Follicular dendritic cell sarcoma/tumour, low to intermediate grade David Parham, MD Chief of Pediatric Pathology Arkansas Children's Hospital Vice-Chair of Pathology University of Arkansas for Medical Sciences

Case History: This 12 year-old Caucasian girl presented to her local pediatrician with swelling above her right clavicle. Examination revealed a large, non-tender, freely movable soft tissue mass. CT scans revealed a 2.8 x 3.0 x 5.0 cm, mass in the right supraclavicular region (Figure 1). There was an indistinct margin of fat. The right clavicle showed no evidence of bone destruction. A 1.5 cm lymph node was also noted in the right axilla, but no other lesions were found in the thorax or abdomen. Following an incisional biopsy, an excision was performed, with removal of the right clavicle and en bloc resection. Figure 1: Computed tomograph of upper thorax, indicating a well-marginated, oval supraclavicular mass (arrow). There was no bony involvement. Gross examination: The specimen consisted of a portion of bone with attached soft tissue and measured 6 x 3.5 x 3 cm. On sectioning, a soft to firm tan white soft tissue lesion measured 3 x 1.5 x 2 cm and showed no gross bone invasion. Microscopic examination: The lesion consisted of uniform, relatively bland, plump spindle cells arrayed in fascicles and whorls. Some whorls resembled those of meningothelial meningioma and other areas evoked burned out germinal centers. Focally abundant infiltrates of lymphocytes and plasma cells were present. Abundant reticulin fibers surrounded tumor cells. Immunostains revealed uniform CD21 positivity, variable HLA-DR staining, and weak focal EMA positivity. Immunostains for pan-cytokeratin, smooth muscle actin, S100, and vimentin were negative. Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Ultrastructural examination: Micrographs revealed spindle cells with oblong nuclei and abundant, marginated heterochromatin. The cytoplasm contained abundant dilated cisternae of rough endoplasmic reticulum. Numerous intercellular junctions connected cytoplasmic processes and showed features of rudimentary desmosomes, such as interconnecting filaments (Figure 2). A single structure resembling a rudimentary lumen was noted in one micrograph. Admixed cells had features of histiocytes, such as ruffled borders and lysosomes. Extracellular matrix consisted of collagen fibrils and amorphous material. Figure 2: Electron micrograph showing tumor cells with spindly contours. Desmosomes connect cytoplasmic processes. Diagnosis: Follicular dendritic cell sarcoma/tumour, low to intermediate grade. Follow-up: Resection margins were close (less than 1 mm) but free of tumor. The patient received external beam irradiation and chemotherapy with ifosfamide, carboplatin, and etoposide with no significant side effects. Four years after completing her therapy, she showed no evidence of tumor in a return clinic visit. Differential diagnosis: Synovial sarcoma, fibrosarcoma, malignant peripheral nerve sheath tumor, leiomyosarcoma, rhabdomyosarcoma, fibromatosis, epithelioid sarcoma, interdigitating dendritic cell sarcoma/tumour, fibroblastic reticular cell tumour, Langerhan cell histiocytosis, anaplastic large cell lymphoma. Discussion: Definition: Follicular dendritic cell sarcomas are low to intermediate grade neoplasms that possess phenotypic features of the follicular dendritic cells found in the germinal centers of lymph nodes [1, 2]. Because these lesions have variable grades and often show indeterminate clinical behavior, the term "follicular dendritic cell tumour" is preferred by some. As a result, the WHO designates these lesions as "follicular dendritic cell sarcoma/tumour" [2]. Classification of dendritic cell tumours: Dendritic cells are antigen-presenting cells found in lymph nodes and skin and having features akin to histiocytes, particularly Langerhan cells. For this reason dendritic cell tumours are typically included among histiocytic neoplasms such as Langerhan cell histiocytosis and histiocytic sarcoma. This group also includes the similar but distinct neoplasms interdigitating dendritic cell sarcoma/tumour and the recently described fibroblastic reticular cell tumour [3]. Dendritic cells share phenotypic features of antigen presenting cells but are distinguished by their recipients. Follicular dendritic cells present antigens to B cell and interdigitating dendritic cells present to T cells. As the name implies, they are also found in different regions of the lymph node [4]. As such, they are antigenically distinct, with interdigitating cells more closely resembling Langerhan cells. Occurrence in children: Like "true" histiocytic sarcomas, dendritic cell tumours of all types are vanishingly rare lesions that are typically the subject of case reports. Thus, tumours occurring in children are generally not well recognized and may be mistaken for more common spindle cell neoplasms. A recent report collected a series of four paediatric cases of interdigitating cell sarcoma and reviewed the world literature on the subject [5]. These cases arose in the left chest wall, vertebral body, lymph nodes, and urinary bladder, respectively, suggesting a relatively high incidence of extranodal disease as compared to adults. The authors found an additional four patients less than 20 years of age in their literature search, which yielded a total of 33 other cases. Chan's series of 17 cases of follicular dendritic cell tumours included two in older adolescents, one arising in the tonsils and the other in the soft tissue of the neck [6]. No paediatric cases were included among a slightly smaller series from Memorial Sloan-Kettering Cancer Center [7]. The rarity of the latter lesions suggests that they are under-reported, possibly due to lack of readily available immunohistochemical reagents necessary for their diagnosis. On the other hand, three adolescents are included among the initial series of 11 fibroblastic reticulum cell tumours [3]. Nonaka, Birbe, and Rosai have suggested that the inflammatory myofibroblastic tumour represents a proliferative lesion of fibroblastic reticulum cells [8]. This view is not widely accepted, but it illustrates the possibilities these cell types offer when defining poorly understood spindle cell lesions. Defining features: Follicular dendritic cell sarcomas appear as low grade spindle cell lesions with a characteristic whorled pattern reminiscent of meningioma. The constituent cells vary from elongate to ovoid in profile, and their cytoplasm possesses a lightly eosinophilic hue. Generally the nuclei appear low grade, with finely dispersed chromatin and a small central nucleolus, and as in meningioma pseudonuclear inclusions may be seen. Worrisome features include a high cellularity, nuclear atypia, and significant mitotic activity with atypical figures (although 1-10 per 10 hpf is the rule). Uninvolved lymphoid tissue is usually present, so that germinal centers may be seen. Cases occurring in the liver and spleen have histologic features highly resembling inflammatory myofibroblastic tumour and have been associated with EBV infection [9]. Confirmation of the diagnosis requires ultrastructural examination and/or immunohistochemistry. Follicular dendritic cell tumours have a distinctive ultrastructural appearance, with elongate, slender, cytoplasmic processes connected by desmosomes. In contradistinction to other histiocytic tumours, Birbeck granules or numerous lysosomes are not seen [9]. Immunohistochemical findings in follicular dendritic cell tumours are also distinctive, but the stains required are not widely available. Happily, they can usually be performed by reference laboratories. The primary finding is positivity for markers of complement receptors, such as CD21 and CD35, and the Fc receptor CD23. Of note is that the latter marker is also the EBV receptor in B cells, explaining the susceptibility of these cells to EBV infections. Positivity for one or a combination of these markers may be present. However, they are not absolutely specific and may be found in other haematopoietic cells, particularly B cells, but in the context of spindle cell lesions they are reliable. When performing immunostaining for these antigens, a good epitope retrieval method is critical, and CD35 appears to be the most consistent marker [10]. The combination of desmosomes and positivity for these markers is diagnostic. New data suggests that clusterin expression may be used in lieu of the CD markers [11], but to date its immunostain is not available in reference laboratories. EMA and/or cytokeratin may also be positive [12]. Unlike the present case, vimentin in usually (but not always) positive, and not unexpectedly, HLA-DR [2] and desmoplakin [12] can also be positive. CD20, CD45 and actin positivity may also be observed [2]. These tumours are variably positive for S100 and CD68, as opposed to the uniform reactivity of interdigitating follicular cell tumours for the former marker and histiocytic sarcoma for the latter. Interdigitating follicular cell tumours do not stain with complement receptor markers [12]. Negativity for CD1a serves to distinguish follicular dendritic cell tumours from Langerhan cell histiocytosis [12]. Distinction from other lesions: The cardinal rule to observe for diagnosis of these lesions is to remember that they are rarer than hens' teeth, particularly in children, so that a careful work-up is in order. Also they span features of epithelial, hematopoietic, and mesenchymal tumours, so the differential diagnosis includes a number of diverse entities. Involvement of lymphoid organs is typical, but extranodal sites may be involved [9]. Some lesions may be associated with Castleman's disease, so the clinical setting can be helpful. In the present case, the surgeon's original assumption that the involved tissue was a supraclavicular lymph node proved correct, in spite of considerations by other specialists that this was a soft tissue lesion. Important considerations for differential diagnosis include soft tissue tumours with epithelial differentiation, such as synovial sarcoma and epithelioid sarcoma. These should be negative for lymphoid markers, and molecular studies may be helpful in confusing cases. The features listed above, especially complement receptor expression and processes with desmosomes, should separate follicular dendritic cell tumours from other hematopoietic neoplasms. Clinical outcome: Generally follicular dendritic cell tumours have a good outcome, similar to the present case. As such their behavior more closely parallels a low grade soft tissue tumour than a hematopoietic malignancy. Local recurrences occur in about one-third of cases, and distant metastases in about one-sixths. About five per cent of patients have died of their disease [7]. Recurrent lesions may show cytohistologic evidence of tumour progression [9]. References Warnke RA, Weiss LM, Chan JKC, Cleary ML, Dorfman RF. Atlas of Tumor Pathology, Third Series, Fascicle 14. Tumors of the Lymph Nodes and Spleen. Ed. Washington,D.C.: Armed Forces Institute of Pathology, 1995. 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