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Clinical features of Rosai-Dorfman disease
c.351A>T (K117N) mutation who had a recurrence in the trachea after the resection of subcutaneous nodules. The three cases that required subsequent systemic therapy had multiple subcutaneous lesions and lymph node involve- ment at presentation.
Corticosteroids were used as the first-line therapy in 17 (27%) patients. Of these, responses were observed in in 56% of the cases, with a maximum response duration of 71 months and a relapse rate of 53%. The agent used in most cases was prednisone at doses of 1 mg/kg with pro- longed but variably designed taper of 6-12 weeks. Responses were seen both clinically as well as radiologi- cally, although uniform imaging re-assessment was not performed in over 50% cases. Twelve (70%) of the patients who received corticosteroids had lymph node involvement. Of these, seven responded, with a median duration of response of eight months (range, 3-25 months). There were two RDD patients with CNS involvement (dural and cerebellar, respectively) who noted improvement in symptoms after prednisone treat- ment. One patient had ocular (scleral) involvement and noted improvement in vision with corticosteroid eye drops. Corticosteroids were well-tolerated overall, and no major dose-limiting toxicities were reported. Radiation therapy was utilized in two cases (one subcutaneous and one bone) without any response. Other first-line therapies included combinations of rituximab, azathioprine, or 6- mercaptopurine with prednisone and resulted in universal responses in the four patients treated. The organs involved in these patients were mostly lymph nodes and subcuta- neous tissues, and no relapses were noted.
The three patients with overlap RDD/ECD underwent resection of the solitary RDD lesions in the testes (n=2) and vocal cords (n=1). Two of these underwent cladribine chemotherapy that led to an ongoing response at a median follow-up of two years, and one has been observed for 2 years without ECD progression in the perinephric region.
2. Second line and subsequent treatments
Of the 49 patients that were treated initially, 15 (30%) developed recurrent disease after the first course treat- ment and were treated with other empiric modalities (Table 2, Figure 6). The most common chemotherapeutic agent used was cladribine (5 mg/m2/day for five days every 28 days) for 3-4 cycles, primarily used as second line therapy in six (10%) patients, with a 67% ORR. Of those who responded, no relapses were seen at median follow- up of 16 months (range, 2-26). Prednisone in combination with 6-mercaptopurine, azathioprine, or methotrexate was also successfully used in a few cases with subcuta- neous and lymph node involvement. Interestingly, ritux- imab administered as four once-weekly doses in combina- tion with corticosteroids resulted in a sustained ORR of 100% in the three patients who were treated, two of whom had primary lymph node involvement and third with multiple subcutaneous lesions along with lym- phadenopathy. Two of these patients had immune-related RDD (warm autoimmune hemolytic anemia, multiple sclerosis). Other systemic chemotherapies that led to sus- tained responses utilized vinblastine and cyclophos- phamide based regimens (Table 2). Radiation therapy was utilized in four patients (one each subcutaneous, tracheal, orbit, and bone), with a complete radiographic response seen in only one case of tracheal RDD, with an eventual recurrence in the multisystem distribution with an under-
lying KRAS mutation.
Less commonly utilized therapies included pegylated
interferon alfa (135 mcg subcutaneous weekly in one patient) leading to regression of subcutaneous nodules and stability of the optic nerve lesion, and hydroxyurea (1000 mg oral daily in one patient) which initially resulted in some in the vision from orbital masses, but eventually progressed within three months. One of the patients received CVP (cyclophosphamide, vincristine, prednisone) regimen for RDD involving multiple subcutaneous sites, and achieved a sustained partial response.
The median duration of follow-up after diagnosis for the entire cohort was 31 months (range, 0-249). Of the cohort with complete follow-up information (n=49), four patients had died at the time of last follow-up. Of these, three patients died from other malignancies: concomitant peripheral T-cell lymphoma (n=1), acute myeloid leukemia 1 year subsequent to RDD with concomitant myelodysplastic syndrome (n=1), and metastatic gallblad- der carcinoma 12 years subsequent to RDD (n=1). The cause of death for the fourth patient was unknown.
Discussion
In this study, we report a large contemporary series of RDD patients. Over the study period of 23 years, our referral center saw RDD patients at an average rate of three cases per year. However, the recognition of this dis- ease appears to be increasing, with 29 (45%) cases seen within the last 5 years of the study. Contrary to the histor- ically reported RDD cohort with massive lymphadenopa- thy, we found that the majority of cases presented as sub- cutaneous lesions.3 Lymphadenopathies were the second most common manifestation. However, they were not massive or limited to cervical lymph nodes alone as described by Foucar et al. in the initial landmark series of RDD.3 The reason for this difference in organ involvement is unclear, but may be related to a difference in the study population between the two studies. Compared to the historical cohort reported by Foucar et al., our cohort had more patients who were older (mean age 48 versus 20 years), from the United States (97% versus 38%), and Caucasians (63% versus 43%).3 Moreover, our center is a tertiary referral center; hence it may not include some clas- sic RDD cases that received treatment in the community. It may also be biased towards incidentally found RDD when being extensively evaluated by means of imaging studies for other unrelated disorders. However, the major- ity of the patients in our cohort were referred to hematol- ogy for primary RDD diagnosis and received systemic treatments. Our findings highlight that RDD is syndromic in nature with a wide spectrum of manifestations, and our experience may be more representative of RDD in the United States.
The histopathological diagnosis of RDD can be chal- lenging due to its rarity and non-specific histologic find- ings, especially in the extranodal forms. In contrast to LCH and ECD, the RDD tissue may harbor very few lesional cells, and often shows a prominent inflammatory background with plasma cells, or lymphoid follicle forma- tion and neutrophilic infiltrates.15 The difficulty in diag- nosing RDD histopathologically is exemplified by the numerous biopsies required to achieve the diagnosis of RDD in our patients. On some occasions, a histopatholog-
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