Myxoid spindle cell lipoma of the ileum: Clinicopathological features and diagnostic insights

INTRODUCTION

Spindle cell lipoma (SCL) is an uncommon benign neoplasm of adipose tissue, characterized by distinct demographic predilections. It exhibits a striking male predominance, with a reported male-to-female ratio of approximately 9:1.^[1,2] Clinically, this tumor most frequently arises within the subcutaneous tissue of the neck and upper back, particularly in middle-aged and elderly men.

Current research suggests that androgen receptor expression in the tumor may be related to this gender disparity.^[3,4] In contrast, female patients are more likely to present at atypical anatomical sites. They also tend to be younger at diagnosis.^[5] The cellular origin of SCL is not fully understood. Available evidence indicates it may arise from fibroblasts or undifferentiated mesenchymal precursor cells.^[5]

From a clinical standpoint, SCL usually manifests as a solitary, painless subcutaneous nodule characterized by slow progression. Although the posterior neck and upper back are the most typical sites, a small subset of cases may arise in other superficial anatomic locations. These include the head, face, extremities, perineum, and trunk. Occasionally, SCL may involve deeper sites. These include the abdominal cavity, retroperitoneum, and mediastinum.^[1] Based on its main tissue components, SCL can be classified into several subtypes. These include angiomatoid, pauci-fat, myxoid, and plexiform variants.^[6] Among these, the myxoid subtype is characterized by a stroma rich in myxoid material. This often partially or completely replaces the characteristic thick collagen bundles seen in classic SCL. Consequently, its histological appearance becomes atypical. This significantly increases diagnostic difficulty. This challenge is particularly pronounced when the tumor occurs at atypical locations. It can easily lead to misdiagnosis. It may also be confused with other myxoid-rich soft tissue tumors.

A review of domestic and international literature reveals that SCL cases occurring in the abdominal cavity or intestines are extremely rare. According to current reports, only one case of intra-abdominal SCL has been documented in China.^[7] Internationally, only a single case of small intestinal SCL has been reported.^[2] This rarity means that clinical and pathological understanding of its presentation at atypical sites remains limited. This often leads to confusion with other intermediate or malignant tumors that share morphological similarities. Examples include myxoid liposarcoma and low-grade fibromyxoid sarcoma. However, the treatment strategies and prognoses for these conditions are fundamentally different.

Therefore, clarifying the pathological features of this rare subtype at atypical sites holds significant clinical importance. This study aims to conduct a systematic and in-depth analysis of an SCL (myxoid subtype) around the ileum. This analysis will be performed using multiple approaches. These include histomorphological observation, immunohistochemical analysis (involving markers such as Cluster of differentiation 34 (CD34), retinoblastoma protein 1[Rb1], and MDM2), and molecular testing (such as detecting MDM2 gene amplification status). This study aims not only to provide a detailed record of this rare case. It also seeks to enhance understanding of the tumor’s pathological nature and diagnostic key points. This will be achieved through a comprehensive summary of its characteristics. Ultimately, this will offer a solid and reliable pathological foundation. This foundation is crucial for the accurate identification and proper management of similar cases in future clinical practice.

MATERIAL AND METHODS

RESULTS

Histopathological morphology

A complete thin fibrous capsule encloses the ileal nodule. The background consists of spindle cells within an abundant myxoid matrix [Figure 1a and b]. Scattered mature adipocytes are present. There is no evidence of coarse collagen bundles, mast cells, pathologic mitotic figures, or tumor necrosis. The spindle tumor cells exhibit abundant, pale-staining cytoplasm [Figure 1c and d]. Under high magnification, the nuclei appear vesicular with discernible nucleoli and finely dispersed chromatin [Figure 1e and f].

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Figure 1: (a and b) Hematoxylin and eosin (HE) staining showed the spindle cell lipoma tumor is surrounded by a thin fibrous capsule with a well-defined border (HE, ×40) 250 μm. (c) At medium magnification, the tumor shows a background of spindle cells within abundant myxoid stroma, containing scattered mature adipocytes (HE, ×100) 100 μm. (d) No cellular atypia, coarse collagen fibers, or mast cells are observed (HE, ×200) 50 μm. (e and f) High-power view reveals tumor cells with vesicular nuclei, fine chromatin, and discernible nucleoli (HE, ×400) 25 μm.

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The intestinal adenocarcinoma is predominantly tubular, with a minor mucinous component [Figure 2a]. The tumor shows an increased nuclear-to-cytoplasmic ratio and frequent mitotic figures. Necrosis is present [Figure 2b]. Tumor budding is classified as low score (0~4 buds/0.785 mm²). No definitive perineural or vascular invasion is identified. Tumor involvement of the visceral peritoneum is confirmed. All resection margins are negative. No metastatic carcinoma is found in the lymph nodes.

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Figure 2: (a) Hematoxylin and eosin (HE) staining showed that the intestinal adenocarcinoma is predominantly tubular, with a minor mucinous component (HE, ×40) 200 μm. (b) The neoplastic cells exhibit a high nuclear-to-cytoplasmic ratio, accompanied by numerous mitotic figures. Necrosis is present (HE, ×100) 100 μm. (c and d) The intestinal adenocarcinoma is positive for (c) CDX2 and (d) SATB2 (EnVision, ×100) 100 μm. CDX2: Caudal-type homeobox 2, SATB2: Special AT-rich sequence-binding protein 2.

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Immunohistochemical staining results

The intestinal adenocarcinoma is positive for CDX2 [Figure 2c] and SATB2 [Figure 2d]. Rb1 loss is seen in the SCL cells, while Rb1 expression is retained in vascular endothelial cells serving as internal controls [Figure 3a]. SCL cells are positive for CD34 [Figure 3b] and negative for S100 [Figure 3c], CD31 [Figure 3d], MDM2 [Figure 3e], and DDIT3. The Ki67 proliferation index is approximately 1% [Figure 3f]. A list of the immunohistochemical staining results is provided in Table 1.

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Figure 3: Immunohistochemical results in spindle cell lipoma. (a) The tumor cells demonstrate loss of Rb1 expression (EnVision, ×100) 100 μm. (b) CD34 expression is detected in the tumor cells (EnVision, ×100) 100 μm. (c) Tumor cells are negative for S100 expression (EnVision, ×100) 100 μm. (d) Tumor cells are negative for CD31 expression (EnVision, ×100) 100 μm. (e) No MDM2 immunoreactivity is detected within the neoplastic cells (EnVision, ×100) 100 μm. (f) The Ki-67 index of tumor cells is approximately 1% (EnVision, ×100) 100 μm. Rb1: Retinoblastoma transcriptional corepressor 1, CD: Cluster of differentiation, MDM2: Mouse double minute 2, Ki-67: Antigen Kiel 67.

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Table 1: Results of immunohistochemical staining.

Antibody	Intestinal adenocarcinoma	SCL
SATB2	+	−
CDX2	+	−
CK20	+	/
Rb1	+	−
P53	Strong continuous +	/
Ki-67	70%+	1%+
CD34	/	+
S100	/	−
MDM2	/	-
MLH1	+	/
PMS2	+	/
MSH2	+	/
MSH6	+	/
Desmin	/	−
BCL2	/	Weak+
CD99	/	Weak+
STAT6	/	−
CD117	/	−
DOG1	/	−
CKpan	/	−
SMA	/	−
DDIT3	/	−
CD31	/	−

+ indicates positive expression, − indicates negative expression, and/indicates not performed. SCL: Spindle cell lipoma

DISCUSSION

SCL (myxoid subtype) mainly occurs in the neck/back of the neck/neck region, upper back, and shoulders, while a few cases are located in the limbs, face and trunk, epiglottis, mediastinum, large labia, and perineum, etc.^[1] However, SCL occurring around the ileum is extremely rare, with only a few cases reported worldwide, making it easy to overlook. SCL (myxoid subtype) around the ileum is extremely rare in clinical practice. Most patients show no obvious clinical symptoms, and it is often discovered incidentally. In this study, the patient was asymptomatic. The tumor was an incidental finding in a specimen from a right hemicolectomy for colon cancer. Through systematic analysis, this study provides a complete description of its features. This includes histomorphology, immunophenotype (CD34 positive, Rb1 loss, low Ki-67 index), and molecular profile (no MDM2 amplification). Our work contributes valuable clinicopathological data on this rare subtype. It not only fills a gap in existing knowledge but also serves as a key reference for future diagnosis and differential diagnosis of similar cases.

The diverse histological patterns of SCL often pose diagnostic challenges. Significant variation in its adipose tissue component is a major factor contributing to misdiagnosis.^[9,10] Immunophenotypically, SCL typically shows diffuse positivity for Vimentin and CD34. It is consistently negative for cyclin-dependent kinase 4 (CDK4), MDM2, Rb1, STAT6, SMA, and Desmin. Sustained CD34 expression is a key immunohistochemical feature of SCL.^[11]

Molecular studies show that SCL has a characteristic deletion on chromosome 13q14. This leads to loss of Rb1 gene expression. This loss is considered one of the key drivers of tumorigenesis.^[12] The pathological understanding of SCL has deepened. SCL exhibits a spectrum of morphological variations, and recognizing its diverse subtypes is crucial for accurate diagnosis. The classic subtype is characterized by a triad of bland spindle cells, brightly eosinophilic rope-like collagen bundles, and mature adipose tissue in varying proportions. These histological subtypes include the plexiform, low-fat, myxoid, and angiomatoid variants.^[13,14] The fibrous subtype is dominated by densely packed collagen fibers with sparse spindle cells and adipocytes. The myxoid subtype features a prominent myxoid stroma, which may mimic other myxoid neoplasms. The low-fat (or fat-poor) subtype contains minimal to no adipose tissue, consisting almost entirely of spindle cells and collagen, potentially leading to confusion with other spindle cell lesions.^[6] The pseudoangiomatous subtype is distinguished by the presence of pseudo-vascular spaces lined by spindle cells, which can simulate a vascular tumor. Finally, the fat-rich subtype is composed predominantly of mature adipocytes with only rare, inconspicuous spindle cells and collagen, resembling a conventional lipoma. Recognizing these variants is essential to prevent misdiagnosis, particularly when they occur at unusual anatomical sites. Although these subtypes of SCL are all benign in terms of biological behavior, recognizing them is crucial for pathological diagnosis. Particularly in atypical locations (such as the ileum in this case) or in small core needle biopsy specimens, a lack of awareness of its morphological spectrum may lead to misdiagnosis as other types of sarcoma or malignancy. The reason this case was diagnosed as the myxoid subtype is primarily due to the presence of scattered mature adipocytes within a background of spindle cells embedded in an abundant myxoid stroma, with an absence of collagen.

The tumor in this study lacks typical coarse collagen bundles. This is due to a shift in the secretory phenotype of the neoplastic spindle cells. Their primary secretory product becomes mucinous matrix. This mucin-rich extracellular microenvironment inhibits the formation and deposition of thick, dense collagen fiber bundles. Therefore, the absence of coarse collagen is not a diagnostic exception. It is, in fact, a characteristic feature of SCL (myxoid subtype). Diagnosing this subtype relies on recognizing its key components. These are CD34-positive spindle cells and mature adipocytes within a myxoid background. Immunohistochemistry and, when necessary, molecular testing are essential. They help differentiate it from morphologically similar yet more aggressive tumors, such as myxoid sarcoma.

It is important to note that some SCLs can easily be confused with other tumors. These include fibroblastic/ myofibroblastic tumors and liposarcoma. This is due to their lack of fat components.^[13] Therefore, a definite diagnosis requires extensive sampling of the specimen. This helps avoid sampling error and misdiagnosis.

SCL must be carefully distinguished from several diseases. The 5^th edition of the World Health Organization Classification of Soft Tissue Tumors (2020) includes atypical spindle cell lipomatous tumor as a distinct entity. It shares the same morphological spectrum, immunophenotype, and genetic alterations as SCL.^[15] In contrast to the myxoid subtype of SCL, this tumor is usually unencapsulated. It shows an infiltrative growth pattern. The tumor border is often poorly defined. The spindle cells exhibit mild to moderate atypia. They have coarse nuclear chromatin. Polymorphous cells are frequently observed within the stroma.^[16] Second, atypical lipomatous tumor/well-differentiated liposarcoma. In well-differentiated cases, only scattered atypical cells are seen within the spindle stromal cells. Differential diagnosis from the myxoid subtype of SCL based solely on histomorphology is difficult. However, atypical lipomatous tumor/well-differentiated liposarcoma often shows necrosis.^[17] Immunophenotypically, the tumor is typically diffusely positive for MDM2 and CDK4. FISH testing frequently reveals MDM2 amplification.^[18,19] Third, myxoid liposarcoma resembles the myxoid subtype of SCL in histomorphology. Both tumors are often rich in myxoid stroma. However, myxoid liposarcoma usually occurs in deep soft tissue. Its stroma contains delicate, branching “chicken-wire” vessels. This tumor shows greater atypia. Lipoblasts, mitotic figures, and necrosis are often present. But it lacks coarse collagen fibers.^[20] Molecularly, it typically has characteristic FUS-DDIT3 or EWSR1-DDIT3 gene fusions.^[21] In the present case, although FUS/EWSR1-DDIT3 fusion testing was not performed, immunohistochemistry demonstrated negative DDIT3 expression in the tumor. This finding provides supportive evidence against the presence of the FUS/EWSR1-DDIT3 fusion and helps distinguish this tumor from myxoid liposarcoma. Fourth, dendritic fibromyxolipoma is characterized by short spindle or stellate cells proliferating alongside mature adipocytes; dendritic fibromyxolipoma shows no cellular atypia. Immunohistochemically, it demonstrates a distinctive dendritic pattern of CD34 expression, which serves as a key differentiating feature from SCL (myxoid subtype).^[22] Fifth, solitary fibrous tumor is characterized by dense, hyalinized collagen fibers, and staghorn-shaped blood vessels. It typically shows diffuse positivity for CD34 and STAT6. SFT lacks Rb1 deletion. Genetically, it harbors a characteristic NAB2-STAT6 gene fusion.^[23] Sixth, dermatofibrosarcoma protuberans typically exhibits infiltrative growth into subcutaneous adipose tissue. Immunophenotypically, it commonly expresses CD34 and P75. At the molecular level, it is characterized by the COL1A1-PDGFB gene fusion.^[24]

Besides, in the ileum, the differential diagnosis for myxoid spindle cell lesions encompasses a broad and heterogeneous group of tumors, all of which may exhibit spindle cell morphology and occasionally present with a myxoid stroma, thereby complicatigng the diagnostic process. Therefore, careful differentiation is also required. Although gastrointestinal stromal tumor can exhibit spindle cell morphology and myxoid change, it is typically positive for DOG1 and CD117. In contrast, the tumor cells in our case were diffusely positive for CD34 but negative for DOG1 and CD117. Leiomyomas are composed of well-differentiated smooth muscle cells. They are consistently positive for smooth muscle markers (SMA, desmin) and negative for CD34. Our case showed no expression of SMA or desmin, effectively excluding a smooth muscle neoplasm. Schwannomas are diffusely and strongly S100-positive and usually show characteristic nuclear palisading (Verocay bodies) and perivascular hyalinization. They are typically CD34-negative in the cellular areas (though the capsule may be positive). The tumor cells in our case were negative for S100, ruling out peripheral nerve sheath differentiation. Neuroendocrine tumors can occasionally show spindle cell morphology, particularly in the gastrointestinal tract. However, they are defined by the expression of Syn and CgA. The complete absence of these markers in our case, combined with the presence of mature adipocytes, makes NET unlikely. Sarcomatoid carcinoma requires evidence of epithelial differentiation, typically through expression of CKpan. Our case was entirely negative for CKpan, effectively excluding carcinoma. Inflammatory myofibroblastic tumor is composed of myofibroblastic spindle cells accompanied by a prominent inflammatory infiltrate (plasma cells, lymphocytes). It typically expresses SMA and anaplastic lymphoma kinase (ALK). Our case lacked a significant inflammatory component, and SMA and ALK were negative. Vascular neoplasms would express erythroblast transformation-specific regulated gene 1 (ERG), CD31, or Fli-1 proto-oncogene (Fli-1). Our case was negative for these markers, despite CD34 positivity. Perineurioma is composed of perineural cells that express epithelial membrane antigen (EMA) and claudin-1 and are typically negative for S100 and CD34. The CD34-positive and EMA-negative profile of our case argues against perineurioma. Ganglioneuroma contains mature ganglion cells and Schwannian spindle cells. The absence of ganglion cells on extensive sampling and the S100-negative immunoprofile exclude this entity. Ganglioneuroma contains mature ganglion cells and Schwannian spindle cells. The absence of ganglion cells on extensive sampling and the negative S100 exclude this entity in this case. In summary, the key evidence confirming this case as SCL (myxoid subtype) includes loss of Rb1 gene expression (a characteristic genetic alteration of SCL), diffuse positivity for CD34, the presence of scattered mature adipocytes within a myxoid background, and the exclusion of specific markers for all the tumors mentioned above.

This study integrates morphological, immunohistochemical, and molecular testing to provide a clear framework for diagnosis and differential diagnosis, offering practical guidance for pathologists.

For the myxoid subtype of SCL, surgical resection remains the primary treatment approach. The tumor is benign and lacks metastatic potential. Complete local excision is generally curative. No cases of recurrence, malignant transformation, or metastasis have been reported in the literature to date, which suggests a favorable prognosis.^[25] In this study, the patient was followed for 2 years postoperatively. No signs of recurrence or metastasis were observed, confirming the favorable outcome. This follow-up result further supports complete excision as a reasonable surgical strategy. This approach helps avoid overtreatment and reduces the medical burden on patients.

This study has several limitations. The small size and inconspicuous gross appearance of the ileal nodule precluded preoperative radiologic detection, intraoperative photography, and gross specimen documentation. This reflects the real-world challenge in identifying SCL at atypical sites. This study demonstrates clear value in integrating pathological diagnosis with clinical management of rare cases, offering referential significance for pathological diagnostic practice. However, limited by its single-case report design, it lacks statistical generalizability, in-depth mechanistic insights, and long-term follow-up data.

Our future research will focus on four key areas. First, we will investigate the molecular mechanisms that regulate this subtype’s unique mucinous matrix formation and suppressed collagen deposition. Second, we aim to better define its clinicopathological features and prognostic factors using larger patient cohorts. Third, we will explore how this rare subtype develops in different anatomic sites, particularly the lower gastrointestinal tract. We will also compare its biological behavior to that of classic SCL. Fourth, we will systematically study its molecular genetic background. This work seeks to identify specific biomarkers for improved diagnosis and differential diagnosis. The goal is to provide a foundation for precision treatment and prevent overtreatment of benign lesions, such as unnecessary adjuvant chemotherapy.

SUMMARY

SCL (myxoid subtype) around the ileum is extremely rare in clinical practice. However, it possesses unique features in morphology, immunophenotype, and molecular alterations. Its treatment and prognosis differ from those of morphologically similar intermediate or malignant tumors. Overall, its prognosis is favorable. Accurate diagnosis of SCL (myxoid subtype) relies on a thorough understanding of the classic SCL morphological spectrum. The comprehensive data provided by this study serve as a valuable reference for the clinical diagnosis and differential diagnosis of similar cases in the future. In addition, it lays a theoretical foundation for further elucidating the molecular biological mechanisms of this tumor type.

AVAILABILITY OF DATA AND MATERIALS

All datasets and material generated and analyzed during the current study are included in this published manuscript.

ABBREVIATIONS

ALK: Anaplastic lymphoma kinase

BCL2: B-cell lymphoma 2

CD117: Cluster of differentiation 117

CD31: Cluster of differentiation 31

CD34: Cluster of differentiation 34

CD99: Cluster of differentiation 99

CDK4: Cyclin-dependent kinase 4

CDX2: Caudal type homeobox 2

CK(pan): Cytokeratin(pan)

CK20: Cytokeratin 20

DAB: 3,3’-Diaminobenzidine

DDIT3: DNA damage-inducible transcript 3

DOG-1: Discovered on GIST-1

EMA: Epithelial membrane antigen

ERG: Erythroblast transformation-specific regulated gene 1

Fli-1: Fli-1 proto-oncogene

GIST: Gastrointestinal stromal tumor

Ki-67: Antigen Kiel 67

MDM2: Murine double minute 2

P53: Tumor protein p53

Rb-1: Retinoblastoma protein 1

S100: S100 protein

SATB2: Special AT-rich sequence-binding protein 2

SMA: Smooth muscle actin

STAT6: Signal transducer and activator of transcription 6

AUTHOR CONTRIBUTIONS

RRF: Performed the experimental work and wrote the manuscript; JG: Provided supervision and guidance throughout the research and writing process. All authors read and approved of the final manuscript. All authors meet ICMJE authorship requirements.