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Subcorneal pustular dermatosis in a patient with aplastic anemia
Journal of the American Academy of Dermatology Volume 39, Number 2, Part 1
Brief communications 287
Subcorneal pustular dermatosis in a patient with aplastic anemia Byung-Soon Park, MD, Kwang-Hyun Cho, MD, Hee-Chul Eun, MD, and Jai-Il Youn, MD Seoul, Korea
Subcorneal pustular dermatosis (SPD) is a chronic, relapsing vesiculopustular eruption that typically affects the trunk and intertriginous areas and usually occurs in women more than 40 years of age.1 We describe a case of SPD in a patient with aplastic anemia induced by antituberculosis medications. Although the association of SPD with paraproteinemia, myeloma, and inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease has been recognized,2,3 an association with aplastic anemia has not been previously reported.
From the Department of Dermatology, Seoul National University College of Medicine. Reprint requests: Byung-Soon Park, MD, Department of Dermatology, Seoul National University Hospital, 28 YongonDong Chongno-Gu, Seoul 110-744, Korea. J Am Acad Dermatol 1998;39:287-9. Copyright © 1998 by the American Academy of Dermatology, Inc. 0190-9622/98/$5.00 + 0 16/54/90798
CASE REPORT A 32-year-old Korean woman had a pustular eruption for 1 month. Five months before, a diagnosis of pulmonary tuberculosis had been made, and she was treated with isoniazid, ethambutol, pyrazinamide, levofloxacin, and kanamycin. Her skin lesion appeared on the trunk as her pancytopenia abruptly worsened. Colony-stimulating factors were never administered. Examination revealed flaccid pustules on an erythematous base on the trunk, groin, and legs. The lesions tended to coalesce, forming large annular and circinate plaques. Peripheral spreading and central healing left hyperpigmentation (Fig 1). She also had fever and hepatosplenomegaly. Laboratory studies showed the following results: white blood cell count, 1200/mm3 with 57% polymorphonuclear leukocytes, 40% lymphocytes, and 2% eosinophils; hemoglobin, 6.8 g/dL with slight macrocytosis; platelets, 90,000/mm3; reticulocyte count, 1.9%; erythrocyte sedimentation rate, 82 mm/h; folate, 1.3 ng/dL (normal, 3 to 15 ng/dL); ferritin, 3860 ng/mL
288 Brief communications
Fig 1. Subcorneal pustular dermatosis showing pustules coalescing to form large annular plaques. Peripheral spreading and central healing leaving hyperpigmentation.
(normal, 10 to 300 ng/mL); albumin, 2.1 g/dL (normal, 3.5 to 5.5 g/dL); AST, 53 U/L; ALT, 40 U/L; serum C3, 56 mg/dL (normal, 70 to 150 mg/dL). Serum immunoelectrophoresis revealed a diffuse polyclonal gammopathy characterized by elevated IgG level of 3602 mg/dL (normal, 408 to 1788 mg/dL). A 24-hour urine specimen showed proteinuria (215 mg/d). Chest roentgenogram showed multiple patchy nodular infiltrates and pleural effusion. Mycobacterium tuberculosis isolated from her sputum showed resistance to isoniazid, rifampin, and pyrazinamide. Total serum protein, blood urea nitrogen, creatinine, urinary Bence-Jones protein, VDRL, serology for viral hepatitis B and C, rheumatoid factor, antinuclear antibody, cryoglobulin, serum vitamin B12, serum IgA, serum IgM, and serum C4 were normal or negative. Cellular immunity, as measured by a standardized skin test with Multitest CMI (Institut Merieux, France) was normal. A biopsy specimen from the advancing edge showed a subcorneal pustule filled mainly with polymorphonuclear leukocytes (Fig 2). Acantholytic cells and eosinophils were rare. A perivascular dermal infiltrate was present, consisting predominantly of neutrophils. A potassium hydroxide preparation as well as tissue cultures and stains for bacteria, fungi, and acid-fast bacilli were negative. An initial bone marrow biopsy specimen revealed hypercellular inflammation without granulomas. Another specimen, obtained after her pancytopenia became evident, showed a hypoplastic marrow with reduced hematopoietic cells, suggestive of aplastic anemia. She was treated with prednisolone cream because her poor general condition did not allow systemic medication. During the next 7 months, her skin lesions recurred as her granulocytopenia waxed and waned. Dissemination of tuberculosis to her pericardium,
Journal of the American Academy of Dermatology August 1998
Fig 2. Biopsy specimen. Subcorneal pustule containing numerous neutrophils. (Hematoxylin-eosin stain; original magnification ×400.) spleen, liver, and kidney was detected. Thirteen months later, the patient died of a cerebral infarction. No autopsy was performed. DISCUSSION
Neutrophilic dermatoses include various noninfectious skin diseases such as SPD, Sweet’s syndrome, pyoderma gangrenosum, neutrophilic eccrine hidradenitis, and erythema elevatum diutinum.4,5 They are considered a continuous spectrum because they share common features: Cutaneous neutrophilic infiltrate, overlapping findings or transition among them, systemic manifestations including extracutaneous neutrophilic infiltration, association with similar systemic diseases, and responsiveness to steroids or dapsone.4,5 Systemic diseases that have been associated with neutrophilic dermatoses include myeloproliferative disorders, monoclonal gammopathies, especially IgA, inflammatory bowel diseases, and rheumatoid arthritis.4-6 The pancytopenia in our patient was caused by hypersplenism, folate deficiency, and the anemia of chronic disease. Isoniazid was regarded as the most probable cause of her aplastic anemia. Hematologic disturbances in the absence of myeloproliferative or lymphoproliferative disorders have been reported in Sweet’s syndrome, pyoderma gangrenosum, and erythema elevatum diutinum.4,7-9 Leukocytosis is frequent in Sweet’s syndrome whereas anemia, leukopenia, and thrombocytopenia, with or without a bone marrow abnormality, are unusual.4,7-10 Granulocyte colony-stimulating factors can induce neutrophilic
Journal of the American Academy of Dermatology Volume 39, Number 2, Part 1
dermatoses,11-13 but our patient did not receive this treatment. Her liver and kidney abnormalities might have been caused by systemic involvement of a neutrophilic dermatosis.8 However, these could also be attributed to disseminated tuberculosis. Our patient also had a polyclonal gammopathy. Although several neutrophilic dermatoses have been noted in patients with monoclonal gammopathy, polyclonal gammopathies are not uncommon in patients with chronic infection and liver disease. Although the concurrence of SPD and neutropenia may be coincidental, and induction of SPD by antituberculosis agents cannot be completely excluded, we believe our patient had a neutrophilic dermatosis related to aplastic anemia for three reasons. First, various neutrophilic dermatoses such as Sweet’s syndrome, neutrophilic eccrine hidradenitis, and pyoderma gangrenosum have been observed in patients with granulocytopenia.5 Second, although chemotherapeutic agents have frequently been implicated in the pathogenesis of neutrophilic eccrine hidradenitis, there have been some reports of the occurrence of a neutrophilic dermatosis preceding a hematologic malignancy without chemotherapy.14 Therefore chemotherapy seems to be only one potential factor in the pathogenesis of neutrophilic dermatoses in patients with granulocytopenia,5 and it is conceivable that what is important in the association between neutrophilic dermatoses and hematologic disorders is neutropenia itself, whether it is caused by chemotherapy for a myeloid malignancy, or other insults to bone marrow. The third reason is the simultaneous onset and parallel activity of SPD and neutropenia.
Brief communications 289 REFERENCES 1. Sneddon IB, Wilkinson DS. Subcorneal pustular dermatosis. Br J Dermatol 1979;100:61-8. 2. Kasha EE, Epinette WW. Subcorneal pustular dermatosis (Sneddon-Wilkinson disease) in association with a monoclonal IgA gammopathy: a report and review of the literature. J Am Acad Dermatol 1988;19:854-8. 3. Delaporte E, Colombel JF, Nguyen-Mailfer C, et al. Subcorneal pustular dermatosis in a patient with Crohn’s disease. Acta Derm Venereol (Stockh) 1992;72:301-2. 4. Vignon-Pennamen MD, Wallach D. Cutaneous manifestations of neutrophilic disease. Dermatologica 1991;183: 255-64. 5. Aractingi S, Mallet V, Pinquier L, et al. Neutrophilic dermatoses during granulocytopenia. Arch Dermatol 1995;131:1141-5. 6. Scerri L, Zaki I, Allen BR. Pyoderma gangrenosum and subcorneal pustular dermatosis, without monoclonal gammopathy. Br J Dermatol 1994;130:398-403. 7. Vignon-Pennamen MD, Zelinsky-Gurung A, Janssen F, Frija J, Wallach D. Pyoderma gangrenosum with pulmonary involvement. Arch Dermatol 1989;125:1239-42. 8. Matta N, Malak J, Tabet E, Kurbana K. Sweet’s syndrome: systemic associations. Cutis 1973;12:561-5. 9. Wong CK, Pun KK, Lum CC, et al. Pyoderma gangrenosum associated with erythroid hypoplasia. Postgrad Med J 1990;66:312-3. 10. Sharma PK, Schwartz RA, Janniger CK, et al. Sweet’s syndrome with acute leukemia. Cutis 1991;47:249-52. 11. Johnson ML, Grimwood RE. Leukocyte colony-stimulating factors: a review of associated neutrophilic dermatoses and vasculitides. Arch Dermatol 1994;130:7781. 12. Shimizu T, Yoshida I, Eguchi H, et al. Sweet’s syndrome in a child with aplastic anemia receiving recombinant granulocyte colony-stimulating factor. J Pediatr Hematol Oncol 1996;18:282-4. 13. Fukutoku M, Shimizu S, Ogawa Y, et al. Sweet’s syndrome during therapy with granulocyte colony-stimulating factor in a patient with aplastic anemia. Br J Haematol 1994;6:645-8. 14. Pierson JC, Helm TN, Taylor JS, Elstom DM, Tuthill RJ. Neutrophilic eccrine hidradenitis heralding the onset of acute myelogenous leukemia. Arch Dermatol 1993;129: 791-2.
Brief communications 287
Subcorneal pustular dermatosis in a patient with aplastic anemia Byung-Soon Park, MD, Kwang-Hyun Cho, MD, Hee-Chul Eun, MD, and Jai-Il Youn, MD Seoul, Korea
Subcorneal pustular dermatosis (SPD) is a chronic, relapsing vesiculopustular eruption that typically affects the trunk and intertriginous areas and usually occurs in women more than 40 years of age.1 We describe a case of SPD in a patient with aplastic anemia induced by antituberculosis medications. Although the association of SPD with paraproteinemia, myeloma, and inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease has been recognized,2,3 an association with aplastic anemia has not been previously reported.
From the Department of Dermatology, Seoul National University College of Medicine. Reprint requests: Byung-Soon Park, MD, Department of Dermatology, Seoul National University Hospital, 28 YongonDong Chongno-Gu, Seoul 110-744, Korea. J Am Acad Dermatol 1998;39:287-9. Copyright © 1998 by the American Academy of Dermatology, Inc. 0190-9622/98/$5.00 + 0 16/54/90798
CASE REPORT A 32-year-old Korean woman had a pustular eruption for 1 month. Five months before, a diagnosis of pulmonary tuberculosis had been made, and she was treated with isoniazid, ethambutol, pyrazinamide, levofloxacin, and kanamycin. Her skin lesion appeared on the trunk as her pancytopenia abruptly worsened. Colony-stimulating factors were never administered. Examination revealed flaccid pustules on an erythematous base on the trunk, groin, and legs. The lesions tended to coalesce, forming large annular and circinate plaques. Peripheral spreading and central healing left hyperpigmentation (Fig 1). She also had fever and hepatosplenomegaly. Laboratory studies showed the following results: white blood cell count, 1200/mm3 with 57% polymorphonuclear leukocytes, 40% lymphocytes, and 2% eosinophils; hemoglobin, 6.8 g/dL with slight macrocytosis; platelets, 90,000/mm3; reticulocyte count, 1.9%; erythrocyte sedimentation rate, 82 mm/h; folate, 1.3 ng/dL (normal, 3 to 15 ng/dL); ferritin, 3860 ng/mL
288 Brief communications
Fig 1. Subcorneal pustular dermatosis showing pustules coalescing to form large annular plaques. Peripheral spreading and central healing leaving hyperpigmentation.
(normal, 10 to 300 ng/mL); albumin, 2.1 g/dL (normal, 3.5 to 5.5 g/dL); AST, 53 U/L; ALT, 40 U/L; serum C3, 56 mg/dL (normal, 70 to 150 mg/dL). Serum immunoelectrophoresis revealed a diffuse polyclonal gammopathy characterized by elevated IgG level of 3602 mg/dL (normal, 408 to 1788 mg/dL). A 24-hour urine specimen showed proteinuria (215 mg/d). Chest roentgenogram showed multiple patchy nodular infiltrates and pleural effusion. Mycobacterium tuberculosis isolated from her sputum showed resistance to isoniazid, rifampin, and pyrazinamide. Total serum protein, blood urea nitrogen, creatinine, urinary Bence-Jones protein, VDRL, serology for viral hepatitis B and C, rheumatoid factor, antinuclear antibody, cryoglobulin, serum vitamin B12, serum IgA, serum IgM, and serum C4 were normal or negative. Cellular immunity, as measured by a standardized skin test with Multitest CMI (Institut Merieux, France) was normal. A biopsy specimen from the advancing edge showed a subcorneal pustule filled mainly with polymorphonuclear leukocytes (Fig 2). Acantholytic cells and eosinophils were rare. A perivascular dermal infiltrate was present, consisting predominantly of neutrophils. A potassium hydroxide preparation as well as tissue cultures and stains for bacteria, fungi, and acid-fast bacilli were negative. An initial bone marrow biopsy specimen revealed hypercellular inflammation without granulomas. Another specimen, obtained after her pancytopenia became evident, showed a hypoplastic marrow with reduced hematopoietic cells, suggestive of aplastic anemia. She was treated with prednisolone cream because her poor general condition did not allow systemic medication. During the next 7 months, her skin lesions recurred as her granulocytopenia waxed and waned. Dissemination of tuberculosis to her pericardium,
Journal of the American Academy of Dermatology August 1998
Fig 2. Biopsy specimen. Subcorneal pustule containing numerous neutrophils. (Hematoxylin-eosin stain; original magnification ×400.) spleen, liver, and kidney was detected. Thirteen months later, the patient died of a cerebral infarction. No autopsy was performed. DISCUSSION
Neutrophilic dermatoses include various noninfectious skin diseases such as SPD, Sweet’s syndrome, pyoderma gangrenosum, neutrophilic eccrine hidradenitis, and erythema elevatum diutinum.4,5 They are considered a continuous spectrum because they share common features: Cutaneous neutrophilic infiltrate, overlapping findings or transition among them, systemic manifestations including extracutaneous neutrophilic infiltration, association with similar systemic diseases, and responsiveness to steroids or dapsone.4,5 Systemic diseases that have been associated with neutrophilic dermatoses include myeloproliferative disorders, monoclonal gammopathies, especially IgA, inflammatory bowel diseases, and rheumatoid arthritis.4-6 The pancytopenia in our patient was caused by hypersplenism, folate deficiency, and the anemia of chronic disease. Isoniazid was regarded as the most probable cause of her aplastic anemia. Hematologic disturbances in the absence of myeloproliferative or lymphoproliferative disorders have been reported in Sweet’s syndrome, pyoderma gangrenosum, and erythema elevatum diutinum.4,7-9 Leukocytosis is frequent in Sweet’s syndrome whereas anemia, leukopenia, and thrombocytopenia, with or without a bone marrow abnormality, are unusual.4,7-10 Granulocyte colony-stimulating factors can induce neutrophilic
Journal of the American Academy of Dermatology Volume 39, Number 2, Part 1
dermatoses,11-13 but our patient did not receive this treatment. Her liver and kidney abnormalities might have been caused by systemic involvement of a neutrophilic dermatosis.8 However, these could also be attributed to disseminated tuberculosis. Our patient also had a polyclonal gammopathy. Although several neutrophilic dermatoses have been noted in patients with monoclonal gammopathy, polyclonal gammopathies are not uncommon in patients with chronic infection and liver disease. Although the concurrence of SPD and neutropenia may be coincidental, and induction of SPD by antituberculosis agents cannot be completely excluded, we believe our patient had a neutrophilic dermatosis related to aplastic anemia for three reasons. First, various neutrophilic dermatoses such as Sweet’s syndrome, neutrophilic eccrine hidradenitis, and pyoderma gangrenosum have been observed in patients with granulocytopenia.5 Second, although chemotherapeutic agents have frequently been implicated in the pathogenesis of neutrophilic eccrine hidradenitis, there have been some reports of the occurrence of a neutrophilic dermatosis preceding a hematologic malignancy without chemotherapy.14 Therefore chemotherapy seems to be only one potential factor in the pathogenesis of neutrophilic dermatoses in patients with granulocytopenia,5 and it is conceivable that what is important in the association between neutrophilic dermatoses and hematologic disorders is neutropenia itself, whether it is caused by chemotherapy for a myeloid malignancy, or other insults to bone marrow. The third reason is the simultaneous onset and parallel activity of SPD and neutropenia.
Brief communications 289 REFERENCES 1. Sneddon IB, Wilkinson DS. Subcorneal pustular dermatosis. Br J Dermatol 1979;100:61-8. 2. Kasha EE, Epinette WW. Subcorneal pustular dermatosis (Sneddon-Wilkinson disease) in association with a monoclonal IgA gammopathy: a report and review of the literature. J Am Acad Dermatol 1988;19:854-8. 3. Delaporte E, Colombel JF, Nguyen-Mailfer C, et al. Subcorneal pustular dermatosis in a patient with Crohn’s disease. Acta Derm Venereol (Stockh) 1992;72:301-2. 4. Vignon-Pennamen MD, Wallach D. Cutaneous manifestations of neutrophilic disease. Dermatologica 1991;183: 255-64. 5. Aractingi S, Mallet V, Pinquier L, et al. Neutrophilic dermatoses during granulocytopenia. Arch Dermatol 1995;131:1141-5. 6. Scerri L, Zaki I, Allen BR. Pyoderma gangrenosum and subcorneal pustular dermatosis, without monoclonal gammopathy. Br J Dermatol 1994;130:398-403. 7. Vignon-Pennamen MD, Zelinsky-Gurung A, Janssen F, Frija J, Wallach D. Pyoderma gangrenosum with pulmonary involvement. Arch Dermatol 1989;125:1239-42. 8. Matta N, Malak J, Tabet E, Kurbana K. Sweet’s syndrome: systemic associations. Cutis 1973;12:561-5. 9. Wong CK, Pun KK, Lum CC, et al. Pyoderma gangrenosum associated with erythroid hypoplasia. Postgrad Med J 1990;66:312-3. 10. Sharma PK, Schwartz RA, Janniger CK, et al. Sweet’s syndrome with acute leukemia. Cutis 1991;47:249-52. 11. Johnson ML, Grimwood RE. Leukocyte colony-stimulating factors: a review of associated neutrophilic dermatoses and vasculitides. Arch Dermatol 1994;130:7781. 12. Shimizu T, Yoshida I, Eguchi H, et al. Sweet’s syndrome in a child with aplastic anemia receiving recombinant granulocyte colony-stimulating factor. J Pediatr Hematol Oncol 1996;18:282-4. 13. Fukutoku M, Shimizu S, Ogawa Y, et al. Sweet’s syndrome during therapy with granulocyte colony-stimulating factor in a patient with aplastic anemia. Br J Haematol 1994;6:645-8. 14. Pierson JC, Helm TN, Taylor JS, Elstom DM, Tuthill RJ. Neutrophilic eccrine hidradenitis heralding the onset of acute myelogenous leukemia. Arch Dermatol 1993;129: 791-2.