Thoracic Follicular Dendritic Cell Sarcoma

Abstract

Follicular dendritic cell sarcoma (FDCS), which makes up 0.4% of all soft tissue sarcomas, is an uncommon low-grade malignant tumor that develops from follicular dendritic cells in germinal centres of lymphoid tissue. The pathophysiology of FDCS is unknown. It can arise in both nodal and extra-nodal areas harboring FDCs and is commonly diagnosed in middle-aged individual who are in their fifth decade of life. The extranodal lymph node locations include the liver, spleen, and GI tract, where FDCS occurs most frequently (79.4%). It is quite uncommon to develop a pulmonary follicular dendritic cell sarcoma. At the microscopic scale, the FDCS displays a wide range of architectural patterns, including fascicular, storiform, whorled, and diffuse patterns. It is frequently not considered a differential diagnosis for a spindle cell neoplasm because of its rarity, misdiagnosis, and diagnostic difficulties. There is no effective treatment for this uncommon tumor, and the value of adjuvant therapy is still debatable. The median survival period following surgery for thoracic FDCS is approximately 4.41 years, with a 5-year recurrence-free survival rate of 47%. Patients diagnosed with localized disease exhibit a 5-year overall survival rate of 55%, whereas those with metastatic disease have a lower rate of 38%.

1. Introduction

Tumors related to macrophage/monocyte and dendritic cell morphologies are collectively referred to as histiocytic neoplasms. They include both benign (e.g., Erdheim-Chester illness, Langerhans cell histiocytosis/LCH) and neoplastic (interdigitating dendritic cell sarcoma, histiocytic sarcomas, indeterminate cell sarcomas, FDCS, Langerhans cell sarcoma) conditions [1, 2]. FDCS, a unique and distinctive low-grade sarcoma showing spindle-shaped cells grouped in a whorled pattern, usually manifests as a slowly growing asymptomatic mass. Numerous examples have been reported to date since Monda and Rosai first identified primary malignant neoplasms (PMN) that had traits of follicular dendritic cells (FDC) in 1986 [3]. Perez-Ordonez and Rosai’s 1998 publication was the first in-depth analysis of FDC tumors [4]. Among the lymph node groups, the most affected ones include cervical, axillary, mediastinal, and intra-abdominal sites, whereas the lung, spleen, and liver are the most affected extranodal sites [5, 6]. Although once thought to be a low-grade malignancy, FDCS shows a significant malignant potential. At least, 40% of cases have local recurrence and 25% of cases have metastatic spread. Because of the short follow-up durations in numerous researches in the literature, even these numbers are an understatement [7]. However, due to their rarity compared to spindle cell sarcoma or carcinoma, spindle cell tumors do not necessarily raise concerns for FDCS when they appear as extranodal neoplasms. Moreover, the extensive variety of morphological features in FDCS poses a greater challenge in its diagnosis. It is worth noting that the reported misdiagnosis rate for FDCS in extranodal sites can be as high as 58%, affirming the idea that cases of FDCS have likely remained undetected [8].

2. Epidemiology

Follicular dendritic cell sarcoma (FDCS) is an exceptionally uncommon tumor, and its occurrence within the thoracic region is even rarer. Nevertheless, the precise incidence remains undetermined [9]. Literature consists of a few cases, less than 50 (Table 1). FDCS comprise <0.4% of soft tissue sarcomas. In a meta-analysis of 462 FDCS cases, the median age (range = 8–90 years) of occurrence was fifth decade of life with no gender predilection [6]. FDCS’s unusual and distinctive inflammatory pseudotumor-like variant tends to affect women more than other FDCS variants [25]. The fact that several cases have been documented from East Asia raises the idea that FDCS may be more common among some ethnic groups or regions [6].

Sl no	Authors	Type of Report	Site of FDCs	Age (years)	Gender	Clinical Presentation	Treatment given	Outcome
1	Fassina et al. [10]	Case report	Mediastinal mass	48	Male	Chest pain	NA	NA
2	Shah et al. [11]	Case report	Left lung mass	33	Male	Dry cough	NA	NA
3	Leipsic et al. [12]	Case report	Middle Mediastinum	43	Male	Chest Pain	NA	NA
4	Dening et al. [13]	Case report	Right lower lobe nodule	64	Female	Cough and breathlessness	NA	NA
5	Bushan et al. [14]	Case report	Anterosuperior mediastinal mass	34	Male	Fever and malaise	Surgery followed by chemoradiation	No recurrence at 6 months Follow up.
6	Lee et al. [15]	Case report	Posterior mediastinum	63	Male	Dry cough, breathlessness	Surgery	NA
7	Butler et al. [16]	Case report	Right main bronchus lesion	19	Female	Cough, fever, dyspnoea	Surgery with lymphadenectomy	No recurrence at 2 years Follow up
8	Wang et al. [17]	Case report	Lung parenchyma	76	Female	Dyspnoea	Surgery	Expired
9	Miyoshi et al. [18]	Case report	Posterior Mediastinum	16	Female	Incidental finding	Surgery	No recurrence at 2 years Follow up
10	Ulises et al. [19]	Case report	Posterior mediastinum	59	Male	Oral ulcers/ pemphigus	Complete excision with 1 cycle of Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone.	No recurrence at 2 months Follow up
11	Xu et al. [20]	Case report	Right lateral chest wall	44	Male	Chest wall pain	Tumor resection with lymphadenectomy of level I axillary nodes.	No recurrence at 18 months Follow up.
12	Ilonen et al. [21]	Case report	Posterior Mediastinum	57	Male	Incidental finding	Chemotherapy (Doxorubicin, Ifosfamide, Mesna), Surgery, Radiotherapy	No recurrence at 2 years Follow up
13	He et al. [22]	Case report	Right lower lobe mass	64	Female	Incidental finding	Surgery	No recurrence at 6 months follow-up
14	Li et al. [23]	Case report	Right hila of Lung	29	Male	Cough, expectoration	Surgery; Tacrolimus; Cyclosporine	Symptomatic improvement at 1 month
15	Vinay et al. [24]	Case report	Left upper lobe mass	34	Male	Chest Pain	Surgery	NA

Table 1.

Summary of extranodal follicular dendritic cell sarcomas reported in the thorax (according to year of publication).

3. Pathogenesis

3.1 Origin and function of FDCs

Follicular dendritic cells, also known as dendritic reticulum cells, is a vital component in B-cell follicles. Their primary function is to gather, hold, and deliver antigens to nearby B cells. They are present in lymphoid follicles both primary and secondary [26], and their origin is mesenchymal [27]. Follicular dendritic cells were initially described as ‘embryonal non-phagocytic reticulum cell’ in Maximow’s 1927 illustration of B follicles in human lymph nodes [28]. Under electron microscopy, FDCs exhibited interdigitations and extension of their plasma membranes, closely interacting with other germinal centre cells. This shows their potential significance in the germinal centre response, which has now been proven by a wide range of experiments [29]. Within the immune system, histiocytic and dendritic cells play a vital role by aiding in phagocytosis, processing antigens, and presenting these antigens to B and T cells. FDCs are nonlymphoid, nonphagocytic immune system accessory cells that are crucial for antigen presentation and controlling germinal centre reactivity [7, 30, 31, 32]. They create a dense network inside lymphoid follicles.

A key function of the FDC is luring B and T cells to B follicles through the secretion of CXCL13 (C-X-C chemokine motif ligand 13) and the interaction with B cells through integrins and their appropriate receptors. Immunocomplexes that are ‘exposed’ to germinal centre B-cells border the FDC cell membrane. By releasing numerous B-cell growth factors, mainly B activating factor (BAFF), FDC helps B cells survive and mature. During the germinal centre reaction, FDC plays a role in the apoptosis and phagocytosis of B cells with low-affinity B-cell receptors, a process mediated by Mfge8 produced by FDC [33]. FDCs can impact the adaptive immune response by recognizing environmental innate stimuli, such as microbial lipopolysaccharides, through Toll-like receptor 4 (TLR4). This recognition triggers TLR signaling, which in turn, promotes the synthesis of proteins such as CXCL13, TGF-1, and BAFF that contribute to B cell survival, recruitment, and class-switch recombination (Figure 1) [34].

Figure 1.

By secreting CXCL13 (C-X-C motif chemokine ligand 13) and connecting with B cells via cognate receptors and integrins, FDC plays a critical role in attracting T and B cells to B follicles. Immunocomplexes that are ‘exposed’ to germinal Centre B cells border the FDC cell membrane. FDC promotes B-cell survival and maturation by releasing a number of B-cell growth factors, including BAFF (B-activating factor). The germinal Centre response, which is mediated by Mfge8 generated by FDC, results in the apoptosis and phagocytization of B-cells with low-affinity B-cell receptors. FDC can influence the acquired response by detecting, through TLR-4 (toll-like receptor 4), ambient innate stimuli (such as microbial lipopolysaccharides), which leads to TLR signaling that stimulates the synthesis of proteins (CXCL13, TGF-1, and BAFF) and promote B cell survival, recruitment, and class-switch recombination.

Inflammatory pseudotumor-like fibroblastic/follicular dendritic cell neoplasm is an uncommon neoplasm that arises from dendritic cells. Within the World Health Organization (WHO) classification of hematological and lymphoid organ cancers, sarcoma is recognized as a unique entity. There are unique clinical characteristics of this tumor, including a predilection for young to middle-aged women, an occurrence in the liver or spleen, and the presence of Epstein-Barr virus (EBV) positive neoplastic cells [35]. This could be explained by EBV entering these cells due to FDCs expressing CD21, which functions as a receptor for the virus. Additionally, FDCs have been linked to myasthenia gravis, paraneoplastic pemphigus, and Castleman disease. Epidermal growth factor receptor is expressed in FDCS and non-neoplastic FDCs of Castleman disease, which may encourage the persistence of FDCs and allow for mutations that could lead to FDCS [6, 36].

3.2 Morphology of FDC

Long dendritiform processes and an abundance of poorly defined eosinophilic cytoplasm are characteristics of FDC. The nuclear membrane is clearly defined, the chromatin is finely scattered, and the nucleus is big, ovoid to spherical in shape with a tiny eosinophilic nucleolus. Typically, bi- or multinucleated FDC exhibit a ‘kissing’ pattern of nuclear molding and overlap [37]; these characteristics make it easier to identify FDC in cytological smears. On electron microscopy, the FDC’s cytoplasmic extensions are coated in an amorphous substance that resembles immunocomplexes and form a complex network connected by desmosomes [38]. Various FDC markers, including CD21 (C3d receptor), CD23, CD35 (C3b receptor), R4/23, DRC-1 (R4/25), CNA.42, Ki-M4p, Ki-M4, and Ki-FDC1p, effectively highlight the dendritic characteristics of FDCs on both frozen and paraffin sections. Compared to other malignant histiocytic tumors, FDCS exhibits a unique immunophenotype.

The mechanism of acquiring neoplastic potential by these FDCs is still not well studied, and more research in this is needed. As such, no universal driver translocation or mutation has been identified by comprehensive genomic investigation. A wide range of chromosomal instability, dysregulation of cell cycle progression, activation of nuclear factor kappa beta (NF-kB), mitogen-activated protein kinase (MAPK), and broad immunological evasion are also related to FDCS [39, 40]. BRAF V600E mutations, present in many histiocytic diseases and are affecting 20% of people with FDCS, might be more prevalent in the inflammatory form [41]. Epstein-Barr virus is regularly linked to the inflammatory version [42], while human herpesvirus 8 (HHV-8) is not known to be involved [43].

Association with mutations in TP53, PTEN, and NF-kB pathways has been noted in the literature [40, 44]. The expression of PD-L1 and PD-L2 and copy number increases at 9p24 implying immune surveillance escape may be involved in tumor development [40]. EZH2 was found to be overexpressed in FDCS tumors in 67% of cases, whereas p-ERK1/2 (phospho-extracellular signal-related protein kinases 1 and 2) were robustly expressed in 80% of cases [45]. Notably, nearly all FDCS cases have elevated levels of the epidermal growth factor receptor (EGFR), a hallmark of epithelial malignancies. The survival and expansion of FDCS cells may depend on EGFR signaling, which is triggered by ligands in the microenvironment [46].

4. Clinical presentation

FDCS does not have a gender predilection. It primarily occurs in adults, typically appearing at a median age of 49 years ranging from 8 to 90 years. There have been very few reported instances of this condition in pediatric patients [6]. FDCS has the potential to affect various anatomical regions. A higher frequency of involvement is seen in extranodal sites (79.4%), particularly in the liver, spleen, gastrointestinal tract, tonsil/adenoid, mediastinum, and lungs compared to nodal involvement (15%) [38]. FDCS frequently appears as a gradually developing mass that can either be symptom-free or accompanied by discomfort. The variant resembling an inflammatory pseudotumor (IPT) displays distinctive clinical attributes. Females are more likely to be impacted, as is the existence of EBV infection inside the tumor cells with the involvement of the liver or spleen and frequent systemic symptoms such as fever, malaise, and weight loss [22, 42, 47, 48, 49, 50, 51]. FDCS is found to be associated with many conditions such as paraneoplastic pemphigus with or without myasthenia gravis [52, 53, 54, 55, 56], lymphoproliferative conditions such as Castleman Disease-Hyaline vascular type (HV-CD) [57] and Sjogren’s syndrome [58] manifesting predominantly in extranodal sites. FDCS is also observed in conjunction with neoplasms such as lymphomas, leukemias, and malignant neoplasms of epithelial or melanocytic origin [38].

5. Differential diagnosis

Because of histopathological diversity and the potential to manifest at various locations, FDCS can be mistaken for various types of tumors and even inflammatory processes. The reported rates of misidentification range from 30 to 58% especially when it arises from extranodal sites [59, 60]. It might be mistaken with interdigitating dendritic cell sarcoma (IDCS), Langerhans cell histiocytosis (LCH), Kaposi sarcoma, spindle cell thymoma, metastatic melanoma, metastatic carcinoma, inflammatory myofibroblastic tumor, pleomorphic sarcoma, solitary fibrous tumor, and gastrointestinal stromal tumor (GIST).

IDCSs are uncommon tumors believed to originate from interdigitating dendritic cells within the nodal paracortex. They are typically found in lymph nodes or the spleen and are associated with an aggressive nature. Histologically indistinguishable from FDCS, IDCS generally displays a higher level of atypical features and lacks the bundled structures and spiral growth pattern commonly observed in most cases of FDCS that necessitates immunohistochemical studies for a definite diagnosis. IDCS is positive for S100, negative or focally positive for clusterin. LCH comprises oval-shaped Langerhans cells, characterized by their nuclei exhibiting grooves, folds, or indentations. These nuclei have fine chromatin, inconspicuous nucleoli, and thin nuclear membranes. The cells possess moderately abundant cytoplasm that appears slightly eosinophilic. Langerhans cells are typically positive for CD1a and langerin. In the case of Kaposi’s sarcoma, the condition is characterized by atypical spindle-shaped cells that form slit-like vascular spaces containing red blood cells. Immunohistochemistry (IHC) reveals the presence of positive cells for HHV8.

Spindle cell thymoma is commonly located in the anterior mediastinum. It is characterized by the presence of spindle-shaped cells exhibiting a growth pattern that ranges from fascicular to whorls. These spindle cells test positive for keratin (AE1/AE3). In metastatic carcinoma, the epithelioid cells are found in sheets, clusters, or as single cell with pronounced nuclear atypia. These cells also show positivity for keratin (AE1/AE3). Metastatic melanoma exhibits varying cytology, which may include epithelioid or spindle-shaped cells displaying nuclear atypia and prominent nucleoli. Additionally, the cytoplasm of these cells may contain brown pigment (melanin). IHC in metastatic melanoma shows positivity for S100 and MelanA. Inflammatory myofibroblastic tumor (IMT) comprises spindled myofibroblasts and fibroblasts with bland nuclei. IMT cells are positive for anaplastic lymphoma kinase-1 (ALK1). Pleomorphic sarcoma is composed of pleomorphic cells that exhibit a diverse range of cytological characteristics, which can encompass spindled, plasmacytoid, epithelioid, or multinucleated forms. Notably, this type of sarcoma does not demonstrate positivity for clusterin, CXCL13, CD21, CD23, and CD35. Positivity for DOG1 and STAT6 are seen in solitary fibrous tumors that are usually negative in FDCS [61, 62]. In FDCS, tumor markers CD34 and CD117, typically used to identify gastrointestinal stromal tumors (GIST) tend to show negative results [38, 62].

6. Diagnosis

6.1 Histopathology

Macroscopically, FDCS appears as a gray-yellow firm mass with a well-circumscribed surface. Necrosis can be visible in few areas. This tumor has occasionally been confused with lymphoma, mesenchymal tumors such as gastrointestinal stromal tumors or solitary fibrous tumors, or poorly differentiated carcinoma, depending on the site of its presentation. The diagnosis of FDCS is consistently confirmed through immunohistochemistry, and it often requires the use of multiple FDC markers because the loss of antigens is a common occurrence [37]. Limited studies have described the EBV-associated FDCS. Based on the number and growth pattern of EBV, the degree of lymphoplasmacytic infiltration, and characteristics of the intratumoral blood vessels, the tumors were classified into the following groups: classic type (53.8%), lymphoma-like subtype (38.5%), and hemangioma-like subtype (7.7%) [63].

Most FDCSs are considered low-grade sarcomas. Histological sections reveal a spindle cell proliferation exhibiting diverse architectural arrangements with the most common being storiform or whorled (reminiscent of meningiomas) bundles (Figure 2A and B), fascicles (Figure 2C and D), trabecular formations, or widespread sheets. Multiple growth patterns are frequently observable within the same tumor. Abundant lymphocytes are often dispersed throughout the tumor, occupying the spaces between tumor cells and the areas around blood vessels. Some cases exhibit a predominance of B-cell lymphocytes, whereas others feature a preponderance of T-cell lymphocytes. Occasional multinucleated cells, albeit in small quantities, may be present, resembling Warthin-Finkeldey giant cells. These cells typically exhibit indistinct boundaries, resulting in a syncytial appearance. Their cytoplasm is moderately abundant, with a pale eosinophilic hue and the possibility of having a fibrillary texture. Tumor cells typically feature elongated or ovoid nuclei characterized by a thin nuclear membrane, vesicular or granular chromatin, and small nucleoli (Figure 2E and F). Nuclear pseudoinclusions are sporadically observed, and their frequency may increase following radiation therapy. The mitotic rate is generally low, ranging from 0 to 10 mitoses per 10 high-power fields, and necrosis is infrequently detected. The proliferation index, typically represented by Ki-67, typically falls within the range of 1–25% (Figure 3D). This index can be elevated in cases demonstrating clear atypia [63]. As lymphocytes, including both B and T cells as well as plasma cells, are often commingled with tumor cells in IPT-like variants, recognizing tumor cells can be challenging [38]. The histological features of this disorder may include prominent nuclear atypia, including irregular nuclear membranes and hyperchromatic nuclei, and high mitotic counts ranging from 11 to 35 mitoses per 10 high-power field. Additionally, extensive necrosis may be present. These high-grade features are typically linked to lesions located in deeper tissue layers and are indicative of a higher likelihood of recurrence or metastasis [62].

Figure 2.

Histological sections display a cellular arrangement featuring elongated to spindle-shaped cells with eosinophilic nuclei, interspersed among lymphocytes, eosinophils, and plasma cells (Image 2A & B). The spindle cells are arranged in irregular bundles, and the cytoplasm appears pale or eosinophilic, with nuclei exhibiting moderate cytoplasmic cells organized in fascicles [40× (Image 2C & 2D), 100× (Image 2E & 2F)].

Figure 3.

FDCS cells showing IHC positivity to CD 21 (Image 3A & 3B), podoplanin (Image 3C), and Ki-67 (Image 3D). Negative for CD 34 (Image 3E) and CD 45 (Image 3F).

6.2 Immunophenotype

Diagnosing FDCS typically necessitates support from immunohistochemistry, and the utilization of multiple FDC markers is often imperative due to the frequent occurrence of antigen loss. Tumor cells exhibit varying degrees of positivity for CD21 (as shown in Figure 3A and B) and CD23, as well as CD35. In contrast, clusterin, podoplanin (Figure 3C), and CXCL13 consistently display higher expression levels, demonstrating high specificity in distinguishing them from tumors that may resemble FDCS. As a marker for FDCS, podoplanin (D2-40) exhibits high sensitivity and strong membrane staining [62]. EGFR expression is frequently detected in FDCS, although its specificity is relatively limited. Reports indicate that FDCS may exhibit positive staining for epithelial membrane antigen, CD68, S-100 protein, and, albeit rarely, cytokeratin and CD20 [37]. On occasion, reports have indicated reactivity in FDCS for S100, smooth muscle actin, CD68, and EMA. FDCS usually yields negative results in tests for CD1a, langerin, CD34 (Figure 3E), CD45 (Figure 3F), lysozyme, CD163, myeloperoxidase, CD3, CD79a, cytokeratin, MART1, and HMB45 [38]. In recent advancements, FDC-secreted protein (FDCSP), SSTR2A, and serglycin (SRGN) have surfaced as valuable markers for the purpose of identification [64].

6.3 Electron microscopy

In the realm of electron microscopy, characteristic diagnostic elements in FDCS consists of elongated and intricately interlocking cytoplasmic extensions, occasionally forming a maze-like configuration, as well as desmosome-like connections, whereas cytoplasm typically exhibits limited organelles, notably lacking Birbeck granules and lysosomes [62].

7. Genetics and molecular findings

Vermi and colleagues in their FDCS series examined the prevalent genetic variations in EGFR (specifically substitutions in exons 18 and 21, as well as deletion of exon 19), KRAS (exon 1), NRAS (exons 1 and 2), and PI3KCA (exons 9 and 20). Notably, no mutations in these genes were detected in any of the cases studied. In an FDCS cell line, the EGFR pathway was activated, showing that local cognate ligands are involved, rather than oncogenic mutations [46]. Genomic alterations found in FDCS includes single nucleotide variations, loss/deletions, amplification of genes, copy number gains, and fusion rearrangements [39]. Five unique translocations leading to fusion proteins were identified in four cases: MAP3K1-GCOM1, NTRK1-PDIA3, TYK2-ATPAF2, HDGRFP3-SHC4, and BPTF-WDR72 [38]. FDCS is distinguished by genetic modifications affecting genes within the NF-κB regulatory pathway, encompassing copy number loss or missense mutations in TRAF3, SOCS3, TNFAIP3, and NFKBIA [65]. Additionally, mutated cell-cycle regulators leading to recurrent homozygous deletions of tumor suppressor genes CDKN2A, RB1, and CYLD and BIRC3 has also been observed [39]. Go et al. employed direct Sanger sequencing and peptide nucleic acid clamp quantitative polymerase chain reaction to ascertain the presence of mutations and detected BRAFV600E mutation in 18.5% (5 out of 27) of FDCS cases [41]. PDGFRB N666S mutation occurring in HV-CD was found in FDCS patients with history of Castleman disease. While PD-L1 expression is frequently observed in FDCS, a substantial number of cases within a comprehensive dataset exhibited a low mutational burden, measuring less than six mutations per mega base [65]. This discovery raises doubts about the potential effectiveness of immunotherapy as a treatment approach for this neoplasm [38].

8. Treatment

Various approaches have been addressed such as surgery, chemotherapy, tyrosine kinase inhibitors, and radiotherapy because FDCS lacks specific treatment guidelines. Surgery remains the mainstay of treatment in FDCS patients with localized disease. Systemic therapies used in the metastatic setting include doxorubicin, ifosfamide, or gemcitabine-based regimens, which provided prolonged stable disease [66]. Numerous regimens incorporating gemcitabine have been experimented. The rate of complete responders was 42% for those undergoing gemcitabine combined with taxotere therapy, as reported by Jain et al. [67]. In contrast, gemcitabine and taxane therapy achieved an impressive 80% complete response rate, with a notable median response duration of 13.4 months in docetaxel combination therapy, as highlighted by Conry et al. [68]. Various systemic treatment protocols have been explored, encompassing doxorubicin and ifosfamide; vincristine, doxorubicin, and cyclophosphamide (VAC); ifosfamide and etoposide with or without carboplatin (ICE/IE); cyclophosphamide, doxorubicin, vincristine, and prednisone; as well as gemcitabine, either alone or in combination with docetaxel, carboplatin, and irinotecan. A number of patients received tyrosine kinase inhibitors, including sorafenib, sirolimus, ridaforolimus, sunitinib, brivanib, imatinib, cabozantinib, and pazopanib, which resulted in extended positive outcomes, both when administered as a first-line treatment or in subsequent therapy. Research indicates that the maturation and activation of dendritic cells were impeded by vascular endothelial growth factor (VEGF). However, this inhibitory effect was counteracted using VEGF inhibitors, including bevacizumab, sorafenib, and sunitinib [69]. Enhanced comprehension of the molecular characteristics and causative factors behind this tumor could pave the way for innovative therapeutic approaches.

9. Outcome

The pooled analysis of published case reports indicated that patients who were administered adjuvant radiotherapy (RT; 51 in total) did not experience improved overall survival (OS) when compared to those who underwent surgery alone (78 in total) [6]. In FDCS, pleomorphism or prominent nuclear atypia, a size of 6 cm or more, five or more mitoses per 10 high-power fields, and coagulative necrosis on microscopy are associated with an unfavorable prognosis [70]. In the study conducted by Saygin et al., they documented 2-year survival rates of 82% for early-stage cases, 80% for locally infiltrated tumors, and 42% for cases with distant metastasis [6]. In the study conducted by Gounder M et al., it was observed that the median overall survival (OS) exhibited significance difference among patients with localized disease (9.8 years), in contrast to individuals with metastatic or recurrent disease (2.69 years). Median survival in thoracic FDCS was 4.41 years, and the 5-year overall survival was 0.47. Local recurrence or metastasis has been observed in one-third of the diagnosed FDCS cases. The 5-year survival rate for individuals diagnosed with localized disease is 55%, while it drops to 38% for those with metastatic disease [66].

10. Conclusions

The thoracic extranodal FDCS will probably continue to be an underappreciated tumor. Thoracic FDCs contains several characteristic histological features that should serve as an indication to include the tumor in the differential diagnosis and help avoid misdiagnosis. Recognition needs a high index of suspicion, although thoracic FDC sarcoma has a high number of pathological features. The detection of FDC sarcomas should be aided by a greater understanding of their morphologic spectrum and the proper immunostains (D2-40 and clusterin) for differentiation as it is extremely similar to various cancers with histiocytic or dendritic origin. Given this neoplasm’s substantial potential for recurrence and metastatic spread, accurate characterization is essential. For management aspect, at present, there are no clear indications or guidelines for surgical treatment alone, adjuvant chemotherapy, or radiotherapy in the case of thoracic FDCS. It is challenging for any institute to amass sufficient knowledge on the proper therapy of these patients because of the low prevalence of this condition. Future efforts at their identification, a more thorough characterization of their clinical behavior; potential causal linkages should benefit from a greater understanding of their morphologic spectrum and the appropriate application of FDC markers for any unusual-appearing tumors.

Acknowledgments

Dr. Maria Paul (Senior Resident, Department of Anaesthesiology and Critical Care, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi) sketched the image showing how follicular dendritic cells function (Figure 1), and I would like to extend my deepest gratitude to her.

Conflict of interest

None of the authors have any conflict of interest.

Abbreviation

FDC	follicular dendritic cell
FDCS	follicular dendritic cell sarcoma
LCH	langerhans cell histiocytosis
PMN	primary malignant neoplasm
EBV	Epstein-Barr virus
HHV-8	human herpesvirus 8
CXCL13	C-X-C motif chemokine ligand 13
BAFF	B activating factor
TLR4	toll-like receptor 4
NF-kB	nuclear factor kappa beta
MAPK	mitogen-activated protein kinase
EGFR	epidermal growth factor receptor
IPT	inflammatory pseudotumor
HV-CD	hyaline-vascular subtype of Castleman disease
IDCS	Interdigitating Dendritic Cell Sarcomas
GIST	gastrointestinal stromal tumor
IMT	inflammatory myofibroblastic tumor
ALK1	anaplastic lymphoma kinase-1
FDCSP	FDC secreted protein
SRGN	serglycin
VAC	vincristine, doxorubicin, and cyclophosphamide
ICE/IE	ifosfamide and etoposide+/−carboplatin
VEGF	vascular endothelial growth factor
OS	overall survival