Follicular Dendritic Cell Sarcoma in a Patient With Adolescent-Onset Crohn’s Disease Exposed to Multiple Immunomodulator and Biologic Therapies

Children and adolescents with inflammatory bowel disease are often treated with immunomodulators (thiopurines, methotrexate) and biologics (anti-TNF, anti-integrin) for extended periods despite concerns about long-term safety. Here, we report a case of follicular dendritic cell sarcoma, a very rare malignancy, and the first reported presentation in a patient with inflammatory bowel disease exposed to infliximab, methotrexate, and vedolizumab. We review the key clinical features and diagnostic factors of this malignancy. The pathogenesis of follicular dendritic cell sarcoma is largely unknown, however, knock out of B-cell TNF in mice has been related to follicular dendritic cell dysregulation through its impact on NF-κB pathways and CXCL13 chemokines. It is unknown whether any relationship exists between this patient’s diagnosis of Crohn’s disease and therapeutic exposures to this rare malignancy. We document this case in the literature to raise awareness among other clinicians who may observe a similar case.


INTRODUCTION
Immunomodulators and biologics are considered standard of care for children and adolescents presenting with moderate to severe inflammatory bowel disease (IBD). These therapies are often introduced at diagnosis or shortly thereafter, and thus extended periods of exposure are common. Considerable experience has been published on the efficacy of anti-TNF agents (1) and anti-integrin therapy (2) in children. In this setting, however, concern persists about long-term safety, particularly with thiopurines and anti-TNF agents (3).
A large meta-analysis (4) and a large prospective study (5) examining long-term outcomes found no significant increased risk of lymphoma or other malignancies for pediatric patients on anti-TNF therapy. Less is known about the risks of therapy with newer, more targeted biologics, including gut-selective vedolizumab, particularly in the setting of previous anti-TNF and immunomodulator therapy. Early data reflect fewer and less serious adverse events (3). Here, we report a case of follicular dendritic cell sarcoma (FDCS), a rare malignancy, and to our knowledge, the first reported presentation in a patient with IBD who had exposure to infliximab, methotrexate, and vedolizumab.

CASE REPORT
A 21-year-old male with a history of moderately severe ileocolonic Crohn's disease diagnosed at age 16 presented with 1 day of severe right-sided sharp abdominal pain which was unlike the pain associated with his IBD flares. Magnetic resonance enterography revealed a 5.5 × 4.1 cm mass in the mesentery of the right upper  quadrant and multiple seminecrotic lesions within the liver, measuring up to 7 cm (Fig. 1). The study showed no evidence of active inflammation of the small or large bowel. Laparoscopic biopsy of the mesenteric mass (Fig. 2) revealed a markedly atypical epithelioid malignant neoplasm, with whorled bundles of large, pleomorphic cells with pale-to-eosinophilic cytoplasm, ovoid nuclei, and high mitotic activity (Fig. 3A,B). In addition to characteristic histologic features, by immunohistochemistry the neoplastic cells were positive for CD21, CD23, and CD35, diagnostic for FDCS. The tumor was negative for clusterin and was not tested for CXCL13. Staging proceeded with a computerized tomography (CT) scan of the chest, revealing right axillary lymphadenopathy and no evidence of pulmonary metastases. Positron emission tomography scan identified abnormally FDG-avid lymph nodes in the right inguinal and right axillary regions.
The patient's medical therapy for Crohn's disease included a short initial course of prednisone and mesalamine followed by 1 year of infliximab and methotrexate. Despite the infliximab and methotrexate, repeated flares of disease activity continued, and a follow up colonoscopy approximately 1 year after diagnosis revealed active colonic inflammation. Infliximab was stopped, and vedolizumab was started while continuing low dose methotrexate. With dosing of 300 mg every 5 weeks, the patient achieved clinical remission. Repeat ileocolonoscopy performed 13 months after starting vedolizumab was normal grossly and histologically. Total infliximab exposure was 12 months, total methotrexate exposure was 49 months, and total vedolizimab exposure was 37 months. The patient had been off infliximab for 36 months at the time of diagnosis of the malignancy.

DISCUSSION
FDCS is a rare malignancy, accounting for <0.4% of soft tissue sarcomas, with only several hundred cases reported (6). It is characterized as an intermediate-grade sarcoma of mesenchymal-derived dendritic cells in B-follicles (6,7). The median age of presentation is 50, with a wide range of cases from young children to the elderly (7) and no gender predilection (7,8).
FDCS has been associated with the lymphoproliferative disorder, Castleman Disease, and autoimmune conditions such as pemphigus and myasthenia gravis (7,8). Jain et al, in analyzing 66 cases, found 20% to have a concurrent autoimmune disease (9). No other risk factors are known, and the pathogenesis is largely unclear. FDCS appears to be sporadic without known driver mutations, however cases are reported with identified structural alterations in tumor suppressor genes PTEN and TP53 (9).
The presenting location varies; more recent, larger studies highlight greater incidence of extranodal versus nodal disease (7,9,10). Common nodal sites include cervical, mediastinal, axillary, and intra-abdominal, while extranodal sites most often include the liver, lung, spleen, or GI tract (7,10). FDCS typically presents as a slow-growing, painless mass with no systemic symptoms; however, fever, weight loss, and abdominal pain are common features of intra-abdominal presentations (7,8). Classical FDCS can have aggressive clinical behavior with local recurrence of 50%, often with metastases (7).  The prognosis depends on the extent of disease, tumor size (<5-6 cm), surgical resectability, and histopathologic features (7,10). Poor prognostic factors include abdominal involvement, nuclear atypia, ≥5 mitoses per 10 high-power fields, lack of lymphoplasmacytic infiltration, and age <40 at diagnosis (7,10), all of which are featured in our case.
We can relate aspects of the normal function and the dysregulation of follicular dendritic cells (FDC) to mechanisms of key immunomodulators used to treat IBD. FDC are important for B-cell adaptive immunity (6). B-cell TNF plays an important role in the development and maintenance of FDC, particularly in spleen, lymph nodes, and Peyers patches (12). The homeostatic chemokine CXCL13, a FDCS tumor marker, is produced by FDC and regulated by TNF (11,12). Production of CXCL13 is maintained in transformation of FDC to FDCS and is the primary driver of the lymphocytic invasion often seen in these tumor cells (11). Knockout of B-cell TNF in mice resulted in dysregulation of chemokines, such as CXCL13, which can lead to this improper infiltration of lymphocytes (12). These data also suggest that certain FDC-specific genes, which are TNF dependent, may encode CXCL13. The expression of CXCL13 genes, among other chemokines, is regulated by NF-κB (12). The expression of CXCL13 is thus dependent on TNF activation of NF-κB pathways (12). Additionally, Griffin et al (13) performed a study of targeted sequencing of a panel of several hundred known cancer-associated genes and identified recurrent loss of function alterations in tumor suppressor genes that help regulate activation of NF-κB in 38% of 13 cases of FDCS.
It is unknown whether this patient's diagnosis of Crohn's disease and associated therapeutic exposures are related to this rare malignancy. It is important, nonetheless, to document these cases for other clinicians who might observe a similar case.