Cutaneous Signs of Hematologic Malignancies: Title and subTitle Break“Doctor, Is There Something Wrong With My Blood?”Hematologic Malignancies

As dermatologists who are constantly faced with different types of cutaneous lesions and disorders, we find that it is not uncommon that patients ask about the possible cause or origin of these eruptions. Many patients believe that all the macules, papules, urticaria, or nodules that have appeared on their skin are due to an as-yet undiscovered allergy. In other cases, patients or their companions fear that these eruptions appear because of an internal disease, mostly a “blood disease.” Thus, once we have examined their skin thoroughly, it is not uncommon to hear from them: “Doctor, is there something wrong with my blood?” (In Spanish: “ Doctor, ¿no será que tengo algo en la sangre? ”). Luckily, most of the times we can readily reassure them that their skin is the only place where something is going wrong, for most of these eruptions are common skin diseases, such as urticaria, psoriasis, eczema, and so forth.

Sometimes, dermatologists and dermatopathologists have to investigate further because these patients will truly have some kind of blood disorder that will cause us to refer them to our hematology colleagues, as demonstrated by the reports by New and Callen¹ and Balin et al,² published in this issue of the Archives. Some of these skin diseases are specifically linked to a hematologic condition, like necrobiotic xanthogranuloma and IgG paraproteinemia.³ Other eruptions are less specific and may be associated with a wide range of blood disorders. Sweet syndrome, for example, is most commonly associated with acute myelogenous leukemia, but it can be associated with other hematological malignancies, solid cancers, respiratory and gastrointestinal tract infections, inflammatory bowel disease, or drugs.⁴ Granuloma annulare (GA)-like eruptions may also be a marker of hematologic disorders.^{1 - 2}

Some of these skin disorders are the result of paraprotein deposition in the skin and other organs, as in primary amyloidosis, which is always associated with a proliferation of plasma cells with overproduction of a monoclonal immunoglobulin component. In other cases, cutaneous manifestations mirror the intravascular deposit of the paraprotein, as in type I cryoglobulinemia, in which cryoglobulins are monoclonal immunoglobulins, usually of the IgG or IgM type. In other patients, in addition to the paraproteinemia, there is abnormal cytokine secretion that is believed to produce the skin manifestations, like vascular endothelial growth factor in POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, M-Protein, and Skin Change) syndrome, in which the M stands for monoclonal protein, that is usually IgG,⁵ or interleukin-1 in Schnitzler syndrome, that is mostly associated with monoclonal IgM.⁶ Finally, there is a broader group of paraproteinemia-associated dermatoses in which the role of the paraprotein in the mechanism of the lesions is unknown, for example, necrobiotic xanthogranuloma, which is frequently associated with IgG monoclonal gammopathy, usually of the κ subtype³ ; scleromyxedema (monoclonal IgG)⁷ ; IgA pemphigus and Sneddon-Wilkinson syndrome (associated with monoclonal IgA or even myeloma); normolipemic plane xanthoma; acquired cutis laxa (ACL); erythema elevatum diutinum (usually associated with monoclonal IgA); or pyoderma gangrenosum (associated with myeloma or monoclonal gammopathy, particularly of the IgA type) (Figure 1).

Patients with leukemia may present with a variety of cutaneous manifestations. Some are rather nonspecific, such as purpura or ecchymosis due to thrombocytopenia, or cutaneous lesions in the setting of disseminated infections. Nonetheless, other lesions are specific because they are produced by skin infiltration with leukemic cells, as in leukemia cutis. A range of dermatologic conditions can sometimes be associated with leukemia and should be considered as paraneoplastic dermatoses. Sweet syndrome can be associated with myelodysplasia, different types of myeloid leukemia, or even nonmyeloid hematologic malignancies such as non-Hodgkin lymphoma, hairy cell leukemia, and multiple myeloma.⁴ Some forms of mastocytosis, particularly in adults, can be associated with a smoldering clonal proliferation of mast cells, or even mast cell leukemia.

Although leucocytoclastic vasculitis is infrequently associated with neoplasia, lymphoma or leukemia is a very common cause of paraneoplastic leukocytoclastic vasculitis. Other leukemia-associated paraneoplasic dermatoses are paraneoplastic pemphigus (chronic lymphocytic leukemia)⁸ ; neutrophilic eccrine hidradenitis (acute myelogenous leukemia and chronic myelogenous leukemia, with patients presenting with the cutaneous lesions when treated with chemotherapy); exaggerated insect bite reactions (chronic lymphocytic leukemia or other hematologic malignancies) (Figure 2)⁹ ; juvenile xanthogranuloma (juvenile myelomonocytic leukemia, especially in patients with multiple lesions and neurofibromatosis); pyoderma gangrenosum (myelodysplastic syndromes or myeloid leukemias; some clinical forms like bullous pyoderma gangrenosum may be more commonly associated)¹⁰ ; and eosinophilic cellulitis (also called Wells syndrome). Some cases of Wells syndrome might actually be “exaggerated insect bite reactions.” Some authors have coined the term eosinophilic dermatosis of myeloproliferative disease, a term that probably also accounts for the same process.¹¹

If we exclude the cutaneous lesions that are characteristic of patients with cutaneous lymphoma (both primary and secondary), patients with systemic lymphoma can also present with paraneoplastic cutaneous symptoms and signs. While infrequent, generalized pruritus, acquired ichthyosis, and eczema have been associated with lymphoma. Prurigo nodularis has been associated with Hodgkin lymphoma,¹² and paraneoplastic pemphigus with non-Hodgkin lymphoma.

Cutis laxa is a very rare condition due to a loss of elastic fibers of the skin. Patients present with loose and pendulous skin in the body folds, exhibiting a “premature aging” appearance. The acquired form has been linked to drugs, infections, or inflammatory conditions. Very infrequently, as in the report by New and Callen,¹ ACL has been described as a paraneoplastic phenomenon associated with multiple myeloma and monoclonal gammopathies, or even B- and T-cell lymphomas.^{13 - 14} λ Light chains have been the most frequently involved, although κ light chains have also been reported. Of note, in some cases the destruction of elastic fibers also led to pulmonary involvement with emphysema; pneumothorax; mediastinal emphysema and pneumonia; or gastrointestinal tract, genitourinary tract, and cardiovascular system engagement^{15 - 16} Interestingly, the patient described by New and Callen¹ also had a cutaneous eruption suggestive of GA. Histologically, in addition to the disappearance of elastic fibers, there were interstitial histiocytes and giant cells, as is seen in interstitial granulomatous dermatitis. To our knowledge, these features have not been reported in other cases of ACL associated with monoclonal gammopathy. In this case, the clinicopathologic features suggest that the paraprotein deposited on the dermal elastic fibers led to an activation of phagocytic cells that produced the destruction of these fibers with eventual development of ACL.

New and Callen¹ and Balin et al² raise important questions: Are GA and GA-like lesions associated with malignant disease? Are they associated with hematologic neoplasms in particular? Although in a recent report Li et al¹⁷ could not find a relationship between GA and malignant disease, the nexus between GA and malignant neoplasms remains to be fully elucidated. There are many reports of patients with cutaneous lesions of GA or interstitial granulomatous dermatitis who presented with a variety of neoplasms. These included Hodgkin and non-Hodgkin lymphoma, leukemia (acute myelogenous leukemia, chronic lymphocytic leukemia, myelomonocytic leukemia, large granular lymphocytic leukemia), myelodysplastic syndromes, and solid tumors (breast, cervical, colon, lung, prostate, testicular, and thyroid cancers).^{18 - 19}

In summary, the 2 observations published in this issue of the Archives demonstrate the value of dermatologists—and of medical dermatologists in particular—as physicians who can diagnose internal conditions based on the evaluation of the clinical and pathologic findings presenting in the skin of their patients.²⁰ Knowledge of the cutaneous lesions associated with internal diseases will help to select which patients should be screened in order to rule out an underlying hematologic malignancy, and really know when there is something wrong with their blood.

Correspondence: Dr Mascaró, Department of Dermatology, Hospital Clínic and Barcelona University Medical School, Calle Villarroel 170, 08036 Barcelona, Spain (jmmascaro_galy@ub.edu).

Financial Disclosure: Dr Mascaró has served as a consultant for Basilea Pharmaceuticals Iberia S.L. and for Reckitt Benckiser (España) S.L. and received honoraria for these services. He has also participated as a speaker for Merck Sharp & Dohme España S.A. and for Novartis and received honoraria for these services.