Follicular dendritic cell sarcoma (FDCS) is a rare histiocytic and dendritic neoplasm of intermediate malignant potential. Literature is studded with several hundred case reports and series since it was first described in 1986. Lymph nodes (LN), especially in the cervical, mediastinal, and axillary regions, are the most commonly affected, while approximately one-third of the patients show involvement of extranodal sites such as the tonsil, gastrointestinal tract, retroperitoneum, mediastinum, and soft tissue. These tumors often recur locally and may show distant spread to the lung and liver. FDCS is often misdiagnosed owing to a combination of low incidence, nonspecific clinical, radiological, and histopathology, and above all, failure to include this entity in the differential diagnosis. Awareness, an eye for subtle histopathological clues, and immunohistochemistry (IHC) can help unravel this challenging diagnosis. Here we review the clinical, histopathology, and IHC findings of four cases of FDCS that presented over 6 years. We also briefly discuss the treatment strategies and follow-up of these cases.
The four cases were all adults (3 males and 1 female) with an age range of 22–69 years. Two cases each presented in the abdomen and head and neck regions, respectively. One case involved the nodal region (cervical LN) and had a longer duration of symptoms, while the remaining three cases presented with rapid progression of complaints between 1 and 4 months. The radiological findings along with the clinical impression and differentials were between various malignancies depending upon the age and site and have been summarized in Table 1. The histopathological patterns observed were whorls, sheets, fascicles, and nests, and the usual cell type was spindled to plump epithelioid often varying in the same tumor. However all the cases consistently, albeit in varying amounts, showed an interspersed lymphocytic population [Figure 1]. Other features such as pleomorphism, intranuclear inclusions, mitosis, necrosis, and giant cells were also noted and differed among the cases [Table 2]. The immunostaining was done on Benchmark Ventana platform using several secondary antibodies, viz., leukocyte common antigen (LCA) (2B11 + PD7/26, 1:200, Dako), S100 (polyclonal, 1:300, Dako), Human melanoma black 45(HMB45) (1:100, Dako), desmin (D33, 1:50 Dako), CKIT (YR145, prediluted, CellMarque), smooth muscle actin (SMA) (IA4,1:300, Thermo), inhibin (R1 mouse monoclonal, 1:25, CellMarque); CD34 (QBEND/10, prediluted, Dako), and CD31 (JC/70A, 1:50, Dako) were applied in different cases to rule out lymphoma and melanoma apart from mesenchymal, histiocytic neoplasms and even sex-cord stromal tumors [Figure 2]. The final diagnosis was reached using a combination of CD21 (EP3093, 1:50, CellMarque), CD23 (DAK-CD23, prediluted, Dako), CD35 (outsourced to external laboratory), and D2-40 (prediluted, Dako). PD-L1 (programmed death receptor-ligand 1) was tested using SP142 clone (Ventana) retrospectively in three of the four cases, and membranous positivity was seen in two [Table 3]. On follow-up, case 1 developed local recurrence within the year as well as a secondary malignancy in the breast (invasive duct carcinoma; estrogen receptor (ER), progesterone receptor (PR), and HER2Neu positive) with concomitant lung metastasis after 2 years. The latter was proved to be of dendritic cell origin by IHC (positivity for CD21 and CD23) and needed exclusion the more likely possibility of carcinoma breast, demonstrated by negativity for cytokeratin (CK) [Figure 3]. She subsequently received three cycles of adjuvant chemotherapy CHOP (cyclophosphamide, doxorubicin, oncovin, prednisolone) as did the two cases of abdominal FDCS (Cases 2 and 3). No treatment history or follow-up details were available for the nasopharyngeal mass (case 4) which was received for review with the diagnosis of lymphoma.
The clinical, radiological, histopathology, and immunohistochemical details of patients enrolled in the present series have been summarized in [Tables 123].
FDCS is a rare tumor of histiocytic lineage, described first by Monda et al. in 1986. They arise in young to middle-aged adults and preferentially involve LN. In the present series, males outnumbered females and all cases were seen in adults; the oldest being 70 years of age. One patient had nodal disease, while the others had extranodal tumors in the abdomen and nasopharynx. It is the FDCS of the extranodal sites that deserve a closer look as they are often misdiagnosed as soft tissue tumors resulting in suboptimal treatment and poor outcomes.
The diagnosis of FDCS can be suspected on morphology and confirmed on IHC by using one or more dendritic cell markers. Histologically, the tumor can show any number of growth patterns often showing a mixture within the same tumor [Figure 1]. Previous case series have described a wide range of patterns ranging from storiform (most common), fascicular to syncytial or any combination of these. In the present series, syncytial growth pattern was the most common although the others were seen in varying combinations.
Multinucleated giant cells were seen focally in three out of the four cases, a finding that has similarly been described by Chang K, et al. (2011) and Wang et al. (2014) in their series. Mitosis ranged from low to brisk in the present series, and higher mitotic activity was accompanied by a higher grade of atypia and pleomorphism. In a study by Shia et al. (2008) on 33 cases, a median mitotic count of 3/10HPF and coagulative necrosis in 30% cases have been reported. Saygin et al. also observed classical patterns such as whorls, fascicules, and storiform in the majority, while giant cells (25% cases) and epithelioid cells (18.7% cases) were observed in minority and only one displayed nuclear pseudoinclusions.
Intranuclear inclusions, which were seen in three cases in the present series, have been reported in increased frequencies following radiation therapy. However, a history of radiation was lacking in our cases. Infiltrating lymphocytes were observed in all cases though their density varied from singly scattered cells to focal collections. The perivascular collection has been emphasized as an important finding in the literature. However, we could see it only in one of our four cases. Saygin et al. found a prominent lymphoplasmacytic infiltrate in 93.76% of cases.
Despite the established role of IHC, diagnosis of this entity is often difficult as follicular dendritic markers are often not included in most routine panels. Both nodal and extranodal FDCS have similar immunophenotypes and express CD23, CD21, and CD35; the latter two makers being the most widely used. CD21 was diffusely expressed in all cases, whereas CD23 was positive in two cases in the present series. CD35 was applied in one case where it was negative. In our experience, D2-40 served as a reliable novel maker, which strongly and diffusely stained all cases of the current series [Figure 2]. Xie et al. (2008) compared the specificity and sensitivity of this maker in evaluating reactive and neoplastic follicular dendritic cells and found D2-40 to be superior or equal to CD21. Yu et al. (2007), in their study on 125 dendritic cells, histiocytic, and spindle cell lesions, observed strong membranous D2-40 immunoreactivity in 100% of FDCS, while other spindle cell tumors showed occasional weak cytoplasmic reactivity. In contrast, A. Agaimy et al. found D2-40 staining in only 7 out of 14 cases of FDCS. A combination of D2-40 and CD21 worked better than CD21, CD68, and CD163 in the current series. CD35 could only be performed in one case where it was negative; thus, its role cannot be commented upon vis-à -vis the other IHCs used in this short series.
Markers such as S100, desmin, CK, and LCA were negative in all cases. Histiocytic makers, CD68 and CD163, were applied, and the latter was expressed in a scattered and dot-like pattern in two cases. The role of S100, CD68, and CD163 has been considered by authors as useful but nonspecific. In our series, S100 was uniformly negative in all cases and histiocytic markers were noncontributory in confirming or refuting the diagnosis.
Recently, the role of PD-L1 has been studied in histiocytic and dendritic cell disorders not only for diagnosis but also as a prognostic marker for immunotherapy. Studies have shown moderate to strong membranous PD-L1 staining in more than 5% of the neoplastic cells in up to 50% of cases. Retrospectively, PD-L1 IHC was performed in three out of the four cases of which two were positive. However, none of our cases had received immunotherapy [Figure 2].
Initially, FDCS were considered to have an indolent behavior with a tendency toward local recurrence but a low risk of metastasis. However, larger cohorts with long follow-up periods have proven otherwise. In our series, one of the case presented with progressive local disease and metastatic spread to the lungs within 2 years of diagnosis. The overall rates of recurrence, metastasis, and mortality are 43, 24, and 17%, respectively, indicating its aggressive nature.
All the cases included had a combination of poor prognostic features such as advanced age, male gender, large size, extranodal location, mitosis >5/10HPF, and necrosis, which could have led to their extensive disease burden. The clinical relevance and impact on the treatment of the described histopathology features and novel IHC need to be analyzed further.
FDCS are rare and often misdiagnosed malignancies especially in case of undifferentiated neoplasms where the pathologist fails to reach a definite diagnosis despite extensive immunostains. Awareness of its morphological spectrum and a combination of CD21 and D2-40 along with other follicular dendritic cell markers must be applied to correctly recognize and treat these aggressive tumors.
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1. Chan J, Pileri S, Delsol G, Fletcher C, Weiss L, Grogg KSwerdlow S, Campo E, Harris N, et al Histiocytic and dendritic cell neoplasms World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. 2016 4th Lyon, France International Agency for Research on Cancer (IARC):476–8
2. Perez-Ordoñez B, Rosai J. Follicular dendritic cell tumor: Review of the entity Semin Diagn Pathol. 1998;15:144–54
3. Duan GJ, Wu Y, Sun H, Lang L, Chen ZW, Yan XP. Extranodal follicular dendritic cell sarcoma of the pharyngeal region: A potential diagnostic pitfall Am J Clin Pathol. 2010;133:49–58
4. Monda L, Warnke R, Rosai J. A primary lymph node malignancy with features suggestive of dendritic reticulum cell differentiation. A report of 4 cases Am J Pathol. 1986;122:562–72
5. Wang H, Su Z, Hu Z, Wen J, Liu B. Follicular dendritic cell sarcoma: A report of six cases and a review of the Chinese literature Diagn Pathol. 2010;5:67–72
6. Wang R, Han W, Lei QI, Shan L, Wang Z, Wang L. Extranodal follicular dendritic cell sarcoma: A clinicopathological report of four cases and a literature review Oncol Lett. 2015;9:391–8
7. Chang K, Weiss LJaffe E, Harris N, Vardiman J, Campo E, Arber D. Hematopathology Other Histiocytic and Dendritic Cell Neoplasms. 20111st Philadelphia, PA: Saunders/Elsevier:829–33
8. Shia J, Chen W, Tang LH, Carlson DL, Qin J, Guillem JG, et al Extranodal follicular dendritic cell sarcoma: Clinical, pathologic, and histogenetic characteristics of an underrecognized disease entity Virchows Arch. 2006;449:148–58
9. Saygin C, Uzunaslan D, Ozguroglu M, Senocak M, Tuzuner N. Dendritic cell sarcoma: A pooled analysis including 462 cases with presentation of our case series Crit Rev Oncol Hematol. 2013;88:253–71
10. Chan JK, Fletcher CD, Nayler SJ, Cooper K. Follicular dendritic cell sarcoma: Clinicopathologic analysis of 17 cases suggesting a malignant potential higher than currently recognized Cancer. 1997;79:294–313
11. Lima FEMM, Jorge IF, Kauffman J, Gerson G, Beco MdPFG, Cavalcante JM, et al Follicular dendritic cell sarcoma: Report of two cases and literature review J Bras Patol Med Lab. 2015;51:258–64
12. Xie Q, Chen L, Fu K, Harter J, Young KH, Sunkara J, et al Podoplanin (D2-40): A new immunohistochemical marker for reactive follicular dendritic cells and follicular dendritic cell sarcomas Int J Clin Exp Pathol. 2008;1:276–84
13. Yu H, Gibson JA, Pinkus S, Hornick JL. Podoplanin (D2-40) is a Novel Marker for follicular dendritic cell tumors Am J Clin Pathol. 2007;128:776–82
14. Agaimy A, Michal M, Hadravsky L, Michal M. Follicular dendritic cell sarcoma: Clinicopathologic study of 15 cases with emphasis on novel expression of MDM2, somatostatin receptor 2A, and PD-L1
Ann Diagn Pathol. 2016;23:21–8
15. Wu A, Pullarkat S. Follicular dendritic cell sarcoma Arch Pathol Lab Med. 2016;140:186–90
16. Xu J, Sun HH, Fletcher CD, Hornick JL, Morgan EA, Freeman GJ, et al Expression of programmed cell death 1 ligands (PD-L1
and PD-L2) in histiocytic and dendritic cell disorders Am J Surg Pathol. 2016;40:443–53