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On-line version ISSN 1806-4841
An. Bras. Dermatol. vol.84 no.6 Rio de Janeiro Nov./Dec. 2009
Sweet's syndrome associated withpolycythemiavera*
Ângela Puccini MoreiraI; Flávia Feijó de SouzaII; Neide Kalil GasparIII; Ada Lobato QuattrinoIV; Enoi Aparecida Guedes VilarVIGraduate student of the Dermatology Service of Universidade Federal Fluminense (UFF) Niterói (RJ), Brazil
IIGraduate student of the Dermatology Service of Universidade Federal Fluminense (UFF) Niterói (RJ), Brazil
IIIProfessor and head of Dermatology Service of Universidade Federal Fluminense (UFF) Niterói (RJ), Brazil
IVAssociate professor of the Dermatology Service of Universidade Federal Fluminense (UFF) Niterói (RJ), Brazil
VAssociate professor of the Dermatology Service of Universidade Federal Fluminense (UFF) Niterói (RJ), Brazil
Sweet's syndrome may be associated with hematological malignancies, particularly
with acute myelogenous leukemia, but there are few reports of its association
with polycythemiavera. We describethe case of a 65-year-old male patient, diagnosed
with polycythemiavera, which developedinto paraneoplastic Sweet's syndrome.
Sweet's syndrome may be associated with hematological malignancies, particularly with acute myelogenous leukemia, but there are few reports of its association with polycythemiavera. We describethe case of a 65-year-old male patient, diagnosed with polycythemiavera, which developedinto paraneoplastic Sweet's syndrome.
Keywords: granulocyte colony-stimulating factor; macrophages; polycythemia vera; sweet's syndrome
Polycythemia vera (PV) is a clonal disorder of multipotent bone marrow progenitor cells, characterized by hyperplasia of the hematopoietic cell lineage, increase in erythrocyte mass, leucocytosis and thrombocytosis. Clinical manifestations vary and treatment is oriented toward reducing blood volume and viscosity and the number of platelets, through phlebotomy, administration of radioactive phosphorus and other chemotherapeutic agents. Some cases may evolve to acute myeloid leukemia and mielofibrosis.1
Sweet's syndrome (SS) was originally described by Robert Douglas Sweet, in 1964,2 and it is a rare condition of unknown etiology, with painful red plaques or nodules emerging suddenly, mainly in the face, neck and upper limbs, associated with fever and neutrophil leucocitosis. The condition prevails in women, 30-50 years old, without racial predilection. It may be classified in five groups: idiopathic or classic, para-inflammatory, paraneoplastic, associated with pregnancy, and secondary to drug intake. Systemic corticoids are treatment of choice and obtain a fast clinical response.3-5
SS may be associated with malignancies in 20% of cases, 3,6 especially acute myeloid leukemia. There are few reports on the association with PV. We report a case of a sick male, 65 years old, with PV, who evolved with skin lesions compatible with the neoplastic form of SS.
Caucasian, 65 year old man, admitted to the Dermatology service, referring one year of recurring episodes of small and reddish papules on hands that developed into painful blisters, also accompanied by a 38ºC fever. Systems revision was normal, without evidence of lymphadenomegaly or organ enlargement. Upon physical examination, there were seropurulent blisters, varying 0.5-2 cm in size, circled by erythema, located on palms and distal phalange of the 4th left finger (Figures 1 and 2); small pustules over purpuric lesions, that measured roughly 0 cm and located on back of feet (Figure 3). Mucosas were spared.
Diagnostic assumptions of vasculitis and SS were raised. Lab tests showed a hematocrit of 40.5%, 4,400 leucocytes (with normal neutrophil count), 142,000 platelets and hemosedimentation speed of 50 mm/h. Results of liver function, electrolytes, creatinin, urea, urinalysis, chest x-ray and abdominal ultra-sound were within normal limits. The skin biopsy revealed papillary dermal edema, dense neutrophil infiltrate on dermis, dissociating collagen fibers; leucocitoclasia and leakage of red blood cells were present, confirming the diagnosis of SS (Figure 4). There was an immediate response and complete clearing of lesions in one month with prednisone (0.5 mg/kg/day). No recurrences were observed during a one year follow-up.
The diagnosis of PV had already been made two years before, during an investigation of weight loss and facial plethora, with a hematocrit of 51.2%, hemoglobin of 17.8 g/dl, 16,200 leucocytes and 476,000 platelets. Since then oral hydroxiurea was initiated (500mg/dia), as were two phlebotomies aimed at keeping the hematocrit below 45%; control of the clinical picture was reached.
SS is related to neoplasms in 20% of cases,3,6 with 85% of these related to hematological disorders and 15% to solid tumors. In relation to hematologic neoplasms, acute myeloid leukemia is more frequently observed, while 2/3 of solid tumors correspond to genital-urinary tract carcinomas.3
The paraneoplastic form of SS affects men and women equally, around 60-70 years of age, differently from the classic form. Clinical manifestations may be severe and atypical, with the presence of pustules, blisters, ulcers and purpura. In addition to the usual location, they are also distributed in lower limbs, trunk and back. Extra-cutaneous manifestations may develop and oral mucosa may be affected. Clinical recurrences are frequent and concomitant to tumor recurrences. Lab findings of anemia, abnormal platelet count and absence of neutrophil leucokocytosis reflect the natural history of the primary hematological neoplasm or of chemotherapeutic treatment. The presence and recurrence of hemorrhagic blister, purpura and lab alterations drew our attention to the association with the primary disease.3,6,7
Only seven cases associating PV with SS have been reported in the literature.6-12 In five of them, PV preceded the beginning of SS in years (2-18 years) and, in two of them, skin lesions were intermittent, some years before (4-13 years) the beginning of the blood disorder.6-8 The progression to myelofibrosis was reported in two cases8,9 and to acute myeloid leukemia in only one.10 For the remaining patients progression or transformation to more aggressive stages were not observed. In the case described, PV preceded SS in two years, without concomitant progression of the hematological disorder. The patient has been strictly followed up, given the recurrence of skin lesions is a bad prognosis sign due to the possibility of progression or recurrence of the primary disease.
The patophysiology by which SS is related to PV is unknown.6,7 High levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) are known to be found in SS. GM-CSF is responsible for stimulating the proliferation of stem cells of hematopoietic lineage, and of promoting chemotaxis of these cells and the differentiation and survival of the neutrophil and macrophage linhagem.13 Giasuddin et al.4 have suggested that the pathogenesis of SS would probably be mediated by Th1 cytokines and that there would be an increased production of interleukin-1 (IL-1), responsible for stimulating macrophages to secrete GM-CSF. Regarding PV, a neoplastic clone derived from stem cells are believed to originate the progenitors of the erythroid lineage, capable of proliferating in the presence of minimal amounts of eritropoetin.1 Oehler et al.14 demonstrated, in vitro, that interleukin-10 (IL-10) may inhibit the growth of colonies of granulocytes and macrophages, and also of erythroid progenitor cells, through the suppression of GM-CSF. Geissler et al.1 have suggested that IL-10 may be considered as a therapeutic resource for suppressing the excessive production of red blood cells in PV, in case GM-CSF is considered as responsible for the clonal cell expansion in the disease. The production of IL-10 on the skin is stimulated by exposure to ultra Violet radiation. Stoebner et al.15 demonstrated that a sole exposure to ultra Violet radiation in sub-erythematous doses is capable of inducing the production of IL-10 by T cells in human skin. Could exposure to UV radiation be a possible co adjuvant treatment for PV and SS?
Given the data shown, it is believed that the association of SS with PV probably represents an abnormality in the factors responsible for the control of cell proliferation in susceptible individuals and the main mechanism for explaining the association between both conditions would be GM-CSF freed by tumor cells or infiltrating histiocytes or, still stimulated epidermal cells.
An interesting aspect is the occurrence of SS, reported by Awan et al 5, in a patient with intense neutropenia, although neutrophil aggregates are found in the dermis of these patients. These aspects suggest that these infiltrates are not mandatorily of medullar origin and that they may occur under two conditions. The first one, that multipotent cells residing in the skin territory, may develop into neutrophil lineage and, the second, a more acceptable one, that during the activation of skin cells in an inflammatory reaction, there is production of GM-CSF, with demand for multipotent medullar cells that differentiate in the skin territory. If the assumption is confirmed, patients with SS are strongly suggested to be treated, for a long period, with systemic corticoids, aimed at suppressing the demand for multipotent medullar cells, enabling the likelihood of higher medullar stability.
Another case of SS associated with PV is reported, emphasizing the importance of routine investigation of malignancies, especially hematological ones. In those myeloproliferative disorders, SS may mean an unfavorable prognosis, needing a strict follow up, due to the possibility of conversion into acute myeloid leukemia.
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14. Oehler L, Kollars M, Bohle B, Berer A, Reiter E, Lechner K et al. Interleukin-10 inhibits burst-forming uniterythroid growth by suppression of endogenous granulocyte- macrophage colony-stimulating factor production from T cells. Exp Hematol. 1999;27:217-23. [ Links ]
15. Stoebner PE, Rahmoun M, Ferrand C, Meunier L, Yssel H, Pène J. A single sub-erythematous exposure of solar-stimulated radiation on the elicitation phase of contact hypersensitivity induces IL-10-producing T regulatory cell in human skin. Exp Dermatol. 2006;15:615-24. [ Links ]
Mailing Address: Conflict of interest: None * Study performed
at the Dermatology Service of the Universidade Federal Fluminense (UFF)
Niterói (RJ), Brazil.
Ângela Puccini Moreira
Rua Senador Vergueiro, 238 Ap. 914
22230 001 Rio de Janeiro RJ Brasil
Tel.:/Fax: 21 8111 0355
Suporte Financeiro: Nenhum
Conflict of interest: None
* Study performed at the Dermatology Service of the Universidade Federal Fluminense (UFF) Niterói (RJ), Brazil.