Table 2. Markers used in this IHC study.

IDCS is a rare hematologic malignancy with the highest prevalence reported in lymph nodes, though tumor can occur in extra-nodal sites such as lung, colon, and skin. For this reason, depending on the site of the lesion, different symptoms can take place; in head and neck areas the appearance of a mass or lymphadenopathy, in gastrointestinal tract and spleen, abdominal mass, distension, and pain (1, 8), and in lung and airway it can lead to respiratory symptoms (25). Due to fever, lymphadenopathy, and respiratory symptoms, suspicion of lymphoma can make diagnosis a challenging issue. Final diagnosis is based on histopathologic examination and IHC studies.  Microscopic features of IDCS include spindled, ovoid, and epithelioid cells with eosinophilic cytoplasm and occasional prominent nucleoli, showing storiform, nodular, and fascicular growth patterns. Mitotic figures and necrosis may also be present (2, 3). Infiltration of the stroma with inflammatory cells like plasma cells and lymphocytes can also be observed. Tumoral cells are positive for S100, vimentin, CD68 (26) and are negative for CD1a, CD34, CD35, HMB45, Melan-A, CD21, and lineage markers for B- and T-cells (27). Differential diagnoses include non-hematologic (like melanoma, spindle cell SCC, and several mesenchymal neoplasms) and hematologic neoplasms (follicular DC sarcoma, Langerhans cell histiocytosis, and fibroblastic reticular cell tumor). There is still no consensus on the choice of treatment for this malignancy. However, considering the stage of the disease and whether the lesion is localized, or it has spread, different modalities including surgery, chemotherapy, and radiation are applied. Chemotherapies usually contain CHOP regimen (Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone), ABVD regimen (Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine), DHAP regimen (Cisplatin, Cytarabine, and Dexamethasone), taxol, carboplatin, ifosfamide, and oxaliplatin (2, 8, 15). We chose surgical dissection and carefully monitored the patient because the lesion was localized. There are reports of recurrence of tumor and death despite chemotherapy. Appropriate response to treatment with ABVD regimen has also been observed. Potential side effects should also be considered when choosing chemotherapy, as chemotherapy-induced liver injury which can be fatal.

The etiology of IDCS is not yet fully understood due to its rarity. BRAF mutations (a kinase involved in cell signaling) which frequently occur in some hematologic neoplasms like Langerhans cell histiocytosis (LCH) and hairy cell leukemia (HCL) are found in IDCS too (21, 28). Bailleux et al. (29) applied initial low dose BRAF inhibitor (Vemurafenib) to treat a male patient with relapsed HCL, which led to complete remission (30). Eight months later and due to the relapsed disease, vemurafenib was re-administrated and complete hematologic response was achieved (29). This treatment was also prescribed by Di Liso et al. for their IDCS patient and resulted in tumor shrinkage but toxicity was also noted (21). Programmed death-ligand 1 (PD-L1) is an immune inhibitory protein which suppresses tumor specific immune responses by binding to PD1 on activated T cells. Sakakibara et al. showed membranous and cytoplasmic expression of PD-L1 on IDCS cells of a patient who died from a progressive disease. This is important in terms of how tumoral cells evade detection by the immune cells and potential therapeutic targets (11).

An interesting study performed whole exome sequencing (WES) on the blood and tumor specimens of an IDCS patient; the results showed that alteration in DNA polymerase theta (POLQ) and folliculin interacting protein 1 (FNIP1) genes may be involved in malignant potential of IDCs  (13). IDCS has also been developed in patients who received organ transplantation; so, the question is raised if immunosuppressive agents could be as causes of IDCS (3). Although medical history in several patients is unremarkable, presence of a previous or simultaneous malignancy is observed in some reports. The present patient had a history of multiple skin cancers. Rosenberg et al. presented a female patient with BCC of back skin (31), and Lee et al. reported an IDCS patient with an unknown type of skin cancer (32). So, it is unclear whether previous therapies for cancer have triggered IDCS development or not. There are also observations of increased risk of other malignancies in the following years in IDCS patients. Therefore, it is important to monitor patients even after the malignancy is treated. Finally, our patient responded well to surgery due to the localization of the lesion, but given that many patients have been reported to present with progressive disease and die of IDCS, a chemo-radiation therapy should be considered if the disease is multifocal and other organs are involved.

The authors would like to express their gratitude towards all who helped in the improvement of this paper.

All authors have not received any financial support from any person or organization for this study.

The authors had no conflict of interest to report.