Erdheim–Chester Disease With Multiorgan Involvement, Following Polycythemia Vera

Abstract Erdheim–Chester disease is a rare form of non-Langerhans cell histiocytosis characterized by the migration and infiltration of lipid-laden CD68+, CD1a− and S100− histiocytes to various target organs, which leads to the disruption of physiological tissue architecture and reactive fibrosis, and thus impairs organ function. We describe the first case of a patient with Erdheim–Chester disease with multiorgan involvement developed after 6 years from polycythemia vera diagnosis. During the follow-up, an abdominal ultrasound scan revealed the presence of dense, bilateral perinephric infiltration. A computed tomographic guided core biopsy was performed in order to identify the histological nature of this lesion, and a morphological analysis demonstrated the accumulation of foamy histiocytes surrounded by fibrosis. The BRAFV600E mutation was detected, and a diagnosis of Erdheim–Chester disease was made. The extreme rarity of Erdheim–Chester disease strongly suggests the existence of potentially common element(s) that may have contributed to the pathogenesis of both disorders. Obviously, further studies are needed to clarify the mutual roles and effects of JAK2 and BRAF mutations in this patient, as well as their possible therapeutic implications.


INTRODUCTION
E rdheim-Chester disease (ECD) is a rare form of non-Langerhans cell histiocytosis characterized by the migration and infiltration of lipid-laden CD68 þ , CD1a À , and S100 À histiocytes to various target organs, which leads to the disruption of physiological tissue architecture and reactive fibrosis, and thus impairs organ function. 1,2 It seems to have a slight male predominance, the majority of the patients are diagnosed between the ages of 40 and 70 years, 3 and its severity ranges from mild to life-threatening depending on the site(s) of involvement. 4 It has been found that ECD histiocytes express a proinflammatory network of cytokines and chemokines that is responsible for local activation and recruitment of other pathological histiocytes. 5 They also bear activating mutations in the MAPK-activating pathway, of which NRAS and PIK3CA mutations have so far been described in only a few cases, but the BRAFV600E mutation seems to be present in most patients. 6,7 On the basis of these findings, ECD is now considered to be a clonal disorder associated with the development of a local and systemic pro-inflammatory milieu that plays a crucial role in its pathogenesis and clinical manifestations. 8 Associations between ECD and other hematological malignancies have been rarely reported, 9 and there is no previously published case involving the coexistence of ECD and BCR-ABL1-negative myeloproliferative neoplasms (MPNs). Polycythemia vera (PV) is an MPN that is mainly characterized by increased red cell mass, frequently associated with leukocytosis and thrombocytosis. 10 Sixty percent of PV patients are older than 60 years, and there is no difference in gender distribution. 11 Almost all of the patients present the JAK2V617F mutation and, albeit to a lesser extent, mutations in the gene's exon 12. Furthermore, PV is typically associated with an increased risk of thrombosis and a long-term tendency to transform itself into post-PV myelofibrosis (15-20%) 12 and/ or acute myeloid leukemia (5-8%). 11 We here describe for the first time the case of a patient with a previous diagnosis of PV who developed ECD with multiorgan involvement after 6 years of hematological follow-up.

CASE REPORT
A 66-year-old man was admitted into our Hospital in November 2008 with splenomegaly, a high red cell count, and subnormal serum erythropoietin levels. Cytogenetic analysis showed a normal male karyotype. Molecular studies were negative for the BCR-ABL1 rearrangement, but revealed the JAK2V617F mutation with an allele burden of 44.9%. A diagnosis of PV was made on the basis of a morphological bone marrow analysis according to the WHO 2008 criteria. The patient was started on aspirin, hydroxyurea, and phlebotomies, all of which were well tolerated.
The histological nature of the perinephric infiltration was identified by means of a CT-guided core biopsy of the lesion. Morphological analysis demonstrated the accumulation of foamy histiocytes that were positive for CD68 and negative for the dendritic cell markers CD1a and S100, surrounded by fibrosis and a scanty lympho-monocytic infiltrate ( Figure 1). The detection of the BRAFV600E mutation led to a diagnosis of ECD. Cardiac magnetic resonance imaging (MRI) revealed pseudo-tumoral infiltration of the atrioventricular wall, 14 and a bone scan showed symmetrically irregular radiotracer uptake in the long bones of the limbs consistent with ECD ( Figure 2) 2 ; the findings of cerebral and pulmonary imaging were negative. In accordance with the most recent guidelines for the treatment of ECD, 1 the patient started therapy with pegylated interferon (IFN)-alpha and, after 3 months of treatment, a new abdominal ultrasound scan revealed the complete resolution of the dense bilateral perinephric infiltration, and the normalization of the blood cell counts was achieved.

DISCUSSION
ECD is an extremely rare hematological disorder, as only about 600 cases have been reported in the literature 2 ; PV is also an infrequent disease, with an estimated annual incidence of 2/ 100,000 people. 10 To the best of our knowledge, there is only 1 published report describing ECD in association with another hematological neoplasms: the case of a 14-year-old girl with pre-B cell acute lymphoblastic leukemia in remission who was subsequently diagnosed as having ECD. 9 There are no previously published descriptions of the coexistence of ECD and PV or other BCR-ABL1-negative MPNs.
A critical step in our understanding of the exact pathogenic mechanism underlying PV was the discovery of the JAK2V617F-acquired activating somatic mutation in 2005. 15 Unlike the other BCR-ABL1-negative MPNs, about 95% to 97% of all cases of PV are characterized by the presence of this mutation, which is not seen in patients with lymphoid neoplasms or reactive myeloproliferation, or in healthy volunteers. JAK2V617F is due to a somatic G to T mutation involving JAK2 exon 14, and affects the noncatalytic ''pseudo-kinase'' domain by derailing its kinase regulatory activity. The constitutive activity of JAK2 mainly leads to an excessive transcription of cell survival promoting, anti-apoptotic molecules, and an increased production of pro-inflammatory cytokines, such as interleukin (IL)-6, tumor necrosis factor alpha (TNF-a), IL-8, IL-2R, IL-12, and IL-15 by pathological megakaryocytes and monocytes. 16 As JAK2V617F does not seem to be the diseaseinitiating event but probably defines an MPN subclone, the possibility of the independent emergence of multiple abnormal clones has recently been suggested, which challenges the prevailing view that an abnormal ancestral clone gives rise to mutually exclusive subclones. Such genome instability may lead to a predisposition to acquire additional somatic mutations, including those of the BRAF gene, 17 which is involved in the cell signal transduction that directs cell growth and many other physiological processes, and whose activation is the final downstream component of various signal transduction pathways, including the JAK-STAT pathway. As the cytokine milieu described in PV shares significant similarities to that which promotes histiocyte recruitment, activation, and enhanced survival in ECD lesions, 5,8 it is tempting to speculate that the pro-inflammatory effects of the JAK2V617F mutation may have contributed to the pathogenesis of ECD in our patient. It is important to remember that mutations leading to JAK-STAT pathway activation have been previously described in solid tumors such as head and neck squamous cell carcinomas, hepatitis B associated hepatocellular carcinomas, gastric adenocarcinomas, prostate cancer, nonsmall cell lung cancer, and glioblastomas. 18 Low-dose aspirin and phlebotomies can be effectively and safely used to treat PV in low-risk patients, whereas hydroxyurea is usually added when treating those at high risk. 19 Another treatment option is IFN-alpha, which can reduce the mutant clone, 20,21 control constitutional and microvascular symptoms, and prevent thrombo-hemorrhagic complications in most cases. Furthermore, targeted therapies (mainly JAK1/ 2 inhibitors) are now available and have led to promising results especially in patients who are resistant or intolerant to hydroxyurea. 22 ECD therapy is recommended for all patients at the time of diagnosis, except those with minimally symptomatic disease. The possible therapeutic options include IFN-alpha-2a, pegylated IFN-alpha, corticosteroids, and imatinib, but no standard treatment regimen has yet been established. 1 Interestingly, it has been reported that treatment with the BRAF inhibitor vemurafenib can lead to unprecedented clinical and radiographic improvements in ECD patients bearing the BRAFV600E mutation, but it has so far only been used in a very small number of patients enrolled in clinical trials. 23,24 Furthermore, as BRAF is the final downstream component of the JAK-STAT pathway, it can be speculated that JAK1/2 inhibitors such as ruxolitinib could also be used to treat ECD.