Primary splenic histiocytic sarcoma: A case report and review of literature

Abstract

BACKGROUND

Histiocytic sarcoma (HS) is a rare lymphohematopoietic malignancy with nonspecific clinical manifestations, diagnostic challenges, high aggressiveness, and a poor prognosis. Primary HSs arising in the spleen are extremely uncommon, with few cases reported globally. Here, we present the clinical course of a patient with splenic HS.

CASE SUMMARY

A 67-year-old woman was admitted to our hospital because of a large splenic mass that was detected during a routine health examination 1 month before presentation. Abdominal computed tomography revealed a large occupying lesion in the spleen, which was possibly a lymphangioma. The patient underwent splenectomy, and postoperative pathological examination confirmed the diagnosis of splenic HS. At the 6-month telephonic follow-up, the patient reported feeling well.

CONCLUSION

Given the paucity of cases and the poor prognosis of splenic HS, whose definitive diagnosis hinges exclusively on pathology, and given that all current therapeutic strategies are based on isolated case reports, it is imperative to enhance our understanding of this disease to improve patient diagnosis and management.

Key Words: Spleen; Histiocytic sarcoma; Splenectomy; Lymphohematopoietic malignancy; Case report

Core Tip: Splenic histiocytic sarcoma (HS) is a rare lymphohematopoietic malignancy with nonspecific clinical manifestations, diagnostic challenges, high aggressiveness, and a poor prognosis. A 67-year-old woman was found to have a large splenic mass during a routine physical examination 1 month before presentation. After multidisciplinary discussion, laparoscopic splenectomy was recommended. The pathological findings were most compatible with the diagnosis of HS. A 6-month postoperative telephonic follow-up revealed that the patient felt well. Despite the poor prognosis, HS remains treatable. Early and definitive diagnosis based on pathology is required to optimize treatment.

INTRODUCTION

Histiocytic sarcoma (HS) is a rare and aggressive lymphohematopoietic malignancy with broad age of onset, nonspecific clinical presentation, diagnostic challenges, and a poor prognosis[1]. Primary involvement of the spleen is exceedingly uncommon, with only sporadic cases reported in the literature[2]. Here, we present the clinical course of a patient with splenic HS.

CASE PRESENTATION

Chief complaints

A 67-year-old woman was found to have a large splenic mass during a routine physical examination 1 month before presentation.

History of present illness

The patient was admitted to our hospital on March 9, 2025. She reported only occasional discomfort in the left lumbar region and denied other symptoms such as nausea, vomiting, chills, or fever.

History of past illness

During hospitalization at another hospital in February 2025, the patient was diagnosed with bradycardia and underwent pacemaker implantation. After discharge, her medication regimen included regular oral trimetazidine hydrochloride (20 mg, three times daily) and sotalol hydrochloride (80 mg, twice daily).

Personal and family history

The patient had no relevant personal or family history.

Physical examination

The findings of the physical examination were unremarkable.

Laboratory examinations

Laboratory investigations revealed a hemoglobin level of 97.00 g/L, white blood cell count of 10.85 × 10⁹/L, and platelet count of 330 × 10⁹/L. The level of B-type natriuretic peptide was 351 pg/mL. The patient tested positive for hepatitis B surface antigen, hepatitis B e antibody, and hepatitis B core antibody, with a hepatitis B virus DNA load of 4.06 × 10² IU/mL. The level of the tumor marker cancer antigen-125 was elevated to 220.6 U/mL. All other parameters, including rheumatological, immunological, tuberculosis, and thyroid function test results, were within normal limits.

Imaging examinations

Color Doppler ultrasonography of the liver, gallbladder, pancreas, and spleen (Figure 1A) revealed a cyst in segment 7 of the right hepatic lobe and a large splenic mass (approximately 11.2 cm × 13.6 cm) occupying nearly the whole spleen, the nature of which was undetermined. The spleen was significantly enlarged. Contrast-enhanced computed tomography (CT) of the upper abdomen (Figure 1B-D) revealed a large occupying lesion measuring about 8.8 cm × 11.6 cm × 11.8 cm in the spleen, suggesting a possible lymphangioma, along with an accessory spleen and cysts in segment 2 and segment 8 of the liver. The spleen was significantly enlarged. CT also showed the post-pacemaker implantation status, cardiomegaly, and a moderate amount of pericardial effusion. Cardiac ultrasonography confirmed moderate pericardial effusion, pacemaker implantation, impaired left ventricular diastolic function, and a slightly reduced left ventricular ejection fraction of 52%. Electrocardiogram findings included: (1) Sinus tachycardia; (2) Ventricular paced rhythm; (3) Occasional premature ventricular contractions; (4) First-degree atrioventricular block; (5) Left axis deviation; (6) ST-T segment changes; (7) Prolonged Q-T interval; and (8) Recommendation for pacemaker interrogation.

Figure 1 Ultrasonic, Radiological, gross, and histopathological findings of the splenic tumor. A: Abdominal ultrasound image showing the splenic tumor (approximately 11.2 cm × 13.6 cm); B: Non-contrast axial computed tomography (CT) image of the upper abdomen showing the splenic tumor; C: Contrast-enhanced axial CT image (arterial phase) of the upper abdomen demonstrating the splenic tumor; D: Contrast-enhanced coronal CT image of the upper abdomen revealing the splenic tumor (approximately 8.8 cm × 11.6 cm × 11.8 cm); E: Gross specimen of the resected spleen (the resected spleen measured approximately 14 cm × 12 cm × 7 cm. Upon sectioning, a tumor measuring about 12 cm × 10 cm × 9 cm was observed, occupying nearly the entire splenic parenchyma); F: Photomicrograph of splenic tissue (hematoxylin and eosin staining, × 20 magnification); G: Another photomicrograph of splenic tissue (hematoxylin and eosin staining, × 20 magnification); H: Photomicrograph of splenic tissue showing immunohistochemical staining (× 20 magnification).

MULTIDISCIPLINARY EXPERT CONSULTATION

Following consultation with the Department of Cardiology, priority was given to addressing the splenic lesions. After multidisciplinary discussion, laparoscopic splenectomy was recommended.

FINAL DIAGNOSIS

Biopsy and pathological examination revealed the results (Figure 1E-H).

Gross description

The specimen consisted of one spleen measuring 14 cm × 12 cm × 7 cm, displaying a grayish-white and grayish-red cut surface. A well-defined, grayish-yellow tumor measuring 12 cm × 10 cm × 9 cm was identified within the parenchyma. The tumor was solid with a firm consistency. Extensive areas of necrosis were evident.

Microscopic description

The tumor cells were spindle-shaped to epithelioid, exhibiting significant atypia, abundant cytoplasm, prominent nucleoli, and noticeable mitotic figures. The stroma showed extensive hemorrhage, necrosis, and inflammatory cell infiltration.

Immunohistochemical staining

Positive for CD68 (diffuse+), CD163 (diffuse+), CD4 (+), lysozyme (focal+), lactoferrin antibody (focal+), CD43 (focal+), CD3 (focal+), CD79a (small foci+), epidermal growth factor receptor (focal+); negative for CD1a, D2-40, S-100, anaplastic lymphoma kinase, desmin, CD21, CD35, PD-1, CD23, IgG, IgG4, CD30, v-Raf murine sarcoma viral oncogene homolog B, langerin; internal controls were CD8 (highlighted T cells), ETS-related gene (highlighted vasculature), smooth muscle actin (highlighted vasculature), and CD34 (highlighted vasculature).

Proliferation index

The Ki-67 index was approximately 30%.

Special staining

Both Grocott’s methenamine silver and periodic acid-Schiff staining yielded negative results.

In situ hybridization

Epstein-Barr virus-encoded small RNAs were detected.

Interpretation

The combined morphological features, immunohistochemical profile, specific staining results, and Epstein-Barr virus-encoded small RNA positivity were consistent with those of malignant lymphohematopoietic neoplasms. These findings were consistent with the diagnosis of splenic HS.

TREATMENT

On March 12, 2025 the patient underwent laparoscopic splenectomy under general anesthesia. Intraoperatively, the spleen was significantly enlarged, largely replaced by a tumor measuring approximately 12 cm × 10 cm × 9 cm, and adhered to the surrounding tissues, particularly at the posterior diaphragmatic surface. The patient recovered well after surgery. An oncology consultation recommended initiating chemotherapy 3 weeks after surgery. However, the patient and her family opted for discharge to recuperate before deciding on further treatment.

OUTCOME AND FOLLOW-UP

The patient recovered well and was successfully discharged. A 6-month postoperative telephonic follow-up revealed that she felt well and declined further therapy, preferring to seek reevaluation only if the symptoms progressed.

DISCUSSION

HS, previously termed “malignant histiocytic lymphoma”, “histiocytic medullary reticulosis”, or “malignant histiocytosis”, is a rare, localized tumor. With advancements in immunohistochemistry and molecular biology, it has been recognized that many cases previously diagnosed as HS were actually non-Hodgkin lymphomas of B-cell or T-cell origin or lymphoma-associated hemophagocytosis. The term HS was first introduced by Mathé et al[1]. HS typically involves the skin, lymph nodes, and intestinal tract; however, some patients may later develop disseminated disease with systemic manifestations and multi-organ involvement, a condition sometimes still referred to as malignant histiocytosis. The 2001 World Health Organization classification categorizes HS as a neoplasm of macrophage/histiocyte origin and defines it as a rare lymphohematopoietic tumor. HS has a broad age of onset, affecting infants, children, and adults, with most cases occurring among adults (median age: 46 years; male-to-female ratio: 2:1). The most common symptoms include fever, night sweats, and weight loss. Primary HS of the spleen is extremely rare, with few cases reported in the literature. In contrast, secondary involvement of the spleen, particularly during the terminal stages of the disease, is relatively common[2].

The clinical presentation of splenic HS is often asymptomatic or paucisymptomatic for prolonged periods. Several patients present with splenomegaly and thrombocytopenia. Splenic enlargement is typically insidious and can remain undetected. Reports indicate that thrombocytopenia can be an early sign and sometimes the sole clinical manifestation[3,4]. Other laboratory abnormalities, including anemia and/or lymphocytopenia, vary among patients and at different disease stages[3,4]. In splenic HS, worsening liver function in the absence of other symptoms may be indicative of hepatic infiltration[2]. In this case, the patient was largely asymptomatic, with splenomegaly as the primary finding.

The current diagnosis of HS primarily relies on clinical presentation, cytomorphology, immunohistochemistry, flow cytometry, and molecular genetic features. The diagnostic criteria are as follows: (1) Morphology: Microscopic examination reveals dilated splenic sinuses with extensive tumor cell infiltration. The neoplastic cells are monomorphic or pleomorphic. They are large, measuring 10-26 μm in diameter (average: 10-15 μm), and round to oval in shape, with abundant eosinophilic cytoplasm. The nuclei are large, eccentrically located, and exhibit vesicular chromatin with visible nucleoli. The tumor cells demonstrate the characteristics of phagocytic histiocytes, notably hemophagocytosis[5]; (2) Immunophenotype: Tumor cells must express at least one of the following histiocytic markers: CD68 (KP-1 or PG-M1), CD163, or lysozyme. They may also express immune response markers, such as CD114, CD11c, CD13, and MAC387. The expression of lymphocyte markers, including leukocyte common antigen, human leukocyte antigen-DP, CD4, CD45RO, and CD43, can be observed. They are typically S-100 negative or only weakly/focally positive. The tumor must be negative for CD1a (a Langerhans cell marker), CD21/CD35 (follicular dendritic cell markers), myeloid markers, CD30, and Birbeck granules[6-8]; (3) Lack of specific lymphoid differentiation: There is no specific reactivity for B-cell or T-cell lineages; (4) Proliferation index and ultrastructure: The median Ki-67 proliferation index is approximately 20% (reported range: 10%-90%). Electron microscopy, if performed, reveals numerous lysosomes within the cells and the absence of Birbeck granules, cell junctions (seen in dendritic and Langerhans cells), and cell processes; (5) Molecular genetics: There is an absence of clonal immunoglobulin or T-cell receptor gene rearrangements; and (6) Imaging: Ultrasonography and contrast-enhanced CT may show nonspecific abnormalities. Positron emission tomography-CT can be useful for the diagnosis, clinical staging, and management of HS[2]. Correlation with our case: The immunohistochemical profile of our patient - strongly and diffusely positive for CD68 and CD163; positive for CD4, leukocyte common antigen (focal), CD43 (focal), and lysozyme (focal); and negative for CD1a, CD21, CD35, and CD30 - aligned with the major diagnostic criteria for HS.

The differential diagnosis of HS includes the following: (1) Anaplastic large cell lymphoma and metastatic carcinoma: Anaplastic large cell lymphoma is positive for CD30 and epithelial membrane antigen. Metastatic carcinoma is positive for epithelial markers (e.g., epithelial membrane antigen and cytokeratin). In contrast, HS is negative for both CD30 and epithelial markers; (2) Malignant melanoma: Melanoma cells are diffusely distributed with eosinophilic cytoplasm, prominent nucleoli, and frequent mitoses, exhibiting both epithelial and sarcomatous differentiation. It is positive for human melanoma black 45 and S-100, which helps distinguish it from HS; (3) Langerhans cell histiocytosis: Langerhans cell histiocytosis lacks significant nuclear atypia and is characterized by the presence of eosinophils and a lymphoid background. The tumor cells are positive for CD1a and S-100, and Birbeck granules are visible on electron microscopy. Conversely, HS is negative for CD1a; (4) Acute monocytic leukemia: This is a malignancy of monoblastic cells, primarily involving the bone marrow and peripheral blood, and it often presents as anemia and thrombocytopenia. Serum lysozyme levels are typically elevated in acute monocytic leukemia, whereas hemophagocytosis is generally not a feature that helps differentiate it from HS; (5) Hemophagocytic syndrome (HPS) associated with infection or malignancy: Clinically, HPS presents as hepatosplenomegaly, lymphadenopathy, and pancytopenia. It involves hyperplasia of lymphohematopoietic cells with hemophagocytosis. Histiocytes in HPS lack malignant cytological features[2]; (6) Dendritic cell sarcoma: Interdigitating dendritic cell sarcoma: Tumor cells are predominantly spindle-shaped and arranged in a storiform or whorled pattern. They are typically strongly positive for the S-100 protein, and interdigitating cell processes are visible on electron microscopy. Follicular dendritic cell sarcoma: The inflammatory pseudotumor-like variant of follicular dendritic cell sarcoma - with numerous infiltrating lymphocytes, plasma cells, reactive histiocytes, and mild cellular atypia - can mimic HS. However, HS is positive for CD21, CD23, and/or CD35 and negative for CD68; and (7) Granulocytic sarcoma: This tumor is composed of myeloblasts. A key distinguishing feature is the presence of immature eosinophilic precursors within the tumor. Immunohistochemistry for myeloperoxidase is the definitive diagnostic method. Notably, both granulocytic sarcoma and HS express KP-1 (one clone of CD68); however, granulocytic sarcoma is negative for PG-M1 (another CD68 clone), whereas HS is often positive for it[9].

Molecular evaluation using next-generation sequencing has become increasingly important for diagnosing and understanding HS. Identifying characteristic genetic mutations aids in confirming the neoplasm’s clonal origin and may uncover actionable therapeutic targets. Research has underscored the significant pathogenic role of mitogen-activated protein kinases pathway activation in HS. Furthermore, tumorigenesis is driven by recurrent copy number losses involving cyclin-dependent kinase inhibitor 2A and mutations in suppressor genes like tumor protein 53 and SET domain containing 2. HS reveals a typically intricate genomic landscape, correlating with its high-grade cytomorphology and clinically aggressive behavior[10].

HS is characterized by high malignancy, strong invasiveness, and a poor prognosis, with most patients succumbing to the disease within 2 years of diagnosis[11]. Table 1 summarizes the clinical characteristics of the reported cases of splenic HS. The prognosis is influenced by multiple factors, including tumor location, size, and stage, and no effective treatment regimen has been established. Surgical resection is the most reliable approach for treating localized diseases. Postoperative adjuvant radiotherapy or chemotherapy may reduce recurrence and prolong survival. Chemotherapy is the most common treatment modality. However, none of the existing clinical regimens have proven to be unequivocally effective. The CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen, the most reliable therapy for non-Hodgkin lymphoma, is frequently used because of its low cost, comparable efficacy, and acceptable toxicity profile compared with other options. However, only a minority of patients achieve short-term remission, and long-term follow-up often reveals a relapse. The addition of etoposide [forming the EPOCH (etoposide, prednisone, oncovin, cyclophosphamide, and hydroxydaunorubicin) regimen] or other combination chemotherapies may help overcome drug resistance and delay recurrence[11]. For CHOP-resistant cases, the GDP (gemcitabine, cisplatin, and dexamethasone) regimen has been reported to achieve disease stability for > 1 year in some patients[12]. Although the aforementioned therapies show some efficacy, there is a lack of large-scale multicenter studies to robustly validate their effectiveness[11]. Radiotherapy can also be effective; however, it is rarely used as stand-alone treatment. It is typically reserved for multifocal HS or as adjuvant therapy after resection. Techniques vary, with conformal radiotherapy being common; however, optimal dosing and fractionation schedules are not standardized. Novel therapeutic strategies have recently emerged. HS often expresses vascular proliferation-related factors, such as vascular endothelial growth factor receptor, vascular endothelial growth factor C, and platelet-derived growth factor receptor. Targeted agents such as sorafenib, bevacizumab, and alemtuzumab, guided by their corresponding immunophenotypes, may help inhibit tumor progression[13,14]. Furthermore, the discovery of v-Raf murine sarcoma viral oncogene homolog B V600E mutations in some HS cases has led to the successful use of the targeted inhibitor vemurafenib to improve patient outcomes[8,15]. Additionally, research has indicated programmed death-ligand 1 overexpression in HS, suggesting a potential role for programmed cell death 1/programmed death-ligand 1 inhibitors; however, the low incidence of HS precludes large-scale validation[16]. Autologous hematopoietic stem cell transplantation after chemotherapy has been reported to be beneficial in some cases[17]. Oncolytic virotherapy has recently emerged as a promising treatment approach. Preliminary in vitro studies on a canine HS cell line (DH82) have demonstrated that oncolytic viral infection alters the distribution of endothelial proteins and significantly reduces the invasiveness and metastatic potential of DH82 cells, indicating that cytoskeletal modification is a key mechanism for inhibiting tumor spread[18,19]. This provides a novel rationale for HS treatment, and its application in human HS has been explored[20]; however, its efficacy requires further confirmation.

Table 1 Comparison of the main clinical features of primary splenic histiocytic sarcoma cases.

No.	Age	Sex	Spleen size (cm)	Metastasis	Treatment	Survival	Ref.
1	38	M	NA	NA	S	NA	Franchino et al[21]
2	29	M	17 × 13 × 8	Liver	S	5 years 1 month	Kimura et al[3]
3	60	M	8 × 8 × 8	Liver, BM	S + C	1-year 6 months	Kimura et al[3]
4	66	F	1 × 1 × 3	Liver, BM	R + S + C	2 years 6 months	Kimura et al[3]
5	71	F	14 × 12 × 10	Lymph node	C	6 months	Audouin et al[4]
6	58	F	15 × 9 × 10	Liver	R + S + C	3 months	Oka et al[5]
7	82	F	NA	Liver	R	1 month	Kobayashi et al[22]
8	67	F	14 × 12 × 8	BM	S	6 months	Yamada et al[23]
9	69	M	NA	Liver	C + S	3 years 5 months +	Yamamoto et al[24]
10	81	F	21 × 12 × 5	Liver	S	5 months	Yamamoto et al[25]
11	40	F	12 × 8 × 4	BM	S	5 months +	Huang et al[26]
12	61	M	19 × 13 × 9	None	C + S	6 months +	Kobayashi et al[27]
13	69	F	28 × 18 × 10	None	S	5 months	Zhang et al[2]
14	46	F	15 × 11 × 6	None	S	NA	Liu et al[28]
15	33	M	26 × 19 × 12	Lymph node	S	6 months	Montalvo et al[29]
16	40	F	10.5 × 9.5 × 12.2	Liver	S	NA	Zhou et al[30]
17	67	F	14 × 12 × 7	None	S	5 months +	Our case

M: Male; F: Female; NA: Not available; BM: Bone marrow; S: Surgery; C: Chemotherapy; R: Radiation.

CONCLUSION

In summary, despite its aggressive nature and poor prognosis, HS remains treatable. Early and definitive diagnosis is of paramount importance, and immunohistochemistry plays a pivotal role. Current treatment strategies, including chemotherapy, targeted therapy, and immunotherapy, are primarily based on isolated case reports. Therefore, expanding the sample size and obtaining robust evidence-based medical data are imperative to benefit patients. Continuous efforts to enhance our understanding of this disease are essential for formulating optimal treatment strategies, ultimately improving the patients' quality of life and prolonging their survival.

ACKNOWLEDGEMENTS

The authors are grateful to the staff at the Department of Pathology of the First Affiliated Hospital of Jinan University (Guangdong Province, China).