Histiocytic neoplasms (HNs) are a rare and heterogeneous group of tumors originating from monocytes, macrophages, and dendritic cells [1]. According to the 2024 5th edition of the World Health Organization Classification of haematolymphoid tumours, HNs are classified as a subgroup of hemolymphoid tumors, encompassing entities such as juvenile xanthogranuloma (JXG), Erdheim-Chester disease (ECD), Rosai-Dorfman disease (RDD), anaplastic lymphoma kinase (ALK)-positive histiocytosis (APH), and histiocytic sarcoma (HS) [2]. HNs are very rare diseases, accounting for less than 1% of soft tissue and lymph node tumors [3].

HNs have significant diagnostic challenges due to overlapping clinical and pathological features, especially in atypical locations [1]. For instance, the morphology of JXG, ECD, and APH are often indistinguishable from each other. Emperipolesis, a key histological feature, is commonly observed in JXG, ECD, and APH [1]. Due to these challenges in diagnosis, the interpretation of histological findings in conjunction with clinical, imaging findings and molecular features, also the genetic studies, such as next-generation sequencing (NGS) are also critical for identifying rare mutations and improving diagnostic accuracy. Accurate differentiation among HNs is vital, as their prognoses vary widely. For instance, JXG and RDD are typically benign, whereas HS demonstrates aggressive behavior and the prognoses of ECD and APH are significantly influenced by the location and extent of lesions [1]. Immunohistochemical markers, such as CD68, CD163, and genetic features like ALK fusion, are helpful in diagnosis but are often insufficient without consideration of clinical context.

This report describes a rare case of an isolated central nervous system (CNS) neoplasm with histiocytic features. Through detailed analysis of clinical symptoms, surgical findings, and pathological evaluation, the definitive diagnosis of histiocytic neoplasm, not otherwise specified (NOS), was established. This case underscores the diagnostic complexity of HNs and the necessity of comprehensive diagnostic approaches in managing rare HNs.

A 49-year-old female patient was referred to the outpatient clinic from a local hospital with an initial diagnosis of a brain tumor. Her chief complaint was progressive right-hand weakness that had developed approximately ten days before her presentation. A neurological examination revealed mild hemiparesis in the right hand with diminished grip strength; motor functions in other areas were within normal ranges. Initial magnetic resonance imaging with contrast enhancement displayed a diffuse, infiltrative lesion. Based on the radiological features observed, this prompted a differential diagnosis that included malignant glioma or tumefactive demyelination (Fig. 1).

The patient’s medical history included well-managed hypertension, varicose vein surgery in 2024, and a total thyroidectomy in 2014 due to papillary thyroid carcinoma. The preoperative work-up, comprising a complete blood count, liver function tests, and lipid profile, returned results within normal limits. Cardiac and pulmonary conditions were assessed using echocardiography and a chest X-ray, revealing no abnormalities.

We planned a craniotomy for gross total resection, incorporating 5-aminolevulinic acid (5-ALA) as a fluorescent dye to aid in intraoperative tumor visualization. However, the lesion exhibited no fluorescence when exposed to 5-ALA (Fig. 2A). Distinguishing the tumor from surrounding normal brain tissue was challenging, as no significant morphological differences were macroscopically visible (Fig. 2B). Consequently, we utilized image-guided resection with neuro-navigation technology to localize and achieve maximal safe resection of the lesion. An intraoperative frozen section biopsy was performed to provide rapid histopathological feedback, suggesting a low-grade glioma. The resection proceeded without further complications, resulting in successful tumor removal.

Histopathological analysis of the resected tissue revealed foamy histiocytes interspersed with lymphocytic infiltration. Characteristic findings in XG and RDD were not observed such as touton giant cells and emperipolesis (Fig. 3A and B) [4]. Immunohistochemistry (IHC) results showed positive staining for CD68 (Fig. 3C) and ALK (D5F3) (Fig. 3G), while ALK-1 staining was equivocal (Fig. 3H). The tumor was negative for Langerin (Fig. 3E), CD1a (Fig. 3F), BRAF V600E (Fig. 3D), S100 (Fig. 3I), Cyclin D1 (Fig. 3J) and glial fibrillary acidic protein (GFAP) (Fig. 3K). The tumor showed 5% positive for Ki-67 (Fig. 3L). These findings provided initial clues for differential diagnosis. Given the unusual immunophenotypic profile, further genetic testing was conducted, including ALK fluorescence in situ hybridization (FISH) and NGS. NGS confirmed the absence of ALK gene rearrangements and mutations (Table 1), despite positive immunohistochemical staining with the ALK (D5F3) antibody and equivocal staining with the ALK-1 antibody. These results led us to consider ECD in the differential diagnosis. However, a subsequent positron emission tomography (PET)-CT scan did not reveal any systemic lesions, ultimately leading to a diagnosis of histiocytic neoplasm, NOS.

Following surgery, the patient’s hospital course was tolerable. She was discharged on postoperative day five with a motor grade of IV on her right side and exhibited mild gait disturbances, prompting the initiation of a rehabilitation program. Two months postoperatively, she presented to the emergency department with seizure activity, marking the first presentation of neurological symptoms since her discharge. An MRI conducted at that time suggested possible progression of the lesion. She was admitted for radiation therapy and further evaluation, including an electroencephalogram, which showed intermittent slow theta waves. The neurology team managed her medically with anticonvulsant therapy. A subsequent seizure one month later required adjustments in her medication regimen, and notably, no further seizures have occurred since then. Radiation therapy was administered as involved-site radiation therapy at 50 Gy/25 fractions, followed by whole-brain radiation therapy at 30 Gy/15 fractions over one month.

The patient continues with rehabilitation therapy and, as of the most recent follow-up visit, demonstrates only a right-hand motor grade of IV. Significant improvements in her gait have been observed, and she now ambulates independently without assistance.

The final diagnosis for this patient is histiocytic neoplasm, NOS, as further differentiation could not be determined. On initial examination of the hematoxylin and eosin (H&E) slide, we excluded non-neoplastic conditions with histiocytic accumulation, such as sinus histiocytosis, hemophagocytic syndromes, lysosomal storage diseases (e.g., Niemann-Pick and Gaucher’s diseases), crystal-storing histiocytosis, and infections, as the cytological atypia, high cellularity, and absence of reactive triggers strongly suggest a neoplastic process [15]. Non-HNs were excluded based on the results of IHC. The tumor demonstrated negativity for GFAP and cytokeratin AE1/AE3, significantly reducing the likelihood of tumors of glial or epithelial origin [167]. Additionally, negativity for CD3 and CD20 effectively ruled out lymphoma as a potential diagnosis [189]. The positive IHC result for CD68 supported the possibility of a HN, although a diagnosis cannot be confirmed based solely on CD68 expression [10]. Unfortunately, other IHC markers, including CD163, synaptophysin, and OLIG2, were not evaluated. However, based on the available results, the tumor is most likely classified as a HN.

IHC results enabled us to exclude LCH, as both CD1a and Langerin were negative [3]. Features such as the absence of emperipolesis and cellular regularity also allowed for the exclusion of RDD and HS [5]. The potential diagnosis of APH was considered, given that ALK-1 expression was equivocal and ALK (D5F3) was positive. However, the absence of ALK gene mutations and systemic lesions further diminishes the likelihood of APH. While we considered the possibility of a rare ALK fusion partner [11] or a false-negative FISH result [12], such scenarios are considered unlikely.

Considering the IHC results and the patient’s age, ECD was contemplated as a potential diagnosis. The absence of the BRAF V600E mutation, identified in approximately 50% of ECD cases, significantly reduced the likelihood of this diagnosis [131415]. Also, considering the H&E stain, there were not the typical features of ECD such as touton giant cells [16]. Furthermore, the lesion being isolated to the CNS makes ECD less likely, since ECD typically presents as a multi-systemic disease especially bilateral osteosclerosis of the long bones [1141718].

In the lack of other known entities, this case might represent a previously unrecognized subtype of HN. HNs continue to be a relatively under-characterized group with evolving diagnostic guidelines and classifications. For instance, APH was recognized only in 2008 [19]. As of May 2024, a total of only 17 cases of CNS-isolated APH have been reported [20], and just one case has been documented in an adult as of August 2024 [21]. Additionally, single CNS lesions in ECD have been described in only two cases [2223], both diagnosed without genetic analysis. Therefore, if this case represents one of these entities, it would be extraordinarily rare.

As highlighted in the introduction, HNs present diverse clinical symptoms and prognoses, underscoring the importance of precise subtyping for effective treatment planning, follow-up evaluations, and patient education [125]. However, a more definitive diagnosis beyond histiocytic neoplasm, NOS could not be established. Fortunately, the patient has returned to daily life without neurologic symptom progression.

The prognosis of HNs varies depending on the specific subtype as mentioned. The two probable entities considered in this case were APH and ECD. Consequently, a follow-up plan was developed, taking into account the prognostic implications of these subtypes.

In adults, APH typically manifests as a systemic disease. The most frequently involved sites include, in order of prevalence, the CNS, skin, soft tissue, bone, and lungs [19]. Therefore, careful monitoring for new lesions, particularly in these regions, is essential.

For ECD, current guidelines recommend performing a PET-CT every three months to assess systemic involvement, with the interval potentially increasing once the disease achieves stability [24]. Additionally, organ-specific imaging should be conducted every three months during active disease and every six months after stabilization [25]. Considering the long bone osteosclerotic lesions, which are a hallmark clinical finding of ECD [141726], an immediate bone scan is warranted if the patient experiences bone pain.

Through this case, we aim to share our experience distinguishing HNs from other brain tumors when encountering a single-lesion histiocytosis in the brain. Depending on the lesion location, HNs, depending on lesion location, often exhibit multisystem involvement and diverse clinical presentations. Therefore, an accurate diagnosis requires comprehensive pathological and genetic evaluations, as well as systemic assessments. Consultation with medical specialists, such as pathologists and hematologists, is essential for specialized pathological studies to distinguish these entities from other hematolymphoid tumors.

By reporting this rare case, we aim to contribute to the growing body of literature on CNS HNs, thereby encouraging future studies that explore new treatment options and improve diagnostic criteria within this relatively unexplored group of tumors.