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Disseminated pustular dermatosis in polycythemia vera
Disseminated pustular dermatosis in polycythemia vera Relationship with neutrophilic dermatosis of myeloproliferative disorders: Study of neutrophil function J. J. Grob, M . D . , J. L. Mege, M . D . , A. M. Prax, M . D . , and J. J. Bonerandi, M . D . Marseille, France An unusual case of disseminated pustular eruption associated with polycythemia vera is described. This eruption can be included in the group of neutrophilic dermatoses of myeloproliferative disorders (pyoderma gangrenosum, Sweet's syndrome). A defect in superoxide anion (O2-) generation is detected. The fact that both the clinical condition and the neutrophil function improved with the use of dapsone suggests that the O2- generation defect may play a role in the pathogenesis of the eruption. From an evolutionary standpoint, the occurrence of a neutrophilic dermatosis in polycythemia vera could be an unfavorable sign of preleukemia. (J AM ACAD DERMATOL 1988;18:1212-8.)
P o l y c y t h e m i a vera is classified with myelogenous leukemia, agnogenic m y e l o i d metaplasia, and primary t h r o m b o c y t h e m i a as a myeloproliferative syndrome. Cutaneous symptoms have been reported with p o l y c y t h e m i a vera, including facial plethora, pruritus (particularly after a bath or shower), urticaria, purpura, and pyoderma gangrenosum. We present an unusual case o f diffuse pustular eruption associated with polycythemia vera. CASE REPORT A 72-year-old man had sequelae from previous acute poliomyelitis. For 20 years, he had been under regular surveillance for Vaquez' disease and was treated first by phlebotomy, then with 3~p and, finally, with pipobroman until December 1985. At that time, polycythemia vera stabilized and treatment was discontinued. In June 1986, cutaneous lesions appeared, beginning with
From HOpitalSte. Marguerite. Reprint requests to: Dr. J. J. Bonerandi, H6pital Ste. Marguerite, 270 BD de Ste. Marguerite, 13274 Marseilleeedex 2, France. 1212
a pustular plaque on the temple that was followed by a disseminated pustular rash on the extremities. These lesions were refractory to treatment with antibiotics (josamycin, amoxicillin) and ketoconazole. The patient's admission examination revealed a pustular eruption that was disseminated over the tegument but was more profuse on the extremities (Fig. 1) and in skin folds. There were acnelike lesions on the face, with a pustular plaque on the temple (Fig. 2), and pustules were noted on the scalp. The patient's nails were dystrophic. All but two bacteriologic and mycologic tests on fluid samples taken from pustules were sterile. Escherichia coli and Staphylococcus aureus were detected on two samples. Several biopsy specimens showed essentially intraepidermal pustules with some acantholytic cells (Fig. 3). In places, subcorneal pustules were noted. Direct immunofluorescence showed negative results. Hematologic tests yielded the following values: hemoglobin, 17.8 gm/dl; erythrocytes, 6.10 M / m m 3, white blood cells, 17,000/mm 3, polymorphonuclear leukocytes, 83%; and thrombocytes, 375,000/mm 3. A myelogram showed evidence of myeloid hyperplasia. Marrow biopsy revealed large patches of myelofibrosis. No blast was detected, but a study of bone marrow cell mitosis showed trisomy of chromo-
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Fig. 1. The pustular eruption is disseminated over the tegument but is particularly profuse on the extremities.
Fig. 2. Pustular plaque and acnelike eruption on the face.
some 19, suggesting that this chronic myeloproliferarive disease was about to develop into acute leukemia. The patient underwent an extensive battery of investigative tests. Normal findings were recorded with regard to the following parameters: sedimentation rate, plasma glucose, blood urea nitrogen, serum creatinine, serum lipids, alkaline phosphatase, aspartate transaminase, alanine transaminase, serum and urine bromide (which was not modified after ammonium chlorideinduced diuresis), serum and urine iodide, and serum zinc. Results of VDRL and Treponema pallidum hemagglutinin tests were negative, as were results of assays for circulating immune complexes, cryoglobulins, antinuclear antibodies, antibasement membrane antibodies, and anti-intercellular substance antibodies. CHso, C2, C3, C4, C5, and Clq values were in the normal range. Chest and sinus x-ray films were normal. Colonoscopy with staged biopsies showed negative results. Jejunum biopsy specimens and results of absorption tests were normal. Cutaneous tests with staphylococcal and streptococcal extracts and tuberculin showed faintly positive reactions, but candidin produced no reaction. The T lymphocyte count and subpopulations were in the normal range. Lymphoblastic transformation tests with phytohemagglutinin and pokeweed mitogen showed markedly low values. New attacks of pustular eruption occurred every day. Pustular glossitis and stomatitis developed and became erosive (Fig. 4). Bacterial and mycologic specimens from these lesions revealed only normal microbial populations. Dapsone was prescribed and brought a dramatic improvement within 15 days. Discontinuation of this treat-
ment for 15 days led to recurrence of the pustular eruption. Resolution of the skin lesions was again rapidly obtained with dapsone. Under this treatment, the eruption did not reappear. METHODS
Polymorphonuclear leukocytes were isolated according to the usual procedure. ~ Polymorphonuclear leukocyte mobility was studied by the modified Boyden chamber technique as described elsewhere. 2 Results were expressed in percentage of control values in response to human serum albumin 2% (Calbiochem, France-B iochem, Meudon, France), 10- 8M N- formylmethionyl - leucyl - phenylalanine (Calbiochem), autologous plasma, and zymosan-activated plasma. For investigation of phagocytosis, the ingestion of opsonized zymosan and glutaraldehyde-treated sheep red blood cells was measured as previously described. 3 Superoxide anion (O2-) generation was estimated by continuous recording of the amount of superoxide dismutase-inhibitable reduction of cytochrome C. Lag time of activation was assessed with phorbol myristate acetate4 (Sigma Chemical Co., St. Louis, MO). Three patient and 10 control samples were tested in this study of the oxidation process. RESULTS No significant abnormality in polymorphonuclear leukocyte mobility was discovered, and n o inducer or inhibitor was found in the patient's plasma. Ingestion of zymosan and glutaraldehydetreated sheep red ceils revealed no evidence of phagocytosis impairment, and these findings were
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Fig. 3. Photomicrograph of intraepidermal pustule with some acantholytic cells. DISCUSSION
Fig. 4. The pustular eruption involved the mucosa. The pustules coalesced and formed white membranes. not modified by autologous plasma. Zymosaninduced O2- release was normal. The 02- rate was markedly decreased with phorbol myristate acetate (50 ng/ml) (Fig. 5) and N-formylmethionyl-leucyl-phenylalanine (10 -6, 10-TM) (Fig. 6), and the lag time of activation with phorbol myristate acetate was prolonged. Treatment with dapsone improved the 02- generation rate in response to phorbol myristate acetate and N-formyl-methionyl-leucyl-phenylalanine but did not correct the lag time of activation with phorbol myristate acetate.
Myeloproliferative disorders have been associated with various aspects of neutrophilic dermatosis, 5'6 ranging from pyoderma gangrenosum to Sweet's syndrome and intermediate stages usually designated as "bullous pyoderma gangrenosum.'7 Acute leukemias are the most frequent underlying diseases, but chronic myeloproliferative disorders, such as chronic myeloid leukemia,712 agnogenic myeloid metaplasia, 7'12-14 and, very unusually, polycythemia vera have also been implicated. Although our patient's disseminated pustular eruption is morphologically different from pyoderma gangrenosum previously reported in connection with polycythemia vera,*'t':l: '7:5"17we considered it to be a neutrophilic dermatosis related to polycythemia vera for three main reasons. The first reason is a lack of an alternative etiologic explanation, investigative tests having ruled out
*Basset A, Maleville J, Bergoend H. Eruption vdgdtante des parties ddcouvertes daas une rnaladie de Vaquez traitde par le P32. Bull Dermatol Syphiligr 1969;76:63-4. i'Duveme J, Brizard CP, Voile H, Livoireau M. Pyodermite en placards extensifs et sphac61iques au cours d'une maladie de Vaquez stabilis6e par le P32. Bull Dermatol Syphiligr 1969;76:86-9. :[:Feuerman E, Potruch-Eisenkraft S. Un cas de polycyth6mie vraie. Bull Dermatol Syphiligr 1971;78:260-1.
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Fig. 5. Influence of dapsone on O2- generation induced by phorbol myristate acetate. The 02- generation was measured as superoxide dismutase-inhibitable reduction of cytochrome C by continuous recording in response to phorbol myristate acetate (50 ng/ml). Before treatment the 02- generation rate was markedly low and the lag time of activation was very long. Dapsone corrected the O2- generation rate but did not shorten lag time.
Fig. 6. Influence of dapsone on 02- generation induced by N-formyl-methionyl-leucyl-phenylalanine. The 02generation was measured as superoxide dismutasehibitable reduction of cytochrome C by continuous recording in response to N-formyl-methionyl-leucylphenylalanine (10 -7 M). Before treatment the O2- generation rate was markedly low. With dapsone the 02generation rate was improved but did not return to a normal value.
all other causes of pustulosis, such as infectious pustulosis, pustul,ar psoriasis, dermatitis herpetiformis, ulcerative colitis, bowel bypass syndrome, drug-induced eruption, and bromide intoxication. The second reason is that both pustular eruptions and pyoderma gangrenosum have been observed in association with the same affections, including ulcerative colitis, 18'm rheumatoid or rheumatoidlike arthritis, 2° and monoclonal gammopathy. 2~ Thus, by analogy, it is not surprising to find that a disseminated pustulosis can also be associated with polycythemia vera. Our third reason is that limited pustular lesions have been described in conjunction with polycythemia vera.*'~6
In our patient, dermatosis occurred at an advanced stage of disease, as shown by evidence of medullary fibrosis and bone marrow cell chromosome abnormalities. The association between medullary chromosome abnormalities and neutrophilic dermatosis has already been cited as a criterion of preleukemia. 22 In the literature, most cases of pyoderma gangrenosum with polycythemia vera occurred at the myelofibrosis stage,*"[ ",7,15,17 and in the observation of Perry et al, 7 acute leukemia rapidly developed. Thus, from a hematologic standpoint, neutrophilic der-
*Bureau Y, Guenel J, Barri~re H, et al. Eruption rdcidivante en placards pustuleux chez un maladie atteint de maladie de Vaquez. Bull Dermatol Syphiligr 1967;74:646-7.
*Basset A, Maleville J, Bergoend H. Eruption vdgrtante des parties drcouvertes dans une maladie de Vaquez traitde par le P32. Bull Dermatol Syphiligr 1969;76:63-4. tBureau Y, Guenel J, Barri~re H, et al. Eruption r~cidivante en placards pustuleux chez urt malade atteint de maladie de Vaquez. Bull Dermatol Syphiligr 1967;74:646-7.
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Grob et al
matosis appears to be an unfavorable sign in the course of polycythemia vera. The role played by therapies (32p and pipobroman in particular) in triggering neutrophilic dermatosis is eontroversial,*,t ,7:3 but it is likely that treatment does not induce these cutaneous lesions but simply extends survival time so that the patient reaches the advanced stage of leukemia and myelofibrosis, which is marked by neutrophilic dermatosis. Several disturbances in polymorphonuelear leukocyte function have been reported with pyoderma gangrenosum, but polymorphonuclear leukocyte exploration was most often normal. In fact, since, on one hand, investigative methods were often different and, on the other hand, the affections associated with pyoderma gangrenosum were also different, it is difficult to compare reports. Perturbations include decreased phagocytosis, 23-25 decreased23 or increased~6 random mobility, decreased chemotaxis,27.28 and decreased bactericidal effect. 2. Neither chemotaxis nor phagocytosis impairment was detected in our patient, but O2generation was significantly altered. The mechanism underlying this defect observed in our patient is unclear. O5- generation is achieved by the activation of a membrane enzyme, reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase, which catalyzes the removal of one electron from oxygen to form Oz- .29 Before this reduction step, interaction of ligands with membrane receptors stimulates "transductional pathways" involving diacylglycerol and protein kinase C, which in turn stimulate NADPH oxidase. 3° The ligands involved act on various receptors. Zymosan acts on C3b receptors and mannosyl fucosyl receptors, 3~ N-formyl-methionylleucyl-phenylalanine on specific membrane receptors, 32 and phorbol myristate acetate directly on protein kinase. 33 Thus the observed defect may occur at any one of the following levels: the ligandreceptor interaction, the transductional pathways,
*Basset A, Maleville J, Bergoend H. Eruption vdg6tante des parties d~couvertes dans une maladie de Vaquez trait~e par le P32. Bull Dermatol Syphiligr 1969;76:63-4. tBureau Y, Guenel J, Bard~re H, et al. Eruption r6cidivante en placards pustuleux chez un malade atteint de maladie de Vaquez. Bull Dermatol Syphiligr 1967;74:646-7.
Journal of the American Academy of Dermatology
or NADPH oxidase activation. Since zymosaninduced O2- generation was normal in our patient, it seems likely that enzyme function was normal and thus that the 02- generation defect in response to phorbol myristate acetate and N-formylmethionyl-leucyl-phenylalanine was due either to an abnormality of the ligand-receptor interaction or to faulty transductional pathways. Since treatment with dapsone led to an improvement of 02generation in response to N-formyl-methionylleucyl-phenylalanine and phorbol myristate acetate but did not shorten the lag time of activation with phorbol myristate acetate, which is considered to be a reliable index of transductional pathways,4 it may be inferred that dapsone acted during the early step of activation. Since dapsone probably modulates the phospholipid composition of polymorphonuclear leukocyte membranes,34 this constitutes an attractive basis for explaining the improvement in 02- generation after dapsone. The fact that both the clinical condition and neutrophil function improved under dapsone makes it likely that the neutrophil defect plays a role in the pathogenesis of this pustular eruption. Since disturbances in neutrophil function, including O2- production defects,35 have been associated with leukemia~6-4° even at the earliest stage, 35 it may be speculated that, in our patient, preleukemia was responsible for polymorphonuclear leukocyte anomalies that, in turn, may have triggered neutrophilic dermatosis. This sequence of events would explain why the occurrence of a neutrophilic dermatosis is an unfavorable sign in the prognosis of polycythemia vera. However, one cannot discount the fact that the defect of neutrophils in peripheral blood is only the result of the exhaustion of their oxidation capacities in the skin lesions. A parallel can be drawn between the eruption observed in our patient and other neutrophilic dermatoses. Histologically speaking, our patient's lesions correspond to intraepidermal pustulosis, but in some areas the histologic features were compatible with Sneddon-Wilkinson subcorneal pustulosis. This observation thus adds weight to the body of evidence in favor of unifying pyoderma gangrenosum, Sweet's syndrome, SneddonWilkinson subcorneal pustulosis, and some other
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Disseminated pustular dermatosis in polycythemia vera
unclassified pustular eruptions (as in this observation) in the same group o f diseases. One argument for this view is the histologic kinship of these disorders, all of which feature an influx of polynuclear cells to the skin without cutaneous infection. Another argument is that these disorders occur u n d e r similar conditions: p y o d e r m a gangren o s u m and, more rarely, unclassified pustular eruptions, 18.19Sneddon-Wilkinson subcorneal pustulosis, a9 or Sweet's syndrome *,4° occur in the course o f ulcerative colitis; p y o d e r m a gangrenosum and, m o r e rarely, unclassified pustular eruptions 2° in the course of rheumatoid or rheumatoid-like arthritis; pyoderrna gangrenosum, Sneddon-Wilkinson subcorneal pustulosis, and more rarely, Sweet's syndrome 4~,4~ in the course o f m o n o c l o n a l gammopathies; pyoderma gangrenosum, Sweet's syndrome, and more rarely, unclassified pustular eruptions (as with our case) in the course o f myeloproliferative disorders. Similarly, S w e e t ' s s y n d r o m e - l i k e lesions 43 and unclassified pustular eruptions 44 have been described in bowel bypass syndrome and after other intestinal surgical procedures. The last argument is that these afflictions are often concomitant (i.e., p y o d e r m a gangrenosum with unclassified pustular eruptions, 45 p y o d e r m a gangrenosum with Sweet's syndrome, 46 and pyoderma gangrenosum with Sneddon-Wilkinson subcomeal pustu1osis47'48). There is, however, a major argument against the unicity of these dermatoses: it is unlikely that the influx o f polymorphonuclear leukocytes has the same underlying mechanisms in affections as different as ulcerative colitis and hematologic diseases.
4. 5.
6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.
18.
*Wilkinson DS. Subcornealpustulardermatosis. Bull DermatolSyphilol 1962;69:674.
19.
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1. Bongrand D, Bartolin G, Bouvenot G, et al. Effect of age on different receptors and functions of phagocytic cells. J Clin Lab Immunol 1984;15:45-50. 2. Keler HV, Gerber H, Hess MW, Cottier H. Studies on the regulation of the neutrophil chemotactic response using a rapid and reliable method of measuring random migration and chemotaxis of neutrophil granulocytes. Agents Actions 1976;6:326-39. 3. Mege JL, Capo C, Bongrand P, et al. Monocytes and granulocytes in rheumatoid arthritis phagocytic activation
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of the granulocyte superoxide anion production. Clin Rheumatol 1985;4:433-40. Newburger PE, Chovaniee ME, Cohen HJ. Activity and activation of the granulocyte superoxide-generating system. Blood 1980;55:85-92. Caughman W, Stem R, Haynes H, Neutrophilic dermatosis of myeloproliferative disorders: atypical forms of pyoderma gangrenosum and Sweet's syndrome associated with myeloproliferative disorders. J AM ACAD DERMATOL1983;9:751-8. Cooper PH, Innes DJ, Greer KE. Acute febrile neutrophilic dermatosis and myeloproliferative disorders. Cancer 1983;51:1518-26. Perry HO, Winkelrnann RK. Bullous pyoderma gangrenosum and leukemia. Arch Dermatol 1972;106:901-5. GoldinD. Pyoderma gangrenosum with chronic myeloid leukaemia. Proc R Soc Med i974;67:1239-40. Kovary PM, Lanauer G, Niedorf FI-I, et al. Pyoderma gangrenosym mit Philadelphia Chromosom-negativer chronischer Leukemic. Dermatologiea 1977;154:360-6. Chevrant-BretonJ, Verger JP, Queffenton C, et al. Pyoderma gangrenosum et leucose my61oide chronique: A propos de 2 eas. Semin Hop Pads 1980;56:897-9. Lewis JE. Bullous pyoderma gangrenosum with chronic myelogenous leukemia: report of a ease. Cutis 1980; 25:82-3; Gopinath DK, Wolfe RD, Sabharwal K. Pyoderma gangrenosum with myelofibrosis. J Ky Med Assoc 1974; 72:548-50. Barriere H, Litoux P, Stalder JF, Barrier J. Pyoderma gangrenosum et h6mopathie. Ann Dermatol Venereol 1979;106:427-35. Callen JP, Dubin HV, Gehrke CF. Recurrent pyoderma gangrenosum and agnogenie myeloid metaplasia. Arch Dermatol 1977;113:1585-6. Micha~lsson G, Malin L, Ohman S, et al. Clofazimine: a new agent for the treatment of pyoderma gangrenosum. Arch Dermatol 1976;112:344-9. ShoreRN. Pyoderma gangrenosum, defective neutrophil chemotaxis and leukemia. Arch Dermatol 1976;112: 1792-3. Deschamps P, Leroy D, Dresch C, Michel M. Deficit immunitaire au routs d'un pyoderma gangrenosum associ~ ~t une polyglobulie vraie. Nouv Presse Med 1977;6:2339-41. O'Loughlin S, Perry NO. A diffuse pustular eruption associated with ulcerative colitis. Arch Dermatol 1978;114:1061-4. Fenske NA, Gem JE, Pierce D, Vasey FB. Vesiculopustular eruption of ulcerative colitis. Arch Dermatol 1983;119:664-9. Ayres S Jr, Ayres S. Pyoderma gangrenosum with an unusual syndrome of ulcers, vesicles and arthritis. Arch Dermatol 1958;77:269-80. Powell FC, Schroeter AL, Su WPO, Perry HO. Pyoderma gangrenosum and monoclonal gammopathy. Arch Dermatol 1983;119:468-72. Tikjob G, Kassis U, Thomsem HK, Jensen GG. Acute febrile neutrophilic dermatosis and abnormal bone marrow chromosomes as a marker for preleukemia. Acta Derrn Venereol 1985;65:177-9. Miller E, Dooley R. Deficient random mobility, normal
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ehemotaxis and impaired phagoeytosis: a new abnorma]ity of neutrophil function. Pediatr Res 1974;8:365. 24. Holt PHA, Davis MG, Saunders KC, Nuki G. Pyoderma gangrenosum: clinical and laboratory findings in 15 patients with special reference to polyarthritis. Medicine 1980;59:114-33. 25. Breathnach SM, Wells GC, Valdimarsson H. Idiopathic pyoderma gangrenosum and impaired lymphocyte function: failure of azathioprine and corticosteroid therapy. Br J Dermatol 1981;104:567-73. 26. JacobJC, GoetzEJ. "Streaking leukocyte factof' arthritis and pyoderma gangrenosum. Pediatrics 1975;56:570-8. 27. Norris DA, Weston WL, Thorne EG, Humbert JR. Pyoderma gangrenosum. Arch Dermatol 1978;114:906-11. 28. Nerella P, Daniela A, Guido M, Fabbri P. Leukocyte chemotaxis and pyoderma gangrenosum. Int J Dermatol 1985;24:45-7. 29. Babior BM. The respiratory burst of phagocytes. J Clin Invest 1984;75:559-601. 30. Wolfson M, McPhail LL, Nasrallah VN, Snyderman R. Phorbol myristate acetate mediates redistribution of protein kinase C in human neutrophils: potential role in the activation of the respiratory burst enzyme. J Immunol 1985;135:2057-62. 31. Alan R, Ezekowitz B, Sire RB, et al. Interaction of human monocytes, macrophages and polymorphonuclear leukocytes with zymosan in vitro: role of type 3 complement receptors and macrophage-derived complement. J Clin Invest 1985;76:2368-76: 32, Snyderman R, Pyke ML. Chemoattractant receptors on phagocytic cells. Ann Rev Immunol 1984;2:257-81. ~33. Nishihira J, O'Flaherty JT. Phorbol myristate acetate in human polymorphonuclear neutrophils. J Immunol 1985; 135:3439-47. 34. Shigeura HT. Metabolic studies on dapsone and sulfone derivatives in chick macrophages. Biochem Pharmacol 1975 ;24:687-9. 35. Solberg CO, Schreiner A, Hellym KB, Hamre E. Neu-
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37. 38. 39. 40. 41, 42. 43. 44. 45. 46. 47. 48.
trophil granulocyte function in the early diagnosis of actue myelomonocytic and myeloblastic leukaemia. Acta Med Stand 1975;197:147-51. Odeberg H, Olofsson T, Olsson I. Granulocyte function in chronic granulocytic leukaemia. I. Bactericidal and metabolic capabilities during phagocytosis in isolated granulocytes. Br J Haematol 1975;29:427-35. Mazzone A, Ricewuti G, Ross M, Rizzo SC. Prognostic significance of functional defects of granulocytes in myeloproliferative disease. Oncology 1986;43:176-82. E1 Maalenn H, Fletcher J. Impaired neutrophil function and myeloperoxidase deficiency in myeloid metaplasia. Br J Haematol 1977;37:323-9. Grow KD, Kerdel Vegas F, Rook A. Acute febrile neutrophilic dermatosis, Sweet's syndrome. Dermatologica 1969;139:123-34. Sweet RD. An acute febrile neutrophilic dermatosis. Br J Dermatol 1964;76:349. Holst R, M6backen H. Acute febrile neutrophilic dermatosis. Acta Derm Venereol (Stockh) 1971;51:63-6. Saxe N, Gordon W. Acute neutrophilic dermatosis: four case reports. S Afr Med J 1978;53:253-6. Bechtel M, Callen JP. Acute neutrophilic dermatosis (Sweet's syndrome). Arch Dermatol 1981;117:664-6. Dicken CH, Seehafer JR. Bowel bypass syndrome. Arch Dermatol 115; 115:837-9. Basler RS, Dubin HV. Ulcerative colitis and the skin. Arch Dermatol 1976;112:531-4. Benton EC, Rutherford D, Hunter JA. Sweet's syndrome and pyoderma gangrenosum associated with ulcerative colitis. Acta Derm Venereol (Stockh) 1986;65:77-80. Marsden JR, Millard LG. Pyoderma gangrenosum, subcorneal pustular dermatosis and IgA paraproteinaemia. Br J Dermatol 1986;114:125-9. Wolff K. Subcorneal pustulose Dermatose, Pyoderma gangrenosum mit IgA paraprote'inemie. Dermatol Monatsschr 1971;157:842.
P o l y c y t h e m i a vera is classified with myelogenous leukemia, agnogenic m y e l o i d metaplasia, and primary t h r o m b o c y t h e m i a as a myeloproliferative syndrome. Cutaneous symptoms have been reported with p o l y c y t h e m i a vera, including facial plethora, pruritus (particularly after a bath or shower), urticaria, purpura, and pyoderma gangrenosum. We present an unusual case o f diffuse pustular eruption associated with polycythemia vera. CASE REPORT A 72-year-old man had sequelae from previous acute poliomyelitis. For 20 years, he had been under regular surveillance for Vaquez' disease and was treated first by phlebotomy, then with 3~p and, finally, with pipobroman until December 1985. At that time, polycythemia vera stabilized and treatment was discontinued. In June 1986, cutaneous lesions appeared, beginning with
From HOpitalSte. Marguerite. Reprint requests to: Dr. J. J. Bonerandi, H6pital Ste. Marguerite, 270 BD de Ste. Marguerite, 13274 Marseilleeedex 2, France. 1212
a pustular plaque on the temple that was followed by a disseminated pustular rash on the extremities. These lesions were refractory to treatment with antibiotics (josamycin, amoxicillin) and ketoconazole. The patient's admission examination revealed a pustular eruption that was disseminated over the tegument but was more profuse on the extremities (Fig. 1) and in skin folds. There were acnelike lesions on the face, with a pustular plaque on the temple (Fig. 2), and pustules were noted on the scalp. The patient's nails were dystrophic. All but two bacteriologic and mycologic tests on fluid samples taken from pustules were sterile. Escherichia coli and Staphylococcus aureus were detected on two samples. Several biopsy specimens showed essentially intraepidermal pustules with some acantholytic cells (Fig. 3). In places, subcorneal pustules were noted. Direct immunofluorescence showed negative results. Hematologic tests yielded the following values: hemoglobin, 17.8 gm/dl; erythrocytes, 6.10 M / m m 3, white blood cells, 17,000/mm 3, polymorphonuclear leukocytes, 83%; and thrombocytes, 375,000/mm 3. A myelogram showed evidence of myeloid hyperplasia. Marrow biopsy revealed large patches of myelofibrosis. No blast was detected, but a study of bone marrow cell mitosis showed trisomy of chromo-
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Fig. 1. The pustular eruption is disseminated over the tegument but is particularly profuse on the extremities.
Fig. 2. Pustular plaque and acnelike eruption on the face.
some 19, suggesting that this chronic myeloproliferarive disease was about to develop into acute leukemia. The patient underwent an extensive battery of investigative tests. Normal findings were recorded with regard to the following parameters: sedimentation rate, plasma glucose, blood urea nitrogen, serum creatinine, serum lipids, alkaline phosphatase, aspartate transaminase, alanine transaminase, serum and urine bromide (which was not modified after ammonium chlorideinduced diuresis), serum and urine iodide, and serum zinc. Results of VDRL and Treponema pallidum hemagglutinin tests were negative, as were results of assays for circulating immune complexes, cryoglobulins, antinuclear antibodies, antibasement membrane antibodies, and anti-intercellular substance antibodies. CHso, C2, C3, C4, C5, and Clq values were in the normal range. Chest and sinus x-ray films were normal. Colonoscopy with staged biopsies showed negative results. Jejunum biopsy specimens and results of absorption tests were normal. Cutaneous tests with staphylococcal and streptococcal extracts and tuberculin showed faintly positive reactions, but candidin produced no reaction. The T lymphocyte count and subpopulations were in the normal range. Lymphoblastic transformation tests with phytohemagglutinin and pokeweed mitogen showed markedly low values. New attacks of pustular eruption occurred every day. Pustular glossitis and stomatitis developed and became erosive (Fig. 4). Bacterial and mycologic specimens from these lesions revealed only normal microbial populations. Dapsone was prescribed and brought a dramatic improvement within 15 days. Discontinuation of this treat-
ment for 15 days led to recurrence of the pustular eruption. Resolution of the skin lesions was again rapidly obtained with dapsone. Under this treatment, the eruption did not reappear. METHODS
Polymorphonuclear leukocytes were isolated according to the usual procedure. ~ Polymorphonuclear leukocyte mobility was studied by the modified Boyden chamber technique as described elsewhere. 2 Results were expressed in percentage of control values in response to human serum albumin 2% (Calbiochem, France-B iochem, Meudon, France), 10- 8M N- formylmethionyl - leucyl - phenylalanine (Calbiochem), autologous plasma, and zymosan-activated plasma. For investigation of phagocytosis, the ingestion of opsonized zymosan and glutaraldehyde-treated sheep red blood cells was measured as previously described. 3 Superoxide anion (O2-) generation was estimated by continuous recording of the amount of superoxide dismutase-inhibitable reduction of cytochrome C. Lag time of activation was assessed with phorbol myristate acetate4 (Sigma Chemical Co., St. Louis, MO). Three patient and 10 control samples were tested in this study of the oxidation process. RESULTS No significant abnormality in polymorphonuclear leukocyte mobility was discovered, and n o inducer or inhibitor was found in the patient's plasma. Ingestion of zymosan and glutaraldehydetreated sheep red ceils revealed no evidence of phagocytosis impairment, and these findings were
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Fig. 3. Photomicrograph of intraepidermal pustule with some acantholytic cells. DISCUSSION
Fig. 4. The pustular eruption involved the mucosa. The pustules coalesced and formed white membranes. not modified by autologous plasma. Zymosaninduced O2- release was normal. The 02- rate was markedly decreased with phorbol myristate acetate (50 ng/ml) (Fig. 5) and N-formylmethionyl-leucyl-phenylalanine (10 -6, 10-TM) (Fig. 6), and the lag time of activation with phorbol myristate acetate was prolonged. Treatment with dapsone improved the 02- generation rate in response to phorbol myristate acetate and N-formyl-methionyl-leucyl-phenylalanine but did not correct the lag time of activation with phorbol myristate acetate.
Myeloproliferative disorders have been associated with various aspects of neutrophilic dermatosis, 5'6 ranging from pyoderma gangrenosum to Sweet's syndrome and intermediate stages usually designated as "bullous pyoderma gangrenosum.'7 Acute leukemias are the most frequent underlying diseases, but chronic myeloproliferative disorders, such as chronic myeloid leukemia,712 agnogenic myeloid metaplasia, 7'12-14 and, very unusually, polycythemia vera have also been implicated. Although our patient's disseminated pustular eruption is morphologically different from pyoderma gangrenosum previously reported in connection with polycythemia vera,*'t':l: '7:5"17we considered it to be a neutrophilic dermatosis related to polycythemia vera for three main reasons. The first reason is a lack of an alternative etiologic explanation, investigative tests having ruled out
*Basset A, Maleville J, Bergoend H. Eruption vdgdtante des parties ddcouvertes daas une rnaladie de Vaquez traitde par le P32. Bull Dermatol Syphiligr 1969;76:63-4. i'Duveme J, Brizard CP, Voile H, Livoireau M. Pyodermite en placards extensifs et sphac61iques au cours d'une maladie de Vaquez stabilis6e par le P32. Bull Dermatol Syphiligr 1969;76:86-9. :[:Feuerman E, Potruch-Eisenkraft S. Un cas de polycyth6mie vraie. Bull Dermatol Syphiligr 1971;78:260-1.
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Fig. 5. Influence of dapsone on O2- generation induced by phorbol myristate acetate. The 02- generation was measured as superoxide dismutase-inhibitable reduction of cytochrome C by continuous recording in response to phorbol myristate acetate (50 ng/ml). Before treatment the 02- generation rate was markedly low and the lag time of activation was very long. Dapsone corrected the O2- generation rate but did not shorten lag time.
Fig. 6. Influence of dapsone on 02- generation induced by N-formyl-methionyl-leucyl-phenylalanine. The 02generation was measured as superoxide dismutasehibitable reduction of cytochrome C by continuous recording in response to N-formyl-methionyl-leucylphenylalanine (10 -7 M). Before treatment the O2- generation rate was markedly low. With dapsone the 02generation rate was improved but did not return to a normal value.
all other causes of pustulosis, such as infectious pustulosis, pustul,ar psoriasis, dermatitis herpetiformis, ulcerative colitis, bowel bypass syndrome, drug-induced eruption, and bromide intoxication. The second reason is that both pustular eruptions and pyoderma gangrenosum have been observed in association with the same affections, including ulcerative colitis, 18'm rheumatoid or rheumatoidlike arthritis, 2° and monoclonal gammopathy. 2~ Thus, by analogy, it is not surprising to find that a disseminated pustulosis can also be associated with polycythemia vera. Our third reason is that limited pustular lesions have been described in conjunction with polycythemia vera.*'~6
In our patient, dermatosis occurred at an advanced stage of disease, as shown by evidence of medullary fibrosis and bone marrow cell chromosome abnormalities. The association between medullary chromosome abnormalities and neutrophilic dermatosis has already been cited as a criterion of preleukemia. 22 In the literature, most cases of pyoderma gangrenosum with polycythemia vera occurred at the myelofibrosis stage,*"[ ",7,15,17 and in the observation of Perry et al, 7 acute leukemia rapidly developed. Thus, from a hematologic standpoint, neutrophilic der-
*Bureau Y, Guenel J, Barri~re H, et al. Eruption rdcidivante en placards pustuleux chez un maladie atteint de maladie de Vaquez. Bull Dermatol Syphiligr 1967;74:646-7.
*Basset A, Maleville J, Bergoend H. Eruption vdgrtante des parties drcouvertes dans une maladie de Vaquez traitde par le P32. Bull Dermatol Syphiligr 1969;76:63-4. tBureau Y, Guenel J, Barri~re H, et al. Eruption r~cidivante en placards pustuleux chez urt malade atteint de maladie de Vaquez. Bull Dermatol Syphiligr 1967;74:646-7.
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Grob et al
matosis appears to be an unfavorable sign in the course of polycythemia vera. The role played by therapies (32p and pipobroman in particular) in triggering neutrophilic dermatosis is eontroversial,*,t ,7:3 but it is likely that treatment does not induce these cutaneous lesions but simply extends survival time so that the patient reaches the advanced stage of leukemia and myelofibrosis, which is marked by neutrophilic dermatosis. Several disturbances in polymorphonuelear leukocyte function have been reported with pyoderma gangrenosum, but polymorphonuclear leukocyte exploration was most often normal. In fact, since, on one hand, investigative methods were often different and, on the other hand, the affections associated with pyoderma gangrenosum were also different, it is difficult to compare reports. Perturbations include decreased phagocytosis, 23-25 decreased23 or increased~6 random mobility, decreased chemotaxis,27.28 and decreased bactericidal effect. 2. Neither chemotaxis nor phagocytosis impairment was detected in our patient, but O2generation was significantly altered. The mechanism underlying this defect observed in our patient is unclear. O5- generation is achieved by the activation of a membrane enzyme, reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase, which catalyzes the removal of one electron from oxygen to form Oz- .29 Before this reduction step, interaction of ligands with membrane receptors stimulates "transductional pathways" involving diacylglycerol and protein kinase C, which in turn stimulate NADPH oxidase. 3° The ligands involved act on various receptors. Zymosan acts on C3b receptors and mannosyl fucosyl receptors, 3~ N-formyl-methionylleucyl-phenylalanine on specific membrane receptors, 32 and phorbol myristate acetate directly on protein kinase. 33 Thus the observed defect may occur at any one of the following levels: the ligandreceptor interaction, the transductional pathways,
*Basset A, Maleville J, Bergoend H. Eruption vdg6tante des parties d~couvertes dans une maladie de Vaquez trait~e par le P32. Bull Dermatol Syphiligr 1969;76:63-4. tBureau Y, Guenel J, Bard~re H, et al. Eruption r6cidivante en placards pustuleux chez un malade atteint de maladie de Vaquez. Bull Dermatol Syphiligr 1967;74:646-7.
Journal of the American Academy of Dermatology
or NADPH oxidase activation. Since zymosaninduced O2- generation was normal in our patient, it seems likely that enzyme function was normal and thus that the 02- generation defect in response to phorbol myristate acetate and N-formylmethionyl-leucyl-phenylalanine was due either to an abnormality of the ligand-receptor interaction or to faulty transductional pathways. Since treatment with dapsone led to an improvement of 02generation in response to N-formyl-methionylleucyl-phenylalanine and phorbol myristate acetate but did not shorten the lag time of activation with phorbol myristate acetate, which is considered to be a reliable index of transductional pathways,4 it may be inferred that dapsone acted during the early step of activation. Since dapsone probably modulates the phospholipid composition of polymorphonuclear leukocyte membranes,34 this constitutes an attractive basis for explaining the improvement in 02- generation after dapsone. The fact that both the clinical condition and neutrophil function improved under dapsone makes it likely that the neutrophil defect plays a role in the pathogenesis of this pustular eruption. Since disturbances in neutrophil function, including O2- production defects,35 have been associated with leukemia~6-4° even at the earliest stage, 35 it may be speculated that, in our patient, preleukemia was responsible for polymorphonuclear leukocyte anomalies that, in turn, may have triggered neutrophilic dermatosis. This sequence of events would explain why the occurrence of a neutrophilic dermatosis is an unfavorable sign in the prognosis of polycythemia vera. However, one cannot discount the fact that the defect of neutrophils in peripheral blood is only the result of the exhaustion of their oxidation capacities in the skin lesions. A parallel can be drawn between the eruption observed in our patient and other neutrophilic dermatoses. Histologically speaking, our patient's lesions correspond to intraepidermal pustulosis, but in some areas the histologic features were compatible with Sneddon-Wilkinson subcorneal pustulosis. This observation thus adds weight to the body of evidence in favor of unifying pyoderma gangrenosum, Sweet's syndrome, SneddonWilkinson subcorneal pustulosis, and some other
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Disseminated pustular dermatosis in polycythemia vera
unclassified pustular eruptions (as in this observation) in the same group o f diseases. One argument for this view is the histologic kinship of these disorders, all of which feature an influx of polynuclear cells to the skin without cutaneous infection. Another argument is that these disorders occur u n d e r similar conditions: p y o d e r m a gangren o s u m and, more rarely, unclassified pustular eruptions, 18.19Sneddon-Wilkinson subcorneal pustulosis, a9 or Sweet's syndrome *,4° occur in the course o f ulcerative colitis; p y o d e r m a gangrenosum and, m o r e rarely, unclassified pustular eruptions 2° in the course of rheumatoid or rheumatoid-like arthritis; pyoderrna gangrenosum, Sneddon-Wilkinson subcorneal pustulosis, and more rarely, Sweet's syndrome 4~,4~ in the course o f m o n o c l o n a l gammopathies; pyoderma gangrenosum, Sweet's syndrome, and more rarely, unclassified pustular eruptions (as with our case) in the course o f myeloproliferative disorders. Similarly, S w e e t ' s s y n d r o m e - l i k e lesions 43 and unclassified pustular eruptions 44 have been described in bowel bypass syndrome and after other intestinal surgical procedures. The last argument is that these afflictions are often concomitant (i.e., p y o d e r m a gangrenosum with unclassified pustular eruptions, 45 p y o d e r m a gangrenosum with Sweet's syndrome, 46 and pyoderma gangrenosum with Sneddon-Wilkinson subcomeal pustu1osis47'48). There is, however, a major argument against the unicity of these dermatoses: it is unlikely that the influx o f polymorphonuclear leukocytes has the same underlying mechanisms in affections as different as ulcerative colitis and hematologic diseases.
4. 5.
6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.
18.
*Wilkinson DS. Subcornealpustulardermatosis. Bull DermatolSyphilol 1962;69:674.
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