Inflammatory pseudotumor-like follicular dendritic cell sarcoma of the spleen: A report of six cases with increased IgG4-positive plasma cells


Correspondence: Ji Eun Kim, MD, PhD, Department of Pathology, Seoul National University Boramae Hospital, 425 Shindaebang-2-dong, Dongjak-gu, Seoul 156-707, Korea. Email:


Inflammatory pseudotumor (IPT)-like follicular dendritic cell (FDC) sarcoma is a rare neoplasm typically occurring in the spleen or liver. We present six cases of EBV+ IPT-like FDC sarcoma of the spleen among Koreans along with their clinicopathologic features and IHC results. Most patients presented with an asymptomatic, incidentally detected single splenic mass and were successfully managed by splenectomy alone. Concomitant disease was found in one case, showing EBV+ gastric carcinoma with lymphoid-rich stroma. Histologic features showed fibro-inflammatory lesions that were often accompanied by necrosis and epithelioid histiocytic collection, which are barely distinguishable from IPT. Tumor cells did not frequently express conventional FDC markers, including CD21 (3/6 positive cases), clusterin (4/6), and D2-40 (2/6), but showed uniform positivity for smooth muscle actin (SMA). Noticeably, significant numbers of IgG4+ plasma cells were found within all six tumors. We suggest that the diagnosis of IPT-like FDC sarcoma should be made by the application of a panel of FDC markers, and CD21 negativity or SMA positivity cannot be the criterion for exclusion of IPT-like FDC sarcoma. Relationship of IPT-like FDC sarcoma of the spleen and IgG4-related sclerosing disease should be investigated in further studies.

Follicular dendritic cell (FDC) sarcoma is a very rare disease, and less than 200 cases have been reported in the English literature. Its clinicopathologic characteristics have not been fully investigated; however, it is generally considered to be an aggressive neoplasm, with a wide range of age distribution and organ involvement.[1] Among FDC sarcomas, the inflammatory pseudotumor (IPT)-like variant occurs almost invariably in the spleen or liver, and Epstein-Barr virus (EBV) is clonally expanded in the tumor cells.[2-6] There are several conflicting points of IPT-like FDC sarcoma regarding the origin of tumor cells, causes of the disease and the ambiguity of diagnosis. Because of the striking pathologic resemblance between IPT and IPT-like FDC sarcoma, there may be several cases that could be reclassified as IPT-like FDC sarcoma from the cases previously reported as IPT of the spleen, especially if associated with EBV. Because FDCs and myofibroblasts share numerous morphologic characteristics and immunophenotypes,[7] the distinction of IPT-like FDC sarcoma from IPT or inflammatory myofibroblastic tumor (IMT) is very challenging. Although IPT-like FDC sarcoma is extremely rare, most reported cases presented typical histologic features, consistent EBV infection and an excellent prognosis. The pathogenesis and causes are still unknown, but EBV is designated as one of the most important etiologies of this tumor. A recent study described a case of IPT-like FDC sarcoma of the spleen accompanied by numerous IgG4+ plasma cells and discussed the possible relationship between IgG4-related disease and this tumor. We present six cases of IPT-like FDC sarcoma of the spleen arising in Korea and describe several important findings that would be helpful to identify this tumor. Moreover, we discuss the possible relationship of IPT-like FDC sarcoma to increase of IgG4 in the background of tumor.

Materials and Methods

Six cases of IPT-like FDC sarcoma of the spleen were retrieved from the archives of the pathology departments in five hospitals in Korea. Histopathologic features were reviewed by two pathologists (J.Y.C. and J.E.K.). Clinical data were obtained from medical records. Immunohistochemical staining (IHC) was performed in the most representative 4-μm-thick sections of formalin-embedded paraffin blocks with a Ventana automated immunostainer (Benchmark Ventana, Tuscon, AZ, USA). Various kinds of newly introduced FDC markers were tested in our series and the antibodies tested were as follows:[3, 8-11] anti-CD21, CD23, CD35, fascin, CD31, CD34, caldesmon, desmin, EGFR, IgG, Ki-67, late membrane protein (LMP)-1, S100, and smooth muscle actin (SMA), which were purchased from Dako (Dako, Carpinteria, CA, USA); anti-anaplastic large cell lymphoma kinase (ALK) and clusterin, which were purchased from Novocastra (Novocastra, Newcastle, UK); anti-Class III β-tubulin (TUBB3) (Covance, Emeryville, CA, USA); anti-human herpesvirus-8 (HHV8, Cell Marque, Rocklin, CA); anti-IgG4 (Invitrogen, Carlsbad, CA, USA); anti-D2-40 (Signet Laboratory, Dedham, MA, USA); and γ-synuclein (Epitomics, Burlingame, CA, USA). In situ hybridization for EBV-encoded RNA-1 and RNA-2 (Novocastra) was performed as described elsewhere.[12]


Patient history and clinical findings

The clinical findings of the six patients are summarized in Table 1. The numbers of men and women were equal, and all were adults (range: 53–76 years). There were no immunosuppressed or human immunodeficiency virus+ patients. Five patients were incidentally detected as having a splenic mass, and one patient complained of pain related to a concomitant gastric carcinoma (case no. 6). All cases showed a single, well-demarcated splenic mass in preoperative imaging studies and underwent splenectomy under the clinical suspicion of metastatic tumor or other diseases. One patient (case no. 1) had a history of diffuse large B-cell lymphoma of the palatine tonsil 7 years ago, and another patient (case no. 4) experienced subtotal gastrectomy due to adenocarcinoma of tubular type 5 years ago. In these two patients, the splenic mass was found by routine follow-up examination. Case 6 showed simultaneously occurring gastric cancer, which was histologically proven as EBV-positive gastric carcinoma with lymphoid-rich stroma. After curative surgical resection, no additional therapy was given and all patients were alive, without recurrence or metastatic disease, during 8–78 months of follow-up.

Table 1. Clinical characteristics of splenic inflammatory pseutotumor-like follicular dendritic cell sarcoma, 6 cases
NoAgeSexSymptomDiameter (cm)Associated diseaseMultiplicityTreatmentF/U (months)
  1. Abd. pain, abdominal pain; AGC, advanced gastric carcinoma; DLBCL, diffuse large B-cell lymphoma of the tonsil; EBV+ EGC, EBV+ early gastric carcinoma; F/U, follow-up; NED, no evidence of disease.
164FNo5.5DLBCLNoSplenectomy78, alive, NED
272FNo7.2NoNoSplenectomy18, alive, NED
353FNo3.2NoNoSplenectomy13, alive, NED
476MNo3.2AGCNoSplenectomy8, alive, NED
572MNo6NoNoSplenectomy18, alive, NED
675MAbd. pain3.5EBV+ EGCNoSplenectomy30, alive, NED

Pathologic characteristics of IPT-like FDC sarcoma of the spleen

Grossly, a single well-demarcated but not encapsulated solid mass was noted in all cases (Fig. 1).

Figure 1.

Representative pathologic features of inflammatory pseudotumor-like follicular dendritic cell sarcoma of the spleen. (a) Grossly, a well demarcated solid nodule is found in the spleen (case no. 1). (b) Tumor cells show ovoid nuclei with prominent nucleoli (case no. 1). (c) Some cases show numerous eosinophils and neutrophils (case no. 5). (d) Obliterative vasulitis is found (case no. 3). (e) Necrosis with few multinucleated giant cells is seen (case no. 5). (f) Epithelioid histiocytic collection is prominent in some areas (case no. 4).

Basic histologic features, such as fibroblastic stromal proliferation and heavy inflammatory cell infiltration, which are indistinguishable from IPT/IMT, were the most prominent findings. However, some histologic variations were also found. A storiform or whirling figure of spindle cell proliferation was observed in three cases, and others showed a diffuse and solid pattern. Hyalinized fibrosis was found in two cases, and necrosis was noted in all cases. Tumor cells revealed oval to spindle contour with sometimes prominent nucleoli. The background inflammatory cells were primarily lymphoplasmacytic cells, with occasional eosinophils and neutrophils. Lymphoid follicles were found in one case. The collection of epithelioid histiocytes was observed in four cases and prominent in one (case no. 4). Obliterative vasculitis was found in three cases (Fig. 1) (Table 2).

Table 2. Microscopic features of splenic inflammatory pseudotumor-like follicular dendritic cell sarcoma
  1. aIndicates microscopic pattern at low power magnification (x40).
  2. LF, lymphoid follicle; LP, lymphoplasmacytic cells; N, absent; Y, present.
1DiffuseFocalFocalFocalNYLP, focal eosinophils
3DiffuseNFocalNNYLP, focal eosinophils
4Focal storiformProminentFocalFocalNNLP, focal eosinophils
5Focal storiformFocalY, confluentFocalYYLP, focal eosinophils, neutrophils
6DiffuseFocalFocalFocalNNLP, focal eosinophils

Immunohistochemical findings and detection of EBV

The representative figures and the summary of IHC and EBV results are shown in Figure 2 and Table 3. Among the FDC markers, fascin was expressed most frequently (6 of 6), followed by CD23 (5/6), CD35 (5/6), clusterin (4/6), CD21 (3/6), TUBB3 (3/6), D2-40 (2/6), EGFR (2/6) and γ-synuclein (2/6). Most tumor cells were reactive to SMA (6/6), however, no tumors were positive for ALK, desmin, caldesmon, CD31, CD34 or S100. The Ki-67 labeling index ranged from 3 to 20%. HHV-8 was not detected. Tumor cells were uniformly positive for EBV, and at least focally positive for LMP1 (3 of 6 showed diffuse positivity) in all 6 cases. In contrast, the background splenic tissue revealed no EBV-positive cells. IgG4+ plasma cells were markedly infiltrated in all 6 cases, ranging from 27 to 128 cells/high-power field (×500 magnification), and the ratio of IgG4/IgG was 25 to 75%. Therefore, most cases satisfied the criteria of IgG4-related disease proposed in the previous study.[13] In cases with history of previous illnesses (lymphoma of palatine tonsil, case no. 1; gastric adenocarcinoma, case no. 4), IgG4+ cells were found only in splenic tumors. However, case no. 6, which had concomitant EBV+ gastric carcinoma showed a few IgG4+ cells between the adenocarcinoma cells.

Figure 2.

Immunohistochemical findings and EBV positivity of inflammatory pseudotumor-like follicular dendritic cell (FDC) sarcoma of the spleen. (a) CD21 is focally positive in spindle shaped tumor cells (case no. 1). (b) CD35 is diffusely positive (case no. 4). (c) TUBB3 is positive in both tumor cells and other stromal cells (case no. 3). (d) Fascin is diffusely positive in tumor cells, fibroblasts and vascular endothelial cells (case no. 2). (e) Tumor cells are diffusely positive for smooth muscle actin (case no. 5). (f) EBV is detected in most of the tumor cells (case no. 6). (g) Tumor cells express LMP1 (case no. 6). (h) IgG4+ plasma cells are densely infiltrated in the background of tumor (case no. 2).

Table 3. Immunohistochemical findings and viral status of splenic inflammatory pseudotumor-like follicular dendritic cell sarcoma
NoCD 21CD23CD35FascClustD2-40TUBB3γ-synEGFRSMAEBVLMP1IgG4 (No/HPF)IgG4/IgG
  1. +, focal positive; ++, diffuse positive; Clus, Clusterin; EBV, Epstein-Barr virus tested by in-situ hybridization; Fasc, Fascin; HPF, high power field (x400); SMA, smooth muscle actin; TUBB3, class III β-tubulin; γ-Syn, γ-Synuclein.


We have described six cases of IPT-like FDC sarcoma of the spleen. Most of the patients in our study presented with an asymptomatic, incidentally detected solitary splenic mass, which was successfully managed by simple splenectomy alone. IPT-like FDC sarcoma should be separated from conventional FDC sarcoma, which exhibits a more aggressive clinical behavior, and IPT or IMT. IPT and IMT occur in a wide variety of anatomical locations, although splenic lesions are extremely rare, and show an apparent overlap in their pathological features, except ALK immunoreactivity.[3] The histologic features of IPT-like FDC sarcoma were almost identical to IPT/IMT except for epithelioid cell collection, which is relatively rare in IPT/IMT.[11] Practically, the distinction of IPT-like FDC sarcoma from IPT/IMT is almost impossible without IHC and EBV studies. Some researchers have suggested that these two lesions belong to one disease, representing a spectrum of proliferations ranging from mass-forming FDC proliferations to those resembling IPT, with a predominance of myofibroblasts with minimal FDCs.[4]

In the previous studies, the possibility of FDC sarcoma was excluded by CD21 negativity and SMA positivity.[4, 14] However, the lack of positivity to conventional FDC markers is not sufficient to exclude FDC sarcoma. In addition to conventional FDC markers, such as CD21, CD23 or CD35, many new markers were introduced: fascin,[3] TUBB3,[8] clusterin,[9] D2-40,[10] γ-synuclein[11] and others. Among the FDC markers, CD35 and clusterin were considered to be most reliable in our study. The sensitivity of CD21 was low (3/6, 50%), and the CD23 immunoreactivity of tumor cells was not easily recognizable due to masking of small B lymphocytes expressing CD23. TUBB3, D2-40 and γ-synuclein were faintly positive in a small number of tumor cells. Although fascin showed the highest sensitivity, its diagnostic utility was low because endothelial cells and fibroblasts were also positive for fascin. As observed in our cases, the tumor cells usually lost at least one conventional FDC marker; thus, for the distinction of FDC sarcoma from IPT/IMT, panels of FDC markers should be evaluated with IHC. Moreover, SMA positivity was consistently observed in all six cases; therefore, it cannot be a criterion to exclude FDC sarcoma. SMA positivity in splenic IPT-like FDC sarcoma has already been reported by a study by Neuhauser et al. in which the lesion was described as splenic IPT positive for both CD21 and SMA.[15] This finding is supported by two results: (i) both FDC and myofibroblasts came from a non-hematopoietic mesenchymal precursor; and (ii) cultured FDC cell lines express α-SMA.[7] However, we should consider the possibility that the tumor was mixed with reactive myofibroblasts to a variable degree.

Several diseases can be considered as a differential diagnosis of mesenchymal lesions of the spleen. First, the diagnosis of splenic hamartoma is based on typical histologic findings, i.e. the proliferation of sinus-like small vasculatures, myoid cells and macrophages.[16] An abundant inflammatory background is usually not found in this lesion. Second, sclerosing angiomatoid nodular transformation (SANT) can be considered in differential diagnosis. It is characterized by a rich network of capillaries resembling granulation tissue, a variable degree of fibrosis, and macrophage collection and is frequently multinodular. However, none of these cases show EBV positivity, although FDC markers are expressed in a subset of the cases.[17, 18] Finally, age-related EBV-associated lymphoproliferative disorder could occur in the spleen. It can be accompanied by the heavy infiltration of plasma cells, epithelioid granulomas and numerous EBV-positive cells, which is similar to IPT-like FDC sarcoma.[19] In these cases, the application of various FDC markers is essential.

Because EBV is invariably detected in IPT-like FDC sarcoma, many researchers have postulated that EBV is etiologically related to the pathogenesis of this tumor, but strong evidence is still lacking. EBV provokes inflammation and neoplastic transformation, and most EBV-associated lesions share some histologic features observed in EBV+ carcinoma with lymphoid stroma, EBV+ nasopharyngeal carcinoma, and EBV-associated lymphoproliferative disorders. A dense inflammatory background might be caused by EBV infection. Previous studies revealed that EBV was clonally expanded in the tumor cells.[20] Moreover, the major oncogene of EBV, LMP1, was demonstrated in most cases of IPT-like FDC sarcoma.[5] These findings support the idea that EBV is related to the pathogenesis of IPT-like FDC sarcoma. Of interest, one of our series showed synchronous EBV+ gastric carcinoma and IPT-like FDC sarcoma of the spleen. EBV was densely packed in both carcinoma cells and FDC sarcoma tumor cells, without positivity of non-neoplastic bystander cells. This result suggests that EBV infection is not a coincidental finding but an active participant of the tumor.

Another interesting finding in our study is the predominance of IgG4+ plasma cells in tumor nodules. Previous studies showed the dense infiltration of IgG4+ cells in some cases of IPT of the lung, liver, and pancreas, particularly of the lymphoplasmacytic type,[13, 17] and few or a borderline increase in IgG4+ cells in IMT.[21] There has been no study on IgG4 and IPT-like FDC sarcoma of the spleen, but one study showed significant numbers of IgG4+ cells in splenic SANT.[17] In that study, IPT was categorized as SANT, and one EBV-positive case, in which FDC sarcoma was excluded only by CD21 negativity, was also regarded as IPT/SANT. However, unlike IgG4-related disease affecting other organs, all splenic IPT-like FDC sarcoma cases in our study showed a solitary, localized disease. Additional pathologic features supporting IgG4-related sclerosing disease were still lacking in our study; obliterating vasculitis was found in three cases, and sclerosis was found in four, but focally not diffusely. Because this is a retrospective study, serum IgG4 levels were not checkable in all six cases. Despite the lack of strong convincing evidence, we could not completely exclude the possibility that pathogenesis of the IPT-like FDC sarcoma of the spleen is closely linked with the IgG4-related disease. As proposed by other researchers, IgG4-related diseases might be a precursor lesion of malignant tumor, or IgG4+ cells contribute to the development of secondary malignancy.[22]

The relationship between IgG4 and EBV has not been fully investigated. Takahashi et al. reported a case of EBV+ IgG4-related lymphadenopathy showing a strong granulomatous reaction, which can be included in IPT.[23] Additionally, Cheuk et al. found one case of EBV+ classical Hodgkin lymphoma supervened on IgG4+ cervical fibrosis.[24] Those cases suggest that immune dysregulation caused by EBV can mobilize IgG4+ cells under certain conditions.

In Asian countries, there are a few case reports on IPT-like FDC sarcoma of the spleen and liver.[5, 25, 26] To our knowledge, this is the first collective study on the relationship between IPT-like FDC sarcoma of the spleen and IgG4+ cells. IgG4-related disease is more frequently reported in Japan and Korea and is possibly more prevalent in those areas. Therefore, the intimate relationship between IgG4 and IPT-like FDC sarcoma might be limited to Asian populations. However, based on our findings, we suggest that IPT-like FDC sarcoma of the spleen might be closely related to the IgG4-related disease.


This study was supported by a grant of the National Cancer Control Project, Ministry of Health & Welfare, Republic of Korea (12202201-31204).