Immune-Mediated Cutaneous Paraneoplastic Syndromes Associated With Hematologic Malignancies: Skin as a Mirror of Hematologic Neoplasms

Malignant neoplasms may present as paraneoplastic syndromes with mucocutaneous manifestations, which may or may not be chronologically associated. The pathophysiological mechanism is complex and not completely understood; therefore, definitive diagnosis may be achieved with a precise differential diagnosis based on the morphology of skin lesions, clinical picture, and histological pattern. The complexities, and low frequency, make the therapeutic approach quite challenging; consequently, the cornerstone of therapy is the eradication of the underlying neoplasms. Corticosteroids are the therapy of choice for most of these immune-mediated manifestations, but for the most part, the successful resolution requires the eradication of the underlying malignancy.

Thymoma, or lymphoproliferative entities, may assist the escape of autoreactive T cells, which could therefore trigger disease reactions, such as paraneoplastic pemphigus (PP) [6].
Autoreactive peripheral cells may become anergic if no antigen-presenting cell is found. However, tumor cells, such as Hodgkin's lymphoma (HL) and B-cell chronic lymphocytic leukemia (CLL), may express molecules such as β2 microglobulin, or major histocompatibility complex type I and II, which can favor the expansion and differentiation of the autoreactive cells [7]. Neoplastic cells recruit regulatory T cells, which produce interleukin-10 to avoid immune surveillance, a situation that does not avoid immune reactions, as these cells also produce interleukin-4 and interleukin-17, which promote tumor tolerance and peripheral inflammation [6,7].
HM has been associated with an imbalance among T cells and cytokine production. An example is a shift to a T helper 2 (Th2) response, and the increase of Th2/T helper 1 (Th1) relationship, in diseases such as HL, acute myeloid leukemia (AML), and chronic myeloid leukemia (CML) [8]. This situation may be responsible for different phenomena such as neutrophil cutaneous recruitment or the stimulation of autoantibody production. Furthermore, an increase of interleukin-1 and interleukin-6 is observed in CML, which could be related to neutrophilic dermatosis pathogenesis [9]. Additionally, in HL and B-cell CLL, a microenvironment enriched with Th17 has been observed, which is thought to be related to the pathogenesis of neutrophilic and autoimmune blistering dermatoses. Mechanisms implied on immune-mediated skin disorders' pathogenesis in patients with hematologic malignancies are described in Table 1.

Hematologic malignancy Mechanism
Lymphoid lineage malignancies Central T cell tolerance disorder (immature and autoreactive T cell escape from thymus

Neutrophilic Dermatoses
ND is a heterogeneous group of clinically polymorphic dermatoses characterized by mature neutrophil infiltrates and no evidence of infection [10]. The most frequent ones are Sweet's syndrome, pyoderma gangrenosum (PG), erythema elevatum diutinum (EED), subcorneal pustular dermatosis, and neutrophilic eccrine hidradenitis (NEH) [1,2,11]. Evidence has been found that in these dermatoses, neutrophils may be clonally related to neoplastic cells and may have been differentiated from them [12]. If such a hypothesis is confirmed, these entities could no longer be considered paraneoplastic syndromes.
Sweet's syndrome: About a fifth of the patients diagnosed with Sweet's syndrome suffer from an associated malignancy with a majority (85%) of them related to HM [13], and have a prevalence of AML and myelodysplastic syndrome (MDS) that oscillates between 15% and 27% [14]. It has been well described in CML, B-cell CLL, monoclonal gammopathies (mainly immunoglobulin G [IgG]), and multiple myeloma (MM), and less frequently in HL, non-Hodgkin's lymphoma (NHL), and myeloproliferative disease (MPD) [15]. The mortality rate seen in patients with Sweet's syndrome and associated HM is higher (44%) when compared to 14% in those without HM [15,16].
Clinical presentation of Sweet's syndrome can be easily mistaken as an infection, as it presents with fever, neutrophilia, nodules, erythematous, and/or painful plaques, which may be associated with pseudo vesiculation or pustules, besides blistering and unusual subcutaneous forms [17]. Usually located in the upper limbs, torso, back, head, and neck ( Figure 1A), plaques do not respond to antibiotics generally [14]. Furthermore, patients may also present with extracutaneous manifestations that include conjunctivitis, episcleritis, arthritis, myalgias, glomerulonephritis, hepatitis, neutrophilic alveolitis, encephalitis, myocarditis, splenomegaly, among others [15][16][17]. Cutaneous manifestations usually occur months or years before HM diagnosis (although they can appear simultaneously), and they may recur after clinical remission, during HM relapses [17].
Pyoderma gangrenosum: PG is an uncommon inflammatory disease [18]. In a systematic review with 823 PG cases conducted by DeFilippis et al., it was found that inflammatory bowel disease, polyarthritis, and HM were associated with PG in 65.2%, 16.1%, and 12.5% of the cases, respectively [19]. Of the cases associated with HM, 25% corresponded with MDS, 22% with monoclonal gammopathy of uncertain significance (MGUS), 12% with AML, and 6.4% with MM [20]. The most common types of PG associated with HM are ulcerative and blistering [18], especially in myeloproliferative syndromes. IgG gammopathies are more frequent; however, the ones associated with PG are immunoglobulin A (IgA) [16]. The association between HM and PG has been observed as a cause of death [16,21], mainly in AML, CML, MDS, MM, MGUS, and lymphoma.
Lesions evolve from a papule or inflammatory pustule to a violaceous, extremely painful ulcer, with elevated borders, sterile purulent exudate, and a necrotic base. Other subtypes have been described, such as blistering, pustular, vegetative, and extracutaneous [18]. The affected zones usually are lower limbs, specifically the anterior tibial surface ( Figure 1B) [18].
Subcorneal pustular dermatosis: Also known as Sneddon-Wilkinson disease, it is a rare, relapsing, chronic pustular eruption, characterized by flaccid subcorneal pustules that contain neutrophils in histopathology [25]. The least associated HM is IgA myeloma, aplastic anemia, lymphomas, and CLL [16]. Cutaneous signs may appear years before HM diagnosis, and they may improve with the treatment of the underlying malignancy [16,25,26].
Neutrophilic eccrine hidradenitis: It is a rare dermatosis, characterized by infiltrated papules or plaques like in Sweet's syndrome [16], with neutrophil infiltrates surrounding eccrine glandules. These lesions may be asymptomatic, itchy, or painful, and are usually located in the trunk, face, or limbs. Patients usually present with a self-resolving course [16]. Bachmeyer et al. conducted a literature review of 51 cases of NEH that indicated that 67% had AML [27]. Other HMs associated were B-cell CLL, CML, HL, and NHL [27]. Most patients (84%) received chemotherapy (specifically cytarabine and anthracyclines) before NEH started. Generally, NEH patients present with a spontaneously resolving course in a few days or weeks, and no specific treatment is required [16]. In most cases, it is considered an adverse effect of chemotherapy.

Eosinophilic Dermatoses
ED is a heterogeneous group of cutaneous eruptions that predominantly occur in patients with indolent lymphoproliferative disorders, mainly CLL, in up to 6-8% of these cases [28]. Some patients, mainly those with acute leukemia, chronic myeloproliferative disorders, and plasma cell dyscrasias, may also present this dermatosis [29]. It usually presents months or years after HM diagnosis [30]. Nonetheless, a minority of patients can also present with the cutaneous rash up to 10 years before HM diagnosis [16].
These patients may develop "insect bite-like" reactions, due to T cell proliferation and the release of interleukin-5 [31]. Some controversy surrounds this dermatosis and its denomination as a paraneoplastic syndrome, given some findings of tumor invasion in the skin [16]; hence, two hypotheses have arisen: (1) that tumor cells infiltrate the skin and promote eosinophil activation; or (2) neoplastic treatment may trigger a persistent deviation of T cells to a Th2 phenotype, which may favor T cell recruitment on the skin and eosinophil activation in response to environmental triggers [16].
At least three main clinical patterns have been described [16]: (1) a blistering pattern, similar to bullous pemphigoid; (2) an "insect bite-like" pattern, characterized by discrete urticaria papules, sometimes with abundant vesicles similar to papular urticaria ( Figure 1C); and (3) a cellulitis-like pattern, characterized by diffuse erythematous plaques or nodules similar to Wells syndrome. Patients may present with intense itching, which is often intolerable. Eosinophilic dermatosis (ED) must be differentiated from T cell papulosis associated with B-cell neoplasms; these are characterized by itchy papules, vesicles, plaques, and nodules [32]. Its histopathology shows prominent T cell infiltrates, like cutaneous T cell lymphoma, specifically, folliculotropic mycosis fungoides. Just like ED, the rash presents in a relapsing manner despite treatment.

Blistering Dermatoses
These are characterized by suprabasal acantholysis due to autoantibodies, principally IgG, directed against keratinocytes' intercellular adhesive proteins [33]. Even though a higher prevalence and a possible association of malignancies with pemphigus vulgaris, pemphigus foliaceus, and bullous pemphigoid, the classic paraneoplastic entity is the PP -a rare, devastating autoimmune disease that affects skin and mucosa, presenting in patients with underlying malignancies, although it has been sporadically described even in the absence of tumors [16]. PP occurs in association with a variety of neoplastic disorders, the most frequent are HM-like lymphomas (45%), Castleman's disease (15%), and leukemia (7%) [34]. Clinically, it differs from other forms of pemphigus by a more severe mucous involvement ( Figure 2A) and greater resistance to immunosuppressant treatment, and the skin may present with flaccid or tense bullae, with an atypical target pattern, simulating erythema multiforme or Stevens-Johnson syndrome [16].

Miscellaneous
Plenty of paraneoplastic syndromes with skin involvement have been reported as a result of vascular disturbances, connective tissue abnormalities, or granulomatous infiltration [16].
Paraneoplastic cutaneous vasculitis has a similar clinical course to idiopathic ones, i.e. palpable purpura, erythematous nodules, chronic and painful ulcers, livedo reticularis or racemosa, gangrene, and acral necrosis with a predilection for lower limbs ( Figure 2B). Those with a paraneoplastic origin have a longer duration and present lower response rates to glucocorticoid/immunosuppressive treatment [16,36].
It may represent a diagnostic challenge to distinguish it from leukemic vasculitis, which is a rare presentation of leukemia cutis. This distinction is critical, as leukemic vasculitis is associated with poor prognosis, which correlates with the aggressive biological behavior of the underlying hematologic malignancy [16].
Connective tissue diseases: These diseases, such as systemic lupus erythematosus (SLE), Sjögren's syndrome, and systemic sclerosis, all have been linked to a higher risk of HM, primarily B-cell lymphoma [16]. Marginal zone lymphomas and mucosa-associated lymphoid tissue (MALT) lymphomas are related principally to Sjögren's syndrome, with an incidence 44 times higher than the general population [37].
Malignancies occur in 13-42% of patients with dermatomyositis, with a higher risk in the first two years after diagnosis. Paraneoplastic dermatomyositis is more common in solid tumors, although classic and amyopathic dermatomyositis has been reported in patients with HM (NHL, HL, AML, and MDS) [16]. HMassociated dermatomyositis carries a poor prognosis, with survival rates of 96.9%, 78.1%, and 51.4% at one, three, and five years, respectively [38].
Clinical features include the classic erythematous dermic papules on top of interphalangeal joints (known as Gottron papules), heliotrope rash, erythematous/poikilodermatous macules with a signature distribution (V sign, shawl sign, and holster sign), and nailfold telangiectasias ( Figure 2C). The presence of erythroderma in dermatomyositis is a hallmark of malignancy, specifically of lymphoid source [39].

FIGURE 2: A. Paraneoplastic pemphigus. Oral mucositis with diffuse erosion areas involving lip and tongue mucosa in a patient with thymoma. B. Small vessel vasculitis. Palpable purpura with necrotic crusts in both lower limbs. C. Dermatomyositis. Heliotrope erythema and macules in trunk and shoulder (shawl sign).
Pictures courtesy of the University of Antioquia Dermatology Service.
Granulomatous dermatoses: Clinical entities associated with paraneoplastic syndromes are annular granuloma (AG), cutaneous sarcoidosis, and palisaded neutrophilic granulomatous dermatitis, which have all been associated with a wide range of malignancies, such as HL, NHL, MDS, and CML [40]. Sarcoidosis patients have a five times higher risk of developing a lymphoproliferative disorder (mainly HL) [16].
Regarding the association between AG and lymphoma, AG may precede the lymphoma diagnosis, which occurs subsequently, with times ranging between five and 27 years [41]. Lymphomas are responsible for 56% of malignancy-associated AG, being HL the most common one.

HM-associated paraneoplastic dermatoses diagnosis
The cornerstone of a paraneoplastic syndrome diagnosis is based on the integration of history and physical examination findings. The skin lesion plays a fundamental role to guide any clinical suspicion, which is either ruled in or out according to histopathology. Nonetheless, it is important to highlight that the diagnosis of certain paraneoplastic syndromes is not limited to histologic studies, as these may require additional procedures, such as specific biochemical studies.
After the dermatosis has been identified, it is necessary to look for possible underlying malignancies. The diagnosis of paraneoplastic syndrome with skin manifestations and the diagnostic workup of underlying malignancy are described in Table 2.

Treatment
Steroids play a fundamental role in the treatment of immune-mediated dermatoses -both in idiopathic and paraneoplastic ones. However, there exists a high rate of recurrence in paraneoplastic dermatosis, which leads to therapy extension [16]. Most have a specific targeted therapy, although it depends on the malignancy and the severity of the paraneoplastic syndrome. The main treatment and prognosis of the different entities involved are described in Table 3.

Most common HM Treatment and prognosis
Neutrophilic dermatoses (Sweet's syndrome)

Acute myeloid leukemia
No specific treatment schemes for malignancy-associated Sweet's syndrome have been described [13]. Systemic corticosteroids are usually required at a 1 mg/kg dose for three to four weeks [16].

MDS and MGUS
A systematic review by Montagnon et al. [20] showed that most patients (75%) with HMassociated PG achieved control of the skin lesions with systemic corticosteroids; chemotherapy alone achieved PG resolution in only 7.5% of cases.

Erythema elevatum diutinum
IgA monoclonal gammopathies First-line treatment is dapsone followed by corticosteroids. Therapy with 50 and 100 mg per day is associated with partial or complete resolution of the disease in most cases. However, a relapse risk exists after therapy ceases in 32% of cases [22][23][24].
Subcorneal pustular dermatosis IgA myeloma First-line treatment is dapsone; other therapies may be used as well such as corticosteroids, sulfasalazine, colchicine, systemic retinoids, phototherapy, and other immunosuppressants such as methotrexate or mycophenolate [25].

Eccrine neutrophilic hidradenitis
Acute myeloid leukemia Self-resolving entity within days or weeks, without the need for any specific treatment [27]. Topical corticosteroids may be used to reduce the duration of symptoms. The course of this dermatosis is chronic and relapsing, despite treatment [32].

Blistering dermatoses
Paraneoplastic pemphigus Hodgkin's lymphoma Early directed therapy against malignancy, specifically in the presence of Castleman's disease or thymoma. First-line therapy is systemic corticosteroids associated with a steroid-sparing agent [16]. In severe or refractory cases, rituximab or intravenous immune globulin may be used [16,33].

MDSassociated PAN and hairy cell leukemia
Systemic corticosteroids and HM management have been the cornerstone of management for malignancy-associated vasculitis [35]. This type of vasculitis is characterized by a lower rate of response to corticosteroid/immunosuppressant therapy [16]. Vasculitis

Dermatomyositis
Non-Hodgkin's lymphoma Management is based on immunomodulation with corticosteroids and azathioprine, and malignancy workup for early oncologic treatment [16,42].

Conclusions
Certain hematological neoplasms, such as mycosis fungoides, are generally confined to the skin (and occasionally blood) at diagnosis with no evidence of extracutaneous involvement at the time of presentation. Because of that, it is necessary to know that a heterogeneous group of dermatologic manifestations exists in patients with HM. The presentation may be prior, concurrent, or after the HM diagnosis. Knowing the interaction between neoplastic cells and the immune system is fundamental to developing a specific workup and management for skin diseases associated with HM.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.