Follicular Dendritic Cell Sarcoma of the Parapharyngeal Space Arising in Association With Castleman Disease

ABSTRACT

Follicular dendritic cell sarcoma (FDCS) is a rare malignant neoplasm of follicular dendritic cell origin. It is occasionally associated with unicentric Castleman disease (UCD), particularly the hyaline‐vascular (HV) variant (HV‐UCD). We report a 56‐year‐old woman with FDCS arising in the parapharyngeal space in the background of HV‐UCD. The patient presented with a painless right neck mass and extensive cervical lymphadenopathy without systemic symptoms. Surgical resection of the parapharyngeal mass revealed FDCS in the lymph nodes with features of HV‐UCD. Immunohistochemistry confirmed the follicular dendritic cell lineage of the lesional cells, with positivity for CD21 and CD23. Subsequent lymph node dissection from levels 2A, 2B, 3, and 4 showed features of HV‐UCD without residual FDCS. This case highlights the diagnostic challenge FDCS represents, particularly when arising in an unusual location. While complete surgical excision remains the standard of care, long‐term follow‐up is necessary to monitor for recurrence or metastasis.

Histopathological and immunohistochemical findings from the excisional biopsy of a right parapharyngeal mass in a 56‐year‐old woman with follicular dendritic cell sarcoma arising in Castleman disease. (A) H&E staining reveals atypical tumor cells intimately admixed with lymphocytes. (B) Adjacent areas show “lollipop lesions” characteristic of Castleman disease. (C, D) Immunohistochemical staining confirms the follicular dendritic cell origin of the tumor, with strong positivity for CD21 (C) and CD23 (D).

1. Introduction

Follicular dendritic cell sarcoma (FDCS) is a rare malignant neoplasm that arises from follicular dendritic cells, which are specialized stromal cells within lymphoid follicles of lymph nodes [1]. FDCS affects both nodal and extranodal sites, with extranodal involvement seen in up to 80% of cases, commonly affecting the liver, spleen, and gastrointestinal tract [2, 3]. The tumor predominantly affects adults, with a median onset between 40 and 50 years. FDCS typically presents as a slow‐growing, painless mass, which may be asymptomatic or associated with nonspecific symptoms depending on its location. Despite its generally indolent nature, FDCS has a potential for local recurrence and metastasis, with reported recurrence in about 28% of cases and distant metastasis in 27%; thus, it is considered intermediate malignancy [2, 4].

Castleman disease (CD) is a rare lymphoproliferative disorder characterized by the abnormal growth of lymphoid tissue, which presents as unicentric/oligocentric (UCD), or multicentric (MCD) disease [5, 6]. A subset of MCD is caused by human herpesvirus‐8 (HHV‐8 associated MCD), whereas HHV‐8–negative MCD cases are idiopathic (idiopathic MCD) [7]. UCD typically involves a single lymph node (unicentric) or a group of lymph nodes in the same region (oligocentric) [6], has a generally benign clinical course, and is often curable with surgical resection. In contrast, MCD affects multiple lymph node regions and is associated with systemic symptoms such as fever, night sweats, and weight loss, as well as an increased risk of secondary malignancies [8]. CD can also be classified according to the microscopic findings. The two main histological subtypes are hyaline‐vascular (HV) variant and the plasma cell (PC) variant. Other microscopic variants, such as the mixed HV/PC type and the hypervascular variant, are also recognized [7, 9]. The HV type, predominantly seen in UCD and initially described by Castleman et al. [10] displays lymphoid follicular hyperplasia with variably regressed germinal centers with prominent follicular dendritic cells, “lollipop” (radially‐penetrating) germinal center vessels, “onion‐skin” appearance of mantle zones, interfollicular proliferation of variably hyalinized vessels, and often absence of sinuses [9]. The PC variant, more commonly associated with MCD, features microscopic findings similar to those seen in the HV variant, but also displays interfollicular diffuse infiltrates of mature plasma cells and preserved sinuses [9].

FDCS associated with CD has been described in the literature, particularly with the HV type of UCD (HV‐UCD), where the hyperplastic lymphoid environment may promote the neoplastic transformation of follicular dendritic cells [4]. Herein, we report the case of a 56‐year‐old woman with FDCS arising in a background of HV‐UCD. This case highlights the diagnostic challenge that FDCS represents, particularly when it arises in an unusual location such as the parapharyngeal space.

2. Clinical Summary

The patient was a 56‐year‐old woman with no significant past medical history who presented with sudden onset of painless swelling in the right neck that had gradually increased in size over several months. Physical exam revealed extensive firm right neck lymphadenopathy at levels 2–4, as well as dry cough, bilateral ear fullness, and muffled hearing. She denied systemic symptoms such as fever, weight loss, or night sweats.

An initial CT scan of the neck with contrast revealed a 5.0 × 4.3 × 3.2 cm heterogeneously enhancing mass in the right parapharyngeal space (Figure 1A), causing mild to moderate narrowing. Multiple enlarged right‐sided cervical lymph nodes were also noted (Figure 1B). A follow‐up MRI confirmed a 4.8 × 4.0 × 2.6 cm ovoid mass in the right parapharyngeal space (Figure 1C), along with bulky right cervical lymph nodes, raising concerns for nodal metastatic disease.

Figure 1.

Representative CT and MRI findings. (A) A CT scan of the neck with contrast reveals a 3.2 × 4.3 × 5.0 cm heterogeneously enhancing mass in the right parapharyngeal space (arrow), exerting a mass effect on the oropharynx and causing mild to moderate narrowing. (B) Multiple enlarged right‐sided cervical lymph nodes are also noted, the largest measuring 2.5 × 3.2 × 4.3 cm (arrow). (C) A follow‐up MRI redemonstrates a 4.0 × 2.6 × 4.8 cm ovoid mass in the right parapharyngeal space (arrow).

A core biopsy of the right parapharyngeal mass revealed numerous variably sized atretic secondary lymphoid follicles with polarized germinal centers surrounded by intact, and occasionally expanded, mantle zones, rare germinal center twinning, occasional vascular penetration of germinal centers, and interfollicular areas with unremarkable small lymphocytes, scattered histiocytes, and plasma cells. Given the absence of overt malignancy in the core biopsy of the lymph node, the patient was initially treated with corticosteroids, which resulted in reduction of the size of the mass. However, the dry cough and ear fullness persisted.

An MRI of the neck performed 1 month after the core biopsy identified multiple enlarged right cervical lymph nodes at levels 2B, 3, 4, 5, and 6, with the largest nodal mass measuring 3.4 × 2.6 cm. A circumscribed 4.1 × 2.7 cm mass at the right base of the skull was also noted exerting a mass effect on the nasopharynx and oropharynx.

Approximately 8 months after the initial core biopsy, an excisional biopsy of a right level 3 cervical lymph node was performed, which revealed only histologic benign changes. Following this biopsy, the patient was treated again with a short course of corticosteroids, which led to some improvement in the size of the neck swelling. A subsequent PET‐CT scan of the skull base to mid‐thigh demonstrated FDG‐avid activity concerning for a malignant process in both the right parapharyngeal mass (SUV max of 7.0) and the right cervical lymph nodes (SUV max of 8.9). No other FDG‐avid sites were identified in the body. Approximately 2 months after the excisional biopsy of the cervical lymph node, the patient underwent an excisional biopsy of the parapharyngeal mass.

3. Histopathologic Findings

Microscopic examination of the parapharyngeal mass revealed subtotal replacement of a lymph node by a neoplastic diffuse infiltrate with only very focal residual nodal landmarks, including remnants of the capsule and a few primary and secondary lymphoid follicles (Figure 2). At high magnification, the neoplastic cells were medium‐sized to large, spindle‐shaped, and with indented nuclei, vesicular chromatin, conspicuous nucleoli, and ample clear cytoplasm (Figure 3A,B). These tumor cells, which accounted for > 95% of the mass, were intimately admixed with small, mature‐appearing lymphocytes without atypia (Figure 3B,C). Rare mitoses, without evidence of necrosis, were observed. In the few uninvolved areas of the lymph node, there were changes characteristic of the HV variant of CD, including sclerotic blood vessels penetrating germinal centers (“lollipop” lesions) (Figure 3D), surrounded by concentric layering of mantle zone lymphocytes (“onion‐skin” appearance) (Figure 3E), and regressed hyalinized germinal centers (Figure 3F). A few enlarged follicular dendritic cells with irregular nuclear contours were noted within some residual atretic germinal centers (Figure 3F).

Figure 2.

Representative histological images. H&E staining at low magnification shows a diffuse infiltrative process within a lymph node.

Figure 3.

Representative histological images of the excisional biopsy of the right parapharyngeal mass. (A–C) High magnification images show atypical medium‐sized and large tumor cells with spindle‐shaped morphology (A), including indented vesicular nuclei, conspicuous nucleoli, and ample clear cytoplasm (B), which are intimately admixed with small, mature‐appearing lymphocytes without atypia (C). (D–F) Areas of the lymph node not involved by the atypical spindle‐shaped cells display changes characteristic of Castleman disease, including (D) sclerotic blood vessels penetrating germinal centers (“lollipop” lesions), (E) concentric layering of mantle zone lymphocytes around germinal centers (“onion‐skin” appearance), and (F) regressed hyalinized germinal centers with dysplastic follicular dendritic cells.

Immunohistochemical staining demonstrated that the neoplastic spindle‐shaped cells were diffusely and strongly positive for CD21 and CD23, weakly positive for CD35, and partially positive for D2–40 and p63 (Figure 4), while negative for CD34, CD31, ERG, TFE3, STAT6, ALK1, PAX8, AE1/AE3, INSM1, p40, Iba1, desmin, HMB45, SMA, SSTR2, HHV‐8, and in situ hybridization for EBER. The Ki‐67 proliferative index was < 10%. Only rare scattered TdT‐positive small lymphoid cells were observed, without evidence of overt indolent T‐lymphoblastic proliferation.

Figure 4.

Representative immunohistochemical staining images of the excisional biopsy of the right parapharyngeal mass. (A–C) Immunohistochemical staining of the tumor cells demonstrates diffuse and strong positivity for CD21 (A) and CD23 (B), and focal positivity for D2‐40 (C), confirming the follicular dendritic cell origin of the tumor cells. (D) The Ki‐67 proliferative index is less than 10%.

Flow cytometric analysis of the parapharyngeal mass revealed a predominant population of lymphocytes (99.0% of total events) and rare monocytes (0.7% of total events) without overt immunophenotypic evidence of B‐cell clonality, an abnormal T‐cell or NK‐cell immunophenotype, or the presence of blasts. Fluorescence in situ hybridization (FISH) for ALK rearrangements with dual‐color break‐apart probes (Vysis ALK breakapart FISH probe kit, Abbott, Chicago, Illinois) was negative. Based on these findings, a diagnosis of FDCS arising in a background of HV‐UCD was established.

A month later, the patient underwent a right cervical dissection of lymph nodes in levels 2A, 2B, 3, and 4. Histopathological examination of these lymph nodes revealed features of HV‐UCD without any evidence of FDCS.

4. Discussion

FDCS is a rare neoplasm of follicular dendritic cell origin that typically presents in lymphoid tissue but can also involve extranodal sites [2, 3]. The association between FDCS and CD, particularly the HV‐UCD, is being increasingly recognized, although it remains rare [2, 3, 4]. In these cases, the hyperplastic lymphoid environment characteristic of HV‐UCD is thought to promote the transformation of follicular dendritic cells and ultimately the development of FDCS [4]. Notably, approximately 25% of HV‐UCD cases exhibit atypical follicular dendritic cells within germinal centers and interfollicular areas, often multinucleated and expressing CD21 and CXCL13 [11]. These findings suggest that proliferative or dysplastic changes in follicular dendritic cells may serve as a precursor to neoplastic transformation. However, the frequency of FDCS‐CD association appears to vary by anatomical site. A review of 20 FDCS cases in the parapharyngeal space found CD in only one (5%) [12], compared to 18.6% in the mediastinal FDCS cases [13]. Although these findings suggest potential site‐specific differences, the small sample sizes of available studies preclude definitive conclusions.

Recent genetic studies provide further insights into the potential pathogenesis of HV‐UCD and its relationship with FDCS [14]. Whole‐exome sequencing has identified recurrent PDGFRB mutations, particularly the p.Asn666Ser alteration, in 17% of HV‐UCD cases. These mutations have not been detected in MCD or other hematologic malignancies, suggesting a specific role in HV‐UCD pathogenesis [14]. Since follicular dendritic cells are a stromal component of lymphoid follicles, genetic alterations in the stromal microenvironment, such as PDGFRB mutations, may contribute to their neoplastic transformation and development of FDCS. This aligns with prior observations that atypical follicular dendritic cells are present in a subset of HV‐UCD cases, potentially representing an early stage in tumorigenesis.

Our patient's initial presentation of a painless neck mass without systemic symptoms, along with the nonspecific imaging findings, highlights the difficulty of distinguishing between reactive and neoplastic processes in CD‐associated FDCS. Despite the benign nature of CD, its ability to serve as a nidus for neoplastic transformation should not be underestimated, particularly when imaging or clinical findings raise the suspicion of an underlying malignancy.

The diagnosis of FDCS is challenging due to its rarity and its overlapping histological features with other malignancies. This challenge is further complicated by a presentation in an atypical location such as the parapharyngeal space, which is seen in only 2% of all patients with FDCS [2]. Consequently, the diagnosis of FDCS is occasionally delayed or never established correctly [15]. Up to 58% of extranodal FDCS are misdiagnosed as undifferentiated carcinoma, meningioma, or paraganglioma [4, 16, 17]. Accurate diagnosis relies on a high index of suspicion based on the presence of a diffuse infiltrate of atypical cells and the demonstration by immunohistochemistry of expression of follicular dendritic cell markers such as CD21, CD23, and CD35, which are essential for differentiating FDCS from soft tissue sarcomas and inflammatory myofibroblastic tumor [4, 18, 19].

Our case also highlights the challenges in management and diagnosis of FDCS associated with CD. Initial core biopsy results were nonspecific, reflecting the relevance of a thorough diagnostic workup, including advanced imaging modalities and repeat tissue sampling with an excisional biopsy when clinical suspicion remains high. The clinical management of FDCS is challenging due to the rarity of these cases. Complete surgical excision, as performed in our patient, remains the gold standard treatment for localized FDCS and unicentric/oligocentric CD [20, 21, 22]. Although postsurgical radiation and/or chemotherapy have been used, there is no consensus on their effectiveness [20, 21]. In our patient, the absence of FDCS in the subsequent lymph node dissection suggests that the surgical intervention successfully achieved local control of the disease; however, close follow‐up is required for potential recurrence or metastasis [4, 17]. In a review of 12 patients with FDCS involving the parapharyngeal space, nine developed local recurrence, lung metastasis, or died within 3 years, indicating the poor prognosis associated with this disease [17].

A limitation of our case report is the relatively short follow‐up period, which limits our ability to determine long‐term outcomes, including recurrence or metastasis. Extended follow‐up will be crucial for gaining further insights into the clinical course and prognosis of FDCS associated with HV‐UCD.

In conclusion, our case contributes to the growing body of literature on the association between FDCS and HV‐UCD and highlights the diagnostic and therapeutic challenge that FDCS represents, especially when it arises in an uncommon location and presents in association with CD. A multidisciplinary approach, including surgical excision and careful histopathologic evaluation, remains crucial for improving patient outcomes.

Disclosure

A separate case report focusing on a novel surgical approach using robotic surgery for this patient has been submitted by another group, including the primary surgeon. As our manuscript primarily focuses on the histopathologic and diagnostic aspects, we consider the scopes of the two reports to be distinct and do not regard this as duplicate publication.

Ethics Statement

According to our Institutional Review Board (IRB) at the Hospital of the University of Pennsylvania, this case report does not meet the definition of human subjects research requiring IRB review. This study was conducted in accordance with the Declaration of Helsinki 1975.

Conflicts of Interest

The authors declare no conflicts of interest.