density, to be highly suspicious for peritoneal lymphomatosis. Due to poor visualization of the ovaries, a neoplasm of ovarian origin with diffuse peritoneal carcino-

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Fig. 2. Surgical specimen of the removed greater omentum, showing multiple tumor implants.

matosis could not be excluded. The masses were scattered throughout the abdomen and pelvic organs as well as in the omentum and peritoneal cavity. A 1-cm hypodensity was present in the right anterior hepatic lobe. Minimal ascites was also noted. A chest X-ray revealed clear lung fields, normal mediastinum and osseous structures, and no evidence of metastatic lesions. Repeat tumor markers showed CA-125, 76.1 U/mL; CEA, 0.0 ng/mL; hCG, 0 mIU/mL; LDH, 241 U/L. Fine needle aspiration and open excisional biopsy were considered. After discussion with the hematologic oncologists at our institution, the decision was made to proceed with surgical exploration in order to obtain a more reliable pathologic diagnosis based on tissue architecture. This approach allowed tumor debulking in case of an ovarian primary. Twelve days after initial evaluation, the patient was taken to the operating room for an exploratory laparotomy. Systematic survey of the abdominal cavity showed approximately 100 cc of bloody fluid, multiple tumoral implants in the greater omentum (Fig. 2), massive coalescent tumoral masses within the pelvis, innumerable mesenteric and peritoneal tumoral implants along small intestine and colon, a normal left ovary, and a normal uterus. The right ovary could not be identified due to extensive tumoral infiltration.

The liver, gallbladder, stomach, pancreas, spleen, and kidneys appeared normal on palpation. A frozen section, performed on one of the peritoneal implants, was interpreted as a “spindle cell neoplasm, favoring malignancy.” Free fluid was also sent for cytology. The patient underwent omentectomy, left salpingo-oophorectomy, and suboptimal debulking of the accessible peritoneal and mesenteric implants. She had an uneventful postoperative course and was discharged home on postoperative day 3. The pelvic washings were negative. Sections of the submitted specimens showed a proliferation of spindle cells predominantly arranged in a storiform pattern. The spindle cells showed moderate nuclear enlargement and mild atypia, with some cells having prominent nucleoli (Figs. 3 and 4). There was also increased mitosis noted, with five to six mitoses per 10 high-power fields. No identifiable ovarian or gastrointestinal stroma was detected within the tumor. Immunohistochemical studies showed strongly positive staining of tumor cells for vimentin and c-kit and negative staining for desmin and smooth muscle actin (SMA). Thus the histologic features and immunohistochemical profile strongly supported a diagnosis of a GIST. The patient was started on oral imatinib mesylate (Gleevec) 400 mg daily after final pathology diagnosis was obtained. Baseline imaging studies were repeated at the

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Fig. 3. H&E low-power (10⫻) view showing proliferation of spindle-shaped cells in a storiform pattern.

beginning of therapy. A CT scan of the chest showed no tumor implants. A CT scan of the abdomen and pelvis, performed after surgery, showed an overall decrease in the size of the masses and a new mass posterior to the liver. A SPECT imaging with gallium-67 citrate was also obtained, showing two to three focal areas of uptake in the liver and a questionable focus of uptake in the left upper quadrant, which may represent a splenic lesion. During this time, the patient appeared to tolerate the therapy well. She has been able to continue with her usual activities of daily living and has not experienced any significant side effects as a result of the medication. A follow-up CT scan of the abdomen and pelvis obtained 6 months after the initiation of imatinib therapy showed no change in the size of the masses and no new lesions. These findings are interpreted as consistent with stable disease.

Discussion The term stromal tumors has historically encompassed a rather heterogeneous group of neoplasms that lacked the immunophenotype typical of smooth muscle origin. Among those, a number of tumors having submicroscopic and an-

tigenic features of neural crest elements was described and later subcategorized as gastrointestinal autonomic nerve tumors (GANTs). The histogenesis of these tumors was not well understood until the early 1990s. At that time, it was felt that some of these tumors were truly myogenic, while others showed more neural differentiation and some had either dual or noncharacteristic patterns. Thus, it was necessary to find a reliable marker in order to differentiate this heterogeneous group of mesenchymal tumors. It was not until the late 1990s, when KIT protein overexpression traced the precursor of GISTs to the interstitial cells of Cajal [2]. The expression of KIT is predominantly the result of a variety of gain-of-function mutations in the c-kit proto-oncogene. This discovery led to the development and use of a specific immunostain (CD-117) that allows differentiation between GIST and non-GIST spindle cell neoplasms. A consensus approach for the diagnosis of GI stromal tumors had been proposed, after the National Institute of Health convened a workshop in April 2001 [3]. The term GIST is currently virtually reserved, except for rare exceptions, for tumors positive for KIT (CD-117) and typically negative for desmin. Increased KIT tyrosine kinase activity appears to be responsible of triggering several intracellular responses that induce cell proliferation and block natural apoptotic mechanisms.

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Fig. 4. H&E high-power (40⫻) view showing mild nuclear atypia in the spindle cells.

GISTs have been reported to arise anywhere in the tubular gastrointestinal tract where they represent the most common mesenchymal neoplasm. The appearance of GIST outside of the gastrointestinal tract has also been reported, primarily in the omentum and in the mesentery [4]. When stratifying GI stromal tumors by location, 50 to 60% of the lesions are found in the stomach, 20 to 30% in the small bowel, 10% in the large bowel, 5% in the esophagus, and only 5% elsewhere in the abdominal cavity. Our patient presented clinically with pelvic pain and a palpable pelvic mass with an elevated CA-125. This prompted a potential diagnosis of ovarian neoplasm. The imaging studies were consistent with extrapelvic and omental dissemination from a possible ovarian tumor or primary lymphoma. Although some studies have tried to retrospectively review the imaging studies of patients with GISTs [5], the general radiographic findings of the tumor are very noncharacteristic and a preoperative presumptive diagnosis based on imaging is virtually impossible. Also, though it is uncommon to have extensive ascites, the presence of trace free fluid in the abdomen is common. Patients can also present with peritonitis secondary to tumor rupture. Cytologic examination of the peritoneal fluid obtained intraoperatively from our patient was negative for malignancy. The

final diagnosis of this entity can usually be established based on histopathologic and immunostains of specimens obtained by either endoscopy or laparotomy. Seidal and Edvardsson have shown that preoperative diagnosis of GI stromal tumors can be made, based on fine needle aspiration, with sufficient and adequate material obtained [6]. Prognostic factors indicating the possible malignant potential of GI stromal tumors include mitotic rate, tumor size, and location [7]. Currently, lesions that measure less than or equal to 2 cm and which do not exceed five mitoses per 50 high-power fields are thought to have a lower malignant and metastatic potential. However, a small proportion of tumors with these characteristics may show aggressive behavior. It is uncertain if Ki-67 analogs (proliferation index) may be prognostic. Also the increased number of DNA copies and the presence of genetic gains seem to herald malignant behavior. Tumor rupture before or during surgery has also been linked to poor prognosis. The spread pattern of these tumors shows predilection for liver metastasis and peritoneal dissemination. Therefore, the presence of hepatic or peritoneal lesions on presentation usually represents a sign of poor prognosis. The progression of the disease, in the case which we presented, appeared to be rapid. Thus it was difficult to ascertain whether this represented a case of primary disseminated peritoneal–mesenteric disease. An-

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other possibility included dissemination of a subclinical lesion or a lesion not visualized intraoperatively during her cesarean section 23 months prior to presentation. Mesenchymal tumors of the uterus and ovary rarely express c-kit and the staining for CD-117 in those tumors is usually focal (fewer than 5% of the cells) [8]. Elevated levels of CA-125 have been reported in a variety of peritoneal and gynecologic pathologies but to our knowledge they have not been specifically evaluated on patients with GISTs. Surgery followed by observation had previously been the mainstay of treatment for GIST. Various systemic chemotherapeutic regimes, radiation, and intraperitoneal chemotherapy had been used with little success. Hepatic artery embolization and even segmental resections of liver metastasis had also been attempted in the past with variable responses. In early 2000, Joensuu et al. reported the first use of STI-571 (imatinib mesylate; Gleevec) in a case of recurrent metastatic GIST that failed extensive surgical therapy and chemotherapy [9]. The dramatic response in their case was documented both clinically and histologically. They also documented a marked decrease in tumor activity by 18FDGPET scanning. Shortly after reporting the case, confirmatory data were published [10]. Demetri et al. have summarized their experience in 147 patients with advanced stage GISTs. In their series the therapy proved safe and effective in cases of advanced unresectable or metastatic disease [11]. STI-571 selectively inhibits the activity of various tyrosine kinases (ABL, BCR-ABL, KIT, and PDGFR). It has successfully been used in the treatment of other malignancies, where the enhanced activity of tyrosine kinases plays a pathogenic role, with the most notable successes seen in chronic myelogenous leukemia. KIT-positive stromal tumors tend to respond better than those that are negative. It is still unknown if certain c-kit mutations play a role in predicting the chance of response to this novel therapy. Disease progression has occurred in only 13% of patients during Phase II trials [7]. The therapy is usually well tolerated. Though uncommon, the most significant side effects are secondary to massive tumor lysis. The specific role of STI-571 as a neoadjuvant or adjuvant therapy is currently being evaluated.

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