Diagnostic challenges in gastrointestinal stromal tumors: a case report of concurrent gastrointestinal stromal tumor, lymphangioma, and solid pseudopapillary neoplasm of the pancreas

Introduction

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract and arise from the interstitial cells of Cajal. They comprise 0.1–3% of all gastrointestinal malignancies and are most commonly found in the stomach and small bowel, with a median age of diagnosis in the seventh decade of life (1). On imaging, GISTs appear as well-circumscribed and often exophytic, although they can have a cystic morphology and may appear similar to other pathologies, such as mesenteric cysts, enteric duplication cysts, or other cystic neoplasms (2). GISTs arise most often due to a gain-of-function mutation in KIT or platelet-derived growth factor receptor alpha (PDGFRA), but other genes have also been implicated, including SDHx, NF1, BRAF, and FGFR1 (3). Pathologic diagnosis is confirmed by positive cluster of differentiation 117 (CD117) and/or DOG-1 (discovered on GIST-1) immunohistochemistry (IHC) staining, but this does not delineate molecular subtype.

Nearly half of all patients with GISTs present with advanced disease, with the most common sites of metastases in the liver and peritoneum (4). Standard of care for metastatic disease involves systemic therapy with a tyrosine kinase inhibitor (TKI) in the first line. Ascertaining molecular subtype is important as prognosis is affected by the type of mutation present. GISTs with exon 11 and 9 mutations of KIT are sensitive to imatinib, whereas KIT and PDGFRA wild-type GISTs generally do not respond to TKIs (5). Debulking surgery is an option for select patients if there is disease regression with the initiation of systemic therapy. If there is response to TKI, surgery is planned after 6 to 9 months of therapy, when the maximal tumor response has typically been achieved (4). We present this article in accordance with the CARE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-223/rc).

Case presentation

A 34-year-old woman with biopsy-proven GIST of the jejunum presented to our institution for surgical resection. She had undergone an abdominal ultrasound three years prior for a routine health checkup, which revealed a suspicious upper abdominal lesion, prompting a computed tomography scan, which showed a 4 cm hypodense pancreatic mass and a 7.3 cm cystic mass abutting the pancreas. There was an additional large cystic mass in contact with the lesser curvature of the stomach. She had no notable past medical history and, aside from diminished appetite, was asymptomatic. Physical exam and blood chemistries and counts were normal; notably, there was no abdominal distension or tenderness. Ultrasound-guided biopsy was performed of the mass arising from the jejunum, which showed elongated mesenchymal cells, and immunohistochemical staining was strongly positive for KIT (CD117); however, molecular testing was unable to be performed. Based off imaging and cytology, she was diagnosed with metastatic GIST and deemed not a candidate for cytoreductive surgery; she was started on imatinib 400 milligrams daily, which she tolerated well. Surveillance imaging after 2 years of imatinib revealed regression of the jejunal GIST from 7.3 cm to 3 cm, whereas the pancreatic lesion remained stable (Figure 1A). Interval imaging also showed persistence of the cystic mass associated with the lesser curve of the stomach which did not change in size, measuring 19 cm (Figure 1B). The patient underwent upper gastrointestinal endoscopy, which showed no abnormalities of the esophagus, stomach, or duodenum. Endoscopic ultrasound demonstrated a cystic lesion in the abdomen that obscured visualization of the body and tail of the pancreas. At this time, the patient sought a second opinion at our institution for surgical resection.

Figure 1 Representative cross-sectional imaging. (A) Axial cut of abdominal CT scan showing mass in pancreatic body (asterisk). (B) Coronal cut of abdominal CT showing large upper abdominal cystic mass (white arrow). CT, computed tomography.

After counseling the patient regarding the goals of surgery to be both diagnostic (pancreatic and cystic masses) and therapeutic in intent, the planned extent of cytoreduction including partial or distal gastrectomy, bowel resection, splenectomy, and possible pancreatectomy, the patient was taken to the operating room. Upon opening of the abdomen, a large cystic mass was encountered and dissected free from the lesser curvature of the stomach (Figure 2A). A larger retrogastric cystic mass appeared to be more densely associated with the pancreatic body tumor and contained lymphatic fluid when opened (Figure 2B). The distal pancreas and spleen were removed en bloc after dividing the body of the pancreas just medial to the solid pancreatic mass, revealing the patient’s primary GIST in the proximal jejunum. A small bowel resection was performed to remove the GIST with gross margins, and a duodenojejunostomy was created. There was no intra-operative tumor rupture. Additionally, two simple cystic para-aortic masses were removed.

Figure 2 Intra-operative photographs. (A) Intraoperative finding of large cystic mass. (B) Posterior view of distal pancreas and spleen specimen showing adherent cystic mass.

Final pathology of the lesser curvature, lesser sac, and para-aortic cysts returned as lymphangiomas (Figure 3), whereas the pancreatic resection revealed a solid pseudopapillary neoplasm measuring 2 cm with no tumor extension (Figure 4). Cytology of the lymphatic fluid collected from the cystic mass showed no malignant cells. Final pathology of the jejunal mass was consistent with GIST measuring 5.2 cm in greatest dimension, spindle cell type, and a mitotic rate of less than 2 per 5 mm²; there was no treatment effect identified, and all margins of the specimen were negative for tumor (Figure 5). On IHC, the GIST stained positive for both CD117 (C-KIT) and DOG-1, and retained expression of SDHB. No other lesions resected aside from the jejunal mass were positive for GIST. Next-generation sequencing of the GIST showed a pathogenic exon 11 KIT mutation (p.K550_K558del) with a variant allele frequency of 40%, as well as a pathogenic loss of NF2. The patient had an uncomplicated post-operative recovery and was discharged home.

Figure 3 H&E and IHC pathology slides of gastric and para-aortic masses. (A) Sections of the cystic masses show vascular proliferation with dilated lymphatic channels of varying sizes, lined by bland, flat endothelial cells within a stroma containing lymphoid aggregates (H&E, ×50). (B) The endothelial cells exhibit positivity for CD31 (IHC, CD31, ×100). (C) The endothelial cells show positivity for D2-40 (IHC, D2-40, ×200). H&E, hematoxylin and eosin; IHC, immunohistochemistry.

Figure 4 H&E and IHC pathology slides of pancreatic mass. (A) Sections of the pancreatic mass demonstrate a neoplasm with a solid growth pattern, consisting of uniform cells with moderate amount of eosinophilic cytoplasm, round nuclei with fine chromatin, and inconspicuous nucleoli (H&E, ×100). (B) The tumor cells show nuclear positivity for beta-catenin, supporting the diagnosis of solid pseudopapillary neoplasm (IHC, beta-catenin, ×200). (C) The tumor cells are negative for C-KIT (IHC, C-KIT, ×200). H&E, hematoxylin and eosin; IHC, immunohistochemistry.

Figure 5 H&E and IHC pathology slides of jejunal mass. (A) Sections of the jejunal mass reveal a mesenchymal neoplasm composed of bland spindled cells, morphologically consistent with a gastrointestinal stromal tumor (H&E, ×100). (B) The tumor cells exhibit diffuse C-KIT positivity (IHC, C-KIT, ×200). (C) The tumor cells show retained cytoplasmic positivity for SDHB (IHC, SDHB, ×200). H&E, hematoxylin and eosin; IHC, immunohistochemistry.

All procedures performed in this case were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

This case of three distinct pathologies highlights the importance of careful workup when a patient presents with multiple tumors and potential diagnostic uncertainty. This patient had pathologies originating from the stomach, small bowel, and pancreas; in addition, she had a mixed response to first-line TKI, indicating the possibility of another disease process in addition to GIST.

GISTs are rare tumors (1), and there are numerous case reports in the literature of unusual presentations as well as uncommon sites of primary and metastatic disease. Difficulty in diagnosis is often attributed to vague or no symptoms and heterogenous findings on imaging. While radiologic diagnosis can be challenging, the hallmark of pathological diagnosis is positive CD117 staining, indicating presence of KIT, a receptor tyrosine kinase, encoded by the protooncogene KIT (6). Discovery of this mutation is the foundation for systemic treatment of GISTs with TKIs. Positive staining of KIT is seen in over 95% of GISTs, but there are reports of other tumors expressing KIT, including solid pseudopapillary neoplasms (7), which can confound the diagnosis. In addition to KIT, GISTs commonly express DOG-1, a component of calcium-activated chloride channels, which was originally discovered in GISTs (8). DOG-1 is both highly specific and sensitive in confirming a diagnosis of GIST.

NF2 is a tumor suppressor gene that, when pathogenically mutated in the germline setting, is implicated in neurofibromatosis type 2. Somatic alterations in this gene are associated with mesothelioma, meningiomas, and vestibular schwannomas (9). While not as common, somatic NF2 mutations may also be present in other more common cancers such as breast and colorectal cancer (9). However, mutations in NF2 are not typically encountered in GIST. While next generation sequencing may have helped solidify a diagnosis of GIST at initial presentation, the additional NF2 mutation could have further obscured a clear diagnosis of a single pathology; however, only tissue from the GIST specimen was sent for sequencing in this patient’s case.

Lymphangiomas are benign malformations of the lymphatic system made of cystically dilated vessels containing lymph fluid. They are typically congenital in nature with an incidence of 1 in 2,000 to 1 in 4,000 (10). The majority of lymphangiomas are found in the head and neck region, whereas the patient herein had multiple lymphangiomas located in the retroperitoneum and along the stomach. While rare, there are case reports of patients with intra-abdominal cystic lymphangiomas (11). The vessels comprising lymphangiomas are lined with epithelial cells, which is histologically different from the mesenchymal origin of GISTs. While GISTs often present as solid masses, there are a subset of these tumors which present as cystic lesions and can cause diagnostic ambiguity. Additionally, GISTs may undergo degeneration with imatinib treatment, contributing to a cystic appearance. There are reported cases of cystic GISTs in the lesser sac and in association with the stomach (12,13); on imaging these lesions appear very similar to the lymphangioma present in our patient. While common differentials for cystic lesions of the lesser sac include GISTs, pancreatic cysts, and bowel duplication cysts, lymphangioma is not a histology that is frequently considered and encountered.

Solid pseudopapillary neoplasms of the pancreas are rare findings comprising 2–3% of all pancreatic tumors, and more commonly affect young women (14). They are typically benign in nature, with surgical resection conferring excellent survival (15). The etiology of these tumors is unknown, and presentation varies with the most common symptom being abdominal pain. Our patient fits the demographic group in which these tumors typically arise. Solid pseudopapillary neoplasms appear as well-demarcated lesions of the pancreas with variable amounts of solid and cystic components (16). Additionally, these tumors frequently undergo hemorrhagic cystic degeneration. This patient’s pancreatic tumor adds an additional imaging component which could be mistaken for a GIST, as in this patient’s case where physicians initially deemed this pancreatic lesion a metastatic site of her GIST. Such assumptions should be made very cautiously, though, as pancreatic metastases are exceptionally rare in patients with advanced GIST (17).

Despite the possibility of additional pathologies, this patient was diagnosed with metastatic GIST and subsequently started on imatinib. TKI therapy is not without side effects; symptoms can range from mild skin and gastrointestinal discomfort to life-threatening myelosuppression and cardiotoxicity (18). When a lesion is confirmed on pathology to be GIST and other abdominal lesions are present, presumably the diagnosis is metastatic disease; however, other potential pathologies ought to be ruled out. In the setting of mixed response to systemic therapy and unusual sites of metastases—such as the pancreas, the possibility of synchronous primary tumors should be considered. Additionally, the genotype of this patient’s GIST was not confirmed prior to initiating imatinib, further complicating interpretation of the clinical scenario. Had the patient been found to have a molecular subtype that was resistant to TKIs, the persistence or progression of the pancreatic and gastric lesions after 2 years of imatinib would be expected. Nevertheless, this patient did show response to imatinib and underwent a successful R0 resection of her GIST, highlighting the importance of cytoreductive surgery in carefully selected patients.

Conclusions

Due to the rarity of GISTs, diagnosis and subsequent treatment may not always be straightforward. Patients who present with multiple tumors of differing appearances on imaging should undergo adequate workup in order to clarify the pathology of all lesions, thus allowing for the safest and most effective treatment plan while avoiding unnecessary systemic therapies.

Acknowledgments

We gratefully acknowledge the participation and contributions of the patient herein described.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-223/rc

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-223/prf

Funding: This research was supported by the Intramural Research Program of the Center for Cancer Research within the National Cancer Institute (NCI) of the United States National Institutes of Health (NIH).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-223/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this case were performed as part of NCT04557969, in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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