Autoimmune manifestations may occur in patients with hairy cell leukemia (HCL), and some rare cases of polyarteritis nodosa and leukocytoclastic vasculitis have been reported. However, data regarding the treatment of these cutaneous manifestations are lacking, given the rarity of the concomitance of HCL and vasculitic syndromes.
We present a 37-year-old man with paraneoplastic leukocytoclastic vasculitis complicating newly diagnosed HCL. The vasculitis completely resolved after the first 3 weekly administrations of cladribine, which is regarded as the gold-standard treatment for this disease. The underlying leukemia showed refractoriness to the same agent, thus requiring a second line of treatment.
The clinical picture we have observed is of interest for the following reasons: i) it confirms an existing pathogenetic relationship between this lymphoproliferative disorder and its cutaneous manifestations, as suggested by the prompt resolution of the purpuric lesions upon cladribine administration; ii) it indicates that cladribine is an effective treatment for HCL-related paraneoplastic syndromes, including leukocytoclastic vasculitis; iii) the evolution and the outcomes of the paraneoplastic manifestations may be independent of those of the underlying leukemia, which showed less than a partial response to its initial treatment.
Tumori 2016; 102(Suppl. 2): e124 - e127
Article Type: CASE REPORT
AuthorsAlessandro Broccoli, Letizia Gandolfi, Cinzia Pellegrini, Claudio Agostinelli, Lisa Argnani, Pier Luigi Zinzani
- • Accepted on 09/02/2016
- • Available online on 16/03/2016
- • Published online on 11/11/2016
This article is available as full text PDF.
Hairy cell leukemia (HCL) is a rare chronic lymphoproliferative disorder involving mature and post-germinal center B lymphocytes, generally affecting the bone marrow, peripheral blood and spleen (1). It is characterized by the presence of BRAF V600E mutation in virtually all cases (2). HCL usually manifests with worsening pancytopenia (often with a predominant monocytopenia) and splenomegaly as a result of marrow and spleen substitution and infiltration by leukemic CD20-positive elements, which may also be identified in peripheral blood as mononuclear cells with abundant, slightly basophilic cytoplasm and circumferential cytoplasmic “hairy” projections. Signs and symptoms of bone marrow insufficiency including asthenia and fatigue (correlating with anemia), cutaneous or mucosal bleeding (resulting from severe thrombocytopenia), fever and infectious syndrome (due to prolonged severe neutropenia) are the usual symptoms at onset, and indicate the need for prompt treatment.
Differently from other chronic lymphoproliferative diseases, lymph node infiltration is rather infrequent, as is the involvement of extranodal organs. On the other hand, autoimmune manifestations can often be recognized, varying from immune-mediated hemolytic syndromes that aggravate the initial cytopenia to vasculitic syndromes. Skin manifestations in HCL may be various and are often related to an autoimmune process, since the direct infiltration of the skin (i.e., leukemia cutis) is definitely anecdotal (3): cases of Sweet’s syndrome, polyarteritis nodosa and leukocytoclastic vasculitis have been described since the 1970s, although the existing data refer to isolated case reports or literature reviews (4-5-6-7). Moreover, data regarding the effective treatment of these cutaneous manifestations are generally lacking, as most of the reports refer to an era in which purine analogues – such as cladribine and pentostatin, which nowadays represent the treatment of choice for HCL – were not yet available or not extensively applied (8).
Here we present the case of a young man with newly diagnosed HCL whose most clinically relevant symptom was diffuse skin involvement by purpuric lesions, which were later recognized as a paraneoplastic manifestation of the underlying disease. Remarkably, the skin lesions rapidly and completely responded to first-line treatment with cladribine. The patient gave his consent to the publication of his clinical data.
A 37-year-old man came to our institution complaining of skin lesions on both legs consisting of reddish to purpuric papules without any pain or itching, along with fever and enlargement of the spleen as demonstrated by abdominal ultrasound. Concomitantly, severe pancytopenia was found upon laboratory evaluation, with severe anemia (Hb 7.3 g/dL), neutropenia (leukocytes 1,000/mm3, absolute neutrophil count 200/mm3) and a platelet count of 19,000/mm3, but without any evidence of mucosal or cutaneous bleeding.
The blood film examination revealed the presence of circulating mononuclear elements (approximately 10% of peripheral blood leukocytes), morphologically compatible with hairy cells; these cells turned out to be CD20+, CD11+, CD19+, CD25+ and, more importantly, CD103+ upon flow cytometry. Bone marrow aspiration was a dry tap. Histological examination of a trephine marrow biopsy revealed a cellularity of 80%, characterized by diffuse infiltration of small lymphoid cells with abundant and clear cytoplasm and oval nuclei, showing immunohistochemical positivity for CD20 and annexin A1. The clinical and laboratory findings allowed us to diagnose HCL.
In the course of the staging procedures, the condition of the patient’s skin worsened: the purpuric lesions expanded from the lower extremities to the chest, back and head, ultimately involving almost the entire skin surface (
Skin lesions as they appeared at disease onset: vasculitic lesions involve the chest, back and head and show a tendency to blend together.
The patient was given initial treatment with corticosteroids (1 mg/kg/day of oral prednisone for 1 week, slowly tapered over the following 3 weeks), achieving clinical stability. Meanwhile, in order to ascertain the origin of the skin lesions, we carried out complete serology for hepatitis B and C virus as well as human herpes virus 6 and measles, but found no evidence of active infection. Polyclonal hypergammaglobulinemia was detected, without monoclonal components in the serum. The cryoglobulin test was negative. A punch biopsy of the skin revealed an infiltrate of small- to medium-sized lymphoid cells displaying a perivascular distribution: this appearance was judged to be consistent with leukocytoclastic vasculitis, with an inflammatory infiltrate surrounding the dermal blood vessels. No hairy cell infiltration was observed, as the CD20+ elements were few and scattered (
Histology of skin biopsy: a perivascular inflammatory infiltrate, mainly consisting of small lymphocytes, can be seen in the dermis (hematoxylin and eosin stain) (
Weekly subcutaneous cladribine at a dose of 10 mg/week was administered for 5 consecutive weeks: after the third administration, the vasculitic lesions had completely resolved (
Skin appearance after the third administration of cladribine. The vasculitic lesions have completely resolved.
Autoimmune phenomena are frequently seen in indolent chronic lymphoproliferative disorders, mainly chronic lymphocytic leukemia (CLL), where they preferentially express with autoimmune cytopenias. Nonhemic autoimmunity in CLL is in fact rather infrequent (9, 10). The pathogenesis of autoimmunity in such a context may be explained by a variety of mechanisms, all invoking immune dysregulation and a loss of self-tolerance that characterizes the disease itself and may be elicited by its pharmacological treatment. Polyclonal autoantibody production by normal B cells in CLL patients has been documented, whereas monoclonal antibodies secreted by the leukemic clone are responsible for just a few of the cases of autoimmunity. Moreover, CLL cells show dysfunctional antigen presentation, which may end up stimulating autoreactive T-helper lymphocytes. In addition, abnormal function or loss of regulatory T cells, which maintain peripheral tolerance through the suppression of autoreactive T cells, may play a significant role in the etiology of autoimmune phenomena (11, 12).
Autoimmune disorders are also often encountered in patients with HCL, although their prevalence is hard to be defined: autoimmune cytopenias are far less frequent than in CLL, and vasculitic syndromes probably represent the most relevant autoimmune complication of the disease (13).
Given the overall rarity of both HCL and vasculitic syndromes, it can hardly be hypothesized that the concurrence of the 2 conditions is a matter of chance. However, due to the paucity of cases observed and reported in the literature, the relationship between the 2 diseases is far from clear. Possible explanations may include i) the infiltration of vessel walls by hairy cells, which exert some direct effects on the endothelium and intima; ii) the local production of cytokines, which can mediate inflammatory tissue injury; iii) an immune complex-driven lesion or the presence of antibody cross-reactivity between hairy cells and vessel wall components (possibly elicited by a concomitant infection); iv) a combination of all the above mechanisms (7).
Vasculitic manifestations can occur anytime during the course of HCL, sometimes preceding the clinical manifestations of leukemia and thus being regarded as a paraneoplastic phenomenon. Treatment of the underlying HCL with either alpha-interferon or purine analogues may generally result in rapid improvement of the cutaneous scenario, up to complete regression of the vasculitic syndrome (7, 14, 15). A case of pharmacologically induced cutaneous manifestations in an HCL patient has also been described, as a consequence of the treatment of the disease itself (namely with cladribine) (16).
Cladribine (2-CdA) is the most widely used purine nucleoside analogue in the first-line treatment of HCL. It is not degraded by adenosine deaminase, and tends to accumulate in the cytoplasm of both lymphocytes and monocytes, where it is phosphorylated into its active form, cladribine triphosphate (2-CdATP). 2-CdATP directly inhibits DNA polymerase and DNA-repair mechanisms in dividing lymphocytes, and is also incorporated in the DNA during its replication as an aberrant nucleotide, thus inhibiting DNA chain elongation. Moreover, it exerts its effects on resting cells, as it is a potent inducer of apoptosis through the induction of DNA strand breaks and alteration of the mitochondrial membrane. It also possesses epigenetic properties, as it is capable of inhibiting S-adenosylhomocysteine hydrolase and DNA methylation (17). Due to these mechanisms, cladribine is a potent antilymphocyte agent, and it has shown effectiveness in lymphoproliferative disorders and autoimmune conditions, in particular multiple sclerosis (18).
The clinical picture we have observed is of interest for the following reasons: i) it confirms an existing pathogenetic relationship between this lymphoproliferative disorder and its cutaneous manifestations, as suggested by the prompt resolution of the purpuric lesions upon cladribine administration; ii) it indicates that cladribine is an effective treatment for HCL-related paraneoplastic syndromes including leukocytoclastic vasculitis; iii) the evolution and the outcomes of the paraneoplastic manifestations may be independent of those of the underlying leukemia, which showed less than a partial response to its initial treatment.
It has been recently demonstrated that a short course of vemurafenib – an orally available inhibitor of BRAF V600E – was highly effective in patients with relapsed or refractory HCL (19); whether this agent is also effective in inducing the remission of HCL-associated autoimmune manifestations is yet to be demonstrated, as a relationship between this peculiar genetic lesion and the development of paraneoplastic manifestations has never been elucidated.
We have described an unusual case of histologically documented leukocytoclastic vasculitis complicating clinically active HCL at onset, which required treatment because of the severe cytopenia and systemic symptoms. As a paraneoplastic lesion, it responded well to cladribine administration, although the underlying leukemia showed a lack of response to the same agent, thus requiring a second line of treatment. In this specific clinical setting, the skin response to cladribine we have observed was fast and definitely unmistakable.
- Broccoli, Alessandro [PubMed] [Google Scholar] , * Corresponding Author (firstname.lastname@example.org)
- Gandolfi, Letizia [PubMed] [Google Scholar]
- Pellegrini, Cinzia [PubMed] [Google Scholar]
- Agostinelli, Claudio [PubMed] [Google Scholar]
- Argnani, Lisa [PubMed] [Google Scholar]
- Zinzani, Pier Luigi [PubMed] [Google Scholar]
Institute of Hematology L. and A. Seràgnoli, University of Bologna, Bologna - Italy
Alessandro Broccoli and Letizia Gandolfi have collaborated equally in the production of this paper.