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A generalized cutaneous reaction induced by granulocyte colony-stimulating factor
A generalized cutaneous reaction induced by granulocyte colony-stimulating factor L. Frank Glass, MD, Theodore Fotopoulos, MD, and Jane L. Messina, MD Tampa, Florida
Background: The increasing use of recombinant forms of granulocyte and granulocytemacrophage colony-stimulating factors (GCSF and GMCSF) for neutropenic conditions has resulted in reports of a variety of cutaneous reactions. Objective: We studied the clinical and histologic findings in three patients who underwent bone marrow transplantation and subsequently had a cutaneous eruption associated with the use of GCSF. Methods: Biopsy specimens taken at the height of the eruption were studied histologically and immunohistochemically. Results: The patients had indurated, well-demarcated, occasionally annular, erythematous papules and plaques on the extremities that became generalized and cleared with fine desquamation after withdrawal of the medication. Distinctive histologic features consisted of mild epidermal spongiosis overlying a dermal infiltrate of enlarged, plump macrophages. Increased expression of the vascular adhesion molecules ELAM-1 and VCAM-1, as well as the keratinocyte-produced ICAM-1, was noted. Conclusion: The clinical and histologic findings of the cutaneous reaction to GCSF are characteristic and allow its distinction from other eruptions that occur in bone marrow transplant recipients. (J AM ACADDEP,MATOI. 1996;34:455-9.) The recent availability for clinical use of hematopoietic growth factors such as granulocyte-macrophage colony-stimulating factor (GMCSF) and granulocyte colony-stimulating factor (GCSF) has had a substantial impact on the management of patients with cancer. These agents are used routinely to promote leukocyte recovery after high-dose chemotherapy and the resultant myelosuppression.1 They have also been approved for use in other neutropenic states, such as HIV infection, aplastic anemia, and myelodysplasia.l These cytokines stimulate proliferation and differentiation of hematopoietic progenitor cells. 2 They are produced mainly by monocytes and fibroblasts in vivo and have become commercially available as a result of recombinant DNA technology. Several adverse cutaneous reactions have been reported in response to these hematopoietic factors.
From the Departments of Medicine and Pathology, University of South Florida College of Medicine. Accepted for publication Aug. 15, 1995. Reprint requests: L. Frank Glass, MD, Division of Dermatology, MDC Box 19, 12901 Brace B. Downs Blvd., Tampa, FL 33612. Copyright © 1996 by the American Academy of Dermatology, Inc. 0190-9622/96 $5.00 + 0 16/1/68618
In addition to local reactions at the site of injection,3 many of these have been associated with an accumulation of neutrophils in the skin, such as pyoderma gangrenosum,4 Sweet' s syndrome,57 cutaneous vasculitis,8 and widespread folliculitis.9 However, there have also been some additional reports of a generalized eruption associated with the administration of GMCSF characterized by an accumulation of dermal macrophages. We describe our observations of three patients with a cutaneous reaction induced by GCSF. PATIENTS AND METHODS
Selected patients received human recombinant GCSF as part of a postinduction chemotherapy protocol. Punch biopsy specimens (3 ram) were obtained from patients with an eruption. One patient had a 6 mm specimen taken; half was processed routinely and the other haft was snap frozen for immunohistochemistry. Paraffin sections were stained with hematoxylin and eosin, colloidal iron reagent for acid mucopolysaccharides, and Verhoeff-van Gieson for elastic fibers. Immunohistochemical staining for antiCD68 (Dako) with avidin-biotin methods was conducted. Frozen sections were stained with anti-ICAM-1, antiVCAM-1, and anti-ELAM-1 (Becton Dickinson, Mountain View, Calif.). Bound antibody was detected by the avidin-biotin complex method. 455
456
Glass, Fotopoulos, and Messina
Journal of the AmericanAcademyof Dermatology March 1996
Fig. 1. Patient 1. Discrete papules and plaques in an annular configuration on the thigh. RESULTS In seven patients an eruption developed that coincided with administration of GCSF. Details on three of these patients are summarized below. Patient 1 A 52-year-old woman with refractory acute myelogenous leukemia was treated with fludarabine, cytosine arabinoside, and human recombinant GCSF 10 ~g/kg daily. Approximately 3 weeks later erythematous papules and plaques in a distinctly annular or arcuate configuration developed on her abdomen, scalp, arms, thighs, and hands (Fig. 1). The eruption subsequently became more generalized and morbilliform. Although her eruption was reduced slightly with topical corticosteroid treatment, it failed to clear until she was given a lower dose of GCSF (6.6 lag/kg daily). Patient 2 A 43-year-old woman with metastatic breast carcinoma was treated with taxol, mitoxantrone, and thiotepa; subsequently she underwent autologous bone marrow and peripheral blood stem cell transplantation. Prolonged neutropenia developed, and intravenous human recombinant GCSF 10 pag/kg daily, was started. After 3 weeks the daily dosage was increased to 30 I.tg/kg. Within 1 week, multiple indurated erythematous papules and plaques on her dorsal aspect of her forearms, her hands, her legs
developed. There was also a diffusely erythematous morbilliform eruption on her chest, back, and face. During this time she was being treated with empiric antimicrobial medications for neutropenic fever, including vancomycin, amikacin, metronidazole, ofloxacin, and amphotericin B. However, no positive blood cultures for bacteria or fungi were obtained. Approximately 2 weeks after the eruption began, her neutropenia and fever cleared and all of the antimicrobials were discontinued; there was no change in her eruption. The dosage of GCSF was decreased to the initial level of 10 ~Jg/kg/daily, and within 1 week there was a gradual fading of the eruption with free desquamation. No recurrence was noted during a maintenance regimen with the lower dose of GCSF. Patient 3 A 36-year-old woman with Hodgkin's disease underwent autologous bone marrow and peripheral stem cell transplantation. Profound neutropenia rapidly developed, and she was treated with GCSF 10 ~tg/kg daily for 4 weeks without improvement. During this time a low-grade fever developed, and she was treated with vancomycin, ceftazidime, metronidazole, amphotericin B, gentamicin, pentamidine, amikacin, and ofloxacin. Blood cultures were positive for Escherichia coli and Streptococcus viridans. The daily dosage of GCSF was increased to 30 tag&g; this resulted in rapidly rising absolute granulocyte counts, and the fever subsided. Blood culture remained negative for more than 2 weeks, and all antimicrobials were discontinued. The GCSF dos-
Journal of the American Academy of Dermatology Volume 34, Number 3
Glass, Fotopoulos, and Messina 457
Fig. 2. High-power photomicrograph demonstrates mild spongiosis and dermal infiltrate with numerous large macrophages (arrows). (Hematoxylin-eosin stain; original magnification x250.)
age was reduced to 15 pg/kg daily. She was discharged on a regimen of GCSF 10 jJg/kg daily, but a free macular erythematous eruption was noted. Subsequently, the eruption progressed into well-demarcated, elevated, deeply erythematous papules coalescing into plaques. Initially the eruption was confined to her hands and feet, but advanced to involve her forearms and legs. The GCSF was discontinued, and her eruption resolved within 3 to 5 days.
Histopathologic findings Biopsy specimens obtained from each of the patients showed similar histologic features (Fig. 2). There was mild spongiosis with exocytosis of lymphocytes. A sparse, predominantly lymphohistiocytic, perivascular infiltrate was identified in the papillary dermis. The infiltrate was accompanied by several neutrophils in the specimen obtained from patient 3 but was composed entirely of mononuclear cells in the other two patients. In each of the specimens, there was an accumulation of large, plump macrophages within the dermis. The majority had a pale-staining nucleus with prominent nucleoli and abundant cytoplasm; some were dendritic. Occasional ingestion of elastic fibers was observed. These plump cells stained positively for macrophage marker anti-CD68 (KP-1). Colloidal iron staining demonstrated focal mucin deposition in the dermis, and some mucin was present between keratinocytes in the epidermis.
Immunostaining of frozen tissue from patient 2 showed ELAM- 1 expression in the dermal endothelium. lmmunostaining in two patients showed labeling of keratinocytes with ICAM-1 antibody and endothelial staining with VCAM-1 and ELAM-1 antibodies.
DISCUSSION As more experience has been gained with GCSF and GMCSF in the treatment of cytopenia and infections, several complications in this patient population, many primarily involving the skin, have appeared 1, 10, l a (Table I). GMCSF produces localized reactions such as pruritus and pain at the injection site, as well as phlebitis and epidermolysis bullosa acquisita.2, 10, 12 GCSF has also been associated with bullous pyoderma gangrenosum, 4 Sweet's syndrome, 5-7 hypersensitivity vasculitis, 8 and widespread folliculitis9; each of these is a neutrophilic dermatosis. Recently patients with a generalized eruption characterized by numerous large macrophages in the dermis, rather than neutrophils, have been described. 1°, 13, 14 Biopsy specimens from our patients demonstrated a superficial perivascular infiltrate; occasional eosinophils and neutrophils were found in one, but in the other two the infiltrate was entirely mononuclear. TM13, 14 In addition, there was dermal mucin deposition in the areas occupied by the infiltrate, and small collections of mucin were detected in the epidermis between keratinocytes.
458
Journal of the American Academy of Dermatology March 1996
Glass, Fotopoulos, and Messina
T a b l e I. Summary of cutaneous reactions to colony-stimulating factors No. of reactions
Reaction type
Agent (No. of reactions)
2
Leukocytoclastic vasculitis Pyoderma gangrenosum
GCSF GCSF
3
Necrotizing vasculitis
GCSF (2) GMCSF (1)
6
Swe~'ssyn&ome
GCSF
22
Urticarial or pustular injection site reactions
GCSF (1) GMCSF ( 2 1 )
22
Maculopapular eruption with mixed inflammatory dermal infiltrate Maculopapular eruption with enlarged dermal macrophages
GMCSF
18
Author(s)
Jain8 Johnson and Grimwood2 Ross et al. 4 Dreicer, Schiller and Carbone17 Welte et al. TM Wodzinski, Hampton and Reilly,19 Johnson and Gfimwood2 Paydas et al.5 Fukutoku et al.6 Park et al.7 Samlaska and Noyes3 Mehreganet 13.1.10 Steger et al.20 Mehregan et al.10 Scott TM
GMCSF
Horn et al.ll Peters et al. ~3 Scott 14
This pattern has also been previously associated with the eruption elicited by GMCSF.al Patients with cancer who have marrow aplasia after chemotherapy are susceptible to several cutaneous eruptions as a result of the multitude of medications administered and because of their susceptibility to infection. The eruption elicited by GCSF appears to be distinctive both clinically and histopathologically. Clinically, it could be confused with a drug "hypersensitivity reaction," acute graft-versus-host disease, or perhaps the cutaneous eruption of lymphocyte recovery. However, individual lesions in the cutaneous reaction to GCSF are sharply demarcated and markedly indurated. There is a tendency for lesions to be arranged in geographic or annular patterns reminiscent of granuloma annulare, and the surface may scale like an eczematous process. None of these clinical features is seen in a morbilliform eruption or in hypersensitivity reactions. The histopathologic finding of the cutaneous eruption induced by GCSF is also sufficiently distinctive. The differential diagnosis includes morbilliform reactions, interface dermatitis, spongiotic dermatitis, and granuloma annulare. The usual pattern in morbilliform eruptions is a superficial perivascular dermatitis without significant epidermal involvement. A severe morbilliform eruption may be accompanied by spongiosis, but this would likely be associated with marked interface change and indi-
vidually necrotic keratinocytes along the dermoepidermal junction. 15 Parakeratosis is not a feature of morbilliform eruptions or any of the other forms of interface dermatitis such as erythema multiforme or graft-versus-host disease. None of these eruptions would be accompanied by the accumulation of dermal macrophages as in the cutaneous reaction elicited by GCSF. Some features are associated with this GCSFmediated eruption that overlap histopathologically with spongiotic dermatitis. In general, however, the spongiosis in the GCSF eruption is mild, and the accumulation of macrophages in the dermis is more conspicuous than the usual spongiotic dermatitis. Moreover, spongiotic dermatitis is an uncommon response to medications, with the exception of methotrexate, 5-fluorouracil, and nitrogen mustard. Although the dermal infiltrate of macrophages in our patients is somewhat reminiscent of granuloma annulare, distinction is achieved by the presence of spongiosis in the GCSF eruption. Both GMCSF and GCSF have a similar effect on myelomonocytic precursors: GCSF is more selective for granulocytic lines. 2 GMCSF also enhances the function of mature cells, such as neutrophils, eosinophils, monocytes, and Langerhans cells. 1' 10, 14 Thus it is likely that these substances stimulate fixed tissue macrophages (dermal dendrocytes) causing an increase in their size and number. High concentrations of GCSF in the skin have
Journal of the American Academy of Dermatology Vohune 34, Number 3
Glass, Fotopoulos, and Messina
b e e n postulated to induce the production o f cytokines b y resident cells, including other colony-stimulating factors and interleukins. Activation o f m a c r o p h a g e function could stimulate their production o f t u m o r necrosis f a c t o r - a , w h i c h stimulates keratin o c y t e - d e r i v e d m o n o c y t e c h e m o t a x i s and activating factor. 16 Activated m o n o c y t e s could further e n h a n c e the i n f l a m m a t o r y reaction b y p r o d u c i n g interleukin- 1 and t u m o r necrosis f a c t o r - a . O u r i m m u n o h i s tochemical results indicate that colony-stimulating factors m u s t also play a role in m o d u l a t i n g adhesion m o l e c u l e expression in the skin. B l o o d vessel expression o f E L A M - 1 and V C A M - 1 is not seen in n o r m a l skin and indicates p r i m i n g o f these structures for leukocyte adherence. E n h a n c e d keratinocyte I C A M - 1 expression (a ligand for leukocyte function - a s s o c i a t e d antigen ( L F A - 1 ) - e x p r e s s i n g T l y m phocytes) has b e e n previously reported with G C S F administration 11 and w a s also seen in one o f our patients. T h e latter finding has b e e n postulated to explain the epidermal spongiosis and exocytosis seen with G M C S F administration.ll
7. 8. 9. 10. 11.
12. 13. 14.
15. 16.
REFERENCES
1. Wakefield PE, James WE), Samlaska CP, et al. Colonystimulating factors. J AM ACAODERMATOI.1990;23:90312. 2. Johnson ML, Gfirnwood RE. Leukocyte colony-stimulating factors: a review of associated neutrophilic dermatoses and vasculitides. Arch Dermatol 1994;130:77-81. 3. Samlaska CP, Noyes DK. Localized cutaneous reactions to granulocyte colony-stimulating factor [Letter]. Arch Dermatol 1993;129:645-6. 4. Ross HJ, Moy LA, Kaplan R, et al. Bullous pyoderma gangrenosum after granulocyte colony-stimulating factor treatment. Cancer 1991;68:441-3. 5. Paydas S, Sahin B, et al. Sweet's syndrome associated with G-CSF. Br J Haematol 1993;85:191-2. 6. Fulmtoku M, Shimizu S, et al. Sweet's syndrome during therapy with granulocyte colony-stimulating factor in a
17. 18.
19. 20.
459
patient with aplastic anaemia. Br J Haematol 1994; 86:645-8. Park JW, Mehrota B, et al. The Sweet syndrome during therapy with granulocyte colony-stimulating factor. Ann Intern Med 1992;116:996-8. Jain KK. Cutaneous vascufitis associated with granulocyte colony-stimulating factor. J AM ACAD DERMATOL1994; 31:213-5. Ostlere LS, Harris D, et al. Widespread folliculitis induced by human g~anulocyte-colony-stimulating factor therapy [Letter]. Br J Dermatol 1992; 127:193-4. Mehregan DR, Fransway AF, et al. Cutaneous reactions to granulocyte-monocyte colony-stimulating factor. Arch Dermatol 1992; 128:1055-9. Horn TD, Burke PJ, et al. Intravenous administration of recombinant human granulocyte-macrophage colony-stimulating factor causes a cutaneous eruption. Arch Dermatol 1991;127:49-52. Ward JC, Gitlin JB, et al. Epidermolysis bullosa acquisita induced by GMCSF: a role for eosinophils in treatment related toxicity. Br J Haematol 1992;81:27-32. Peters MS, Argenyi Z, et al. Friday evening slide symposium:case 8. J Cutan Pathol 1993;20:465-78. Scott GA. Report of three cases of cutaneous reactions to granulocyte macrophage-colony stimulating factor and a review of the literature. Am J Dermopathol 1995;17:10714. Ackermarm AB. Histologic diagnosis of inflammatory skin diseases. Philadelphia: Lea & Febiger, 1978:196-7. Barker JN, Sarma V, et al. Marked synergism between tumor necrosis factor e~and interferon ~/in regulation of keralinocyte-derived adhesion molecules and chemotactic factor. J Clin Invest 1990;85:605-8. Dreicer R, Schiller JH, Carbone PP. Granulocyte-macrophage colony stimulating factor and vasctthtis. Ann Intern Meal 1989;111:91-2. Welte Z, Zeidler C, Reiter A, et al. Differential effects of granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor in children with severe congenital neutropenia. Blood 1990;75:1056-63. Wodzinski MA, Hampton KK, Reilly JT. Differential effect of G-CSF and GM-CSF in acquired chronic neutropehia. Br J Haematol 1991;77:249-50. Steger GG, Locker G, et al. Cutaneous reactions to GM-CSF in inflammatory breast cancer [Letter]. N Engl J Med 1992;327:286.
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Background: The increasing use of recombinant forms of granulocyte and granulocytemacrophage colony-stimulating factors (GCSF and GMCSF) for neutropenic conditions has resulted in reports of a variety of cutaneous reactions. Objective: We studied the clinical and histologic findings in three patients who underwent bone marrow transplantation and subsequently had a cutaneous eruption associated with the use of GCSF. Methods: Biopsy specimens taken at the height of the eruption were studied histologically and immunohistochemically. Results: The patients had indurated, well-demarcated, occasionally annular, erythematous papules and plaques on the extremities that became generalized and cleared with fine desquamation after withdrawal of the medication. Distinctive histologic features consisted of mild epidermal spongiosis overlying a dermal infiltrate of enlarged, plump macrophages. Increased expression of the vascular adhesion molecules ELAM-1 and VCAM-1, as well as the keratinocyte-produced ICAM-1, was noted. Conclusion: The clinical and histologic findings of the cutaneous reaction to GCSF are characteristic and allow its distinction from other eruptions that occur in bone marrow transplant recipients. (J AM ACADDEP,MATOI. 1996;34:455-9.) The recent availability for clinical use of hematopoietic growth factors such as granulocyte-macrophage colony-stimulating factor (GMCSF) and granulocyte colony-stimulating factor (GCSF) has had a substantial impact on the management of patients with cancer. These agents are used routinely to promote leukocyte recovery after high-dose chemotherapy and the resultant myelosuppression.1 They have also been approved for use in other neutropenic states, such as HIV infection, aplastic anemia, and myelodysplasia.l These cytokines stimulate proliferation and differentiation of hematopoietic progenitor cells. 2 They are produced mainly by monocytes and fibroblasts in vivo and have become commercially available as a result of recombinant DNA technology. Several adverse cutaneous reactions have been reported in response to these hematopoietic factors.
From the Departments of Medicine and Pathology, University of South Florida College of Medicine. Accepted for publication Aug. 15, 1995. Reprint requests: L. Frank Glass, MD, Division of Dermatology, MDC Box 19, 12901 Brace B. Downs Blvd., Tampa, FL 33612. Copyright © 1996 by the American Academy of Dermatology, Inc. 0190-9622/96 $5.00 + 0 16/1/68618
In addition to local reactions at the site of injection,3 many of these have been associated with an accumulation of neutrophils in the skin, such as pyoderma gangrenosum,4 Sweet' s syndrome,57 cutaneous vasculitis,8 and widespread folliculitis.9 However, there have also been some additional reports of a generalized eruption associated with the administration of GMCSF characterized by an accumulation of dermal macrophages. We describe our observations of three patients with a cutaneous reaction induced by GCSF. PATIENTS AND METHODS
Selected patients received human recombinant GCSF as part of a postinduction chemotherapy protocol. Punch biopsy specimens (3 ram) were obtained from patients with an eruption. One patient had a 6 mm specimen taken; half was processed routinely and the other haft was snap frozen for immunohistochemistry. Paraffin sections were stained with hematoxylin and eosin, colloidal iron reagent for acid mucopolysaccharides, and Verhoeff-van Gieson for elastic fibers. Immunohistochemical staining for antiCD68 (Dako) with avidin-biotin methods was conducted. Frozen sections were stained with anti-ICAM-1, antiVCAM-1, and anti-ELAM-1 (Becton Dickinson, Mountain View, Calif.). Bound antibody was detected by the avidin-biotin complex method. 455
456
Glass, Fotopoulos, and Messina
Journal of the AmericanAcademyof Dermatology March 1996
Fig. 1. Patient 1. Discrete papules and plaques in an annular configuration on the thigh. RESULTS In seven patients an eruption developed that coincided with administration of GCSF. Details on three of these patients are summarized below. Patient 1 A 52-year-old woman with refractory acute myelogenous leukemia was treated with fludarabine, cytosine arabinoside, and human recombinant GCSF 10 ~g/kg daily. Approximately 3 weeks later erythematous papules and plaques in a distinctly annular or arcuate configuration developed on her abdomen, scalp, arms, thighs, and hands (Fig. 1). The eruption subsequently became more generalized and morbilliform. Although her eruption was reduced slightly with topical corticosteroid treatment, it failed to clear until she was given a lower dose of GCSF (6.6 lag/kg daily). Patient 2 A 43-year-old woman with metastatic breast carcinoma was treated with taxol, mitoxantrone, and thiotepa; subsequently she underwent autologous bone marrow and peripheral blood stem cell transplantation. Prolonged neutropenia developed, and intravenous human recombinant GCSF 10 pag/kg daily, was started. After 3 weeks the daily dosage was increased to 30 I.tg/kg. Within 1 week, multiple indurated erythematous papules and plaques on her dorsal aspect of her forearms, her hands, her legs
developed. There was also a diffusely erythematous morbilliform eruption on her chest, back, and face. During this time she was being treated with empiric antimicrobial medications for neutropenic fever, including vancomycin, amikacin, metronidazole, ofloxacin, and amphotericin B. However, no positive blood cultures for bacteria or fungi were obtained. Approximately 2 weeks after the eruption began, her neutropenia and fever cleared and all of the antimicrobials were discontinued; there was no change in her eruption. The dosage of GCSF was decreased to the initial level of 10 ~Jg/kg/daily, and within 1 week there was a gradual fading of the eruption with free desquamation. No recurrence was noted during a maintenance regimen with the lower dose of GCSF. Patient 3 A 36-year-old woman with Hodgkin's disease underwent autologous bone marrow and peripheral stem cell transplantation. Profound neutropenia rapidly developed, and she was treated with GCSF 10 ~tg/kg daily for 4 weeks without improvement. During this time a low-grade fever developed, and she was treated with vancomycin, ceftazidime, metronidazole, amphotericin B, gentamicin, pentamidine, amikacin, and ofloxacin. Blood cultures were positive for Escherichia coli and Streptococcus viridans. The daily dosage of GCSF was increased to 30 tag&g; this resulted in rapidly rising absolute granulocyte counts, and the fever subsided. Blood culture remained negative for more than 2 weeks, and all antimicrobials were discontinued. The GCSF dos-
Journal of the American Academy of Dermatology Volume 34, Number 3
Glass, Fotopoulos, and Messina 457
Fig. 2. High-power photomicrograph demonstrates mild spongiosis and dermal infiltrate with numerous large macrophages (arrows). (Hematoxylin-eosin stain; original magnification x250.)
age was reduced to 15 pg/kg daily. She was discharged on a regimen of GCSF 10 jJg/kg daily, but a free macular erythematous eruption was noted. Subsequently, the eruption progressed into well-demarcated, elevated, deeply erythematous papules coalescing into plaques. Initially the eruption was confined to her hands and feet, but advanced to involve her forearms and legs. The GCSF was discontinued, and her eruption resolved within 3 to 5 days.
Histopathologic findings Biopsy specimens obtained from each of the patients showed similar histologic features (Fig. 2). There was mild spongiosis with exocytosis of lymphocytes. A sparse, predominantly lymphohistiocytic, perivascular infiltrate was identified in the papillary dermis. The infiltrate was accompanied by several neutrophils in the specimen obtained from patient 3 but was composed entirely of mononuclear cells in the other two patients. In each of the specimens, there was an accumulation of large, plump macrophages within the dermis. The majority had a pale-staining nucleus with prominent nucleoli and abundant cytoplasm; some were dendritic. Occasional ingestion of elastic fibers was observed. These plump cells stained positively for macrophage marker anti-CD68 (KP-1). Colloidal iron staining demonstrated focal mucin deposition in the dermis, and some mucin was present between keratinocytes in the epidermis.
Immunostaining of frozen tissue from patient 2 showed ELAM- 1 expression in the dermal endothelium. lmmunostaining in two patients showed labeling of keratinocytes with ICAM-1 antibody and endothelial staining with VCAM-1 and ELAM-1 antibodies.
DISCUSSION As more experience has been gained with GCSF and GMCSF in the treatment of cytopenia and infections, several complications in this patient population, many primarily involving the skin, have appeared 1, 10, l a (Table I). GMCSF produces localized reactions such as pruritus and pain at the injection site, as well as phlebitis and epidermolysis bullosa acquisita.2, 10, 12 GCSF has also been associated with bullous pyoderma gangrenosum, 4 Sweet's syndrome, 5-7 hypersensitivity vasculitis, 8 and widespread folliculitis9; each of these is a neutrophilic dermatosis. Recently patients with a generalized eruption characterized by numerous large macrophages in the dermis, rather than neutrophils, have been described. 1°, 13, 14 Biopsy specimens from our patients demonstrated a superficial perivascular infiltrate; occasional eosinophils and neutrophils were found in one, but in the other two the infiltrate was entirely mononuclear. TM13, 14 In addition, there was dermal mucin deposition in the areas occupied by the infiltrate, and small collections of mucin were detected in the epidermis between keratinocytes.
458
Journal of the American Academy of Dermatology March 1996
Glass, Fotopoulos, and Messina
T a b l e I. Summary of cutaneous reactions to colony-stimulating factors No. of reactions
Reaction type
Agent (No. of reactions)
2
Leukocytoclastic vasculitis Pyoderma gangrenosum
GCSF GCSF
3
Necrotizing vasculitis
GCSF (2) GMCSF (1)
6
Swe~'ssyn&ome
GCSF
22
Urticarial or pustular injection site reactions
GCSF (1) GMCSF ( 2 1 )
22
Maculopapular eruption with mixed inflammatory dermal infiltrate Maculopapular eruption with enlarged dermal macrophages
GMCSF
18
Author(s)
Jain8 Johnson and Grimwood2 Ross et al. 4 Dreicer, Schiller and Carbone17 Welte et al. TM Wodzinski, Hampton and Reilly,19 Johnson and Gfimwood2 Paydas et al.5 Fukutoku et al.6 Park et al.7 Samlaska and Noyes3 Mehreganet 13.1.10 Steger et al.20 Mehregan et al.10 Scott TM
GMCSF
Horn et al.ll Peters et al. ~3 Scott 14
This pattern has also been previously associated with the eruption elicited by GMCSF.al Patients with cancer who have marrow aplasia after chemotherapy are susceptible to several cutaneous eruptions as a result of the multitude of medications administered and because of their susceptibility to infection. The eruption elicited by GCSF appears to be distinctive both clinically and histopathologically. Clinically, it could be confused with a drug "hypersensitivity reaction," acute graft-versus-host disease, or perhaps the cutaneous eruption of lymphocyte recovery. However, individual lesions in the cutaneous reaction to GCSF are sharply demarcated and markedly indurated. There is a tendency for lesions to be arranged in geographic or annular patterns reminiscent of granuloma annulare, and the surface may scale like an eczematous process. None of these clinical features is seen in a morbilliform eruption or in hypersensitivity reactions. The histopathologic finding of the cutaneous eruption induced by GCSF is also sufficiently distinctive. The differential diagnosis includes morbilliform reactions, interface dermatitis, spongiotic dermatitis, and granuloma annulare. The usual pattern in morbilliform eruptions is a superficial perivascular dermatitis without significant epidermal involvement. A severe morbilliform eruption may be accompanied by spongiosis, but this would likely be associated with marked interface change and indi-
vidually necrotic keratinocytes along the dermoepidermal junction. 15 Parakeratosis is not a feature of morbilliform eruptions or any of the other forms of interface dermatitis such as erythema multiforme or graft-versus-host disease. None of these eruptions would be accompanied by the accumulation of dermal macrophages as in the cutaneous reaction elicited by GCSF. Some features are associated with this GCSFmediated eruption that overlap histopathologically with spongiotic dermatitis. In general, however, the spongiosis in the GCSF eruption is mild, and the accumulation of macrophages in the dermis is more conspicuous than the usual spongiotic dermatitis. Moreover, spongiotic dermatitis is an uncommon response to medications, with the exception of methotrexate, 5-fluorouracil, and nitrogen mustard. Although the dermal infiltrate of macrophages in our patients is somewhat reminiscent of granuloma annulare, distinction is achieved by the presence of spongiosis in the GCSF eruption. Both GMCSF and GCSF have a similar effect on myelomonocytic precursors: GCSF is more selective for granulocytic lines. 2 GMCSF also enhances the function of mature cells, such as neutrophils, eosinophils, monocytes, and Langerhans cells. 1' 10, 14 Thus it is likely that these substances stimulate fixed tissue macrophages (dermal dendrocytes) causing an increase in their size and number. High concentrations of GCSF in the skin have
Journal of the American Academy of Dermatology Vohune 34, Number 3
Glass, Fotopoulos, and Messina
b e e n postulated to induce the production o f cytokines b y resident cells, including other colony-stimulating factors and interleukins. Activation o f m a c r o p h a g e function could stimulate their production o f t u m o r necrosis f a c t o r - a , w h i c h stimulates keratin o c y t e - d e r i v e d m o n o c y t e c h e m o t a x i s and activating factor. 16 Activated m o n o c y t e s could further e n h a n c e the i n f l a m m a t o r y reaction b y p r o d u c i n g interleukin- 1 and t u m o r necrosis f a c t o r - a . O u r i m m u n o h i s tochemical results indicate that colony-stimulating factors m u s t also play a role in m o d u l a t i n g adhesion m o l e c u l e expression in the skin. B l o o d vessel expression o f E L A M - 1 and V C A M - 1 is not seen in n o r m a l skin and indicates p r i m i n g o f these structures for leukocyte adherence. E n h a n c e d keratinocyte I C A M - 1 expression (a ligand for leukocyte function - a s s o c i a t e d antigen ( L F A - 1 ) - e x p r e s s i n g T l y m phocytes) has b e e n previously reported with G C S F administration 11 and w a s also seen in one o f our patients. T h e latter finding has b e e n postulated to explain the epidermal spongiosis and exocytosis seen with G M C S F administration.ll
7. 8. 9. 10. 11.
12. 13. 14.
15. 16.
REFERENCES
1. Wakefield PE, James WE), Samlaska CP, et al. Colonystimulating factors. J AM ACAODERMATOI.1990;23:90312. 2. Johnson ML, Gfirnwood RE. Leukocyte colony-stimulating factors: a review of associated neutrophilic dermatoses and vasculitides. Arch Dermatol 1994;130:77-81. 3. Samlaska CP, Noyes DK. Localized cutaneous reactions to granulocyte colony-stimulating factor [Letter]. Arch Dermatol 1993;129:645-6. 4. Ross HJ, Moy LA, Kaplan R, et al. Bullous pyoderma gangrenosum after granulocyte colony-stimulating factor treatment. Cancer 1991;68:441-3. 5. Paydas S, Sahin B, et al. Sweet's syndrome associated with G-CSF. Br J Haematol 1993;85:191-2. 6. Fulmtoku M, Shimizu S, et al. Sweet's syndrome during therapy with granulocyte colony-stimulating factor in a
17. 18.
19. 20.
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patient with aplastic anaemia. Br J Haematol 1994; 86:645-8. Park JW, Mehrota B, et al. The Sweet syndrome during therapy with granulocyte colony-stimulating factor. Ann Intern Med 1992;116:996-8. Jain KK. Cutaneous vascufitis associated with granulocyte colony-stimulating factor. J AM ACAD DERMATOL1994; 31:213-5. Ostlere LS, Harris D, et al. Widespread folliculitis induced by human g~anulocyte-colony-stimulating factor therapy [Letter]. Br J Dermatol 1992; 127:193-4. Mehregan DR, Fransway AF, et al. Cutaneous reactions to granulocyte-monocyte colony-stimulating factor. Arch Dermatol 1992; 128:1055-9. Horn TD, Burke PJ, et al. Intravenous administration of recombinant human granulocyte-macrophage colony-stimulating factor causes a cutaneous eruption. Arch Dermatol 1991;127:49-52. Ward JC, Gitlin JB, et al. Epidermolysis bullosa acquisita induced by GMCSF: a role for eosinophils in treatment related toxicity. Br J Haematol 1992;81:27-32. Peters MS, Argenyi Z, et al. Friday evening slide symposium:case 8. J Cutan Pathol 1993;20:465-78. Scott GA. Report of three cases of cutaneous reactions to granulocyte macrophage-colony stimulating factor and a review of the literature. Am J Dermopathol 1995;17:10714. Ackermarm AB. Histologic diagnosis of inflammatory skin diseases. Philadelphia: Lea & Febiger, 1978:196-7. Barker JN, Sarma V, et al. Marked synergism between tumor necrosis factor e~and interferon ~/in regulation of keralinocyte-derived adhesion molecules and chemotactic factor. J Clin Invest 1990;85:605-8. Dreicer R, Schiller JH, Carbone PP. Granulocyte-macrophage colony stimulating factor and vasctthtis. Ann Intern Meal 1989;111:91-2. Welte Z, Zeidler C, Reiter A, et al. Differential effects of granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor in children with severe congenital neutropenia. Blood 1990;75:1056-63. Wodzinski MA, Hampton KK, Reilly JT. Differential effect of G-CSF and GM-CSF in acquired chronic neutropehia. Br J Haematol 1991;77:249-50. Steger GG, Locker G, et al. Cutaneous reactions to GM-CSF in inflammatory breast cancer [Letter]. N Engl J Med 1992;327:286.
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