Mediastinal follicular dendritic cell sarcoma: a rare, potentially under-recognized, and often misdiagnosed disease

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.

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.

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.

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.

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.

The information of 3 patients with mediastinal FDCS in ours is summarized in Table 2. Cough and expectoration were the main manifestations of case 1 and 2, whereas chest tightness and chest pain were presented in case 3. No fever, fatigue, loss of appetite, or weight loss was observed in all cases.

Computed tomography (CT) images of case 1 showed that in the right upper anterior mediastinum adjacent to trachea, there was a mass of 5.0 × 4.9 × 4.7 cm, which had relatively distinct border and adhered tightly to the mediastinal vessels. After enhanced scan, the lesion had obviously heterogeneous enhancement (Fig. 1a, b). CT images of case 2 revealed that in the right posterior mediastinum, there was a giant lobulated shadow measured 13.0 × 12.6 × 7.6 cm. Post-contrast CT scaning displayed moderately heterogeneous enhancement of the lesion. The boundaries between the lesion and right pulmonary artery, esophagus and right bronchus were not clear (Fig. 1c, d). CT images of case 3 showed a mass in the middle mediastinum, 9.5 × 9.2 × 8.8 cm in size, which had clear boundary. The adjacent tracheae was slightly stenotic due to tumor compression. Positron emission tomography and CT (PET-CT) revealed significantly increased fluorodeoxyglucose (¹⁸F-FDG) uptake (SUVmax = 11.95), with most being internal uptake (Fig. 1e, f).

Microscopic examination of the core needle biopsy of case 1 showed a few large round or ovoid cells scattered in the inflammatory background composed of lymphocytes, plasma cells and histocytes. These cells had delicate chromatin and large nuclei with distinct nucleoli, and were reminiscent of Hodgkin and Reed-Sternberg (HRS) cells (Fig. 2a, b, arrows). Immunohistochemical staining showed that these large cells were negative for cytokeratin (CK), P63, CD3, CD20, but a few were CD30 positive. Thus, the tumor was suspected to be classical Hodgkin lymphoma (CHL). However, the patient suffered haemorrhage during the puncture, which prompted emergency resection of the mediastinal mass. The resulting specimen was a grey mass with clear boundary and partial capsule. Microscopic examination showed the following findings: the main element of the tumor was composed of ovoid and spindle-shaped cells with fascicular, woven or storiform patterns, in the background, there were infiltrations of varying levels of lymphocytes, plasma cells, and eosinophils; some areas exhibited classical morphology of hyaline-vascular Castleman’s disease (HVCD). Between hyperplastic follicular dendritic cells in HVCD areas and surrounding spindle-shaped cells, there were transitional zones (Fig. 2c, d). Multinucleated giant cells and HRS-like cells were disseminated in HVCD areas, hyperplastic lesions of spindle-shaped cells, and the transitional zone in-between (Fig. 2e, f, arrows). Immunohistochemical staining showed that spindle-shaped cells (including some scattered large cells) expressed CD21 (Fig. 2g), CD23, CD35 (Fig. 2h), D2–40 (Fig. 2i, arrows), CXCL-13 and SMA at various degrees, a few large cells were CD30-positive, and the ki-67 labeling index was 10%. All of these cells were negative for CK, P63, Desmin, ALK, S-100 and EBV-LMP-1. Based on these results, the patient was diagnosed with FDCS combined with HVCD.

In case 2, microscopically, the needle biopsy specimens revealed that the tumor cells were round or ovoid with light red or clear cytoplasm, large and hyperchromatic nuclei, which were arranged into nests. Between these tumor nests, fibrosis and varying levels of lymphocytes infiltration were observed (Fig. 3a, b). Immunohistochemical staining showed that the tumor cells were negative for CK, P63, CD3, CD20, CD30, S-100, and weak positive for placental alkaline phosphatase (PLAP). So, a malignant tumor without further classification was made. During the surgery, the tumor was found to locate in the right posterior mediastinum and to have invaded into the right lung and oesophageal external wall. The resected specimen was a grey to white lobulated mass with clear boundary but no capsule. The tumor was tightly connected to partial pulmonary tissues; the cross-section was grey to brown with moderate texture, and contained bleeding and necrosis. Microscopic examination revealed that round to ovoid epithelioid tumor cells with marked atypia were tightly arranged into nested or a diffuse pattern. There were multifocal coagulative necrosis and a few dispersed lymphocytes in the background. The surrounding pulmonary tissue was invaded by tumor cells (Fig. 3c-e). Immunohistochemical analysis revealed that the tumor cells were positive for CD21 (Fig. 3f), CD35 and CXCL-13, focal positive for CD23, while negative for D2–40, CK, P63, CD30, SALL4, PLAP, EBV-LMP-1. The ki-67 labeling index was 30%. Thus the posterior mediastinal FDCS with right lung involvement was diagnosed.

In core needle biopsy of case 3, two different histopathological morphology was identified, with some areas resembling that of case 1, specifically, in the inflammatory background composed of with lymphocytes, plasma cells and histocytes, there were scattered large round or ovoid cells resembling lacunar Reed-Sternberg (LHS) cells (Fig. 4a, b, arrows). In other areas, there were ovoid and spindle-shaped tumor cells with bundles and woven patterns, the tumor cells had abundant and slightly eosinophilic cytoplasm, and hyperchromatic nuclei (Fig. 4d, e). Immunohistochemical staining showed that tumor cells in both areas were positive for CD21, CD23 (Fig. 4c, f) and D2–40, while negative for CD35, CXCL-13, CK, P63, CD30, S-100, EBV-LMP-1. The ki-67 labeling index was 15%. The patient was diagnosed with FDCS.

The tumor cells were all negative for EBER by ISH in 3 cases.

Literature retrieved 40 cases of mediastinal FDCS (Table 2), plus with 3 cases in ours, generated a total of 43 cases for statistical analysis, including 26 males and 17 females. The ages arrange was from 16 to 76 years old (mean age 46 years, and median age 45 years). The maximal tumor diameters were 3–17 cm (mean 8.6 cm and median 8.2 cm). Of 24 cases, concurrent necrosis was found in 12 cases (including 5 cases with extensive necrosis), but another 19 subjects had no relevant records.

Among the 43 cases, 18 underwent preoperative needled biopsy, 15 of which (83.3%) were misdiagnosed initially. Mediastinal FDCS was often diagnosed as other types of tumor or non-tumor lesions, including lymphoma (7 cases), malignant tumor (without classification, 3 cases), malignant schwannoma (2 cases), undifferentiated carcinoma (2 cases), thymoma (1 case), germ cell tumors (1 case), or no atypical cells (2 cases).

Available follow-up data was obtained from 32 subjects, the follow-up duration was 6–312 months, averaging 43 months. The rates of recurrence, metastasis, and mortality were 12.5, 18.8 and 28.1%, respectively. The 1-, 3-, and 5-year total survival rates were 80.4, 68.5, and 58.8%, respectively, and the 1-, 3-, and 5-year tumor-free total survival rates were 76.9, 51.7, and 32.3%, respectively (Fig. 5a, b).

Given the limitations in sample numbers and availability of clinical data (reliable data were not easy to obtain for mitotic figures and nuclear pleomorphism), we only analyzed the associations of poor prognosis with the following clinical factors: gender, age, maximal tumor diameter, and presence of necrosis. Our analysis revealed that there were no significant differences in either total survival rate or tumor-free survival rate within sex, age, tumor size and necrosis subgroups (Fig. 6a-h). Next, we compared prognosis differences between different treatments (8 underwent surgery only vs 18 underwent surgery plus adjuvant radiotherapy/chemotherapy), and there was no differences in either total survival rate or tumor-free survival rate (Fig. 6i-j).