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G. Goyal et al.
ical re-review of previous biopsy slides by our expert pathologists yielded the diagnosis of RDD. This suggests that there is value in having the suspicious biopsy speci- men reviewed by centers with expertise in histiocytic dis- orders, such as those listed by the Histiocytosis Association (https://www.histio.org) or Erdheim-Chester dis- ease Global Alliance (http://erdheim-chester.org). There is also a need for a systematic study of the spectrum of histopathologic manifestations of RDD, as has been undertaken in ECD.18
The pathogenesis of RDD is not well understood, and it is unclear whether it should be classified as a neoplastic or benign disorder. Historical studies found the RDD cells to be polyclonal in nature.19 However, there are recent reports of MAP-ERK pathway alterations in about a third of RDD patients, which suggests that at least a subset may be neoplastic in nature.5,7,20,21 We recently reported on tis- sue NGS results of 10 RDD patients that demonstrated oncogenic alterations among four (40%), including the one patient with a RDD/ECD overlap and the one with KRAS-K117N included in the report herein.22 Interestingly, in the series, only 1 of 5 RDD cases without any onco- genic mutations required systemic therapy while all patients with molecular alterations (PTEN copy loss, SMARCA4 frameshift loss, KRAS-K117N) had progressive disease requiring chemotherapy.22 Furthermore, about a third of the patients in the current series had a disease behaving more like a malignant hematological neoplasm, requiring second line systemic treatments. We also report a novel finding of a RDD/ECD overlap in three patients, two of whom were found to harbor MAP2K1 mutations. In the past, a RDD/LCH overlap has been described as well.23 These findings, in conjunction with the accumulat- ing molecular and clinical data, add further evidence to the contention that a subset of RDD may be neoplastic and related to the other histiocytic neoplasms.
There is a paucity of systematic studies analyzing first- line treatments and outcomes in RDD. Historically, it was reported that about 50% of the RDD cases with involve- ment of lymph nodes or cutaneous disease may experi- ence spontaneous remissions.24,25 In our series, about 40% of the patients who were observed subsequently required treatment. This suggests that there is a role for monitoring without therapy in a subset of RDD patients who are asymptomatic and have no internal organ involvement. Surgical resection has been suggested as a curative option for some isolated RDD cases.15,26,27 In our series, one-third of the patients who underwent initial surgery required subsequent therapy. Our series also suggests that corticos- teroids may be considered as a treatment option for nodal only disease, or to relieve symptoms from CNS/ocular involvement. However, the duration of response may be short-lived. The optimal duration of therapy is unknown and the patients need to be monitored for the adverse effects from steroids.
Although several RDD patients were treated adequately by corticosteroids or surgical resection, about a third in our series had recurrent disease. The most commonly used therapeutic agent was cladribine and resulted in high overall response rates (~70%). This is similar to that reported in previous case reports.28,29 Some other empiri- cally used agents that led to sustained clinical responses were prednisone in combination with other immunosup- pressive therapies (6-mercaptopurine, azathioprine, and low-dose oral methotrexate) or anti-CD-20 monoclonal
antibody, rituximab, especially in immune-related RDD. These agents have been reported to provide benefit in RDD in the past as well.25,30-32 Vinblastine in combination with other immunosuppressive agents led to partial response in the lymphadenopathy, consistent with prior reports of its benefit.33,34 Although the second-line regimen were heterogeneous, our study suggests that patients with immune-related RDD may benefit from rituximab or immunosuppressive agents, and others may be treated with cytotoxic agents such as cladribine as used in ECD.
Prior reports suggested the potential role of radiation therapy in refractory disease causing imminent symptoms such as airway obstruction or vision loss.25,31,35,36 In our experience, radiation therapy resulted in a response in only one of six patients. This patient had an isolated tra- cheal lesion. Hence, there might be a potential role for radiation therapy in patients who have a single site of dis- ease.
Our study’s major strength is that it is the largest con- temporary case series among adult patients with RDD. We show that the most common manifestation of RDD may be dermatologic in nature, and the lymphadenopathy may not be massive as previously thought to be. We also report the unique entity of a “hybrid” RDD/ECD overlap, which has not been previously reported. A major limita- tion of our study is the lack of uniform imaging and response assessment in all patients. However, the charts were independently reviewed by two investigators to minimize bias. Another limitation is the lack of genetic sequencing data on all the patients, and our focus was pri- marily on the clinical manifestations, treatments and out- comes. Additionally, one of the challenges in conducting a study of a rare and chronic disease such as RDD is the lack of long-term follow-up data on the patients. Of the patients that had complete follow-up data (n=49), no one died from RDD. In the previous largest reported series, 4 of 238 (~2%) patients with sufficient follow-up died from effects of RDD.3 Although the mortality from RDD appears low, it may cause significant morbidity through end organ damage, and is potentially lethal if left untreat- ed.
Despite the progress made in the understanding of the biology of LCH and ECD, our knowledge regarding the ontogeny and pathogenesis of RDD has lagged behind. Our study provides important information regarding the clinical spectrum and natural history for this entity. Due to the varying outcomes with similar histopathology, RDD may be considered a syndrome rather than a single disease entity. On one end of the spectrum are patients with “benign” single-system unifocal RDD such as a solitary subcutaneous nodule that can be observed or excised, and may lead to sustained remissions. On the other end, how- ever, are the patients who are truly “neoplastic” and may need closer monitoring or systemic therapy. Although both these entities demonstrate similar histopathologic features to be diagnosed as RDD, there may be differences in the molecular/genetic architecture that differentiate benign from neoplastic RDD. Hence, more studies are needed to appropriately correlate phenotypic and molecu- lar characteristics of RDD. Further studies focused at the hematopoietic stem cell compartment are also needed to ascertain the cell of origin of RDD, as that may provide insights into the pathogenesis and therapeutics. As discov- ery of MAP-ERK mutations in other histiocytic neoplasms has enabled successful targeted therapy with MEK-
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haematologica | 2020; 105(2)