Primary Dedifferentiated Liposarcoma of the Duodenum with Intestinal Bleeding: A Case Report and Literature Review.

Introduction
Liposarcoma accounts for 11-20% of malignant soft tissue sarcomas (STSs) (1,2). It occurs most frequently in the retroperitoneum and lower extremities, whereas primary occurrence in the gastrointestinal tract is rare (3), and duodenal occurrence is particularly uncommon. According to the 2020 World Health Organization classification, liposarcoma can be classified into five subtypes: well-differentiated, dedifferentiated, myxoid, pleomorphic, and myxoid pleomorphic (3). Dedifferentiated liposarcoma (DDLPS) accounts for approximately 15-20% of all liposarcoma cases (4).
We herein report a rare case of DDLPS originating in the duodenum that presented with gastrointestinal bleeding. The patient underwent radiotherapy (RT) combined with chemotherapy with eribulin, which initially resulted in tumor reduction, but ultimately allowed disease progression. This case highlights the challenges of managing unresectable DDLPS and underscores the need for further investigation into the efficacy of multimodal therapy for this rare entity.

Case Report
A 51-year-old woman presented to the emergency department with syncope and palpitations. She had a history of appendectomy at 14 years old, with no other significant medical history or comorbidities. She had experienced loss of appetite and weight loss of 5 kg over the previous 5 months.
On arrival, her vital signs were as follows: temperature, 37.0°C; blood pressure, 123/76 mmHg; heart rate, 107 bpm; saturation of percutaneous oxygen, 97% on room air; and respiratory rate, 30 breaths per minute. Her abdomen was flat and soft without tenderness or palpable masses; however, her conjunctiva and face appeared pale. Blood tests revealed an Hb level of 4.5 g/dL, a mean corpuscular volume of 95.2 fL, a mean corpuscular hemoglobin concentration of 32.6 g/dL, a blood urea nitrogen level of 34.4 mg/dL, a creatinine level of 0.72 mg/dL, an albumin level of 3.2 g/dL, and an lactate dehydrogenase (LDH) level of 117 U/L. Contrast-enhanced computed tomography revealed a 7-cm mass centered in the horizontal portion of the duodenum, with multiple mesenteric and pancreatic lesions (Fig. 1a). Upper gastrointestinal endoscopy revealed a solid tumor in the duodenum with active bleeding (Fig. 2a), rendering endoscopic hemostasis impossible. Embolization is not feasible because of the challenges in identifying the feeding vessels of the tumor. Surgery was considered for bleeding control; however, the tumor was deemed unresectable owing to extensive infiltration of an unknown histological type. The patient was kept nil per os, and total parenteral nutrition was initiated. Blood transfusion and palliative RT (30 Gy/10 fractions) were administered to the duodenal tumor to control bleeding (Fig. 2b). Although the anemia was alleviated, gastrointestinal obstruction soon developed, requiring gastrojejunostomy.
A biopsy of the tumor revealed proliferation of round to spindle-shaped cells, with positive staining for vimentin and negative staining for AE1/3 and epithelial membrane antigen, consistent with a mesenchymal tumor (Fig. 3a). An immunohistochemical analysis confirmed the presence of mouse double minute 2 homolog (MDM2) (Fig. 3b), cyclin-dependent kinase 4 (CDK4) (Fig. 3c), and cyclin D1, supporting the diagnosis of DDLPS. To further differentiate the tumors from other mesenchymal tumors, additional immunohistochemical markers were assessed. The tumor was negative for c-KIT (CD117) and DOG1, which ruled out gastrointestinal stromal tumor. Negative staining for SMA and desmin excluded smooth muscle tumors, whereas S-100 negativity ruled out schwannomas. The tumor was negative for melanocytic markers (HMB-45 and Melan-A). In addition, the tumor was negative for all hematopoietic and lymphoid markers, including CD45, CD20, Pax5, CD79a, CD30, MUM-1, and CD38, excluding hematologic malignancies. The tumor was partially positive for CD138; however, plasma cell morphology was not observed.
The patient received systemic chemotherapy with eribulin (1.4 mg/m2 every 2 weeks, based on an expert consultation with the Department of Medical Oncology at our institution and considering the patient's performance status and tolerance) while receiving home parenteral nutrition and oral intake, without adverse events (Fig. 4). The size of the irradiated duodenal lesion decreased significantly (Fig. 1b), allowing parenteral nutrition to be discontinued. Serum LDH levels decreased. Given the tumor's radiosensitivity, RT (30 Gy/10 fractions) was administered alongside chemotherapy to treat pancreatic metastasis; however, the pancreatic lesion remained unchanged. The primary duodenal lesion progressed (Fig. 1c), leading to a decline in the performance status, and chemotherapy was discontinued. Additional RT (20 Gy/5 fractions) for the primary lesion resulted in tumor reduction; however, the patient's overall condition deteriorated, and the patient died 9 months after the initial presentation.

Discussion
This case involved an extremely rare unresectable duodenal DDLPS that initially presented with gastrointestinal bleeding. Primary liposarcomas of the gastrointestinal tract are rare, with most cases reported in the esophagus and stomach, followed by the colon and esophagogastric junction (5). The clinicopathological findings of patients with intestinal liposarcoma reported to date are outlined in Table 1 (6-22). All previously reported cases have been surgically treated. This is the first report of an unresectable duodenal DDLPS managed with a combination of RT and eribulin chemotherapy. Although treatment provided symptom relief and transient tumor control, disease progression ultimately occurred. This case highlights the potential and limitations of multimodal therapy for the management of unresectable DDLPS.
The prognosis of DDLPS varies depending on the primary tumor site. Retroperitoneal DDLPS is often associated with a poor prognosis because of late detection and a high recurrence rate. The reported 5-year mortality rate for retroperitoneal cases is 23-30% (23), with a median survival of 63.8 months (24). The standard treatment for DDLPS, similar to that for other STSs, is wide-margin surgical resection (25,26), which remains the most effective approach for achieving long-term disease control.
However, the prognosis of duodenal DDLPS is unclear because of its extreme rarity. Although complete surgical resection is theoretically the best curative treatment, extensive local invasion often precludes radical surgery, as was observed in this case. The patient exhibited significant mesenteric and pancreatic involvement, rendering surgical resection unfeasible. Owing to the anatomical complexity of the duodenum and its proximity to vessels, surgical resection is often a major challenge.
DDLPS has a high risk of local recurrence and an aggressive nature with distant metastasis, both of which contribute to a poor overall survival (OS). The local recurrence rate has been reported to reach 41% (27), with unresectable local recurrence often leading to fatal outcomes (28). The distant metastasis rate is approximately 17% (27), and the disease frequently progresses rapidly, as observed in this case.
Although DDLPS is classified as “dedifferentiated,” it can either arise from preexisting well-differentiated liposarcoma (WDLPS) through progressive genetic alterations or develop de novo without a well-differentiated precursor (27,29). Amplification of MDM2 and CDK4 from the long arm of chromosome 12 can be performed to obtain a key diagnostic marker that distinguishes WDLPS and DDLPS from other mesenchymal tumors (30). Immunohistochemical staining for MDM2 and CDK4 was a useful tool for the pathological diagnosis (31) and confirmed the diagnosis in this case. Although fluorescence in situ hybridization for MDM2 amplification might have provided additional confirmation (32), in the present case, the immunohistochemical profile and absence of markers for other mesenchymal neoplasms, including CD34, DOG1, and desmin, supported this diagnosis.
Several reports have described variations in the symptomatology of small-intestinal liposarcomas (Table 2a). Although the number of cases is limited, duodenal liposarcomas appear to present more frequently with intestinal bleeding, whereas liposarcomas of the jejunum or ileum commonly cause obstructive symptoms. This difference may not necessarily reflect tumor biology but rather anatomical factors. In the duodenum, narrowing of the tract by the tumor may not initially cause typical obstructive symptoms because of the proximal outlet into the stomach. However, the duodenum is directly exposed to bile and pancreatic secretions, which may induce tumor damage and bleeding.
Early detection and complete surgical resection are critical for improving the survival outcomes of patients with intestinal liposarcomas. In our review, tumors in the disease-free group tended to be smaller (median size of 3.0 cm) than those in the recurrence or death group (Table 2b). However, further studies are needed to confirm this relationship owing to the limited sample size.
In addition, submucosal lesions located in the deep portion of the duodenum can be difficult to detect because of the limited accessibility during upper gastrointestinal endoscopy. Even when such lesions are identified, establishing a definitive diagnosis can be challenging owing to the frequent sampling of fatty tissue within the tumor (33-35), and these lesions may not receive appropriate follow-up. In the present case, the patient had undergone upper gastrointestinal endoscopy as part of a medical checkup several months earlier, during which mild anemia had been detected. These findings highlight the importance of careful evaluation and follow-up of submucosal lesions, which may contribute to improved outcomes in rare but aggressive tumors, such as DDLPS.
Given the high recurrence rate and metastatic potential of DDLPS, reliable prognostic markers are crucial for treatment decision making. Recent studies have emphasized the prognostic significance of LDH, C-reactive protein (CRP), and albumin levels in STSs, including liposarcoma. High LDH levels at the diagnosis correlate with distant metastases, a high tumor grade, and a poor disease-specific survival (DSS) in patients with STS (36). Furthermore, LDH elevation during treatment often signals disease progression and therapeutic resistance (36). CRP has been identified as an independent predictor of the OS and progression-free survival (PFS) in STS patients (37-39). Elevated CRP levels were associated with a worse DSS and PFS, reflecting the role of tumor-promoting inflammation (37). Hypoalbuminemia is associated with a poor OS and increased recurrence rates (40). Since the CRP-to-albumin ratio (CAR) integrates both CRP and albumin, it provides a comprehensive marker of systemic status, with a high CAR value being a strong predictor of a poor prognosis in patients with STS (41).
In the present case, the LDH levels initially decreased following eribulin treatment, indicating a positive response, but later increased with disease progression, which is consistent with its role as a tumor burden marker. CRP levels remained stable throughout the disease course, suggesting that systemic inflammation did not play a significant role in tumor progression in this patient. Albumin levels progressively declined, reflecting nutritional deterioration and the systemic effects of disease progression.
For unresectable or advanced cases, such as that described herein, systemic chemotherapy and RT remain viable treatment options. Although no standard regimen has been established for DDLPS, doxorubicin is widely used, as with other soft tissue tumors (42), despite its gastrointestinal and hematological toxicities (43). Compared to doxorubicin, eribulin, trabectedin, and pazopanib have demonstrated efficacy with more favorable toxicity (43,44). However, their response rates and treatment durations remain limited (45).
Eribulin, the key drug used in this case, is a non-taxane microtubule inhibitor, and the response to eribulin treatment in STS may be associated with a decrease in phosphorylated AKT in the tumor. (46) In the present case, eribulin was selected because of its relatively favorable toxicity profile, which led to partial tumor reduction and thus allowed the patient to discontinue parenteral nutrition. However, despite initial tumor shrinkage, disease progression eventually necessitates discontinuation of chemotherapy, highlighting the limitations of current systemic therapy.
Several novel systemic therapies for liposarcoma are currently under investigation. CDK4 inhibitors, which target the aberrant cell cycle progression observed in MDM2/CDK4-amplified sarcomas, have shown promise in preclinical and early-phase clinical studies. Similarly, MDM2 inhibitors, which counteract the oncogenic effects of MDM2 overexpression, are being evaluated for their potential efficacy in DDLPS (47). Immune checkpoint inhibitors are emerging as potential treatment options, although their efficacy in treating liposarcoma remains unclear (44). A clinical trial of the combination of immunotherapy and RT with STS, including DDLPS, is currently ongoing (48). Further studies are warranted to assess these novel therapies for unresectable DDLPS.
Although RT has been used as a palliative treatment for STSs, its efficacy against DDLPS remains unclear. A previous study reported that preoperative RT improved local control in patients with retroperitoneal sarcomas (49), although its impact on the survival is controversial (50).
In the present case, RT played a crucial role in reducing the tumor burden, alleviating symptoms, and effectively controlling gastrointestinal bleeding. However, the treatment response differed by anatomical site; RT was effective in reducing the duodenal tumor but had a limited impact on pancreatic invasion, suggesting heterogeneity in radiosensitivity between the primary and metastatic DDLPS.
Although surgical resection remains the primary treatment for gastrointestinal liposarcoma, multimodal approaches combining chemotherapy and RT can be considered for unresectable cases (51). In a small-scale safety trial of preoperative eriblin + RT for resectable retroperitoneal DDLPS, a preoperative decrease in tumor size was achieved, and in some cases, significant tumor necrosis or fibrosis was observed with tolerable side effects (52).
In the present case, the combination of eribulin and RT initially led to tumor shrinkage and symptom improvement, but disease progression ultimately occurred. Compared to previous cases in which patients were treated with doxorubicin or pazopanib, our case demonstrates both the potential benefits and limitations of eribulin in combination with RT. Variability in treatment response may be attributed to differences in liposarcoma subtypes, tumor locations, and intrinsic radiosensitivity.
In conclusion, the patient with unresectable DDLPS presented with gastrointestinal bleeding. An immunohistochemical analysis confirmed the diagnosis, and multimodal therapy, including RT and chemotherapy, successfully controlled the bleeding and reduced tumor size. This case highlights the need for optimized therapeutic strategies to improve disease control and demonstrates the potential of multimodal therapy for symptom management. However, the observed disease progression despite the initial treatment response underscores the limitations of the current systemic approaches. Further research on this rare and aggressive malignancy is required.

The authors state that they have no Conflict of Interest (COI).