Skin changes in hairy cell leukemia

Skin lesions have been reported in about 10–12% of hairy cell leukemia (HCL) patients. Most are etiologically related to autoimmune or infectious processes, although secondary cutaneous neoplasms and drug-induced lesions are also reported. However, leukemia cutis with the direct infiltration of the skin by leukemic cells is extremely rare in HCL patients. This paper reviews the epidemiology, pathogenesis, clinical symptoms, diagnosis, and approach to treating skin lesions in HCL. A literature review of the MEDLINE database for articles in English concerning hairy cell leukemia, skin lesions, leukemia cutis, adverse events, infectious, cutaneous, drug reactions, neutrophilic dermatoses, secondary neoplasms, and vasculitis was conducted via PubMed. Publications from January 1980 to September 2020 were scrutinized. Additional relevant publications were obtained by reviewing the references from the chosen articles.


Introduction
Hairy cell leukemia (HCL) is a rare form of B cell indolent lymphoid leukemia involving mature and post-germinal center B lymphocytes, generally affecting the bone marrow, peripheral blood, and spleen. The disease comprises 2-3% of all leukemias [1,2]. There is a 4:1 male predominance, and Caucasians are more frequently affected than other ethnic groups. The annual incidence is between 2.9 and 4.7 per million people per year [3][4][5]. HCL is characterized by progressive pancytopenia, splenomegaly, and hypercellular bone marrow. Lymph node infiltration and involvement of extranodal organs are rather infrequent. Rare clinical manifestations of HCL are occasionally reported [6][7][8]. These include bulky abdominal lymphadenopathy; tumor masses in the mediastinum; paravertebral masses; pleural effusion and ascites; skin lesions; ocular-corneal involvement; uveitis; retinal artery thrombosis; neurological-meningeal compression; esophageal, gastric, and hepatic involvement; and skeletal lesion [1,2]. Leukemic cells may also be identified in peripheral blood as mononuclear cells with abundant, slightly basophilic cytoplasm and circumferential cytoplasmic "hairy" project i o n . H C L c e l l s t y p i c a l l y s h o w a d i s t i n c t i v e immunophenotype coexpressing CD19, CD20, CD11c, CD25, CD103, and CD123. Recently, BRAF-V600E mutation has been discovered as specific oncogenic mutation for classic HCL. Another characteristic feature of classic HCL is the expression of annexin A1, which is easily detectable by immunohistochemical staining. Thanks to treatment with purine analogs, cladribine and pentostatin, the prognosis for classic HCL has improved from poor to highly treatable with nearnormal survival [9,10]. Purine analogs induce a durable and unmaintained remission in 76 to 98% of patients, with relapse rates of about 30 to 40% after 5 to 10 years of observation, and overall survival (OS) can be longer than 20 years in many cases [11,12]. Moreover, in relapsed patients, subsequent complete remission (CR) can be achieved with re-treatment. However, treatment with purine analogs causes significant side effects, including infections and secondary malignancies related to profound and long-lasting immunosuppression [1]. Treatment with cladribine or pentostatin is not recommended for patients presenting with active infection and severe neutropenia when the risk of infection is high. Interferon-α (IFN-α) is rarely recommended front-line therapy for HCL because of its low CR rate. However, it may be still used in patients presenting with neutropenia below 0.2 × 109/L and during pregnancy [13,14]. In the majority of patients, only partial responses (PR) can be achieved and prolonged treatment is necessary to maintain remission [15]. Another active drug in the treatment of HCL is rituximab. It can be given as a single agent or in combination with other agents, including purine nucleoside analogs [16]. The overall response (OR) rate ranges from 26 to 80% and CR rate from 13 to 53% of refractory or relapsing patients [17,18]. Better results were observed when rituximab was combined with cladribine [19]. Recently, anti-CD22 immunotoxin moxetumomab pasudotox (Lumoxiti, Astra Zeneca) has been approved by the FDA for the treatment of relapsed or refractory HCL patients who have received at least two prior systemic therapies, including a purine nucleoside analog [20,21]. The oral BRAF inhibitor vemurafenib (Zelboraf™, Roche) has been also shown to have antitumor activity in BRAF V600-mutated HCL [22]. It has been approved by the FDA for the therapy of BRAF V600E mutant metastatic melanoma. Vemurafenib exhibits a remarkable activity in multiple-relapsed and refractory HCL. Two other BRAF inhibitors, dabrafenib (Tafinlar®, GlaxoSmithKline) and encorafenib (LGX818, Novartis), are also potentially useful in the treatment of HCL [23]. Cutaneous symptoms have been reported in 10-12% of HCL patients [24]. While most of them were autoimmune or infectious in nature, secondary cutaneous neoplasms and drug-induced lesions have also been reported [25]. The direct infiltration of the skin (i.e., leukemia cutis) is extremely rare in HCL patients. However, cutaneous manifestations of HCL are not generally recognized as a diagnostic source and biopsies are seldom performed. This review examines the epidemiology, pathogenesis, clinical symptoms, diagnosis, and treatment of skin lesions in HCL.

Leukemia cutis
Leukemia cutis is defined as infiltration of the epidermis, the dermis, and the subcutaneous tissue by leukemic cells [26,27]. The most common types of leukemia cutis are observed in acute T cell leukemia/lymphoma (ATLL), chronic lymphocytic leukemia (CLL), and acute myeloid leukemia (AML) with monocytic or myelomonocytic subtypes, chronic lymphocytic leukemia (CLL), and T cell leukemia/lymphoma [27,28]. Clinically, leukemia cutis manifests as maculopapular eruptions, nodules, infiltrative plaques, and ulcers. In most reported cases, biopsy has indicated that cell infiltrates are perivascular, involving the dermis and sparing the epidermis [27,[29][30][31][32][33][34][35]. Direct infiltration of the skin by leukemic cells is only occasionally observed in HCL. In addition, in most patients with HCL, the leukemic lesions were diagnosed only based on clinical examination without supporting histology [29]. Although the molecular mechanisms of the pathogenesis of leukemia cutis are not well defined, chemokine receptors and adhesion molecules may play important roles in the migration of leukemic cells into the skin via skin-selective homing processes [27]. CLA and CCR4 receptors on the circulating leukemic cells may interact with E-selectin and/or TARC/CCL17 on the dermal post-capillary venules; these may stimulate the rolling and tethering of leukemic cells into the dermis. The resulting interaction between integrins and endothelial-bound chemokines may stimulate the arrest of the leukemic cells and their transmigration into the dermis.
Clinical data from lager series and detailed single case reports have been published since 1980 [26,[29][30][31][32][33][34][35]. In a study of 48 patients reported as leukemia cutis among 600 HCL patients (8%), the condition was confirmed histologically in only eight (1.6%) [29]. Elsewhere, only one patient in a series of 113 patients (1.1%) with cutaneous findings had leukemic skin lesions; the other patients had non-specific cutaneous findings including recurrent infections, ecchymoses, petechiae, pallor, drug reactions and reactions to transfusions, and non-herpetic ulcerations [33]. While leukemia cutis has been diagnosed in the course of the disease in some patients, in most cases, it was observed at presentation of HCL [27,[29][30][31][32][33][34][35][36]. Seven cases of HCL with leukemia cutis that were described in detail in English language literature are summarized in Table 1. The diagnosis of leukemia cutis is based on a morphological pattern of skin infiltration, cytologic features, and the immunophenotype of the neoplastic cells [27]. Skin biopsy and immunophenotyping must be performed in all patients with suspicion of leukemia cutis. An established diagnosis of systemic leukemia is needed before a diagnosis of leukemia cutis can be confirmed. It is recommended that skin changes should be correlated with clinical features as well as with bone marrow and peripheral blood findings [27,34].
Leukemia cutis involvement in HCL has a variety of clinical appearances, including papules, plaques, or nodules ranging from violaceous to red-brown in color or flesh-colored nodules, occasionally with central ulceration. Skin lesions may be localized to one region or lesions can be generalized in many places. A differential diagnosis of leukemia cutis should include secondary cancers and inflammatory and infectious skin lesions [34]. Leukemia cutis in HCL patients responds well to antileukemic treatment with purine analogs. In most cases, cutaneous infiltrates disappeared with a complete resolution of the skin lesions when treatment with cladribine was used (Table 1) [27,35].

Secondary skin neoplasms
The association between HCL and second primary malignancies remains controversial [37][38][39][40][41]. The overall incidence of second primary tumors in patients with HCL ranges from 19.9 to 24% [41][42][43][44][45]. The most common include second primary malignancies of the skin, melanoma and non-melanoma skin cancer [43,44]. Existing data suggests that patients with HCL have a higher risk of nonmelanoma skin cancers [45]; therefore, these patients should be closely examined, especially when secondary risk factors exist like fair skin and extensive sun burden. In contrast, there is no clear evidence of increased melanoma cases in patients with HCL [45]. Recent data demonstrated a 10year combined melanoma and non-melanoma skin cancer incidence of 11.3%, including 4.4% for melanoma and 6.9% for non-melanoma skin cancers [45]. In addition, data from Surveillance, Epidemiology and End Results (SEER) based on 4750 patients with HCL indicated a subsequent diagnosis of melanoma in 1.2%. However, standardized incidence ratios (SIRs) suggest that melanoma is not more common in HCL patients than in the general population.
In addition, HCL patients diagnosed before the introduction of purine analog therapy in 1990 showed a similar incidence of melanoma to those diagnosed afterwards [45]. In contrast to these results other study showed higher rates of second primary malignancies since the introduction of purine analog treatment [41]. A recent study by Watts et al. reported no significantly increased risk of melanoma in HCL patients, compared to the general population [45]. Importantly, skin cancers in HCL patients have a high frequency of RAS mutations [46]. In a recent report, 33.3% of HCL patients with skin cancers had activating RAS mutations. Vemurafenib can further increase the incidence of secondary skin cancer events in melanoma patients [47,48]. BRAF inhibition can accelerate the growth of cutaneous squamous cell carcinomas and melanoma resulting from the activation of MAPK signaling [49,50]. However, the combination of a MEK inhibitor with a BRAF inhibitor can improve antileukemic efficacy and reduce the frequency of secondary cutaneous malignancies in melanoma and HCL patients [51][52][53][54][55].
The development of cutaneous T cell lymphoma and HCL is a very rare phenomenon. We found six cases of concurrent mycosis fungoides and HCL in the English language literature [56][57][58][59]. Another report describes a case of reactive polyclonal T cell lymphocytosis mimicking Sezary syndrome in an HCL patient [60]. The simultaneous diagnosis of a primary cutaneous form of peripheral T cell lymphoma (PTCL) and a variant of HCL has been also reported [56].
Concurrent metastatic Merkel cell carcinoma (MCC) and HCL have also been observed at initial presentation [61]. The authors describe a patient with a markedly swollen left leg, with several small skin nodules and similar lesions on the right upper back. Bone marrow biopsy revealed concurrent HCL and MCC. The biopsy from the skin lesion also confirmed MCC.
A retrospective analysis of 129 patients with HCL between 1976 and 1983 identified two cases with symptoms of systemic vasculitis [68]. Another study of 42 HCL patients with coexisting vasculitis identified 21 patients with cutaneous leukocytoclastic vasculitis (CLCV) and 17 cases with panarteritis nodosa (PAN) [69]. PAN generally occurred after HCL and splenectomy and was often preceded by infection. Vasculitis with skin erythema can be an initial manifestation of early-stage HCL [67,70]; it can also precede the clinical manifestations of HCL or follow a diagnosis of HCL ( Fig. 1) [67,69,71,72]. Although the pathogenesis of vasculitis is unknown, it is believed that immune complex injury and crossreactions between autoantibodies to hairy cells and endothelial cells may take part [68,69,73]. In some patients, perivascular accumulation of leukemic cells among the cells of the perivascular infiltrations in the skin biopsy can occur [70]. In most cases, resolution of symptoms was observed after specific antileukemic treatment, and HCL is considered an underlying etiology for leukocytoclastic vasculitis, particularly in newly diagnosed patients [72]. Several reports indicate that HCL patients with coexisting vasculitis respond well to corticosteroids, splenectomy, and cytotoxic therapy with IFN-α or purine analogs [74]. In particular, treatment with cladribine improves the cutaneous symptoms and complete regression of vasculitis was usually achieved [61,67,69,70,74]. On the other hand, cladribine itself can induce vasculitis in HCL patients [75,76].
Behçet's disease is a multisystemic vasculitis involving both arteries and veins, which is characterized by recurrent oral and genital ulcers with characteristic cutaneous and ocular features recognized by a positive pathergy test [77]. This disease is observed in various hematological malignancies, including leukemias. However, it is often difficult to establish whether Behçet's disease is associated with leukemia, or it is merely a coexisting, leukemia-independent disease. Only two cases of HCL being associated with Behçet's disease have been reported in the literature: the first described a patient with HCL who developed Behçet's disease [78], and the second described the initial presentation as arthritis, oral and genital ulcerations, and papulopustular skin lesions in addition to pancytopenia [79].
Polyarteritis nodosa is an immune complex-mediated necrotizing vasculitis of small-and medium-sized arteries typically with multiorgan involvement. It is characterized by segmental transmural inflammation of muscular arteries.
Patients may present with cutaneous involvement, especially livedo reticularis, painful peripheral neuropathy, musculoskeletal pain, and vascular nephropathy. Several investigators have indicated an association between HCL and PAN, and an etiologic relationship between the two conditions has been suggested [69,[80][81][82]. The pathogenetic mechanism of PAN in HCL includes hepatitis B antigenemia, direct invasion of blood vessel wall by leukemic cells, cross-reactivity of antibodies that target surface determinants on hairy cells with epitopes on endothelial cells, and splenectomy [68,83,84].

Neutrophilic dermatoses
Neutrophilic dermatoses include Sweet's syndrome, pyoderma gangrenosum and neutrophilic eccrine hidradenitis [85]. Sweet's syndrome, also known as acute febrile neutrophilic dermatosis, is a rare inflammatory condition that can be associated with drugs, infections, inflammatory bowel disease, pregnancy, and cancer among others. It typically presents with acute onset dermal neutrophilic lesions, leukocytosis, and fever. The skin symptoms are characterized by erythematous painful lesions on the skin, which are distinctive, asymmetric, erythematous, and often tender plaques. The pathogenetic mechanism of the disease is not completely defined, but it may occur as a hypersensitivity reaction to an infection, cancer, or other diseases. Sweet's syndrome has been rarely reported in association with HCL [86,87]. A chemoattractant substance released from leukemic cells, including IL-8, and IFN-γ and granulocyte colony-stimulating factor (G-CSF) may be involved in developing neutrophilic tissue infiltration. Several studies have suggested a link between HCL and Sweet's syndrome [88][89][90][91][92][93][94]. It can be the first manifestation of HCL, or diagnosed at relapse of leukemia. In the reported cases, the skin symptoms regressed after splenectomy or treatment with IFN-α [92,93]. However, treatment with cladribine and prednisone seems to be the treatment of choice in HCL-associated Sweet's syndrome [86,89,91,93].
Pyoderma gangrenosum is a rare painful neutrophilic, reactive, non-infectious, inflammatory dermatosis involving the skin, mucosal areas, and other organs. Pyoderma gangrenosum is seen mostly in association with systemic diseases like hematologic disorders, inflammatory diseases, and arthritis [94]. The disease is manifested as painful erythematous lesion rapidly progressing to a blistered or necrotic ulcer (Fig. 2). Pyoderma gangrenosum exists as ulcerative, vegetative, pustular, bullous, and peristomal variants [95]. Although its pathogenesis is not fully understood, immune dysregulation involving neutrophil chemotaxis has been suggested as an important pathogenic factor. The disease can be associated with systemic disorders including hematologic malignancies. Pyoderma gangrenosum is rarely reported in HCL, and only few cases have been reported so far [96][97][98][99]; however, in such cases, the condition can be treated successfully with cladribine, without any additional use of immunosuppressive drugs such as corticosteroids or cyclosporine [97,98]. The high efficacy of cladribine is believed to result from its antileukemic and immunosuppressive properties.

Cutaneous infections
Approximately 30% of HCL cases present as an infectious episode. Infections are also the most common cause of morbidity and mortality in HCL patients. These are most often bacterial or viral, especially Zoster infections (Fig. 3). In a study of 113 patients, 62 demonstrated both cutaneous and extra cutaneous infections (55%) [100]. Herpetic lesions were the most common, observed in 25 patients, including herpes simplex in 17 patients, Zoster in seven, and generalized varicella in one patient. Verrucae, dermatophyte, candidal infections, and pyogenic infections (i.e., abscesses, cellulitis, folliculitis, and pyoderma) were less frequently observed.
Opportunistic skin infections, including atypical mycobacterial skin infections, have also been reported in HCL patients [101,102]. Trizna et al. present the case of a patient with HCL, who developed cutaneous tumor caused by Mycobacterium kansasii: surgical removal of the tumor and subsequent combination antituberculotic treatment with IFN-α led to resolution of infection and remission of HCL [103]. Another report described the successful ethambutol, cycloserine, and isoniazid treatment of a patient with HCL and pulmonary infection diagnosed with disseminated cutaneous Mycobacterium malmoense infection [104]. Maurice et al. describe the case of a 66-year-old man with HCL treated successfully with IFN-α, who developed widespread cutaneous and subcutaneous nodules caused by intracellular Mycobacterium avium infection [105]. The skin lesions progressed slowly on quadruple antituberculous chemotherapy; however, a marked improvement of all skin lesions was observed on erythromycin therapy.
Rare cases of opportunistic fungal infection were also described in HCL patients. Kumar et al. reported a case of cutaneous Sporotrichosis infection as a presenting manifestation of HCL. The lesions resolved following antifungal therapy [106]. Opportunistic infection due to Listeria monocytogenes manifesting as cerebritis and cutaneous lesions was also reported in a patient with HCL [107].
Ecthyma gangrenosum is a rare cutaneous ulcerative lesion associated with Pseudomonas aeruginosa infection, but is also observed in patients with other bacterial, viral, and fungal infections. Typically it starts as a painless red macule that rapidly becomes pustular with surrounding erythema, followed by hemorrhagic bullae and cutaneous ulcerative lesions (Fig. 4) [108]. Ecthyma gangrenosum has been rarely observed in HCL patients [109]. As ecthyma gangrenosum is typically associated with Pseudomonas aeruginosa bacteremia, the diagnosis should be followed by immediate empiric antimicrobial therapy with an antipseudomonal antibiotic [109]. However, in HCL patients, simultaneous treatment with purine analogs can be more effective. A recent study reported no clinical improvement in a patient simultaneously diagnosed with HCL and ecthyma gangrenosum, despite adequate antibiotic treatment with ceftazidime, clindamycin, and gentamicin [109]; however, the ecthyma gangrenosum resolved completely within 3 months after treatment with cladribine, and CR was achieved for HCL.

Cutaneous adverse drug reactions
A high incidence of cutaneous adverse drug reactions has been reported in patients with hairy cell leukemia treated with cladribine [66,[110][111][112]. Although cladribine has been reported to cause rash during therapy, any adverse skin reactions are unlikely to be directly attributable to cladribine itself in most patients, but rather to other concomitantly used drugs, particularly antibiotics. It is suspected that cladribine predisposes patients with HCL to hypersensitivity to concomitant medications, most commonly allopurinol, penicillins, Fig. 2 Ulcerative pyoderma gangrenosum on the right tibial surface in the patient with hairy cell leukemia before treatment. Lesions completely resolved after treatment with cladribine treatment Fig. 3 Herpes zoster infection in a patient with hairy cell leukemia treated with cladribine trimethoprim-sulfamethoxazole, or granulocyte-colony stimulating factor [110,113,114].
Recently, Castagna et al. described 12 HCL patients treated with cladribine who developed cutaneous adverse drug reactions during the aplasia stage, with a median occurrence at 12 days (10-15) after cladribine initiation [115]. Eight patients had maculopapular exanthema with systemic symptoms, two patients had acute generalized exanthematous pustulosis, and another two had DRESS (drug rash with eosinophilia and systemic symptoms) syndrome. Eleven patients were demonstrated drug allergies.
Meher-Homji et al. compared the prevalence of antibiotic allergy labels (AAL) in 43 cladribine-treated HCL patients, with those in patients with hematological malignancies not treated with cladribine and those in patients with CLL or follicular lymphoma treated with fludarabine [111]. A higher prevalence of antibiotic allergy was observed in cladribinetreated patients with HCL (26/43 patients, 60.47%), than in non-HCL cladribine-treated controls (14%) and controls treated with fludarabine (25%). Among the 26 antibiotic-allergic patients, only five had undergone allergological investigations with skin tests, four of whom were found to be positive for antibiotics. Another study reported that the development of halogenoderma with skin necrosis over the forearm, requiring excision and skin grafting, was also reported in a patient with HCL treated with intravenous cladribine [116].
IFN-α treatment is associated with the incidence of common rashes in 2% of patients, as indicated by the drug manufacturer. IFN-α can also induce alopecia universalis and cutaneous polyarteritis nodosa. Localized reactions include hyperpigmentation of the tongue and facial erythema. Severe polymorphic erythema and blisters have been also reported after the application of IFN-α to treat HCL. In this case, the patient developed a rash and erythema without pruritus and fever after the first injection of IFN-α, a rash on the neck after the second injection, and diffuse erythema, rashes, and blisters after the third injection. Histopathological examination of a skin biopsy showed lymphocytic exocytosis and a perivascular lymphocytic infiltration. The skin symptoms receded after treatment with methylprednisolone [117].
Another study describes the occurrence of disseminated ulcerating lupus panniculitis during IFN-α therapy of HCL [118]. The patient initially responded to oral prednisone and hydroxychloroquine became resistant to the treatment after several months. However, the skin lesions were controlled by treatment with cladribine and rituximab. The responsiveness of skin disease and HCL to cladribine and rituximab suggests a common denominator in pathogenesis of both disorders.
The adverse effects of vemurafenib are mostly associated with the skin. These include Grover's disease, photosensitivity, rash, palmar fibrosis, and warts. Vemurafenib was also associated with other hyperkeratotic cutaneous adverse reactions including squamous cell carcinoma, plantar hyperkeratosis, verrucal keratosis, and keratosis pilaris-like reactions [119,120]. Grover's disease is an acquired skin disorder characterized by pruritic papulovesicular eruptions, edematous papules, and/or papulovesicles of the trunk with acantholysis of the epidermis in histopathological examination [121]. Grover's disease was observed in 42.9% of metastatic melanoma patients treated with a single BRAF inhibitor [119]. However, Grover's disease has also been observed in HCL patients not treated with BRAF inhibitors [122].

Conclusions
Specific lesions occur in approximately 10-12% of HCL patients. Cutaneous manifestations are varied and are mostly related to the occurrence of infection, autoimmune processes, secondary neoplasms, medication use, or specific leukemic infiltration. Vasculitic manifestations are relatively uncommon events in HCL patients and can occur anytime during the course of HCL, sometimes preceding the clinical manifestations of leukemia. Many vasculitides have been associated with HCL, including polyarteritis nodosa, leukocytoclastic vasculitis, and pyoderma gangrenosum. Treatment of the underlying HCL, especially with purine analogs, may generally result in a rapid improvement of the cutaneous lesions and potentially complete regression of the vasculitis. The direct leukemic infiltration of the skin (i.e., leukemia cutis) is a relatively rare manifestation of the disease; however, a response to the specific treatment for HCL resulted in the disappearance of cutaneous infiltrates in most presented cases. The HCL Fig. 4 Ecthyma gangrenosum in the patient with hairy cell leukemia associated with Pseudomonas aeruginosa bacteremia, manifested as painless red macule with surrounding erythema, followed by hemorrhagic bullae and cutaneous ulcerative lesions population seems to be more susceptible to the incidence of secondary cutaneous malignancies, particular melanoma, than the general population. In addition, skin cancers have a high frequency of RAS mutations in HCL patients and may behave unusually aggressively. A high incidence of cutaneous adverse drug reactions, especially in treated patients with HCL, was observed, particularly in patients receiving cladribine and concomitant medications. Finally, the use of antileukemic drugs in HCL predisposes the patient to viral, fungal, and bacterial skin infections, including opportunistic infections.
Author contributions All authors examined the available material, wrote the review, reviewed and revised the manuscript, and provided their approval of the final version of the manuscript. All authors agree to be accountable for all aspects of the work.

Compliance with ethical standards
Conflict of interest The authors declare that they have no conflicts of interest.
Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
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