Background
Follicular dendritic cell sarcoma (FDCS) is a rare malignancy that originates from follicular dendritic cells featuring antigen-presenting activities [
1]. Although the tumor has been found in both lymph nodes and extranodal sites, it is very scarce in the mediastinum, with approximately 40 cases so far reported in the English literature [
2‐
32]. The clinical manifestations, radiological and pathological features of the tumor remain to be concluded. Due to potential under-recognization of mediastinal FDCS in clinicians and pathologists, it happens to be misdiagnosed or missed, especially on core needle biopsy, which may lead to a completely different treatment plan.
In this study, we presented detailedly 3 cases of mediastinal FDCS in our clinic practice, including core needle biopsy and resected specimens. Interestingly, our examination revealed that the morphology of core needle biopsy of 2 subjects were highly similar to those of classical Hodgkin’s lymphoma (CHL) and, therefore, had a high likelihood of misdiagnosis. Meanwhile, we reviewed 40 cases of mediastinal FDCS reported previously to explore their clinicopathological characteristics, and paid particular attention to the diagnostic difficulties and potential pitfalls in the preoperative biopsy. Furthermore, we analyzed, for the first time, the factors correlated to adverse prognosis of the tumor.
Methods
Clinical samples
We retrieved our pathological archives from 2006 to 2017 in 3 hospitals affiliated to the Third Military Medical University and Chongqing University Cancer Hospital, 3 cases of mediastinal FDCS were found. Case slides were reviewed again by 2 independent pathologists to confirm the diagnosis. Related clinical information was from the hospital medical records. Preoperative radiologic images were verified by radiologist in our hospital. Follow-up information was obtained by tracing the regular review of the patients.
Histological examination
The 10% neutral buffered formalin-fixed, paraffin-embedded tissue blocks were cut into 4-μm-thick sections for hematoxylin and eosin (HE) staining and light microscopy.
Immunohistochemistry
The immunohistochemical detection was performed on the automatic immunohistochemical staining device (BenchMark
XT, Roche), and the antibodies were listed below in Table
1. The known positive sections were used for positive controls, and the phosphate buffer saline (PBS) buffer solution was used for negative control.
Table 1
Antibodies used for immunohistochemical staining and results
CD21 | EP64 | ZSGB | + | + | + |
CD23 | EP75 | ZSGB | + (Focal) | + (Focal) | + |
CD35 | EP197 | ZSGB | + | + | – |
CXCL-13 | None | ZSGB | + | + | – |
D2–40 | D2–40 | ZSGB | + | – | + |
CD3 | EP41 | ZSGB | – | – | – |
CD20 | EP7 | ZSGB | – | – | – |
CD30 | EP154 | ZSGB | + (scattered) | – | – |
CD15 | MMA + BY87 | ZSGB | – | / | – |
S-100 | 4C4.9 | ZSGB | – | – | – |
PLAP | EP194 | ZSGB | / | + (Weak) | / |
SALL4 | 6E3 | ZSGB | / | – | / |
CK | AE1/AE3 | ZSGB | – | – | – |
P63 | UMAB4 | ZSGB | – | – | – |
SMA | 1A4 | ZSGB | + (Focal) | / | – |
Desmin | D33 | ZSGB | – | / | – |
ALK | OTI1H7 | ZSGB | – | / | / |
EBV-LMP-1 | CS1–4 | ZSGB | – | – | – |
Ki-67 | MIB1 | ZSGB | 10% | 30% | 15% |
EBV-encoded RNA (EBER) in situ hybridization (ISH)
ISH for EBER was performed in 3 cases using a detection kit (Zhong Shan Golden Bridge, Beijing, China). The brown signal on the nuclei of the tumor cell was defined as a positive reaction. The tissue of nasopharyngeal carcinoma was used for positive control, and the reactive hyperplasia of the lymph node was used for negative control.
Literature review
Mediastinal FDCS cases reported in English literature (before December 31, 2017) were retrieved by using PubMed, the references of which were also studied, so as to ensure the completeness of cases obtained from the literature. The clinicopathological information of the patients, such as the age, gender, tumor size and necrosis, imaging alterations, diagnosis and treatment process, prognostic information etc., was also collected.
Statistical analysis
The Software Packages for Social Science 19.0 for Windows (SPSS, Inc. Chicago, IL, USA) was used for statistical analyses. Overall survival and disease-free survival rates were analyzed by Kaplan-Meier method. The correlation of the clinicopathological parameters with the adverse outcome (i.e. local recurrence, distant metastasis or death) were analyzed using the log-rank test. P value less than 0.05 was considered statistical significance.
Discussion
Mediastinal FDCS is a rare disease. Currently, there is a lack of systematic, large-sample studies on its clinical manifestations, radio-pathological links, and prognosis-correlated factors. In this study, we analyzed a large group of mediastinal FDCS (43 cases), including patients admitted in our hospital and those from the literature [
3‐
32]. The subjects were an average of 46 years old, and sex ratio was 1.5:1 (M:F). The clinical manifestations were not specific, but closely associated with the site of tumor occurrence. A few patients were occasionally found lesions during physical examination. Interestingly, 4 cases had paraneoplastic pemphigus (PNP) as the first clinical manifestation [
9,
13,
24,
26], whereas 3 cases had myasthenia gravis (MG) as the main symptom [
5,
15,
17]. Because MG is common in patients with thymoma, preoperative diagnosis is expected to be a challenge for these cases.
Among the 43 cases, 19 cases published with radiological image data, which indicated that the tumors often presented a round or lobulated shadow with clear border. After enhanced scan, the tumor showed obviously enhancement. The tumors were commonly relatively large in size. Calcification was found in 52.6% of the cases, although bleeding and necrosis were rare. It was proposed that if a mediastinal mass had clear border, calcification, but rare bleeding and necrosis, the condition was highly likely FDCS [
11,
27]. Some cases may develop HVCD-like imaging alterations. For example, Case 1 in ours had concurrent HVCD and displayed obvious enhancement, which was highly similar to HVCD and practically indistinguishable from it in CT images [
21]. Of note, Case 1 suffered haemorrhage during preoperative puncture, which also occurred for one of the cases in the literature [
18]. Above-mentioned cases remind us if the tumor image displays apparent intensification after enhance scan, which indicates it may be rich blood supply and vulnerable to haemorrhage, the puncture risk assessment is necessary. There are very few reports on the PET-CT features of mediastinal FDCS (only 4 cases), with SUVmax values ranging from 2.7 to 11.4. The SUVmax of Case 3 was 11.95, indicating that the tumor had a relatively high metabolic level.
Most cases with mediastinal FDCS manifest the typical morphology of conventional FDCS. However, some cases may develop marked atypia or epithelioid or CHL-like features, which present a great challenge to diagnosis, particularly preoperative needle-based diagnosis. Of the 43 cases analyzed in this study, 18 received core needle biopsy but had an overall misdiagnosis rate of 83.3%, illustrating the extraordinary difficulty involved in identifying the disease. Core needle biopsy is of vital importance to mediastinal tumors, in particular for those that are difficult to remove surgically, because their subsequent therapeutics almost rely on the preoperative examination. Based on our diagnostic experience and literature, the causes of diagnostic difficulty may be attributed to the following: (1) mediastinal FDCS lacks unique clinical signs and may present unusual symptoms such as PNP or MG; (2) although radiologic image is indicative to a certain extent, its diagnostic value is limited; (3) the tumors are heterogeneous, often with concurrent inflammation and fibrosis, thus small needle specimen can not fully represent the whole tumor; and (4) mediastinal FDCS is so scarce that clinicians and pathologists often do not considered it during diagnosis. Hence, increased awareness of this rare mediastinal tumor and consideration of detection of the FDC-associated markers are crucial to avoid pitfalls.
An important scenario that should raise a red flag is that, based on the data from the literature and our experience, mediastinal FDCS is the most likely to be diagnosed as lymphoma (7/18 cases). Two of the biopsy specimens obtained in our hospitals also displayed a CHL-like appearance; specifically, such morphology refers to the scattered Reed-Sternberg-like large cells and multinucleated giant cells, which may express CD30, in a mixed inflammatory background. This critical issue can potentially be a diagnostic trap because once a patient is diagnosed as CHL, he/she likely receives unsuitable treatments. As for the differential diagnosis between the two entities, there are several points to note. (1) Reed-Sternberg-like large cells and CD30 positivity are very limited role, because these scattered large cells are often found in FDCS in different locations [
2,
33,
34], and part of which could expression CD30 [
35]. (2) It is the most important that when such lesion is presented in a needle biopsy of mediastinal mass, it should be considered not only the possibility of CHL but also that of FDCS. (3) The markers correlated to FDCS and CHL should be detected, including EBER ISH. If the large cells are positive for CD30, CD15, Mum-1, GATA3, PAX5 (weak positive) and EBER, but FDC-associated markers are negative, CHL is considered. On the contrary, if only CD30 and FDC-associated markers are positive, it should be considered as FDCS.
Previously, it was considered that adverse outcome of FDCS could be attributed to the following aspects: its intra-abdominal location, its large size (often > 6 cm in diameter), the presence of coagulative necrosis, the high proportion of mitotic figures (> 5/10 HPF), and the marked nuclear atypia. However, whether these factors are suitable for mediastinal FDCS is unclear. Current limited data suggested that none of the factors (gender, age, tumor size, and presence of necrosis) were correlated with the adverse outcome. Of course, an accumulated large sample size and long follow-up duration are needed to better investigate this issue.
Currently, there is a lack of consensus on treatment of FDCS, but radical resection is the predominant option, and adjuvant radiochemotherapy remains controversial [
1,
25,
36]. In this study, a comparison of prognosis between the surgery only group and the surgery plus adjuvant therapy group found no differences in either total or tumor-free survival. However, it is note that the cases available for analysis are scarce, and the survival curves based on a compliation of small series and case reports, so the aboved results may be insufficiently valid. Thus, further studies are needed to better explore the effects of adjuvant therapy.
The aetiology of FDCS remains elusive. It has been reported that its occurrence is closely related to HVCD, which, rather than a reactive alteration in tumor stroma, is more likely a type of precancer lesion [
28,
37]. Chan et al. reported a clinical case in which HVCD evolved into FDCS [
38]. Of the 43 cases of mediastinal FDCS, 8 (18.6%) had concurrent HVCD. For example, case 1 had a transitional zone between the HVCD and the FDCS, corroborating that they might correspond to different phases of the same disease. Hence, when examining a patient with a putative mediastinal HVCD, it is important to maximize the sample areas and to perform a thorough microscopic examination, thereby avoiding potential FDCS lesions being missed. Epstein-Barr virus (EBV) infection is considered to be closely linked to the occurrence of inflammatory pseudotumor-like FDCS, but conventional FDCS seldom have concurrent EBV infection [
33,
39]. Of the 43 cases, 10 were detected by EBER ISH, which were all negative.
Little is known about the pathogenesis of FDCS, only a few studies have been reported so far [
35]. Go et al. performed BRAF sequencing and identified V600E mutations in 5 of 27 FDCS cases (18.5%) [
40]. In our 3 cases, BRAF mutation analysis was also performed by fluorescent PCR, but no V600E mutation was detected
(data not shown). Recurrent loss-of-function alterations were revealed in tumor suppressor genes involved in the negative regulation of NF-κB (38%) and cell cycle (31%) through targeted sequencing [
41]. Based on microRNA (miRNA) profiling of 31 FDCSs, Hartmann et al. identified two subgroups with high and low miRNA expression levels, which related to fibroblasts and myopericytomas or Castleman’s disease, respectively [
42]. Two newly researches on the whole transcriptome have shed new light on the pathobiology of FDCS. Laginestra et al. demonstrated FDCS has a distinct FDC-related transcriptional profile which allows differentiation from other mesenchymal tumors. The results also provide evidence of a peculiar immune microenvironment associated with FDCS that may have clinical utility [
43]. By whole transcriptome sequencing, Lorenzi et al. identified two novel FDC markers, the FDC secreted protein and serglycin, and proposed an efficient marker panel for the diagnosis of this enigmatic tumor [
32].