Histiocytic Sarcoma Treated With Autologous Stem Cell Transplantation: A Case Report and Literature Review of the Role of Autologous and Allogenic Stem Cell Transplantation

Introduction

Histiocytic sarcoma (HS) is a rare and aggressive hematopoietic malignancy, characterized by tumor cells exhibiting features of histiocytes or dendritic cells, as classified by the World Health Organization [1]. HS can occur across all age groups, with a median age at diagnosis of 46 years [2]. Most cases present as extranodal tumors, commonly affecting the gastrointestinal (GI) tract, skin, and soft tissues. Patients typically present with symptoms related to unifocal or multifocal disease, and systemic involvement is associated with a severe clinical course and poor prognosis [3,4]. Due to its rarity, standardized treatment guidelines are lacking. In localized disease, surgical resection followed by adjuvant radiotherapy is often preferred over systemic therapy. In contrast, multifocal or disseminated disease is generally managed with multi-agent chemotherapy [4,5]. Despite treatment, HS is associated with a high relapse rate and poor outcomes. Hematopoietic stem cell transplantation (HSCT) has been explored in selected patients achieving complete remission after systemic therapy, given the substantial risk of recurrence [4–6]. Given the aggressive nature and high relapse rate of HS, allogeneic stem cell transplantation (allo-SCT) may have potential to provide more effective disease control compared to autologous stem cell transplantation (auto-SCT). However, no direct comparative studies have been conducted to date. In this report, we present a case of histiocytic sarcoma treated with autologous stem cell transplantation and include a literature review of transplantation strategies, emphasizing the need for further investigation.

Case Report

On July 2, 2021, a 44-year-old woman presented with edema in both legs, and initial laboratory tests revealed pancytopenia with a white blood cell count of 2580/mm3, a hemoglobin level of 7.3 g/dL, and a platelet (PLT) count of 20 000/mm3 (Figure 1). A comprehensive evaluation for pancytopenia was initiated. Serologic testing identified anti-PLT antibodies, suggesting immune thrombocytopenic purpura (ITP). Abdominal computed tomography (CT) revealed splenomegaly (Figure 2). Bone marrow (BM) examination indicated iron deficiency anemia with features suggestive of ITP or myelodysplastic syndrome with multilineage dysplasia. The patient was treated with intravenous immunoglobulin and prednisolone (1 mg/kg), tapered in accordance with the American Society of Hematology 2019 guidelines for ITP [7]. Despite therapy, the PLT count remained refractory at 10 000/mm3 (Figure 1), and abdominal CT showed multiple low-attenuation masses within the spleen, raising concern for malignant involvement (Figure 2). Therefore, a splenectomy was performed on August 3, 2021 for differential diagnosis. Histopathological analysis of the spleen confirmed a diagnosis of HS (Figures 3, 4). Postoperatively, the PLT count temporarily increased to 214 000/mm3 (August 10, 2021) (Figure 1). However, follow-up imaging on November 29, 2021 revealed multiple hepatic and adrenal metastases (Figure 2). Follow-up BM aspiration confirmed HS with BM involvement. She was subsequently started on cyclophosphamide, doxorubicin, vincristine (Oncovin), etoposide, and prednisone (CHOEP) chemotherapy (Table 1). After 6 cycles of CHOEP, a BM biopsy on May 17, 2022 showed no evidence of malignancy. This response was accompanied by hematologic recovery, with a PLT count of 100 000/mm3 recorded on June 10, 2022 (Figure 1). Despite the initial response, CT on June 21, 2022 revealed increased size and number of hepatic masses, indicating disease progression (Figure 2). Allo-SCT was initially considered for disease control, and we searched for an HLA-matched donor, but no suitable donor was available. Moreover, there were significant concerns regarding early transplant-related mortality (TRM) and the potential development of graft-versus-host disease (GVHD), which limited the feasibility of allo-SCT in this setting. Given that the conditioning regimen was expected to provide effective cytoreduction of residual histiocytic sarcoma, auto-SCT was considered a reasonable alternative. Following a detailed discussion with the patient, we decided to proceed with auto-SCT, and stem cell collection yielded an adequate number of cells to successfully perform the procedure. The patient received high-dose chemotherapy followed by auto-SCT on June 30, 2022 (Figure 1). The conditioning regimen included intravenous busulfan (3.2 mg/kg/day for 3 days), etoposide (350 mg/m2/day for 2 days), and cyclophosphamide (50 mg/kg/day for 2 days) (Table 1). One month after transplantation, the PLT count improved to 42 000/mm3, and imaging suggested a partial response (Figure 1). However, on September 29, 2022 follow-up BM aspiration indicated a suspected HS relapse and persistent lung and hepatic metastases confirmed residual disease. The patient was treated with ifosfamide, carboplatin, and etoposide (ICE) chemotherapy, but died due to progressive disease (Table 1).

Discussion

HS is an exceptionally rare and aggressive hematopoietic malignancy that can arise in lymph nodes and various extranodal sites, including the skin, GI tract, liver, lungs, and central nervous system [2,4]. Depending on the site of involvement, the disease can present as either localized or disseminated. Clinical manifestations vary by location, and the overall prognosis is poor. Systemic involvement and refractory disease are often fatal within months to a year [3]. Owing to its low incidence, large-scale clinical trials are lacking, and neither the National Comprehensive Cancer Network (NCCN) nor the European Society for Medical Oncology (ESMO) has established formal, disease-specific guidelines for the management of HS. As a result, management is generally guided by disease extent. Localized disease can be treated with surgical resection followed by adjuvant radiation therapy, whereas disseminated disease typically requires multi-agent chemotherapy. Due to its aggressive clinical behavior, resembling that of high-grade lymphomas, therapeutic approaches are typically adapted from regimens used for aggressive non-Hodgkin lymphomas, such as cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) and ICE [2–4]. In selected cases, hematopoietic SCT or targeted therapies might also be considered. However, no large-scale phase III trials have directly compared autologous versus allogenic SCT, and standardized treatment guidelines are lacking, highlighting the need for further research. Moreover, it remains unclear whether HSCT should be considered as part of first-line treatment in high-risk patients immediately after diagnosis, or should be reserved as a salvage strategy following relapse or refractory disease. Prospective, multicenter studies are warranted to define the optimal timing and role of HSCT in HS.

Several case reports have described therapeutic approaches to HS. Gergis et al reported a 64-year-old woman with HS involving retroperitoneal and thoracic lymph nodes who was treated with thalidomide in combination with CHOP chemotherapy, followed by auto-SCT due to high transplant-related comorbidity risk, which precluded allo-SCT. Thalidomide was resumed as maintenance therapy 3 months after transplant. At 6 months, the patient remained in remission, with improved performance status (Table 2) [8]. In another study, Nam et al analyzed 9 HS cases, reporting poor prognosis marked by resistance or relapse after chemotherapy. Anthracycline-based regimens were used as first-line therapy, with 3 of 8 patients achieving complete remission (CR), although all subsequently relapsed. Four patients underwent allo-SCT, and 3 achieved CR after transplantation, with 2 maintaining long-term remission. Notably, 3 of these 4 patients had previously undergone auto-SCT; however, only 1 achieved CR, which was followed by early relapse; the others attained partial remission (PR) (Table 2) [6]. These findings, although limited by a small sample size, suggest a potential benefit of allo-SCT in achieving durable remission, while auto-SCT demonstrates notable limitations in sustaining long-term remission. The possible therapeutic benefit of allo-SCT may be attributed to its graft-versus-tumor effect, which is absent in auto-SCT. This immune-mediated anti-tumor activity could be particularly valuable in HS, where residual disease frequently leads to relapse. However, the clinical application of allo-SCT is often limited by donor availability, the risk of transplant-related mortality, and the potential for severe GVHD, especially in older or heavily pre-treated patients. According to a study by Huang Z et al, the use of blinatumomab as a salvage therapy followed by allo-SCT in patients with relapsed Philadelphia chromosome-positive acute lymphoblastic leukemia resulted in the rapid achievement of minimal residual disease negativity and CR, with sustained CR over the long term [9]. These findings suggest that allo-SCT could be an effective treatment strategy for improving outcomes in patients with relapsed or refractory leukemia and may also be considered as a potential therapeutic approach in HS, an aggressive hematopoietic malignancy, with the expectation of similar benefits. Tomlin et al reported the case of a patient with multifocal HS refractory to CHOP and ICE chemotherapy, who achieved PR following cladribine, high-dose cytarabine, granulocyte colony-stimulating factor, and mitoxantrone therapy, and subsequently attained CR after myeloablative allo-SCT (Table 2) [10]. Therefore, despite the limitations that may hinder the clinical application, allo-SCT may be considered a potential therapeutic option in the treatment of HS. Although the sample size is extremely limited, calculating the CR rate by SCT type shows that, among allo-SCT cases, 6 of 7 (85.7%) achieved CR, wheareas among auto-SCT cases, all 3 (100%) achieved CR. However, in the study by Nam et al, among 4 allo-SCT cases, 3 had previously undergone auto-SCT; of these, 1 experienced early relapse after achieving CR, and 2 achieved PR. If these are all included in the auto-SCT group, the total becomes 6 auto-SCT cases, of which 4 (66.7%) achieved CR. A closer examination of individual cases reveals that in auto-SCT, CR was either not achieved or, if achieved, was often followed by early relapse; however, no TRM was reported. In contrast, allo-SCT demonstrated a higher CR rate than auto-SCT, but 4 of 7 patients (57.1%) died from transplant-related causes or post-transplant complications. This does not necessarily indicate that allo-SCT is less effective due to higher TRM, as it is possible that many of these patients had been heavily pre-treated, had never achieved CR before transplant, or had relapsed after a prior auto-SCT. Therefore, further investigation is needed to identify prognostic factors and to determine which treatment modality offers superior outcomes in the management of HS. Although data are limited due to the rarity of HS and the small number of published case reports, certain factors, such as disease burden, bone marrow involvement, and molecular alterations, may be potential prognostic indicators. In our case, despite an initial response to CHOEP chemotherapy followed by auto-SCT, the disease relapsed with BM and systemic involvement, ultimately resulting in death due to disease progression. This outcome underscores the limited long-term efficacy of auto-SCT in HS, despite its potential to offer temporary disease control in selected cases. By contrast, several case reports have indicated that allo-SCT, particularly following intensive chemotherapy, might provide more sustained disease control and potentially curative outcomes. These findings suggest a potential advantage of allo-SCT in relapsed or refractory HS, but further sudies are needed to confirm this.

Conclusions

HS remains a therapeutically challenging malignancy with no established standard of care. This case highlights the limited long-term efficacy of auto-SCT in relapsed or refractory HS. Although allo-SCT may offer a potential therapeutic advantage, this observation should be interpreted cautiously and considered hypothesis-generating due to the limited supporting data. While various treatment modalities have been explored, their efficacy remains uncertain due to limited data and the absence of prospective clinical trials. Our findings highlight the importance of developing multicenter registries and prospective, large-scale studies to establish optimal treatment strategies and improve outcomes for this rare and lethal disease.