Cranial and Orbital Follicular Dendritic Cell Sarcoma

Key Points at a Glance

Highlights of This Disease

• Follicular dendritic cell sarcoma (FDCS) is a rare low-grade tumor accounting for 0.4% of soft tissue sarcomas.
• Only 3 cases of intracranial occurrence and 1 case of orbital occurrence have been reported.
• Invasion of the cavernous sinus or clivus can cause diplopia, vision loss, and proptosis.
• Definitive diagnosis requires biopsy and immunohistochemical staining for CD21, CD23, and CD35.
• Treatment primarily involves complete surgical resection, with adjuvant radiotherapy and chemotherapy.
• The 2-year survival rate for localized disease is approximately 83%, but drops to about 43% in metastatic cases.

1. What is Cranial and Orbital Follicular Dendritic Cell Sarcoma?

Follicular dendritic cell sarcoma (FDCS) is a rare tumor arising from follicular dendritic cells of mesenchymal origin. It accounts for only 0.4% of all soft tissue sarcomas.

In a pooled analysis of 343 cases, the median age at diagnosis was 50 years ¹⁾. The sex ratio is nearly equal, and there is a relatively higher proportion of Asian patients ¹⁾. About two-thirds occur within lymph nodes, and the remaining one-third occur extranodally. Recent reports indicate that extranodal occurrence reaches 79.4% ⁶⁾. Common extranodal sites include the head and neck, gastrointestinal tract, liver, and spleen.

Only 3 cases of extranodal FDCS arising intracranially have been reported. Orbital occurrence is extremely rare, with only 1 case reported. 10–20% of cases are associated with Castleman disease (a non-clonal lymphoproliferative disorder) ⁴⁾.

Q How rare is follicular dendritic cell sarcoma?

A

It accounts for only 0.4% of all soft tissue sarcomas. Furthermore, cranial and orbital involvement is extremely rare, with only 3 intracranial cases and 1 orbital case reported.

2. Main Symptoms and Clinical Findings

Subjective Symptoms

FDCS typically presents as a slowly enlarging, painless lymphadenopathy. In extranodal cases, B symptoms (fever, night sweats, weight loss) may be present.

When occurring intracranially, subjective symptoms are as follows:

• Confusion and memory impairment: caused by compression from the intracranial mass
• Diffuse headache: reflecting increased intracranial pressure
• Binocular horizontal diplopia: due to abducens nerve palsy from clivus and sphenoid sinus invasion

When occurring in the orbit, the following symptoms appear:

• Blurred vision and decreased visual acuity: due to compression or invasion of the optic nerve
• Ptosis: suggests oculomotor nerve dysfunction
• Proptosis: due to increased orbital content volume

Clinical Findings (Findings Confirmed by Physician Examination)

The following findings are confirmed on ophthalmic examination:

• Relative afferent pupillary defect (RAPD): an objective indicator of optic nerve damage
• Restricted eye movement: reflects cranial nerve invasion within the cavernous sinus
• Papilledema: a finding of increased intracranial pressure or optic nerve compression
• Proptosis: Quantified by palpation or Hertel exophthalmometry

When infiltration into the cavernous sinus or clivus progresses, multiple cranial nerve deficits may occur simultaneously.

Q What ocular symptoms occur when the tumor arises in the orbit?

A

Blurred vision, decreased visual acuity, ptosis, proptosis, and diplopia may appear. On examination, RAPD, restricted eye movements, and papilledema are observed. Infiltration into the cavernous sinus can also cause multiple cranial nerve deficits simultaneously.

3. Causes and Risk Factors

The mechanism of tumorigenesis in FDCS remains largely unknown. The following molecular abnormalities are thought to be involved.

• Chromosomal instability: Widespread chromosomal abnormalities have been reported
• Activation of the NF-κB pathway: Including mutations in its components
• Activation of the MAPK pathway: p-ERK1/2 is expressed in 80% of cases
• PTEN mutations and TP53 mutations: Indicating loss of function of tumor suppressor genes
• BRAF V600E mutation: Found in approximately 20% of all cases

The inflammatory variant of FDCS is known to be associated with EBV infection. This variant mainly occurs in the liver and spleen and is characterized by abundant lymphoplasmacytic infiltration.

10–20% of cases are associated with hyaline vascular Castleman disease ⁴⁾. It is hypothesized that follicular dendritic cell hyperplasia associated with Castleman disease progresses to tumorigenesis.

Prevention and Daily Care

There is currently no established method for preventing FDCS. If unexplained lymphadenopathy persists or ocular symptoms such as proptosis or diplopia appear, please seek medical attention promptly.

4. Diagnosis and Examination Methods

Histological Examination (Definitive Diagnosis)

Tissue biopsy and immunohistochemical staining are essential for the definitive diagnosis of FDCS.

Histologically, spindle-shaped cells with weakly eosinophilic cytoplasm exhibit a storiform or whorled pattern. Infiltration of small mature lymphocytes is characteristic.

The main immunohistochemical markers are as follows:

• CD21, CD23, CD35: Definitive markers for follicular dendritic cells
• Clusterin: Shows high sensitivity (100%) and high specificity (93%) ³⁾
• Vimentin, Fascin, HLA-DR: Usually positive
• CXCL13, Podoplanin, FDCSP, Serglycin: Expressed in many cases
• EGFR: Overexpressed in almost all cases
• PD-L1: Positive in 50–80% of cases ⁴⁾

Imaging Studies

• CT/MRI: Used to evaluate tumor location and extent. MRI is most useful for orbital tumors; T2-weighted STIR and T1-weighted gadolinium-enhanced fat-suppressed sequences are recommended.
• PET/CT: May be necessary to search for distant metastases or occult lesions.

Ophthalmic Examination

If intracranial or intraorbital lesions are suspected, perform the following comprehensive ophthalmic examination.

• Visual acuity test and visual field test
• Eye position test and stereopsis test
• Fundus examination (evaluation of papilledema)

Differential Diagnosis

The main differential diagnoses and key points for differentiation are shown below.

Differential Diagnosis	Key Points for Differentiation
Indeterminate dendritic cell tumor	S100 positive, clusterin negative
Langerhans cell histiocytosis	CD1a and langerin positive
Rosai-Dorfman disease	S100 positive, emperipolesis
Malignant melanoma	S100, HMB45, Melan A positive

It is also necessary to evaluate the presence of Castleman disease or paraneoplastic phenomena (such as myasthenia gravis).

Q What tests are needed for a definitive diagnosis?

A

Pathological confirmation by tissue biopsy is essential. Immunohistochemical staining should confirm positivity for CD21, CD23, and CD35. Clusterin shows high diagnostic accuracy with 100% sensitivity and 93% specificity ³⁾. Imaging studies (CT, MRI, PET) are used for localization assessment.

5. Standard Treatment

Surgical Treatment

The mainstay of treatment is complete surgical resection of the tumor. Compared to patients treated with chemotherapy or radiotherapy alone, those undergoing complete resection have better outcomes.

In a pooled analysis of 462 cases, FDCS behaves as an intermediate-grade sarcoma, with a local recurrence rate of 28.1% and a distant metastasis rate of 27.2% ¹⁾. It has been reported that adding adjuvant radiotherapy after complete resection significantly improves local control ²⁾.

Radiotherapy

Adjuvant radiotherapy with 50–55 Gy is commonly administered. It is indicated for cases with close or positive margins after surgery ⁵⁾.

Chemotherapy

Systemic chemotherapy is selected for unresectable, recurrent, or metastatic cases.

• Gemcitabine + Docetaxel: This regimen shows the highest efficacy with a response rate of 80% ⁴⁾
• CHOP therapy: Used as a lymphoma regimen, but consensus has not been established ⁴⁾
• ABVD therapy: Reported as a second-line treatment ⁴⁾

In cases where chemotherapy is used, a median recurrence-free survival of 2.9 years has been reported.

Management of Ocular Symptoms

For diplopia secondary to abducens nerve palsy, the following approaches are considered.

• Prism glasses: Used to reduce diplopia
• Strabismus surgery: May be indicated in cases with fixed ocular misalignment

Follow-up

No standardized surveillance protocol has been established. Regular follow-up by a multidisciplinary team including the primary physician, oncologist, neuroradiologist, and ophthalmologist is essential. Repeat imaging is recommended until stability is achieved.

Precautions and Side Effects in Treatment

FDCS is an extremely rare disease, and evidence regarding treatment is limited to small retrospective studies and case reports. Since no established treatment guidelines exist, careful discussion of treatment strategies by a multidisciplinary team is necessary.

Q What measures are available for diplopia?

A

For diplopia due to abducens nerve palsy, prism glasses are first used to alleviate symptoms. If ocular misalignment becomes fixed, strabismus surgery may be indicated. Ultimately, treatment of the primary tumor is important.

6. Pathophysiology and Detailed Mechanisms

Follicular dendritic cells (FDCs) are mesenchymal-derived immune accessory cells present in the germinal centers of lymphoid follicles. They present antigens to B cells and T cells and contribute to the structural maintenance of lymphoid follicles. They belong to a lineage distinct from other hematopoietic-derived dendritic cells.

Regarding the origin of FDCs, it has been reported that they derive from perivascular precursor cells (PDGFRb-positive) ⁴⁾. This finding supports that FDCs are stromal cells.

Molecular abnormalities involved in tumorigenesis are shown below.

Signal Pathway Abnormalities

NF-κB pathway: Mutations in components lead to constitutive activation.

MAPK pathway: p-ERK1/2 is expressed in 80% of cases.

BRAF V600E mutation: Found in 20% of all cases.

Epigenetics

EZH2 overexpression: Confirmed in 67% of FDCS tumors.

RB1 loss-of-function mutation: Contributes to disruption of cell cycle regulation.

Tumor suppressor genes

TP53 mutation: Reported in multiple cases.

PTEN mutation: Leads to disinhibition of the PI3K-AKT pathway.

FBXW7 mutation: Indicates abnormality in the ubiquitin pathway ⁷⁾.

Histologically, it is classified as a low-grade sarcoma. Tumor cells are spindle-shaped to oval, forming a storiform or whorled pattern. Weakly eosinophilic cytoplasm and infiltration of small mature lymphocytes are characteristic. Nuclear pseudoinclusions are often observed.

EGFR overexpression is observed in almost all cases, and it is unique that the epithelial growth factor receptor is highly expressed despite being a sarcoma.

7. Latest research and future perspectives (research-stage reports)

For patients: Please read this

The following content is currently at the research stage or under clinical trial, and is not standard treatment available at general hospitals. It is reference information for experts regarding future medical developments.

Research into new treatments for FDCS is ongoing. Since PD-L1 is positive in 50–80% of cases, there is high expectation for immune checkpoint inhibitors ⁴⁾.

Lei et al. (2021) administered a combination of the PD-1 antibody sintilimab and lenvatinib as third-line therapy for a case of intestinal FDCS that progressed after multi-agent chemotherapy. Progression-free survival was 7 months, exceeding the 3 months of second-line therapy. PD-L1 expression rate was 90% ⁴⁾.

Additional reports on immune checkpoint inhibitors include two cases where stable disease was achieved with a combination of nivolumab and ipilimumab ⁴⁾. On the other hand, there is also a report of a case where nivolumab monotherapy was ineffective ⁴⁾.

The following reports exist for molecular targeted therapy:

• Pazopanib (multi-kinase inhibitor): partial response lasting 9 months after multiple prior treatments ⁴⁾
• Imatinib + gemcitabine + cisplatin: complete pathological remission in a CD117-positive case ⁴⁾

A phase II clinical trial of pembrolizumab (NCT03316573) is ongoing, evaluating its efficacy against dendritic cell tumors including FDCS ⁴⁾.

Advances in molecular profiling using NGS (next-generation sequencing) are also noteworthy. Loss-of-function mutations in TP53, RB1, and FBXW7 have been repeatedly reported ⁷⁾, and developing treatments targeting these molecular abnormalities is a future challenge.

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8. References

1. Saygin C, Uzunaslan D, Ozguroglu M, et al. Dendritic cell sarcoma: a pooled analysis including 462 cases with presentation of our case series. Crit Rev Oncol Hematol. 2013;88(2):253-271.
2. Jain P, Milgrom SA, Patel KP, et al. Characteristics, management, and outcomes of patients with follicular dendritic cell sarcoma. Br J Haematol. 2017;178(3):403-412.
3. Rajan R, Roshni DG, Mathew SM, et al. Follicular dendritic cell sarcoma of the thigh: a clinicopathological report and management approach. BMJ Case Rep. 2022;15(4):e244812.
4. Lei Y, Zhao S, Jiang M. Unexpected favorable outcome to PD-1 antibody plus lenvatinib in a patient with recurrent intestinal follicular dendritic cell sarcoma: a case report and literature review. Front Immunol. 2021;12:653319.
5. Ilonen IK, Meltzer AJ, Ellozy S, et al. Follicular dendritic cell sarcoma of the chest. Ann Thorac Surg. 2022;113(4):e263-e266.
6. Jha T, Sharma A, Kalakkunath S, et al. Extranodal follicular dendritic cell sarcoma of the lung. Indian J Thorac Cardiovasc Surg. 2024;40(2):219-223.
7. Aslam S, Ibe I, Zhang Y, et al. Follicular dendritic cell sarcoma involving the parotid gland with expression of the melanocytic marker PRAME. J Hematopathol. 2024;17:271-274.